Ibuprofen Gargle for Quality of Life and Pain Improvement in Oral Lichen Planus: Randomized Crossover and Long-Term Extension Phase II Study

Ibuprofen Gargle for Quality of Life and Pain Improvement in Oral Lichen Planus: Randomized Crossover and Long-Term Extension Phase II Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Ibuprofen Gargle for Quality of Life and Pain Improvement in Oral Lichen Planus: Randomized Crossover and Long-Term Extension Phase II Study Yumi Kitahiro, Yasumasa Kakei, Takeshi Ioroi, Nanae Yatagai, Masahiko Kashin, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7803748/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 08 Jan, 2026 Read the published version in Journal of Pharmaceutical Health Care and Sciences → Version 1 posted You are reading this latest preprint version Abstract Background Oral lichen planus (OLP) is a chronic immune-mediated inflammatory disease of the oral mucosa that frequently causes erosive lesions accompanied by pain, thereby impairing the patient’s ability to eat and drink and their overall quality of life (QOL). Current guidelines recommend topical corticosteroids as first-line treatments; however, their efficacy is limited for pain relief, and long-term safety remains a concern. Nonsteroidal anti-inflammatory drug mouthrinse formulations can deliver high local drug concentrations to the symptomatic mucosa with minimal systemic exposure. This study evaluated the short- and long-term safety and efficacy of ibuprofen gargling in patients with painful OLP. Methods We conducted a randomized, double-blind, placebo-controlled crossover study (Days 1–7), followed by a 6-month open-label long-term extension (LTE) study (Days 8–176). Patients with OLP and baseline oral pain of ≥ 20 mm on a 100-mm visual analog scale (VAS) were enrolled. The LTE study’s primary endpoint was safety, and secondary endpoints included changes in the VAS in resting oral pain and oral health-related QOL, which was measured using the Patient-Reported Oral Mucositis Symptom (PROMS) scale. Results The crossover study enrolled 24 patients, and 18 patients continued the LTE study. No serious adverse events were observed. One patient discontinued treatment because of grade 2 oral pain, while the remaining patients tolerated long-term treatment exhibiting stable laboratory values. During the LTE study, ibuprofen gargling was associated with significant improvements in several PROMS domains. The most pronounced effects were observed in the dietary domains, including eating restriction (β day = − 0.083, p < 0.001) and difficulty eating hard foods (β day = − 0.067, p < 0.001). Modest but significant improvements were observed for mouth pain (β day = − 0.038, p = 0.029), difficulty eating soft foods (β day = − 0.021, p < 0.001), swallowing (β day = − 0.007, p < 0.001), and drinking (β day = − 0.006, p = 0.043). Conclusions A 6-month regimen of ibuprofen gargling may be safe and potentially associated with sustained pain and oral function-related QOL improvements in patients with OLP. It represents a promising therapeutic approach for alleviating the symptomatic burden of this chronic and often debilitating disease. Trail registration: The Registry of Clinical Trials; jRCTs051220009 and jRCTs051220010, date of registration: 22 April 2022. oral lichen planus ibuprofen gargle PROMS oral pain long-term extension study Figures Figure 1 Figure 2 Figure 3 Background Oral lichen planus (OLP) is a chronic immune-mediated inflammatory disorder that affects the oral mucosa and frequently presents as erosive lesions, which are accompanied by pain. OLP adversely affects the patient’s oral function and quality of life (QOL), particularly with regard to eating and drinking [ 1 , 2 ]. Current guidelines as well as systematic reviews recommend topical corticosteroids as the first-line symptomatic treatment; however, evidence supporting their pain reduction efficacy is limited, and concerns regarding their long-term tolerability, such as candidiasis or mucosal atrophy, remain prevalent in clinical practice [ 3 ]. Mouthrinse formulations can deliver high drug concentrations directly to the painful mucosal surfaces while minimizing systemic exposure to the drug. A previous study has demonstrated the feasibility of topical nonsteroidal anti-inflammatory drugs (NSAIDs) gargles, such as ibuprofen and diclofenac, for painful orofacial conditions, including treatment-related oral mucositis or postoperative periodontal pain [ 4 ]. Therefore, locally administered NSAIDs may be beneficial as adjuncts or alternatives to support OLP treatments. In particular, ibuprofen, as a non-selective cyclooxygenase inhibitor with well-established analgesic properties, is particularly promising for short-contact topical use, as a brief swish-and-spit regimen may provide rapid symptom relief with minimal systemic dose exposure. In a previous feasibility study, an ibuprofen gargle reduced mucositis-related pain within minutes and exhibited an acceptable safety profile, thus suggesting that a targeted oral mouthrinse formulation may be clinically beneficial despite potential local irritation [ 4 ]. Measures of patient-reported outcomes that reflect mouth-related function are essential to evaluate the meaningful benefits of OLP treatments [ 5 ]. The Patient-Reported Oral Mucositis Symptom (PROMS) scale is a validated tool that captures various domains, such as mouth pain, eating and drinking difficulties, and speech, which closely align with the symptomatic burden of erosive oral diseases such as OLP [ 6 ]. Furthermore, its measurement properties and clinical interpretability support its use as a practical QOL endpoint for interventional studies. Therefore, we designed a placebo-controlled, double-blind, randomized crossover study that was followed by a long-term extension (LTE) study to evaluate the short-term analgesic effects and the long-term patient-centered outcomes of ibuprofen mouthrinse gargling for OLP lesion-related pain [ 7 ]. The study protocol prespecified a change in pain based on a visual analog scale (VAS) at 5 min after gargling as the primary endpoint of the crossover phase. There was no significant difference in the degree of pain reduction in the VAS values between the ibuprofen and placebo groups before and 5 min after gargling. However, as the secondary endpoint, the PROMS scale values revealed a significant reduction in the dietary domain restrictions ( p = 0.032) in favor of the ibuprofen gargle compared to that of the baseline [ 8 ]. In the LTE study, the primary endpoint was the safety assessment of the ibuprofen gargle, which was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Furthermore, the secondary endpoints were to evaluate the PROMS assessments to characterize the trajectories of the patients’ mouth-related QOL. In this report, we focused on the integrated outcomes of the short-term and LTE studies, which included (i) the long-term safety of ibuprofen gargling, (ii) the long-term changes in pain perception using ibuprofen gargling, and (iii) the long-term changes across the various PROMS domains. Methods Study design This study was designed as a placebo-controlled, double-blind, randomized crossover study (Days 1–7) followed by an open-label LTE study (Days 8–176). The study aligned with the CONSORT 2010 statement guidelines [ 9 ]. Inclusion and exclusion criteria In the crossover study, individuals aged ≥ 20 years at the time of consent, diagnosed with OLP, and with an oral lesion averaging ≥ 20 mm on a 100-mm VAS during 7 days before enrollment were included. Patients were excluded from the study for the following reasons: peptic ulcer disease, uncontrolled comorbidities, hypersensitivity to ibuprofen or its excipients, clinically important cardiac disease, aspirin-induced asthma, frequent use of systemic analgesics for chronic pain, pregnancy or lactation, neuropsychiatric conditions that precluded compliance with study procedures, and other concerns determined by the investigator as valid cause for exclusion. Ongoing local and systemic therapies for oral lesions were permitted if the dose was stable for ≥ 28 days prior to enrollment. In the LTE study, the eligibility criteria included patients who had completed the crossover study and wished to continue using the ibuprofen gargle. The exclusion criteria included patients who met the termination criteria within 2 days of the crossover study start. Interventions The study drug was prepared by the Department of Pharmacy at Kobe University Hospital. Furthermore, for the short-term crossover study, to maintain investigator blinding, a non-blinded pharmacist prepared the study medication. For the short-term crossover study (Days 1–7), patients were randomly assigned to receive either “ibuprofen followed by placebo” or “placebo followed by ibuprofen” during the first two days, with both groups then receiving ibuprofen gargle on Days 3–5 [ 7 ]. During the LTE phase (Days 8–176), all patients received ibuprofen gargle every day. They were instructed to use the gargle at least once a day. Moreover, the patients were allowed to initiate new treatments for oral lesions, thereby reflecting clinical conditions during the LTE study. Endpoints The primary endpoint of the LTE study was the evaluation of adverse events according to the CTCAE version 5.0. The secondary endpoints included the gargle’s effectiveness based on changes in the VAS for resting oral pain from the baseline (i.e., before gargling) and oral health-related QOL improvements, as measured by the various PROMS domains. In this report, we present the integrated outcomes of the short-term and LTE studies, with a particular focus on long-term pain perception and long-term changes across the various PROMS domains, compared with using ibuprofen gargle on Day 1. Assessments Safety assessment Adverse events related to the study drug were assessed by the investigator. In addition, follow-up visits were scheduled every 56 days (Days 64, 120, and 176) with an allowable visit window of ± 14 days. Evaluation of the long-term efficacy of the ibuprofen gargle Patients reported the severity of pain using the VAS, ranging from 0 mm (no pain) to 100 mm (worst pain), which was recorded immediately before as well as 5 and 15 min after gargling every 7 days. These endpoint times were based on a previous study, which investigated the efficacy of ibuprofen gargles for oral mucositis [ 10 , 11 ]. QOL evaluation using the various PROMS domains Patients each assessed their QOL using the various PROMS domains from 0 mm (no problem) to 100 mm (worst difficulty), and this was recorded every 7 days. The prespecified PROMS domains included mouth pain; difficulty in speaking, drinking, swallowing, and eating soft and hard foods; and restriction of speech, eating, and taste. Statistical analysis The safety data, including all treatment-related adverse events, were summarized as counts. The effectiveness set included patients in the LTE study with at least one post-baseline PROMS assessment. The safety set included patients who used the ibuprofen gargle at least once during the LTE study. All statistical tests were two-sided, with α = 0.05. The longitudinal changes in the various PROMS domains and VAS scores were analyzed using linear mixed-effects models (LMMs). These models included a fixed effect for day (as a continuous variable) and a random intercept for each patient to account for repeated measurements. This was represented as value ~ day + (1/subject) in the analysis code. The degrees of freedom were calculated according to the Kenward-Roger approximation. The model-estimated slope (β day ​) was used to quantify the average daily change for each outcome. These analyses were performed using R software (R Foundation for Statistical Computing, version 4.2.1). Results Patient characteristics Figure 1 shows the CONSORT flowchart of the study. In the initial crossover study, a total of 24 patients signed an informed consent form between June 2, 2022, and July 11, 2024. Thereafter, in the follow-up LTE study, 18 patients were included between June 23, 2022, and July 19, 2024. The baseline characteristics of the patients are presented in Table 1 . Safety assessment No serious adverse events were observed during the LTE study. However, one patient experienced grade 2 oral pain on Day 9, which was considered a treatment-related adverse event, and this event resolved after the patient discontinued study treatment. No other patients discontinued the study due to adverse events. Laboratory data, including renal and liver function values, remained stable throughout the study, and no clinical changes were detected between Days 8 and 176 ( Table 2 ). Long-term effectiveness of the ibuprofen gargle Resting oral pain The mean change in the pain VAS at 5 and 15 min post-gargling is presented in Figure 2 , which demonstrates the long-term analgesic effect of the ibuprofen gargle. The longitudinal trajectory of resting (pre-gargle) oral pain during the LTE study mirrored the improvements observed in the mouth pain PROMS domain. As shown in Figure 3 , which plots individual and population-level trajectories for mouth pain and is most closely associated with the change in oral pain VAS, the mouth pain PROMS domain scores demonstrated a modest but significant improvement over the 176 days of observation. The LMMs estimated a significant mean decrease per day (β day = −0.038, 95% Confidence Interval (CI): −0.072 to −0.004; p = 0.029). PROMS domains Significant improvements were observed across various other PROMS domains ( Table 3 ). The most pronounced effects were associated with diet, including restriction of eating (β day = −0.083, p < 0.001) and difficulty eating hard foods (β day = −0.067, p < 0.001). In addition, significant improvements were found for difficulty eating soft foods (β day = −0.021, p < 0.001), difficulty swallowing (β day = −0.007, p < 0.001), and difficulty drinking (β day = −0.006, p = 0.043). Discussion To the best of our knowledge, this is the first long-term phase II study to evaluate the safety and efficacy of ibuprofen mouthrinse gargling in patients with OLP. Previous studies have primarily focused on short-term symptomatic relief or on the use of topical corticosteroids [ 12 ], rather than on NSAIDs gargles over extended periods. Our study revealed a favorable safety profile and significant improvements in patient-reported outcomes, particularly with regard to oral function, such as eating and drinking. These findings highlight the potential of locally administered NSAIDs as adjunctive therapeutic options for patients with OLP, a condition that remains challenging to manage with currently available treatments. The most clinically relevant observation was the sustained improvement in the dietary-related PROMS domains, which included restrictions on eating and difficulty in consuming hard and soft food. As OLP pain often manifests most severely during mastication, improvements in these domains are a direct reflection of the functional benefits in the patients’ daily QOL. In contrast to the immediate but modest analgesic effect observed in the crossover phase, results of the long-term study suggest that continued use of the ibuprofen gargle provides incremental and cumulative benefits, not only in reducing resting oral pain but also in alleviating functional impairment in essential activities, such as eating, drinking, and swallowing. These improvements are of particular importance because food-related QOL is consistently reported as one of the most burdensome aspects of OLP. A previous study reported that over 90% of patients with OLP reported discomfort with specific types of food, and many reported limiting the texture and types of food that they consumed [ 13 ]. Effects such as difficulty eating certain foods, which can lead to weight loss or, in severe cases, malnutrition, have been reported. Therefore, dietary satisfaction is a risk that can influence patients’ happiness and social abilities [ 14 , 15 ]. Another positive advantage of ibuprofen gargling is its safety profile. The targeted swish-and-spit administration allows high local ibuprofen concentrations while minimizing the systemic absorption thereof, thereby reducing the risks associated with long-term NSAIDs use, including gastrointestinal bleeding, renal impairment, or cardiovascular complications. Furthermore, after six months of daily use, no serious adverse events were observed, and laboratory data findings remained stable, thus reinforcing the tolerability of this approach in a chronic disease population. This study has several limitations that should be acknowledged. First, the LTE phase was performed in an open-label manner without a placebo control, which potentially introduced placebo effects and observer bias. Although patients served as their own longitudinal controls, the absence of a comparator arm limits causal inference. Second, the relatively small sample size restricts the generalizability of these results and impedes the detection of rare adverse events. Third, concomitant therapies for oral lesions were permitted; while this reflects real-world practice, it may have confounded the treatment effect of ibuprofen gargling. Fourth, we analyzed multiple PROMS domains simultaneously without adjusting for multiple comparisons, thereby increasing the risk of Type I errors. Therefore, the further application of appropriate statistical corrections may render some of our significant findings non-significant, particularly for those with p -values close to 0.05. Fifth, although we demonstrated significant improvements in various PROMS scores, the clinical meaningfulness of these changes remains uncertain because of the absence of established minimal clinically important difference thresholds for the PROMS domains in patients with OLP. The observed daily improvements, though significant, may not represent the perceptible benefits for individual patients. Future research should be conducted to validate these findings in larger multicenter randomized controlled trials. In addition, comparative studies against established therapies, such as topical corticosteroids, are required to define the relative efficacy of ibuprofen gargling and explore any potential synergistic effects in combination regimens. Moreover, pharmacokinetic and mechanistic studies would further elucidate the extent of systemic exposure and the pathways that underlie the observed functional improvements. Finally, research identifying patient subgroups that would most likely benefit from this treatment, such as those with predominant pain during mastication, may enable more personalized treatment approaches. Conclusions In conclusion, this study suggests that a six-month regimen of ibuprofen gargling may potentially be safe and associated with sustained pain and oral function-related QOL improvements in patients with OLP. Furthermore, it presents a promising therapeutic approach for alleviating the symptomatic burden of this chronic and often debilitating disease. Abbreviations CTCAE: the Common Terminology Criteria for Adverse Events LMMs: linear mixed-effects models LTE: long-term extension NSAIDs: nonsteroidal anti-inflammatory drugs OLP: oral lichen planus PROMS: patient-reported oral mucositis symptom QOL: quality of life VAS: visual analogue scale Declarations Ethics approval and consent to participate The study complied with the Declaration of Helsinki and the Japanese Clinical Trials Act. The Kobe University Clinical Research Ethics Committee reviewed and approved the protocol (C210022 and C210023), and the clinical trial identifiers are jRCTs051220009 and jRCTs051220010. Written informed consent was obtained from all patients before any study procedures were conducted. Consent for publication Consent for the publication was obtained from the patients. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests The authors declare that there are no competing interests. Funding This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors’ contributions Concept and design: YKakei and IT. Acquisition, analysis, or interpretation of data: YKakei, YKitahiro, IT, NY, MKashin, MKobayashi, AM, TH, MA, and KY. Drafting of the manuscript: YKitahiro, YKakei, and IT. Critical review of the manuscript for important intellectual content: NY, MKashin, MKobayashi, AM, KY, TH, MA, and IY. Supervision: IY. All authors have read and agreed to the published version of the manuscript. Acknowledgments The authors express their gratitude to all the patients who participated in this study. They also acknowledge Mr. Toru Hibi from PHARMA SEEDS CREATE, LIMITED LIABILITY CO. (4-12-10, Tsutsujigaoka-Minami, Sanda, Hyogo 669-1347, Japan) for his guidance in the manufacturing of the ibuprofen gargle used in this study. We also want to thank Editage (www.editage.com) and Enago for performing the English-language review. References López-Jornet P, Camacho-Alonso F. Quality of life in patients with oral lichen planus. J Eval Clin Pract. 2010;16(1):111–3. https://doi.org/10.1111/j.1365-2753.2009.01124.x . Ashshi RA, Stanbouly D, Maisano PG, et al. Quality of life in patients with oral potentially malignant disorders: oral lichen planus and oral epithelial dysplasia. Oral Surg Oral Med Oral Pathol Oral Radiol. 2023;135(3):363–71. https://doi.org/10.1016/j.oooo.2022.11.006 . Lodi G, Manfredi M, Mercadante V, et al. Interventions for treating oral lichen planus: corticosteroid therapies. Cochrane Database Syst Rev. 2020;28(2):CD001168. https://doi.org/10.1002/14651858.CD001168.pub3 . Ioroi T, Kiyota N, Imamura Y, et al. Ibuprofen gargle for chemo- or Chemoradiotherapy-induced Oral Mucositis: a feasibility study. J Pharm Health Care Sci. 2020;1:612. https://doi.org/10.1186/s40780-020-00168-6 . Yuwanati M, Gondivkar S, Sarode SC, et al. Impact of Oral Lichen Planus on Oral Health-Related Quality of Life: A Systematic Review and Meta-Analysis. Clin Pract. 2021;7(2):272–86. https://doi.org/10.3390/clinpract11020040 . Kushner JA, Lawrence HP, Shoval I, et al. Development and Validation of a Patient-Reported Oral Mucositis Symptom (PROMS) Scale. J Can Dent Assoc. 2008;74(1):59. Kitahiro Y, Ioroi T, Kakei Y, et al. Efficacy and Long-Term Safety of Ibuprofen Gargle for Oral Lichen Planus: A Study Protocol of Randomized Crossover and Long-Term Extension Trials. Methods Protoc. 2023;6(7):1–11. https://doi.org/10.3390/mps6010007 . Kakei Y, Kitahiro Y, Ioroi T, et al. Efficacy of Ibuprofen Gargle for Oral Lichen Planus: A Single-Center, Placebo-Controlled, Double-Blind, Randomized Crossover Study Trial. Cureus. 2025;17(8):e91242. https://doi.org/10.7759/cureus.91242 . Dwan K, Li T, Altman DG, Elbourne D. CONSORT 2010 statement: extension to randomised crossover trials. BMJ. 2019;366:l4378. https://doi.org/10.1136/bmj.l4378 . Ioroi T, Kiyota N, Imamura Y, et al. Ibuprofen gargle for chemo- or chemoradiotherapy-induced Oral Mucositis: A feasibility study. J Pharm Health Care Sci. 2020;6(12). https://doi.org/10.1186/s40780-020-00168-6 . Kakei Y, Ioroi T, Ito T, et al. Efficacy of Ibuprofen Gargle for Postoperative Pain After Mandibular Third Molar Extraction: Protocol for a Phase II, Placebo-Controlled, Double-Blind, Randomized Crossover Trial. JMIR Res Protoc. 2022;11(5):e35533. https://doi.org/10.2196/35533 . Ku JK, Park SY, Hwang KG, et al. The effect of mouthrinse with 0.05% dexamethasone solution on the oral bacterial community of oral lichen planus patients: Prospective pilot study. Appl Sci. 2021;11(14):6286. https://doi.org/10.3390/app11146286 . Almazrooa S, Alamoudi W, Akeel S, et al. Impact of Oral Lichen Planus on Quality of Life: A Cross-Sectional Study. Eur J Dent. 2025;26. https://doi.org/10.1055/s-0045-1811214 . Riordain RN, Meaney S, McCreary C. Impact of chronic oral mucosal disease on daily life: Preliminary observations from a qualitative study. Oral Dis. 2011;17:265–9. https://doi.org/10.1111/j.1601-0825.2010.01734.x . Czerninski R, Zadik Y, Kartin-Gabbay T, et al. Dietary alterations in patients with oral vesiculoulcerative diseases. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117(3):319–23. https://doi.org/10.1016/j.oooo.2013.08.006 . Tables Table 1. Patient characteristics N = 18 Age, years 1 60 (36−85) Sex, female, n (%) 15 (83.3) Duration of OLP, month 1 24 (2−180) Lesion site, n Number of lesion sites per patient 1 Buccal mucosa (total number of right and left) Maxillary gingiva (total number of right and left) Mandibular gingiva (total number of right and left) Tongue (total number of right and left) 2 (1−4) 21 5 6 0 Ongoing treatment for oral lesions, n Azunol Gargle liquid Dexamethasone Ointment 3 3 1 Data are presented as the median (range). Some patients had multiple lesions at a single site; therefore, the total number of buccal mucosa lesions exceeds the total number of patients (N = 18). OLP: oral lichen planus Table 2. Laboratory data Day 8 (N = 18) Day 176 (N = 14) WBC (cells/μL) 6,400 (3,700−10,800) 5,150 (3,900−8,500) Plt (10 4 /μL) 22.1 (8.3−32.2) 25.5 (7.7−36.3) Hb (g/dL) 13.3 (10.6−16.3) 13.3 (9.9−16.4) AST (U/L) 21 (10−72) 20 (16−76) ALT (U/L) 17 (10−96) 19 (10−62) γ-GTP (U/L) 18 (12−223) 24 (12−324) T-Bil (mg/dL) 0.7 (0.4−1.1) 0.6 (0.4−1.3) Alb (g/dL) 4.2 (3.0−4.6) 4.1 (3.3−4.6) SCr (mg/dL) 0.64 (0.41−0.98) 0.63 (0.47−0.94) BUN (mg/dL) 13.4 (7.3−26.3) 13.3 (8.2−22.1) All data are presented as the median (range). The post-laboratory data on Day 176 were obtained with an allowable visit window of ±14 days. Alb: albumin, ALT: alanine aminotransferase, AST: aspartate aminotransferase, BUN: blood urea nitrogen, γ-GTP: γ-glutamyl transpeptidase, Hb: hemoglobin, Plt: platelet count, SCr: serum creatinine, T-Bil: total bilirubin, WBC: white blood cell count Table 3. Linear mixed-effects estimates of time trends in each Patient-Reported Oral Mucositis Symptom (PROMS) domain (Days 1–176). PROMS domain β day SE 95% CI p-value Mouth pain −0.038 0.017 −0.072 to −0.004 0.029 Difficulty speaking −0.017 0.009 −0.035 to 0.000 0.054 Restriction of speech −0.006 0.008 −0.021 to 0.010 0.479 Difficulty eating hard foods −0.067 0.015 −0.096 to −0.038 <0.001 Difficulty eating soft foods −0.021 0.005 −0.031 to −0.010 <0.001 Restriction of eating −0.083 0.012 −0.107 to −0.059 <0.001 Difficulty drinking −0.006 0.003 −0.012 to −0.000 0.043 Restriction of drinking −0.007 0.004 −0.015 to 0.001 0.090 Difficulty swallowing −0.007 0.002 −0.011 to −0.003 <0.001 Change in taste 0.017 0.009 −0.001 to 0.035 0.064 For each domain, β day is the estimated mean daily change in the score from a model with a fixed effect for day and random intercepts by individual patient ( value ~ day + (1|Subject)). Days 1–7 correspond to the randomized crossover phase; Days 8–176 correspond to the long-term extension (LTE), aligned by adding 7 to the LTE days. Entries are the estimate (β day ), standard error (SE), 95% confidence interval (CI), and a two-sided p-value was employed. Negative β day indicates decreasing domain scores (i.e., improvement). No adjustment for multiple testing was applied. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 08 Jan, 2026 Read the published version in Journal of Pharmaceutical Health Care and Sciences → Version 1 posted 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. 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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-7803748","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":533107681,"identity":"1d78e532-262e-43fa-81d6-dbbb7299312e","order_by":0,"name":"Yumi Kitahiro","email":"","orcid":"","institution":"Kobe University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yumi","middleName":"","lastName":"Kitahiro","suffix":""},{"id":533107683,"identity":"cec992bb-9728-4074-9e83-c9776105ad88","order_by":1,"name":"Yasumasa 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Medicine","correspondingAuthor":false,"prefix":"","firstName":"Masaki","middleName":"","lastName":"Kobayashi","suffix":""},{"id":533107689,"identity":"847a4b9e-894f-499f-a817-6098c420593a","order_by":6,"name":"Asami Morioka","email":"","orcid":"","institution":"Kobe University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Asami","middleName":"","lastName":"Morioka","suffix":""},{"id":533107690,"identity":"fff89fe9-af33-44b2-9758-a32bb9bd608c","order_by":7,"name":"Kazuhiro Yamamoto","email":"","orcid":"","institution":"Kobe University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kazuhiro","middleName":"","lastName":"Yamamoto","suffix":""},{"id":533107691,"identity":"ca74de3b-ba6d-4f58-aaba-516bfa7842c9","order_by":8,"name":"Takumi Hasegawa","email":"","orcid":"","institution":"Kobe University Graduate School of 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04:18:06","extension":"html","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":82555,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7803748/v1/9614d0704436ef274a5e5437.html"},{"id":94622612,"identity":"433159ac-b44f-43c9-9de8-e602fc2495db","added_by":"auto","created_at":"2025-10-29 04:18:24","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1148642,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT flowchart showing the study design\u003c/p\u003e\n\u003cp\u003eOLP: oral lichen planus\u003c/p\u003e","description":"","filename":"FigureOLPLTEfinalFig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7803748/v1/ce6ee320404aeed2d2275336.jpg"},{"id":94622234,"identity":"fdd22483-26cc-4146-843e-3e16d52f989a","added_by":"auto","created_at":"2025-10-29 04:18:12","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1042630,"visible":true,"origin":"","legend":"\u003cp\u003eMean change in the pain VAS at 5 and 15 min post-gargling\u003c/p\u003e\n\u003cp\u003eVertical means standard deviation. VAS: visual analogue scale\u003c/p\u003e","description":"","filename":"FigureOLPLTEfinalFig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7803748/v1/f2054d793fb32813fea8f378.jpg"},{"id":94622842,"identity":"baa3228f-fb73-4a5a-88dd-766da5bfdc0d","added_by":"auto","created_at":"2025-10-29 04:18:35","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1587327,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual and population-level trajectories for the PROMS domain of mouth pain\u003c/p\u003e\n\u003cp\u003eThe black line represents the mean of the population. PROMS: patient-reported oral mucositis symptom\u003c/p\u003e","description":"","filename":"FigureOLPLTEfinalFig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7803748/v1/9ed4c1c45375150f48198d72.jpg"},{"id":100069420,"identity":"5b40f5e7-fcf8-4656-bf11-73a0258ab092","added_by":"auto","created_at":"2026-01-12 16:13:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4559429,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7803748/v1/048939d4-c9e6-469f-bd20-8e9fe5f57871.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Ibuprofen Gargle for Quality of Life and Pain Improvement in Oral Lichen Planus: Randomized Crossover and Long-Term Extension Phase II Study","fulltext":[{"header":"Background","content":"\u003cp\u003eOral lichen planus (OLP) is a chronic immune-mediated inflammatory disorder that affects the oral mucosa and frequently presents as erosive lesions, which are accompanied by pain. OLP adversely affects the patient\u0026rsquo;s oral function and quality of life (QOL), particularly with regard to eating and drinking [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Current guidelines as well as systematic reviews recommend topical corticosteroids as the first-line symptomatic treatment; however, evidence supporting their pain reduction efficacy is limited, and concerns regarding their long-term tolerability, such as candidiasis or mucosal atrophy, remain prevalent in clinical practice [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMouthrinse formulations can deliver high drug concentrations directly to the painful mucosal surfaces while minimizing systemic exposure to the drug. A previous study has demonstrated the feasibility of topical nonsteroidal anti-inflammatory drugs (NSAIDs) gargles, such as ibuprofen and diclofenac, for painful orofacial conditions, including treatment-related oral mucositis or postoperative periodontal pain [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Therefore, locally administered NSAIDs may be beneficial as adjuncts or alternatives to support OLP treatments. In particular, ibuprofen, as a non-selective cyclooxygenase inhibitor with well-established analgesic properties, is particularly promising for short-contact topical use, as a brief swish-and-spit regimen may provide rapid symptom relief with minimal systemic dose exposure. In a previous feasibility study, an ibuprofen gargle reduced mucositis-related pain within minutes and exhibited an acceptable safety profile, thus suggesting that a targeted oral mouthrinse formulation may be clinically beneficial despite potential local irritation [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMeasures of patient-reported outcomes that reflect mouth-related function are essential to evaluate the meaningful benefits of OLP treatments [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The Patient-Reported Oral Mucositis Symptom (PROMS) scale is a validated tool that captures various domains, such as mouth pain, eating and drinking difficulties, and speech, which closely align with the symptomatic burden of erosive oral diseases such as OLP [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Furthermore, its measurement properties and clinical interpretability support its use as a practical QOL endpoint for interventional studies.\u003c/p\u003e\u003cp\u003eTherefore, we designed a placebo-controlled, double-blind, randomized crossover study that was followed by a long-term extension (LTE) study to evaluate the short-term analgesic effects and the long-term patient-centered outcomes of ibuprofen mouthrinse gargling for OLP lesion-related pain [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. The study protocol prespecified a change in pain based on a visual analog scale (VAS) at 5 min after gargling as the primary endpoint of the crossover phase. There was no significant difference in the degree of pain reduction in the VAS values between the ibuprofen and placebo groups before and 5 min after gargling. However, as the secondary endpoint, the PROMS scale values revealed a significant reduction in the dietary domain restrictions (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.032) in favor of the ibuprofen gargle compared to that of the baseline [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. In the LTE study, the primary endpoint was the safety assessment of the ibuprofen gargle, which was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Furthermore, the secondary endpoints were to evaluate the PROMS assessments to characterize the trajectories of the patients\u0026rsquo; mouth-related QOL. In this report, we focused on the integrated outcomes of the short-term and LTE studies, which included (i) the long-term safety of ibuprofen gargling, (ii) the long-term changes in pain perception using ibuprofen gargling, and (iii) the long-term changes across the various PROMS domains.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design\u003c/h2\u003e\u003cp\u003eThis study was designed as a placebo-controlled, double-blind, randomized crossover study (Days 1\u0026ndash;7) followed by an open-label LTE study (Days 8\u0026ndash;176). The study aligned with the CONSORT 2010 statement guidelines [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eInclusion and exclusion criteria\u003c/h3\u003e\n\u003cp\u003eIn the crossover study, individuals aged\u0026thinsp;\u0026ge;\u0026thinsp;20 years at the time of consent, diagnosed with OLP, and with an oral lesion averaging\u0026thinsp;\u0026ge;\u0026thinsp;20 mm on a 100-mm VAS during 7 days before enrollment were included. Patients were excluded from the study for the following reasons: peptic ulcer disease, uncontrolled comorbidities, hypersensitivity to ibuprofen or its excipients, clinically important cardiac disease, aspirin-induced asthma, frequent use of systemic analgesics for chronic pain, pregnancy or lactation, neuropsychiatric conditions that precluded compliance with study procedures, and other concerns determined by the investigator as valid cause for exclusion. Ongoing local and systemic therapies for oral lesions were permitted if the dose was stable for \u0026ge;\u0026thinsp;28 days prior to enrollment. In the LTE study, the eligibility criteria included patients who had completed the crossover study and wished to continue using the ibuprofen gargle. The exclusion criteria included patients who met the termination criteria within 2 days of the crossover study start.\u003c/p\u003e\n\u003ch3\u003eInterventions\u003c/h3\u003e\n\u003cp\u003eThe study drug was prepared by the Department of Pharmacy at Kobe University Hospital. Furthermore, for the short-term crossover study, to maintain investigator blinding, a non-blinded pharmacist prepared the study medication.\u003c/p\u003e\u003cp\u003eFor the short-term crossover study (Days 1\u0026ndash;7), patients were randomly assigned to receive either \u0026ldquo;ibuprofen followed by placebo\u0026rdquo; or \u0026ldquo;placebo followed by ibuprofen\u0026rdquo; during the first two days, with both groups then receiving ibuprofen gargle on Days 3\u0026ndash;5 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. During the LTE phase (Days 8\u0026ndash;176), all patients received ibuprofen gargle every day. They were instructed to use the gargle at least once a day. Moreover, the patients were allowed to initiate new treatments for oral lesions, thereby reflecting clinical conditions during the LTE study.\u003c/p\u003e\n\u003ch3\u003eEndpoints\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint of the LTE study was the evaluation of adverse events according to the CTCAE version 5.0. The secondary endpoints included the gargle\u0026rsquo;s effectiveness based on changes in the VAS for resting oral pain from the baseline (i.e., before gargling) and oral health-related QOL improvements, as measured by the various PROMS domains. In this report, we present the integrated outcomes of the short-term and LTE studies, with a particular focus on long-term pain perception and long-term changes across the various PROMS domains, compared with using ibuprofen gargle on Day 1.\u003c/p\u003e\n\u003ch3\u003eAssessments\u003c/h3\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eSafety assessment\u003c/h2\u003e\u003cp\u003eAdverse events related to the study drug were assessed by the investigator. In addition, follow-up visits were scheduled every 56 days (Days 64, 120, and 176) with an allowable visit window of \u0026plusmn;\u0026thinsp;14 days.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEvaluation of the long-term efficacy of the ibuprofen gargle\u003c/h3\u003e\n\u003cp\u003ePatients reported the severity of pain using the VAS, ranging from 0 mm (no pain) to 100 mm (worst pain), which was recorded immediately before as well as 5 and 15 min after gargling every 7 days. These endpoint times were based on a previous study, which investigated the efficacy of ibuprofen gargles for oral mucositis [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eQOL evaluation using the various PROMS domains\u003c/h3\u003e\n\u003cp\u003ePatients each assessed their QOL using the various PROMS domains from 0 mm (no problem) to 100 mm (worst difficulty), and this was recorded every 7 days. The prespecified PROMS domains included mouth pain; difficulty in speaking, drinking, swallowing, and eating soft and hard foods; and restriction of speech, eating, and taste.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe safety data, including all treatment-related adverse events, were summarized as counts. The effectiveness set included patients in the LTE study with at least one post-baseline PROMS assessment. The safety set included patients who used the ibuprofen gargle at least once during the LTE study. All statistical tests were two-sided, with α\u0026thinsp;=\u0026thinsp;0.05. The longitudinal changes in the various PROMS domains and VAS scores were analyzed using linear mixed-effects models (LMMs). These models included a fixed effect for day (as a continuous variable) and a random intercept for each patient to account for repeated measurements. This was represented as value\u0026thinsp;~\u0026thinsp;day + (1/subject) in the analysis code. The degrees of freedom were calculated according to the Kenward-Roger approximation. The model-estimated slope (β\u003csub\u003eday\u003c/sub\u003e​) was used to quantify the average daily change for each outcome. These analyses were performed using R software (R Foundation for Statistical Computing, version 4.2.1).\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003ePatient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1\u003c/strong\u003e shows the CONSORT flowchart of the study. In the initial crossover study, a total of 24 patients signed an informed consent form between June 2, 2022, and July 11, 2024. Thereafter, in the follow-up LTE study, 18 patients were included between June 23, 2022, and July 19, 2024. The baseline characteristics of the patients are presented in \u003cstrong\u003eTable 1\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo serious adverse events were observed during the LTE study. However, one patient experienced grade 2 oral pain on Day 9, which was considered a treatment-related adverse event, and this event resolved after the patient discontinued study treatment. No other patients discontinued the study due to adverse events. Laboratory data, including renal and liver function values, remained stable throughout the study, and no clinical changes were detected between Days 8 and 176 (\u003cstrong\u003eTable 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLong-term effectiveness of the ibuprofen gargle\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResting oral pain\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mean change in the pain VAS at 5 and 15 min post-gargling is presented in \u003cstrong\u003eFigure 2\u003c/strong\u003e, which demonstrates the long-term analgesic effect of the ibuprofen gargle. The longitudinal trajectory of resting (pre-gargle) oral pain during the LTE study mirrored the improvements observed in the mouth pain PROMS domain. As shown in \u003cstrong\u003eFigure 3\u003c/strong\u003e, which plots individual and population-level trajectories for mouth pain and is most closely associated with the change in oral pain VAS, the mouth pain PROMS domain scores demonstrated a modest but significant improvement over the 176 days of observation. The LMMs estimated a significant mean decrease per day (β\u003csub\u003eday\u003c/sub\u003e = −0.038, 95% Confidence Interval (CI): −0.072 to −0.004; \u003cem\u003ep\u003c/em\u003e = 0.029).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003ePROMS domains\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSignificant improvements were observed across various other PROMS domains (\u003cstrong\u003eTable 3\u003c/strong\u003e). The most pronounced effects were associated with diet, including restriction of eating (β\u003csub\u003eday\u003c/sub\u003e = −0.083, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) and difficulty eating hard foods (β\u003csub\u003eday\u0026nbsp;\u003c/sub\u003e= −0.067, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). In addition, significant improvements were found for difficulty eating soft foods (β\u003csub\u003eday\u003c/sub\u003e = −0.021, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), difficulty swallowing (β\u003csub\u003eday\u003c/sub\u003e = −0.007, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001), and difficulty drinking (β\u003csub\u003eday\u003c/sub\u003e = −0.006, \u003cem\u003ep\u003c/em\u003e = 0.043).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, this is the first long-term phase II study to evaluate the safety and efficacy of ibuprofen mouthrinse gargling in patients with OLP. Previous studies have primarily focused on short-term symptomatic relief or on the use of topical corticosteroids [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], rather than on NSAIDs gargles over extended periods. Our study revealed a favorable safety profile and significant improvements in patient-reported outcomes, particularly with regard to oral function, such as eating and drinking. These findings highlight the potential of locally administered NSAIDs as adjunctive therapeutic options for patients with OLP, a condition that remains challenging to manage with currently available treatments.\u003c/p\u003e\u003cp\u003eThe most clinically relevant observation was the sustained improvement in the dietary-related PROMS domains, which included restrictions on eating and difficulty in consuming hard and soft food. As OLP pain often manifests most severely during mastication, improvements in these domains are a direct reflection of the functional benefits in the patients\u0026rsquo; daily QOL. In contrast to the immediate but modest analgesic effect observed in the crossover phase, results of the long-term study suggest that continued use of the ibuprofen gargle provides incremental and cumulative benefits, not only in reducing resting oral pain but also in alleviating functional impairment in essential activities, such as eating, drinking, and swallowing. These improvements are of particular importance because food-related QOL is consistently reported as one of the most burdensome aspects of OLP. A previous study reported that over 90% of patients with OLP reported discomfort with specific types of food, and many reported limiting the texture and types of food that they consumed [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Effects such as difficulty eating certain foods, which can lead to weight loss or, in severe cases, malnutrition, have been reported. Therefore, dietary satisfaction is a risk that can influence patients\u0026rsquo; happiness and social abilities [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAnother positive advantage of ibuprofen gargling is its safety profile. The targeted swish-and-spit administration allows high local ibuprofen concentrations while minimizing the systemic absorption thereof, thereby reducing the risks associated with long-term NSAIDs use, including gastrointestinal bleeding, renal impairment, or cardiovascular complications. Furthermore, after six months of daily use, no serious adverse events were observed, and laboratory data findings remained stable, thus reinforcing the tolerability of this approach in a chronic disease population.\u003c/p\u003e\u003cp\u003eThis study has several limitations that should be acknowledged. First, the LTE phase was performed in an open-label manner without a placebo control, which potentially introduced placebo effects and observer bias. Although patients served as their own longitudinal controls, the absence of a comparator arm limits causal inference. Second, the relatively small sample size restricts the generalizability of these results and impedes the detection of rare adverse events. Third, concomitant therapies for oral lesions were permitted; while this reflects real-world practice, it may have confounded the treatment effect of ibuprofen gargling. Fourth, we analyzed multiple PROMS domains simultaneously without adjusting for multiple comparisons, thereby increasing the risk of Type I errors. Therefore, the further application of appropriate statistical corrections may render some of our significant findings non-significant, particularly for those with \u003cem\u003ep\u003c/em\u003e-values close to 0.05. Fifth, although we demonstrated significant improvements in various PROMS scores, the clinical meaningfulness of these changes remains uncertain because of the absence of established minimal clinically important difference thresholds for the PROMS domains in patients with OLP. The observed daily improvements, though significant, may not represent the perceptible benefits for individual patients. Future research should be conducted to validate these findings in larger multicenter randomized controlled trials. In addition, comparative studies against established therapies, such as topical corticosteroids, are required to define the relative efficacy of ibuprofen gargling and explore any potential synergistic effects in combination regimens. Moreover, pharmacokinetic and mechanistic studies would further elucidate the extent of systemic exposure and the pathways that underlie the observed functional improvements. Finally, research identifying patient subgroups that would most likely benefit from this treatment, such as those with predominant pain during mastication, may enable more personalized treatment approaches.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003e In conclusion, this study suggests that a six-month regimen of ibuprofen gargling may potentially be safe and associated with sustained pain and oral function-related QOL improvements in patients with OLP. Furthermore, it presents a promising therapeutic approach for alleviating the symptomatic burden of this chronic and often debilitating disease.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCTCAE: the Common Terminology Criteria for Adverse Events\u003c/p\u003e\n\u003cp\u003eLMMs: linear mixed-effects models\u003c/p\u003e\n\u003cp\u003eLTE: long-term extension\u003c/p\u003e\n\u003cp\u003eNSAIDs: nonsteroidal anti-inflammatory drugs\u003c/p\u003e\n\u003cp\u003eOLP: oral lichen planus\u003c/p\u003e\n\u003cp\u003ePROMS: patient-reported oral mucositis symptom\u003c/p\u003e\n\u003cp\u003eQOL: quality of life\u003c/p\u003e\n\u003cp\u003eVAS: visual analogue scale\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study complied with the Declaration of Helsinki and the Japanese Clinical Trials Act. The Kobe University Clinical Research Ethics Committee reviewed and approved the protocol (C210022 and C210023), and the clinical trial identifiers are jRCTs051220009 and jRCTs051220010. Written informed consent was obtained from all patients before any study procedures were conducted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent for the publication was obtained from the patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConcept and design: YKakei and IT. Acquisition, analysis, or interpretation of data: YKakei, YKitahiro, IT, NY, MKashin, MKobayashi, AM, TH, MA, and KY. Drafting of the manuscript: YKitahiro, YKakei, and IT. Critical review of the manuscript for important intellectual content: NY, MKashin, MKobayashi, AM, KY, TH, MA, and IY. Supervision: IY. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors express their gratitude to all the patients who participated in this study. They also acknowledge Mr. Toru Hibi from PHARMA SEEDS CREATE, LIMITED LIABILITY CO. (4-12-10, Tsutsujigaoka-Minami, Sanda, Hyogo 669-1347, Japan) for his guidance in the manufacturing of the ibuprofen gargle used in this study. We also want to thank Editage (www.editage.com) and Enago for performing the English-language review.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eL\u0026oacute;pez-Jornet P, Camacho-Alonso F. Quality of life in patients with oral lichen planus. J Eval Clin Pract. 2010;16(1):111\u0026ndash;3. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/j.1365-2753.2009.01124.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1365-2753.2009.01124.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAshshi RA, Stanbouly D, Maisano PG, et al. Quality of life in patients with oral potentially malignant disorders: oral lichen planus and oral epithelial dysplasia. 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Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;117(3):319\u0026ndash;23. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.oooo.2013.08.006\u003c/span\u003e\u003cspan address=\"10.1016/j.oooo.2013.08.006\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Patient characteristics\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"501\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 369px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003eN = 18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 369px;\"\u003e\n \u003cp\u003eAge, years\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e60 (36\u0026minus;85)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 369px;\"\u003e\n \u003cp\u003eSex, female, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e15 (83.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 369px;\"\u003e\n \u003cp\u003eDuration of OLP, month\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e24 (2\u0026minus;180)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 369px;\"\u003e\n \u003cp\u003eLesion site, n\u003c/p\u003e\n \u003cp\u003eNumber of lesion sites per patient\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eBuccal mucosa (total number of right and left)\u003c/p\u003e\n \u003cp\u003eMaxillary gingiva (total number of right and left)\u003c/p\u003e\n \u003cp\u003eMandibular gingiva (total number of right and left)\u003c/p\u003e\n \u003cp\u003eTongue (total number of right and left)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (1\u0026minus;4)\u003c/p\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 369px;\"\u003e\n \u003cp\u003eOngoing treatment for oral lesions, n\u003c/p\u003e\n \u003cp\u003e Azunol Gargle liquid\u003c/p\u003e\n \u003cp\u003e Dexamethasone Ointment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eData are presented as the median (range).\u003c/p\u003e\n\u003cp\u003eSome patients had multiple lesions at a single site; therefore, the total number of buccal mucosa lesions exceeds the total number of patients (N = 18).\u003c/p\u003e\n\u003cp\u003eOLP: oral lichen planus\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Laboratory data\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003eDay 8\u003c/p\u003e\n \u003cp\u003e(N = 18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003eDay 176\u003c/p\u003e\n \u003cp\u003e(N = 14)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003eWBC (cells/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e6,400 (3,700\u0026minus;10,800)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e5,150 (3,900\u0026minus;8,500)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003ePlt (10\u003csup\u003e4\u003c/sup\u003e/\u0026mu;L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e22.1 (8.3\u0026minus;32.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e25.5 (7.7\u0026minus;36.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003eHb (g/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e13.3 (10.6\u0026minus;16.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e13.3 (9.9\u0026minus;16.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003eAST (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e21 (10\u0026minus;72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e20 (16\u0026minus;76)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003eALT (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e17 (10\u0026minus;96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e19 (10\u0026minus;62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003e\u0026gamma;-GTP (U/L)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e18 (12\u0026minus;223)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e24 (12\u0026minus;324)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003eT-Bil (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e0.7 (0.4\u0026minus;1.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e0.6 (0.4\u0026minus;1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003eAlb (g/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e4.2 (3.0\u0026minus;4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e4.1 (3.3\u0026minus;4.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003eSCr (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e0.64 (0.41\u0026minus;0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e0.63 (0.47\u0026minus;0.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 168px;\"\u003e\n \u003cp\u003eBUN (mg/dL)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e13.4 (7.3\u0026minus;26.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 184px;\"\u003e\n \u003cp\u003e13.3 (8.2\u0026minus;22.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAll data are presented as the median (range). The post-laboratory data on Day 176 were obtained with an allowable visit window of \u0026plusmn;14 days. Alb: albumin, ALT: alanine aminotransferase, AST: aspartate aminotransferase, BUN: blood urea nitrogen, \u0026gamma;-GTP: \u0026gamma;-glutamyl transpeptidase, Hb: hemoglobin, Plt: platelet count, SCr: serum creatinine, T-Bil: total bilirubin, WBC: white blood cell count\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Linear mixed-effects estimates of time trends in each Patient-Reported Oral Mucositis Symptom (PROMS) domain (Days 1\u0026ndash;176).\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"589\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 222px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePROMS domain\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026beta;\u003csub\u003eday\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e95% CI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003ep-value\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 222px;\"\u003e\n \u003cp\u003eMouth pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026minus;0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026minus;0.072 to \u0026minus;0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.029\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 222px;\"\u003e\n \u003cp\u003eDifficulty speaking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026minus;0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026minus;0.035 to 0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.054\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 222px;\"\u003e\n \u003cp\u003eRestriction of speech\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026minus;0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026minus;0.021 to 0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.479\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 222px;\"\u003e\n \u003cp\u003eDifficulty eating hard foods\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026minus;0.067\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026minus;0.096 to \u0026minus;0.038\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 222px;\"\u003e\n \u003cp\u003eDifficulty eating soft foods\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026minus;0.021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026minus;0.031 to \u0026minus;0.010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 222px;\"\u003e\n \u003cp\u003eRestriction of eating\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026minus;0.083\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026minus;0.107 to \u0026minus;0.059\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 222px;\"\u003e\n \u003cp\u003eDifficulty drinking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026minus;0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026minus;0.012 to \u0026minus;0.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.043\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 222px;\"\u003e\n \u003cp\u003eRestriction of drinking\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026minus;0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026minus;0.015 to 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 222px;\"\u003e\n \u003cp\u003eDifficulty swallowing\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u0026minus;0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026minus;0.011 to \u0026minus;0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 222px;\"\u003e\n \u003cp\u003eChange in taste\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 71px;\"\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026minus;0.001 to 0.035\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.064\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFor each domain, \u0026beta;\u003csub\u003eday\u003c/sub\u003e is the estimated mean daily change in the score from a model with a fixed effect for day and random intercepts by individual patient (\u003cem\u003evalue\u003c/em\u003e ~ \u003cem\u003eday\u003c/em\u003e + (1|Subject)). Days 1\u0026ndash;7 correspond to the randomized crossover phase; Days 8\u0026ndash;176 correspond to the long-term extension (LTE), aligned by adding 7 to the LTE days. Entries are the estimate (\u0026beta;\u003csub\u003eday\u003c/sub\u003e), standard error (SE), 95% confidence interval (CI), and a two-sided \u003cem\u003ep-value\u0026nbsp;\u003c/em\u003ewas employed. Negative \u0026beta;\u003csub\u003eday\u003c/sub\u003e indicates decreasing domain scores (i.e., improvement). No adjustment for multiple testing was applied.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"oral lichen planus, ibuprofen gargle, PROMS, oral pain, long-term extension study","lastPublishedDoi":"10.21203/rs.3.rs-7803748/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7803748/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eOral lichen planus (OLP) is a chronic immune-mediated inflammatory disease of the oral mucosa that frequently causes erosive lesions accompanied by pain, thereby impairing the patient\u0026rsquo;s ability to eat and drink and their overall quality of life (QOL). Current guidelines recommend topical corticosteroids as first-line treatments; however, their efficacy is limited for pain relief, and long-term safety remains a concern. Nonsteroidal anti-inflammatory drug mouthrinse formulations can deliver high local drug concentrations to the symptomatic mucosa with minimal systemic exposure. This study evaluated the short- and long-term safety and efficacy of ibuprofen gargling in patients with painful OLP.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a randomized, double-blind, placebo-controlled crossover study (Days 1\u0026ndash;7), followed by a 6-month open-label long-term extension (LTE) study (Days 8\u0026ndash;176). Patients with OLP and baseline oral pain of \u0026ge;\u0026thinsp;20 mm on a 100-mm visual analog scale (VAS) were enrolled. The LTE study\u0026rsquo;s primary endpoint was safety, and secondary endpoints included changes in the VAS in resting oral pain and oral health-related QOL, which was measured using the Patient-Reported Oral Mucositis Symptom (PROMS) scale.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe crossover study enrolled 24 patients, and 18 patients continued the LTE study. No serious adverse events were observed. One patient discontinued treatment because of grade 2 oral pain, while the remaining patients tolerated long-term treatment exhibiting stable laboratory values. During the LTE study, ibuprofen gargling was associated with significant improvements in several PROMS domains. The most pronounced effects were observed in the dietary domains, including eating restriction (β\u003csub\u003eday\u003c/sub\u003e = \u0026minus;\u0026thinsp;0.083, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and difficulty eating hard foods (β\u003csub\u003eday\u003c/sub\u003e = \u0026minus;\u0026thinsp;0.067, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Modest but significant improvements were observed for mouth pain (β\u003csub\u003eday\u003c/sub\u003e = \u0026minus;\u0026thinsp;0.038, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029), difficulty eating soft foods (β\u003csub\u003eday\u003c/sub\u003e = \u0026minus;\u0026thinsp;0.021, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), swallowing (β\u003csub\u003eday\u003c/sub\u003e = \u0026minus;\u0026thinsp;0.007, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and drinking (β\u003csub\u003eday\u003c/sub\u003e = \u0026minus;\u0026thinsp;0.006, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003e A 6-month regimen of ibuprofen gargling may be safe and potentially associated with sustained pain and oral function-related QOL improvements in patients with OLP. It represents a promising therapeutic approach for alleviating the symptomatic burden of this chronic and often debilitating disease.\u003c/p\u003e\u003ch2\u003eTrail registration:\u003c/h2\u003e\u003cp\u003eThe Registry of Clinical Trials; jRCTs051220009 and jRCTs051220010, date of registration: 22 April 2022.\u003c/p\u003e","manuscriptTitle":"Ibuprofen Gargle for Quality of Life and Pain Improvement in Oral Lichen Planus: Randomized Crossover and Long-Term Extension Phase II Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-29 04:00:20","doi":"10.21203/rs.3.rs-7803748/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b1e3c5a9-c3c2-4b4d-a8a6-d1d5e7046926","owner":[],"postedDate":"October 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:06:04+00:00","versionOfRecord":{"articleIdentity":"rs-7803748","link":"https://doi.org/10.1186/s40780-025-00536-0","journal":{"identity":"journal-of-pharmaceutical-health-care-and-sciences","isVorOnly":false,"title":"Journal of Pharmaceutical Health Care and Sciences"},"publishedOn":"2026-01-08 15:59:09","publishedOnDateReadable":"January 8th, 2026"},"versionCreatedAt":"2025-10-29 04:00:20","video":"","vorDoi":"10.1186/s40780-025-00536-0","vorDoiUrl":"https://doi.org/10.1186/s40780-025-00536-0","workflowStages":[]},"version":"v1","identity":"rs-7803748","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7803748","identity":"rs-7803748","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}