Comparative evaluation of the efficacy of topical Amlexanox 5%, Triamcinolone Acetonide 0.1%, and Tacrolimus 0.03% in the treatment of oral erosive lichen planus – A double-blinded randomized clinical trial

Vaibhav Seth; Rajendra G Patil; Ganapathi Moger; Udita Singh; Abhinav Sharma; Smriti Saxena

doi:10.4103/jiaomr.jiaomr_16_21

ORIGINAL ARTICLE

Year : 2022 | Volume : 34 | Issue : 2 | Page : 136-140

Comparative evaluation of the efficacy of topical Amlexanox 5%, Triamcinolone Acetonide 0.1%, and Tacrolimus 0.03% in the treatment of oral erosive lichen planus – A double-blinded randomized clinical trial

Vaibhav Seth¹, Rajendra G Patil¹, Ganapathi Moger², Udita Singh¹, Abhinav Sharma³, Smriti Saxena⁴
¹ Department of Oral Medicine and Radiology, Kothiwal Dental College and Research Centre, Moradabad, Uttar Pradesh, India
² Private Practitioner, Bhatkal, Karnataka, India
³ Department of Oral Medicine and Radiology, Subharti Dental College, Meerut, India
⁴ Department of Public Health Dentistry, Institute of Dental Sciences, Bareilly, Uttar Pradesh, India

Date of Submission	18-Jan-2021
Date of Decision	17-May-2022
Date of Acceptance	18-May-2022
Date of Web Publication	22-Jun-2022

Correspondence Address:
Vaibhav Seth
Senior Lecturer, Department of Oral Medicine and Radiology, Kothiwal Dental College and Research Centre, Moradabad - 244 001, Uttar Pradesh
India

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/jiaomr.jiaomr_16_21

Abstract

Objective: The objective of this study was to evaluate the short-term efficacy and safety of the topical application of amlexanox paste with triamcinolone acetonide paste and tacrolimus paste in the treatment of oral erosive lichen planus. Study Design: This study was a randomized double-blinded placebo-controlled clinical trial. Forty patients aged 18–70 years with erosive oral lichen planus received amlexanox 5% paste (n = 10), triamcinolone acetonide 0.1% paste (n = 10), tacrolimus 0.03% paste (n = 10), and glycerin as placebo (n = 10) for 15 days. Outcome measures included pain using visual analog scale (VAS) scores, and the erosive area in cm² was evaluated both before (baseline) and during the trial (i.e., days 7 and 15). Results: After 15 days of treatment, all the groups showed significant reductions in erosive areas and VAS scores (P <.001) except for the glycerin-treated group, where it was found to be non-significant. No systemic side effects and adverse reactions were observed in the present study. Conclusion: It was found that the topical application of 5% amlexanox paste appeared as effective as 0.1% triamcinolone acetonide paste and 0.03% tacrolimus paste in the treatment of oral erosive lichen planus.

Keywords: Amlexanox, erosive lichen planus, pre-malignant condition, randomized clinical trial, tacrolimus, triamcinolone acetonide

How to cite this article:
Seth V, Patil RG, Moger G, Singh U, Sharma A, Saxena S. Comparative evaluation of the efficacy of topical Amlexanox 5%, Triamcinolone Acetonide 0.1%, and Tacrolimus 0.03% in the treatment of oral erosive lichen planus – A double-blinded randomized clinical trial. J Indian Acad Oral Med Radiol 2022;34:136-40

How to cite this URL:
Seth V, Patil RG, Moger G, Singh U, Sharma A, Saxena S. Comparative evaluation of the efficacy of topical Amlexanox 5%, Triamcinolone Acetonide 0.1%, and Tacrolimus 0.03% in the treatment of oral erosive lichen planus – A double-blinded randomized clinical trial. J Indian Acad Oral Med Radiol [serial online] 2022 [cited 2023 Feb 2];34:136-40. Available from: http://www.jiaomr.in/text.asp?2022/34/2/136/347910

Introduction

Oral lichen planus is a chronic inflammatory mucocutaneous disorder affecting the stratified squamous epithelium in the fifth to sixth decade of life. However, patients of all ages can be affected with a more female preponderance.^[1] The etiology of oral lichen planus is unknown. Still, evidence shows that it is a T-cell-mediated immunological response to an antigen expressed at the basal layer of the oral mucosa.^[2] Many of the treatments documented in the literature point toward the use of high-potency corticosteroids both topically and systemically as a mainline of therapy in oral lichen planus.^[3]

Oral lichen planus can cause symptoms that range from burning sensation to severe pain, especially during the intake of hot and spicy foods, causing difficulty in eating, speaking, and brushing the teeth and ulcerations, thereby reducing the quality of life.^[4] Various treatment regimens have been designed to improve the management of oral erosive lichen planus, but a permanent cure is not yet possible.^[5]

Topical corticosteroids and immunosuppressive drugs are most commonly used to treat oral lichen planus. Because of the chronicity and recurrence of erosive oral lichen planus, many patients need to apply topical glucocorticoids repeatedly to keep the condition stable,^[6] which may cause side effects such as insomnia, mood swings, fatigue, and fluid retention.^[7]

The safety of long-term topical treatment with these drugs in oral erosive lichen planus is still doubtful as they are associated with the potential risk of malignancy.^[8] The risk of malignant transformation associated with the oral lichen planus is 0.44% to 1.4% in the general population.^[9] Therefore, alternative local therapy with well-demonstrated efficacy and safety is needed.

Amlexanox (C₁₆H₁₄N₂O₄) is a topical anti-inflammatory and anti-allergic drug developed as a 5% topical oral paste for treating recurrent aphthous ulcers.^[10] Amlexanox potently inhibits the release of histamine and leukotrienes from mast cells, basophils, and neutrophils in in vitro settings, possibly through increasing intra-cellular cyclic adenosine monophosphate content in inflammatory cells, a membrane-stabilizing effect or inhibition of calcium influx.^[11] To determine if amlexanox could have a beneficial effect on oral erosive lichen planus, we conducted the present study to evaluate the short-term efficacy, safety, and adverse effects of the topical application of amlexanox paste in the treatment of oral erosive lichen planus.

Materials and Methods

This study was a prospective randomized double-blinded, placebo-controlled clinical trial. Patients satisfying the inclusion criteria with clinically and histopathologically diagnosed oral erosive lichen planus, aged between 18 to 70 years, were selected for the study after obtaining informed consent. Inclusion criteria involve normal values before medication (including complete blood cell count, renal and hepatic chemistry, and hyper-sensitivity tests for amlexanox paste, triamcinolone acetonide paste, and tacrolimus paste).

Patients with severe systemic and oral mucous diseases, using antibiotics within 1 month or immunomodulating drugs within 3 months, having a history of topical treatment within a week, showing the presence of lichenoid reaction, pregnant and lactating mothers, showing recent use of steroid-based contraceptives, or showing psychiatric disorders were excluded.

Out of 40 patients, there were 18 males and 22 females. The four drugs were divided into four groups containing ten patients in each group; that is, amlexanox oral cream in a concentration of 5%, triamcinolone acetonide oral cream in a concentration of 0.1%, tacrolimus oral cream in a concentration of 0.03%, and glycerin as placebo were used in this study.

The patients with oral erosive lichen planus were assigned to one of the four groups with ten patients. Amlexanox, triamcinolone acetonide, tacrolimus pastes, and a plastic container with glycerin were used with the help of a computer-generated random number list.

All patients were instructed to apply a dab of one agent to the lesions three times a day (after meals) for 15 days. The first application was monitored, and the subjects were observed for more than 30 min for potential allergic events and other adverse effects. Effectiveness and safety evaluations were made on days 7 and 15. If the erosive lesions completely healed and the pain disappeared, subjects were instructed to discontinue the medication and be evaluated.

Clinical assessment

The response was evaluated by the size of the erosive area and the pain or burning sensation. Both the values of erosive area (cm²) and the level of pain or burning sensation were assessed and recorded on days 1, 7, and 15. A calibrated dental probe was used to measure the maximum diameter of single erosive lesions and the maximum width perpendicular to the maximum diameter.

Erosive area (cm²) = maximum diameter (cm) X maximum width (cm).

The main examiner assessed the pain or burning sensation using the visual analog scale (VAS) using a 10 cm horizontal line with 0 indicating no pain and 10 indicating extreme pain. The information and data obtained across pre-treatment, during treatment, and post treatment for all the patients were sorted, tabulated, and subjected to appropriate tests for statistical analysis.

Statistical analysis

The data were analyzed using SPSS version 16.0. Wilcoxon signed rank test and Kruskal Wallis test analyzed the differences between the four groups. The Mann–Whitney U test made the comparison between two groups at a site. The P value of < 0.05 was considered to be as statistically significant.

Results

There were significant differences in the mean values of pain or burning sensation, which were found to be 0.20 ± 0.63, 0.50 ± 1.08, and 0.40 ± 0.84 on the 15^th day of visit in the topical amlexanox, triamcinolone acetonide, and tacrolimus groups, except for the topical glycerin group, where it was 6.8 ± 1.61, with a % difference of 97.77% in the topical amlexanox group as compared to the % difference of 94.02% in the topical triamcinolone acetonide group, 94.64% in the topical tacrolimus group, and 3.09% in the topical glycerin group on the 15^th day of treatment [Table 1], [Graph 1].

Table 1: Data distribution based on VAS scores on the 1^st, 7^th, and 15^th days among the study subjects

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The mean values of erosive area (cm²) for the topical amlexanox group, topical triamcinolone acetonide group, and topical tacrolimus group also showed significant differences, which were 0.009 ± 0.02, 0.01 ± 0.03, and 0.02 ± 0.05 (p < 0.01) in the left buccal mucosa (LBM) [Table 2], [Graph 2] and 0.02 ± 0.03, 0.002 ± 0.006, and 0.01 ± 0.02 (p < 0.01) in the right buccal mucosa (RBM) [Table 3], [Graph 3] on the 15^th day of visit, except for the topical glycerin group, where it was statistically non-significant 1.15 ± 0.41 (p-value at 0.317 LBM) and 1.05 ± 0.35 (p-value at 1.00 RBM). The % difference was 99.30%, 97.68%, 98.37%, and -0.26% for LBM and 98.70%, 99.87%, 99.17%, and 0.00% for RBM at the 15^th day of treatment.

Table 2: Distribution of erosive area of LBM on the 1^st, 7^th, and 15^th days among the study subjects

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Table 3: Distribution of erosive area of RBM on the 1^st, 7^th, and 15^th days among the study subjects

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A maximum reduction in the mean size of the erosive area was observed in the topical amlexanox-treated group [Figure 1]. None of the patients in the present study groups developed any adverse effects locally or systemically during the treatment course.

Figure 1: Clinical changes after treatment with amlexanox: (a) pre-treatment and (b) post-treatment

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Discussion

Oral lichen planus is one of the most common oral mucosal diseases affecting the general population. It presents clinically as reticular, papular, plaque-like, erosive, atrophic, or bullous lesions. Erosive oral lichen planus can be very symptomatic and sometimes may be recalcitrant to medical management and predispose to squamous cell carcinoma.^[10]

Topical immunosuppressive drugs such as tacrolimus have been tested in open or double-blinded trials with variable results; however, their high cost, toxicity, and potential increased risk of malignancy restrict their use.^[12] Therefore, alternative local therapy with well-demonstrated efficacy and safety is needed.

Amlexanox is a topical anti-inflammatory drug that can inhibit the de-granulation of mast cells and thus will inhibit the formation and release of histamine, TNF-α, and leukotrienes. Histamines and leukotrienes are vasoactive inflammatory mediators that can increase the permeability of vessels and, therefore, cause swelling of the involved tissues and contribute to inflammation by affecting the functions of other leukocytes in the involved area.^[13]

In our study, on the 15^th day of treatment of oral erosive lichen planus, there was improvement and reduction of the erosive area in the topical amlexanox-treated group where a % difference of 99.30% on LBM and 98.70% on RBM was observed along with a marked reduction in the VAS scores with a % difference of 97.77%. Our result is similar to the study performed by Fu J et al.,^[10] in which after 7 days of treatment, both groups (topical amlexanox and topical dexamethasone) showed a significant reduction in erosive area and VAS scores with no severe adverse reactions. Another study by Mostafa EI-Shennawy showed a significant reduction in erosive area and VAS scores in 3 weeks of treatment.^[14]

Moreover, in most of the previously reported studies, the treatment with topical amlexanox was only in recurrent aphthous ulcers and stomatitis. In our study, topical amlexanox was safe and effective in all patients included in the group. A clinical study performed by Atul Khandwala et al.^[15] also showed no significant irritation or sensitization associated with 5% amlexanox paste.

Pharmacokinetic studies indicated that systemic levels of amlexanox are most likely because of normal gastro-intestinal absorption with only limited absorption directly through the ulcer, indicating that 5% amlexanox paste is safe for the treatment. A study performed by Girish Katti et al. and Suraksha Bhat et al. in their study on RAS and RAU concluded that amlexanox could reduce the frequency, duration, and symptoms associated with the aphthous ulcers with no side effects attributed to the drug for the treatment of RAU.^[16],[17]

In our study, topical triamcinolone acetonide and topical tacrolimus showed improvements of 97.68% and 98.37% in the erosive area and 94.02% and 94.64% in the erosive area VAS scores on the 15^th day of treatment, respectively. Similar results were found in a study conducted by Ronald Laeijendecker et al.^[18] Topical tacrolimus 0.1% ointment induced a better initial therapeutic response than triamcinolone acetonide 0.1% ointment. However, relapse occurred frequently within 3–9 weeks of the cessation of treatment.

In another study by Javed A Qazi et al.,^[19] topical tacrolimus ointment induced a better initial therapeutic response than triamcinolone acetonide ointment. However, relapse occurred in 12 cases within 6–8 weeks of the cessation of the therapy. A study performed by Todd W. Rozycki revealed that flare-ups were typically manifested within 1–2 weeks of stopping the tacrolimus.^[20] A similar study performed by Amber Kiyani et al.^[21] showed that tacrolimus 0.1% was an ineffective option for managing erosive oral lichen planus.

The results of our study showed that there was a significant improvement in the topical amlexanox-treated group, topical triamcinolone acetonide-treated group, and tacrolimus-treated group in the reduction of clinical signs (erosive areas) and the alleviation of clinical symptoms (pain and burning sensation) after 15 days of treatment, indicating that amlexanox was as effective as triamcinolone acetonide and tacrolimus in the topical treatment of oral erosive lichen planus.

Limitations

Studies with a larger duration and sample size should be performed to assess the better clinical impact of these drugs for this lesion.

Conclusion

We noticed that the topical application of amlexanox paste 5% appeared as effective as triamcinolone acetonide and tacrolimus paste in treating oral erosive lichen planus, and no adverse effects were found in the present study.

Ethical considerations

Permission from the Institutional Ethical Board was obtained. Ref No.:-KDCRC/IERB/12/2013/01

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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