Randomized Placebo Controlled Trial of Phytoterpenes in DMSO for the Treatment of Plantar Fasciitis

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Burke, Jon-Eric Baillie This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3802529/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Jul, 2024 Read the published version in Scientific Reports → Version 1 posted 10 You are reading this latest preprint version Abstract Sixty-two patients with plantar fasciitis were randomized to a placebo controlled trial testing the efficacy of a topical solution of plant terpenes containing camphor, menthol, eugenol, eucalyptol, and vanillin. Skin permeation of the mixture was enhanced with 15% dimethylsulfoxide (DMSO), 1% limonene, and rosemary oil. Using the validated foot function index 78.1% of patients reported an 85% or greater decrease in their total pain score by day 10 with twice daily application, while placebo treatment was without effect. ClinicalTrials.gov Identifier: NCT05467631 Health sciences/Diseases Health sciences/Medical research Figures Figure 1 Figure 2 INTRODUCTION Plantar fasciitis (PF) is the most common cause of heel pain in adults, accounting for approximately 1 million patient visits per year, with 60% of these visits being to primary care physicians [1,2]. The lifetime incidence is estimated at 10% [3], with a peak incidence in women 40-60 years of age [2]. Risk factors for PF include [4,5] limited ankle dorsiflexion which causes the foot to overpronate and stress the fascia, BMI greater than 27kg/m2, occupations requiring prolonged standing or walking such as the military, sedentary lifestyle, and excessive running where it occurs with an incidence of 5-10% [4]. Plantar fasciitis is an overuse syndrome resulting in degenerative changes at its attachment to the calcaneus, where the fascia originates from the calcaneal tuberosity, and continues on to form the longitudinal arch of the foot as it inserts into the metatarsal heads. Plantar fasciitis is a clinical diagnosis made by patient history and physical exam. The classic presentation is sharp stabbing pain in the anteromedial aspect of the heel when first stepping out of bed in the morning [6]. Pain will also present with weight bearing after a period of rest and improve somewhat as walking continues. Paresthesia is uncommon and its presence should raise suspicion of possible Baxter’s nerve entrapment (entrapment of the first branch of the lateral plantar nerve) rather than PF [7]. This entrapment is responsible for up to 20% of chronic heel pain [7]. Over 75% of patients with PF will improve with conservative non-operative treatment within 12months [8]. This generally consists of some combination of decreased weight bearing activity, ice massage, NSAIDs, stretching, strengthening regimen, and heel padding [1]. However, most treatment modalities are not supported by sufficient evidence to recommend one particular strategy over another [1,9]. The impact of PF on patient quality of life and lost work should not be underestimated [10], and this highlights the need for a more clearly defined and rapid treatment modality. In this study we investigated the efficacy of a topical solution of plant terpenes FDA approved for topical use which included camphor, menthol, eugenol, eucalyptol, and vanillin, formulated for enhanced skin permeation utilizing DMSO, rosemary oil, and limonene. These terpene agents have analgesic, anti-nociceptive, and anti- inflammatory activity [11]. The cohort consisted of 62 patients with PF in a placebo controlled trial. Using the pain subsection of the validated foot function index [12] as modified [13] 78.7% of patients had an 85% or greater decrease in their subjective pain score by day 10. Methods This trial was conducted in compliance with institutional guidelines for clinical trials and in accordance with the principles of the Declaration of Helsinki, 2013 revision, on research with human subjects. This study was approved by the Institute for Biomedical Sciences institutional review board and, registered 26/10/2021 ClinicalTrials.gov Identifier: NCT05467631. Detailed informed consent was obtained from each patient and archived. Figure 1 shows the CONSORT flowchart. Patients 18 years of age or older without history of diabetes or peripheral neuropathy, and with physician-diagnosed plantar fasciitis were recruited from a primary care practice and a physical therapy clinic between 01/08/2022 and 01/12/2022 and randomized into a placebo controlled blinded trial on a rolling basis. The active formulation (US Patent # 10,980,856) contained a mixture of essential oils so that the final formulation was standardized to 10% camphor from rosemary oil, 5% menthol from peppermint oil, 5% eugenol from clove oil, 2% eucalyptol (1,8-cineole) from eucalyptus oil, and 3% vanillin in a base of 10% (v/v) tea tree oil (M. alternifolia), with 15% DMSO and 1% limonene as skin permeation enhancers. Placebo consisted of 10% (v/v) tea tree oil in canola oil as a carrier. All materials were obtained from Sigma Chemical Co, St. Louis, MO and were USP grade. Sixty-two patients, 27 male and 35 female, completed the protocol, and study results for this cohort of patients are presented. Sample size was determined using a population estimate in the clinics of 12,000 and applying a PF prevalence of 0.006 nationwide in the US. The mean age for the active treatment group was 46 + 12.9 yrs. and for the placebo group 49 + 10.4 yrs. There was no statistical age difference between the groups. Average duration of symptoms was 4 + 4.4 months in the placebo group and 5 + 2.7 in the active group and was not statistically different between the two groups. Patients were randomized by blindly choosing a token numbered 1-10 out of a box. Thirty-two patients chose odd numbered tokens and were randomized to the placebo group and 34 who chose even numbered tokens to the active treatment group. Two patients in each treatment arm withdrew citing the pungent aroma of the formulation as the reason. Patients were blinded to allocation group. Upon enrollment, patients rated their pain over the previous 10 days using the validated Foot Function Index, FFI [12], modified to a 5point verbal rating scale [13]. All patients completed the FFI-5pt on Day 1 (Time 0). The items of the FFI-5pt are rated on a 5point verbal rating scale, “no pain” (0) to “intense pain” (4) on the pain scale. The FFI-5pt is a suitable generic self-administered measurement of the effect of foot complaints on foot function, with good test-retest reliability [13]. The item scores are summed, divided by the maximum possible score, which is 20, then multiplied by 100. This normalizes the scores to a percentage of the maximum possible pain score. Patients were asked to complete the FFI-5pt on Day 0, Day 1, Day 3, and Day 10. Participants rated their pain on five questions with the largest score for each question being 4 and the maximum total score 20. Positive result was a score change >20. Foot pain at worst Foot pain in the morning Pain walking barefoot Pain standing barefoot Foot pain end of the day Patients were instructed to wash the bottom of the affected foot prior to application with soap and water, pat dry, then apply 1ml of placebo or active treatment solution to the bottom of the heel of the affected foot using a calibrated dropper, then spread the solution with a small cuticle brush attached to the bottle cap. Application was twice a day. Patients were seen in follow up 1 day (2 applications), 3 days (6 applications) and 10 days (20 applications) from the date of enrollment (Day 0). Analysis is for participants completing the study. The 4 patients who withdrew were not included in analysis. RESULTS The mean score upon enrollment for the placebo group was 65.4 + 11.6 and 61.1 + 13.6 for the active group. There was no difference in mean pain scores between the two groups at the start of the study. After 10 days of treatment with placebo, the mean pain score was 60.8 + 9.2, and was not statistically different from mean scores prior to placebo treatment. The mean pain score for the active treatment group after 10 days of treatment decreased to 8.8 + 5.2. This was statistically significant at p<0.01 compared to placebo treatment (One Way ANOVA; post-hoc Tukey p<0.02). There were no differences between the placebo before, placebo after, and active before groups mean pain scores. There was a noticeable decrease in the mean pain scores in the active group on Days 1 and 3, but the differences in pain scores did not reach statistical significance until measured on Day 10. It is not known if the score differences would have reached significance after day 3 but before Day 10. However, a clear trend is suggested, and it can be inferred that a therapeutic response initiated after one day of use. This trend is illustrated in Figure 2. Table 1 Summarizes the data. Twenty-five out of 32 (78%) patients were essentially pain free after 10 days (score <15) and only 4 out of 32 (12.5%) participants failed to respond at all (had less than 20 point drop in their pain scores after 10 days of treatment). None of the placebo treatment group participants reported significant improvement in their pain scores. No adverse events were reported in either group. Table 1: Pain Scores of Study Participants on Day 0, Day 1, Day 3, and Day 10. Questionnaire Item scores were summed, divided by the largest possible sum of the item scores which was 20, then multiplied by 100 to normalize the scores to a percentage of the maximum possible pain score. DISCUSSION Plantar fasciitis is the most common cause of heel pain in adults with a lifetime incidence of 10%. It accounts for approximately 1 million patient visits per year in the US, with most patients (60%) being seen initially in a primary care setting. Plantar fasciitis is associated with a variety of sports, being reported in recreational and elite runners with an incidence of 5-10% [14]. A variety of treatment options are available including physical therapy with stretching and strengthening, foot orthoses, heel padding, ice massage, NSAIDS, decreased weight bearing activity, taping, dry needling/acupuncture, night splints, extracorporeal shock wave therapy, steroid injections, and surgery. These approaches have been reviewed [1,3]. However, most treatment modalities are not supported by sufficient evidence to recommend one strategy over another [1,9]. The majority (over 75%) of patients with PF will improve with conservative non- operative treatment within 12 months [8], but during the interim patients often suffer from significant impairment of recreational and activities of daily living, as well as lost time from work [10]. The anti-inflammatory and anti-nociceptive actions of a variety of essential oils has been receiving increased scrutiny [15,16], including rosemary oil [17], clove oil [18], eucalyptus [19], tea tree oil [20], and peppermint [21] among others. The mechanism of action of a complex mixture of oils such as the current formulation is difficult to elucidate, however the three main anti-inflammation properties of essential oils include inhibition of arachidonic acid metabolism, cytokine production, and pro-inflammatory gene expression [11]. Camphor is known to desensitize the pain-mediating TRP1A receptor [33], eugenol (a small phenolic compound and not strictly a terpene) is best known for its original use in dentistry with local analgesic and antiseptic effects [34], 1,8-cineole from eucalyptus is a natural antagonist of human TRPA1 that has analgesic and anti-inflammatory effects possibly due to its inhibition of TRPA1 [35]. Menthol from wintergreen oil is known as a topical analgesic postulated to work in part as a counterirritant [36] and, more recently has been shown to inhibit the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) [37]. Vanillin (also a small phenolic compound) is the archetypic agonist for the TRPV (transient receptor potential channel subclass vanilloid) from which the classification derives its name, and which plays a central role in pain transduction [38]. Tea tree oil also has reported topical analgesic properties [39], although no effect was seen by itself in this study. Given the complexity of the current formulation it is not possible to determine a precise mechanism of action, nor if efficacy is due solely to the known active agents as discussed or to a complex synergy with other oil components. The simplicity of the current approach, however, is its novel application of a mixture of agents with an established history of safety to achieve a result superior to earlier combinations. Terpenes are the main constituents of essential oils and consist of isoprene (C5H8) units. Terpenes of natural origin have a ‘Generally Regarded As Safe’ (GRAS) status with the Food and Drug Administration [22,23], confirming the topical safety of the oils in this current formulation [23] and making their use low-risk. The major constituents of the formulation used in this study include agents known to have topical therapeutic effects for pain relief as discussed, and in addition each of these agents is FDA approved for topical use OTC with long track records of safety. It is likely that skin permeation enhancement by limonene [28,29], rosemary oil [30], and DMSO [31] contributed to the efficacy seen in this study. The clinical use of pharmaceutical-grade DMSO as a penetration enhancer is supported by the robust data that have accumulated over the past 3 decades demonstrating the favorable safety and tolerability profile as well as its anti-inflammatory actions [31]. Diclofenac in DMSO has recently been FDA approved for topical use for osteoarthritis with a gel containing 45% DMSO [32]. The concentration in the current formulation of 15% delivers approximately 300ul of DMSO per day when 1ml of the formula is applied twice daily, a very modest amount. Limitations of this study include the lack of racial diversity (87% white), relatively small sample size, and lack of patient stratification based on activity level. However, given these limitations, the results appear generalizable and clinically applicable to large numbers of those who suffer from PF. The need exists for a reliable, effective, and rapid treatment for plantar fasciitis. In this study we evaluated the efficacy of a solution containing essential oils with concentrations of known therapeutic agents for topical use, formulated with the skin permeation enhancers limonene and small amounts of DMSO in the treatment of plantar fasciitis. After 10 days of twice daily application 78% of patients had an 85% or greater reduction in their pain scores. No adverse events were reported. Declarations Addendum: Samples of the formulation used in this study are available for clinical use upon request. Author Contributions BB: conceptualization, investigation, data curation, formal analysis, project administration, writing JEB: conceptualization, supervision, manuscript review & editing Data availability statement The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing Interest Statement Dr. Burke reports he has served as a paid consultant for Naturopathix, Inc. and HeelAid, LLC, both companies which develop, clinically assess, and market natural products for the consumer market. Dr. Baillie reports no conflicts. Funding This trial received no outside funding from. Submission Declaration of Interest We agree that the work described has not been published previously that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder References Trojian, T., Tucker, A.K. Plantar Fasciitis. Am. Fam. Physician. 99, 744-750 (2019). Riddle, D.L., Schappert, S.M. 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Cite Share Download PDF Status: Published Journal Publication published 31 Jul, 2024 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 19 Mar, 2024 Reviews received at journal 18 Mar, 2024 Reviewers agreed at journal 15 Mar, 2024 Reviews received at journal 18 Feb, 2024 Reviewers agreed at journal 08 Feb, 2024 Reviewers invited by journal 05 Feb, 2024 Editor assigned by journal 05 Feb, 2024 Editor invited by journal 04 Jan, 2024 Submission checks completed at journal 31 Dec, 2023 First submitted to journal 24 Dec, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3802529","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":264589570,"identity":"58f5be2a-f430-4598-84ce-a551cd941964","order_by":0,"name":"Briant E. Burke","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYBACAwkGBsYGIO5nbwBxLUjQMrPnAJRLtJYNNxJAfCK0mEv3mH2cUbFNtuHm86sbfhRIMPC3dyfg1WI554zxzA1nbhs3zs4pu9kDtFTizNkN+B12I8eY8WHb7cRm6Zy0GzxALQYSucRo+Xc7sU3yTNrNP0Rr2dhwO7FHgv3YbaJssZxzrJhxxrHbxjN4cthuyxhI8BD0i7l082bGnprbsvuPH392880fGzn+9l78WpAAjwGYJFY5CLA/IEX1KBgFo2AUjCAAAPTdTk0lK5+tAAAAAElFTkSuQmCC","orcid":"","institution":"Institute for Biomedical Sciences, Boise, Idaho","correspondingAuthor":true,"prefix":"","firstName":"Briant","middleName":"E.","lastName":"Burke","suffix":""},{"id":264589571,"identity":"3f9f62c2-7320-4b01-ac76-c60dbd42a4da","order_by":1,"name":"Jon-Eric Baillie","email":"","orcid":"","institution":"Institute for Biomedical Sciences, Boise, Idaho","correspondingAuthor":false,"prefix":"","firstName":"Jon-Eric","middleName":"","lastName":"Baillie","suffix":""}],"badges":[],"createdAt":"2023-12-25 01:14:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3802529/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3802529/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-65979-1","type":"published","date":"2024-07-31T15:57:44+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49129454,"identity":"fd6c3b18-30d8-4ba6-8188-135f254cf2bc","added_by":"auto","created_at":"2024-01-03 15:15:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26113,"visible":true,"origin":"","legend":"\u003cp\u003eEnrollment algorithm for 10-day endpoint\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3802529/v1/8ccf7ffcd26d6198b0251a1a.png"},{"id":49129455,"identity":"d6734d6d-afc3-45ca-ba34-affa1698193f","added_by":"auto","created_at":"2024-01-03 15:15:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":26805,"visible":true,"origin":"","legend":"\u003cp\u003ePain Scores Over Time\u003c/p\u003e\n\u003cp\u003ePain Scores Over Time. Pain scores of 62 plantar fasciitis patients treated topically twice daily for 10 days with placebo vs. terpene mixture in DMSO. * p\u0026lt;0.01 for terpene treatment at Day 10 vs. Day 0 and vs. placebo Day 10. One-Way ANOVA, Post-hoc Tukey p\u0026lt;0.02.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3802529/v1/7b112624a80d3436dac85ad0.png"},{"id":61793924,"identity":"6207d07c-5089-4846-8c10-ff84a6f3f5d3","added_by":"auto","created_at":"2024-08-05 16:16:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":338313,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3802529/v1/9ae26df8-8ef0-441c-b7f8-cfade17d1cb2.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Randomized Placebo Controlled Trial of Phytoterpenes in DMSO for the Treatment of Plantar Fasciitis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003ePlantar fasciitis (PF) is the most common cause of heel pain in adults, accounting for approximately 1 million patient visits per year, with 60% of these visits being to primary care physicians [1,2]. The lifetime incidence is estimated at 10% [3], with a peak incidence in women 40-60 years of age [2]. Risk factors for PF include [4,5] limited ankle dorsiflexion which causes the foot to overpronate and stress the fascia, BMI greater than 27kg/m2, occupations requiring prolonged standing or walking such as the military, sedentary lifestyle, and excessive running where it occurs with an incidence of 5-10% [4].\u003c/p\u003e\n\u003cp\u003ePlantar\u0026nbsp;fasciitis\u0026nbsp;is\u0026nbsp;an\u0026nbsp;overuse\u0026nbsp;syndrome\u0026nbsp;resulting\u0026nbsp;in\u0026nbsp;degenerative\u0026nbsp;changes\u0026nbsp;at\u0026nbsp;its\u0026nbsp;attachment to the calcaneus, where the fascia originates from the calcaneal tuberosity, and continues on to form the longitudinal arch of the foot as it inserts into the metatarsal heads.\u003c/p\u003e\n\u003cp\u003ePlantar fasciitis is a clinical diagnosis made by patient history and physical exam. The classic presentation is sharp stabbing pain in the anteromedial aspect of the heel when first stepping out of bed in the morning [6]. Pain will also present with weight bearing after a period of rest and improve somewhat as walking continues. Paresthesia is uncommon and its presence should raise suspicion of possible Baxter\u0026rsquo;s nerve entrapment (entrapment of the first branch of the lateral plantar nerve) rather than PF [7]. This entrapment is responsible for up to 20% of chronic heel pain [7].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOver 75% of patients with PF will improve with conservative non-operative treatment within 12months [8]. This generally consists of some combination of decreased weight bearing activity, ice massage, NSAIDs, stretching, strengthening regimen, and heel padding [1]. However, most treatment modalities are not supported by sufficient evidence to recommend one particular strategy over another [1,9]. The impact of PF on patient quality of life and lost work should not be underestimated [10], and this highlights the need for a more clearly defined and rapid treatment modality. In this study we investigated the efficacy of a topical solution of plant terpenes FDA approved for topical use which included camphor, menthol, eugenol, eucalyptol, and vanillin, formulated for enhanced skin permeation utilizing DMSO, rosemary oil, and limonene. These terpene agents have analgesic, anti-nociceptive, and anti- inflammatory activity [11]. The cohort consisted of 62 patients with PF in a placebo controlled trial. Using the pain subsection of the validated foot function index [12] as modified [13] 78.7% of patients had an 85% or greater decrease in their subjective pain score by day 10.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis trial was conducted in compliance with institutional guidelines for clinical trials and in accordance with the principles of the Declaration of Helsinki, 2013 revision, on research with human subjects. This study was approved by the Institute for Biomedical Sciences institutional review board and, registered 26/10/2021 ClinicalTrials.gov Identifier: NCT05467631. Detailed informed consent was obtained from each patient and archived. Figure 1 shows the CONSORT flowchart. \u003c/p\u003e\n\u003cp\u003ePatients 18 years of age or older without history of diabetes or peripheral neuropathy, and with physician-diagnosed plantar fasciitis were recruited from a primary care practice and a physical therapy clinic between 01/08/2022 and 01/12/2022 and randomized into a placebo controlled blinded trial on a rolling basis. The active formulation (US Patent # 10,980,856) contained a mixture of essential oils so that the final formulation was standardized to 10% camphor from rosemary oil, 5% menthol from peppermint oil, 5% eugenol from clove oil, 2% eucalyptol (1,8-cineole) from eucalyptus oil, and 3% vanillin in a base of 10% (v/v) tea tree oil (M. alternifolia), with 15% DMSO and 1% limonene as skin permeation enhancers. Placebo consisted of 10% (v/v) tea tree oil in canola oil as a carrier. All materials were obtained from Sigma Chemical Co, St. Louis, MO and were USP grade.\u003c/p\u003e\n\u003cp\u003eSixty-two patients, 27 male and 35 female, completed the protocol, and study results for this cohort of patients are presented. Sample size was determined using a population estimate in the clinics of 12,000 and applying a PF prevalence of 0.006 nationwide in the US. The mean age for the active treatment group was 46 \u003cu\u003e+\u003c/u\u003e 12.9 yrs. and for the placebo group 49 \u003cu\u003e+\u003c/u\u003e 10.4 yrs. There was no statistical age difference between the groups. Average duration of symptoms was 4 \u003cu\u003e+\u003c/u\u003e 4.4 months in the placebo group and 5 \u003cu\u003e+\u003c/u\u003e 2.7 in the active group and was not statistically different between the two groups. Patients were randomized by blindly choosing a token numbered 1-10 out of a box. Thirty-two patients chose odd numbered tokens and were randomized to the placebo group and 34 who chose even numbered tokens to the active treatment group. Two patients in each treatment arm withdrew citing the pungent aroma of the formulation as the reason. Patients were blinded to allocation group.\u003c/p\u003e\n\u003cp\u003eUpon enrollment, patients rated their pain over the previous 10 days using the validated Foot Function Index, FFI [12], modified to a 5point verbal rating scale [13]. \u003c/p\u003e\n\u003cp\u003eAll patients completed the FFI-5pt on Day 1 (Time 0). The items of the FFI-5pt are rated on a 5point verbal rating scale, \u0026ldquo;no pain\u0026rdquo; (0) to \u0026ldquo;intense pain\u0026rdquo; (4) on the pain scale. The FFI-5pt is a suitable generic self-administered measurement of the effect of foot complaints on foot function, with good test-retest reliability [13]. The item scores are summed, divided by the maximum\u003c/p\u003e\n\u003cp\u003epossible score, which is 20, then multiplied by 100. This normalizes the scores to a percentage of the maximum possible pain score. Patients were asked to complete the FFI-5pt on Day 0, Day 1, Day 3, and Day 10. Participants rated their pain on five questions with the largest score for each question being 4 and the maximum total score 20. Positive result was a score change \u0026gt;20.\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003eFoot pain at worst\u003c/li\u003e\n\u003cli\u003eFoot pain in the morning\u003c/li\u003e\n\u003cli\u003ePain walking barefoot\u003c/li\u003e\n\u003cli\u003ePain standing barefoot\u003c/li\u003e\n\u003cli\u003eFoot pain end of the day\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003ePatients were instructed to wash the bottom of the affected foot prior to application with soap and water, pat dry, then apply 1ml of placebo or active treatment solution to the bottom of the heel of the affected foot using a calibrated dropper, then spread the solution with a small cuticle brush attached to the bottle cap. Application was twice a day. Patients were seen in follow up 1 day (2 applications), 3 days (6 applications) and 10 days (20 applications) from the date of enrollment (Day 0). Analysis is for participants completing the study. The 4 patients who withdrew were not included in analysis. \u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eThe mean score upon enrollment for the placebo group was 65.4 \u003cu\u003e+\u003c/u\u003e 11.6 and 61.1 \u003cu\u003e+\u003c/u\u003e 13.6 for the active group. There was no difference in mean pain scores between the two groups at the start of the study. After 10 days of treatment with placebo, the mean pain score was 60.8 \u003cu\u003e+\u003c/u\u003e 9.2, and was not statistically different from mean scores prior to placebo treatment. The mean pain score for the active treatment group after 10 days of treatment decreased to 8.8 \u003cu\u003e+\u003c/u\u003e 5.2. This was statistically significant at p\u0026lt;0.01 compared to placebo treatment (One Way ANOVA; post-hoc Tukey p\u0026lt;0.02). There were no differences between the placebo before, placebo after, and active before groups mean pain scores.\u003c/p\u003e\n\u003cp\u003eThere was a noticeable decrease in the mean pain scores in the active group on Days 1 and 3, but the differences in pain scores did not reach statistical significance until measured on Day 10. It is not known if the score differences would have reached significance after day 3 but before Day 10. However, a clear trend is suggested, and it can be inferred that a therapeutic response initiated after one day of use. This trend is illustrated in Figure 2.\u003c/p\u003e\n\u003cp\u003eTable 1 Summarizes the data. Twenty-five out of 32 (78%) patients were essentially pain free after 10 days (score \u0026lt;15) and only 4 out of 32 (12.5%) participants failed to respond at all (had less than 20 point drop in their pain scores after 10 days of treatment).\u003c/p\u003e\n\u003cp\u003eNone of the placebo treatment group participants reported significant improvement in their pain scores. No adverse events were reported in either group.\u003c/p\u003e\n\u003cp\u003eTable 1: Pain Scores of Study Participants on Day 0, Day 1, Day 3, and Day 10.\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" width=\"548\" height=\"370\"\u003e\u003c/p\u003e\n\u003cp\u003eQuestionnaire Item scores were summed, divided by the largest possible sum of the item scores which was 20, then multiplied by 100 to normalize the scores to a percentage of the maximum possible pain score.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003ePlantar fasciitis is the most common cause of heel pain in adults with a lifetime incidence of 10%. It accounts for approximately 1 million patient visits per year in the US, with most patients (60%) being seen initially in a primary care setting. Plantar fasciitis is associated with a variety of sports, being reported in recreational and elite runners with an incidence of 5-10% [14].\u003c/p\u003e\n\u003cp\u003eA variety of treatment options are available including physical therapy with stretching and strengthening, foot orthoses, heel padding, ice massage, NSAIDS, decreased weight bearing activity, taping, dry needling/acupuncture, night splints, extracorporeal shock wave therapy, steroid injections, and surgery. These approaches have been reviewed [1,3]. However, most treatment modalities are not supported by sufficient evidence to recommend one strategy over another [1,9]. The majority (over 75%) of patients with PF will improve with conservative non- operative treatment within 12 months [8], but during the interim patients often suffer from significant impairment of recreational and activities of daily living, as well as lost time from work [10].\u003c/p\u003e\n\u003cp\u003eThe anti-inflammatory and anti-nociceptive actions of a variety of essential oils has been receiving increased scrutiny [15,16], including rosemary oil [17], clove oil [18], eucalyptus [19], tea tree oil [20], and peppermint [21] among others. The mechanism of action of a complex mixture of oils such as the current formulation is difficult to elucidate, however the three main anti-inflammation properties of essential oils include inhibition of arachidonic acid \u0026nbsp;metabolism, cytokine production, and pro-inflammatory gene expression [11]. Camphor is known to desensitize the pain-mediating TRP1A receptor [33], eugenol (a small phenolic compound and not strictly a terpene) is best known for its original use in dentistry with local analgesic and antiseptic effects [34], 1,8-cineole from eucalyptus is a natural antagonist of human TRPA1 that has analgesic and anti-inflammatory effects possibly due to its inhibition of TRPA1 [35]. Menthol from wintergreen oil is known as a topical analgesic postulated to work in part as a counterirritant [36] and, more recently has been shown to inhibit the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-\u0026alpha;) and interleukin-6 (IL-6) [37]. Vanillin (also a small phenolic compound) is the archetypic agonist for the TRPV (transient receptor potential channel subclass vanilloid) from which the classification derives its name, and which plays a central role in pain transduction [38]. Tea tree oil also has reported topical analgesic properties [39], although no effect was seen by itself in this study. Given the complexity of the current formulation it is not possible to determine a precise mechanism of action, nor if efficacy is due solely to the known active agents as discussed or to a complex synergy with other oil components. The simplicity of the current approach, however, is its novel application of a mixture of agents with an established history of safety to achieve a result superior to earlier combinations.\u003c/p\u003e\n\u003cp\u003eTerpenes are the main constituents of essential oils and consist of isoprene (C5H8) units. Terpenes of natural origin have a \u0026lsquo;Generally Regarded As Safe\u0026rsquo; (GRAS) status with the Food and Drug Administration [22,23], confirming the topical safety of the oils in this current formulation [23] and making their use low-risk. The major constituents of the formulation used in this study include agents known to have topical therapeutic effects for pain relief as discussed, and in addition each of these agents is FDA approved for topical use OTC with long track records of safety.\u003c/p\u003e\n\u003cp\u003eIt is likely that skin permeation enhancement by limonene [28,29], rosemary oil [30], and DMSO [31] contributed to the efficacy seen in this study. The clinical use of pharmaceutical-grade DMSO as a penetration enhancer is supported by the robust data that have accumulated over the past 3 decades demonstrating the favorable safety and tolerability profile as well as its anti-inflammatory actions [31]. Diclofenac in DMSO has recently been FDA approved for topical use for osteoarthritis with a gel containing 45% DMSO [32]. The concentration in the current formulation of 15% delivers approximately 300ul of DMSO per day when 1ml of the formula is applied twice daily, a very modest amount.\u003c/p\u003e\n\u003cp\u003eLimitations of this study include the lack of racial diversity (87% white), relatively small sample size, and lack of patient stratification based on activity level. However, given these limitations, the results appear generalizable and clinically applicable to large numbers of those who suffer from PF.\u003c/p\u003e\n\u003cp\u003eThe need exists for a reliable, effective, and rapid treatment for plantar fasciitis. In this study we evaluated the efficacy of a solution containing essential oils with concentrations of known therapeutic agents for topical use, formulated with the skin permeation enhancers limonene and small amounts of DMSO in the treatment of plantar fasciitis. After 10 days of twice daily application 78% of patients had an 85% or greater reduction in their pain scores. No adverse events were reported.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAddendum: Samples of the formulation used in this study are available for clinical use upon request. \u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBB: conceptualization, investigation, data curation, formal analysis, project administration, writing JEB: conceptualization, supervision, manuscript review \u0026amp; editing\u003c/p\u003e\n\u003cp\u003eData availability statement\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting Interest Statement\u003c/p\u003e\n\u003cp\u003eDr. Burke reports he has served as a paid consultant for Naturopathix, Inc. and HeelAid, LLC, both companies which develop, clinically assess, and market natural products for the consumer market. Dr. Baillie reports no conflicts.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis trial received no outside funding from.\u003c/p\u003e\n\u003cp\u003eSubmission Declaration of Interest\u003c/p\u003e\n\u003cp\u003eWe agree that the work described has not been published previously that it is not under consideration for publication elsewhere, that its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electronically without the written consent of the copyright-holder\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTrojian, T., Tucker, A.K. Plantar Fasciitis. \u003cem\u003eAm. Fam. Physician. \u003c/em\u003e\u003cstrong\u003e99, \u003c/strong\u003e744-750 (2019).\u003c/li\u003e\n\u003cli\u003eRiddle, D.L., Schappert, S.M. 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