|Year : 2022 | Volume
| Issue : 1 | Page : 17-21
Therapeutic Evaluation of 5% Topical Amlexanox Paste and 2% Curcumin Oral Gel in the Management of Recurrent Aphthous Stomatitis- A Randomized Clinical Trial
Jeevitha Gauthaman1, Anuradha Ganesan2
1 Department of Oral Medicine and Radiology, Madha Dental College and Hospital, Kundrathur, Chennai, Tamil Nadu, India
2 Professor and Head, Department of Oral Medicine and Radiology, SRM Dental College, Ramapuram, Chennai, Tamil Nadu, India
|Date of Submission||11-Aug-2021|
|Date of Decision||29-Oct-2021|
|Date of Acceptance||15-Dec-2021|
|Date of Web Publication||25-Mar-2022|
Dr. Jeevitha Gauthaman
Madha Dental College and Hospital, Kundrathur, Chennai - 600 069, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Recurrent aphthous stomatitis (RAS) minor is a painful oral condition that is characterized by shallow ulcers with an erythematous halo. These ulcers cause difficulty in mastication and speech and have a high recurrence rate. Objective: The present study aims to compare the size of the ulcer, erythema, pain score, and recurrence rates in patients using 5% topical amlexanox and 2% curcumin oral paste in the management of RAS minor. Materials and Methods: The present study was conducted among 48 participants who were randomly assigned into two groups. Group A comprised participants who were given 5% topical amlexanox paste and Group B comprised participants who were given 2% curcumin oral gel for application. The participants were evaluated on days 1, 4, and 7 for the size of ulcers, erythema level, and pain score. They were reviewed on days 30, 60, 90, and 180 and recurrence episodes were documented. Results: There was a significant reduction in erythema (0.041) and pain scores (0.012) in Group B participants who used curcumin. The size of the ulcer had reduced in both the groups though there was no significance. Recurrence rates were high in participants who used amlexanox (92%) and were comparatively low in the curcumin using group (50%). Conclusions: Curcumin is a potent, safe substitute in the management of RAS minor for its effectiveness in reducing erythema, pain, and recurrence rates. Further studies should be conducted for evaluating the efficacy of curcumin in various clinical types of RAS.
Keywords: Curcumin, oral gel, recurrence, recurrent aphthous stomatitis, topical amlexanox
|How to cite this article:|
Gauthaman J, Ganesan A. Therapeutic Evaluation of 5% Topical Amlexanox Paste and 2% Curcumin Oral Gel in the Management of Recurrent Aphthous Stomatitis- A Randomized Clinical Trial. J Indian Acad Oral Med Radiol 2022;34:17-21
|How to cite this URL:|
Gauthaman J, Ganesan A. Therapeutic Evaluation of 5% Topical Amlexanox Paste and 2% Curcumin Oral Gel in the Management of Recurrent Aphthous Stomatitis- A Randomized Clinical Trial. J Indian Acad Oral Med Radiol [serial online] 2022 [cited 2022 Dec 6];34:17-21. Available from: http://www.jiaomr.in/text.asp?2022/34/1/17/340739
| Introduction|| |
Recurrent aphthous stomatitis (RAS) is a common oral mucosal condition that has a multifactorial etiology. They are recurrent and also known as “canker sores.” They appear as recurrent, multiple, small, round, or ovoid ulcers, with circumscribed margins, having yellow or gray floors, and are surrounded by erythematous haloes. The global incidence of aphthous ulcers was found to be 20%.
This condition is characterized by intense pain and discomfort, crippling normal activities of the oral cavity such as chewing and swallowing. Being a condition of multifactorial nature, several etiologies such as local trauma, psychological stress, allergy to products containing sodium lauryl sulfate (oral care products such as toothpaste), hormonal fluctuations such as ovulation, and menstruation in women, and alterations in oral microbial flora have been related to the occurrence of RAS. Additionally, it has been linked to systemic conditions like malabsorption, enteropathy, celiac disease, hematinic deficiencies (iron, folate, vitamin B6, and B12), and vitamin D, zinc, and thiamine related deficiencies. Several therapeutic modalities including topical anesthetics, antibiotics, corticosteroids, nutritional supplements, immune-modulatory drugs, laser therapy, and combination therapies have been in vogue for effective pain management and reduction of recurrence. Amlexanox (C16H14N204), a topical anti-inflammatory and anti-allergic drug is the only clinically proven drug approved by the US Food and Drug Administration for the management of RAS. It inhibits the formation and release of histamine and leukotrienes from mast cells, neutrophils, and mononuclear cells. Curcuma longa is a potent herbal counterpart that has been evaluated for its anti-inflammatory and anti-oxidant effects in many oral diseases as an alternative for corticosteroids. The primary objective of the present study was to compare the efficacy of 5% topical amlexanox and 2% topical curcumin in the management of RAS (minor). The second objective was to evaluate the recurrence rate of RAS (minor) over 6 months.
| Material and Methods|| |
The present study was a single-center, open, parallel, and single-blinded interventional randomized clinical trial conducted in the out-patient department of a private dental college and hospital in Chennai, Tamil Nadu. The ethical approval was obtained from the Institutional Ethics Committee, Madha Dental College & Hospital, Kundrathur, Chennai (MDCH/MDS/EC/-026) dated May 12, 2019. The study was designed and conducted according to the CONSORT guidelines (2010) for randomized clinical trials. All study procedures were planned and executed according to the committee on human experimentation (institutional or regional) and the Helsinki declaration of 1975 (revised 2000). Prior informed consent was obtained in written form from all participants of the study. The sample size was determined by considering a confidence level of 95% and an error rate of 5%. A total of 48 participants were included in the randomized clinical trial with an allocation ratio of 1:1. They were divided into two study groups: Group A received 5% amlexanox oral paste and Group B received 2% curcumin oral gel. Randomization was done using computer-generated sequence numbers.
- Age group: 18–30 years
- Participants giving a history of RAS minor (ulcers that measure <10 mm, and heal within 4–14 days without scarring) with a minimum of two episodes in a year
- Participants with 1–3 minor RAS of less than 48 h duration.
- Participants with any systemic disorders
- Pregnant, lactating women
- Participants with the habit of smoking or alcoholism
- Participants undergoing orthodontic therapy
- Participants who had undergone tooth extraction or any dental surgical procedure in the past 2 weeks
- Participants under any Non-steroidal anti-inflammatory drugs (NSAIDS)/systemic steroids/immune suppressant drugs
- Participants allergic to medicines or foods.
A detailed oral examination was done for all 48 participants and all baseline parameters such as the site, size, number, pain, erythema, and exudation were recorded on the first day. The clinical diagnosis and evaluation were supervised by the staff from the department of oral medicine and radiology. The researcher gave thorough instructions on the application of the drug in both verbal and written format. Topical 5% amlexanox ointment (amlenox oral paste containing 5% amlexanox, Zuventus laboratories) and 2% curcumin oral gel (curenext oral gel containing 10 mg Curcuma longa extract and colors such as erythrosine from Abbott pharmaceuticals) were randomly packed in identical packages and allotted to the participants. The participants were not aware of the drug. The participants were asked to wipe the affected area clean with a piece of cotton. Group A participants were instructed to take ¼ inch (0.5 cm) of the paste approximately and apply it at the site of the lesion. Group B participants were asked to apply a very little amount of the gel just enough to form a thin smear over the lesions.
Both groups were asked to apply the drug four times a day; in the morning after performing oral hygiene, after lunch, after dinner, and before going to bed.
The maximum diameter of the ulcers was measured with William's calibrated periodontal probe on days 1, 4, and 7. For assessing pain, a Visual Analog Scale (VAS) containing a 10 cm horizontal line between two points connoting no pain and excruciating pain was used. The subjects were asked to identify the line on the scale, which best represented their present pain level. The degree of erythema was evaluated with a 4-point scale (modified Greer et al. scale) in which “0” referred to no erythema, “1” denoted light red/pink color, “2” denoted red but not dark in color, and “3” referred to very red, dark color. All participants were evaluated on days 1, 4, and 7 and checked for all parameters. The subjects were followed up on days 30, 60, 90, and 180 to check for recurrences. Complete oral examinations were performed on all visits, and the subjects were specifically interrogated about any adverse events.
All data were analyzed using SPSS version 22. An independent t-test with Welch's correction of variance was done for both groups. The intergroup comparison and intragroup comparisons for non-categorical data on days 1, 4, and 7 were done using the Chi-square test. A P value of ≤ 0.05 was considered significant.
| Results|| |
Forty-eight participants were included in the present study of which, 18 were male (37.5%) and 30 participants were female (62.5%).
The mean ulcer size on days 1, 4, and 7 in Group B participants were more when compared to Group A participants [Table 1].
The mean erythema levels on day 1 for Group A and Group B was 1.75 ± 1.12 and 1.58 ± 0.78, respectively. The erythema levels on days 4 and 7 were 1.42 ± 1.72 and 0.58 ± 0.77 for Group A and 1.23 ± 1.32 and 0.27 ± 0.51 for Group B, respectively [Figure 1].
The mean pain scores measured on days 1, 4, and 7 were lower in Group B participants when compared to Group A participants [Table 2] and [Figure 2]. When the participants were checked for recurrence, those who used amlexanox had a high recurrence rate (92%) when compared to those who used curcumin (50%).
|Figure 2: Line diagram showing the reduction in pain score between groups A and B|
Click here to view
| Discussion|| |
The term “aphthae” originated from the Greek word “aphthi” which means “to set on fire” or “to inflame”. It is believed to be coined by the Greek philosopher, Hippocrates. The RAS occur as shallow ulcers with well-defined erythematous margins with a pseudomembranous crater. There are three clinical types of RAS namely; major aphthae affecting 10% of the population, minor RAS affecting >70%, and herpetiform ulcers affecting around 10% of the population.
The prevalence of RAS was 21.7% in a nationwide survey conducted in 2010–2012 in India. Though many drug therapies can be chosen to treat this condition, the primary objective remains the same: to reduce the ulcer size, reduce erythema, pain, and prevent a recurrence. To the best of our knowledge, the present study is the only attempt that compared topical amlexanox with an equally competent herbal formulation of curcumin in the management of RAS minor.
In the present study, 18 participants were male (37.5%) and 30 participants were female (62.5%), which shows a female predominance (1:1.7) similar to previous studies.,, The average age of the participants was 22.5 years as we had included participants who were in the age range of 18–30 years only. This sample selection was done considering previous studies said that reported that the prevalence of RAS was high among the population in the age groups of 18–24 years and 20–29 years. The most common site of the minor aphthous ulcers was the lower labial mucosa (47%), followed by the upper labial mucosa (21%), tongue (16%), buccal mucosa (11%), and the floor of the mouth (5%). A predominance of RAS among female participants occurred in the lower labial mucosa (61%), similar to that reported in the study by Raman and Pitty. In our study, a majority of 83% (40) participants reported a single ulcer during each episode and 17% (8) participants reported varying numbers of ulcers ranging from 1 to 3. Our findings were similar to a previous study done among dental students.
Curcumin is a phytochemical that is obtained from the plant, C. longa, which belongs to the family Zingiberaceae. It has been used in Indian traditional medicinal practices from time immemorial. It is a potent anti-inflammatory and anti-oxidant that is being explored in several clinical trials for its innumerable benefits. Apart from curcumin, the other essential compounds present in C. longa are dimethoxycurcumin and bisdemethoxycurcumin.
In our study, the erythema on day 3 was reduced in Group B participants when compared to Group A participants. On day 7, there was a significant reduction in erythema in participants using curcumin oral gel compared to those who used amlexanox (P = 0.041). Pain scores were also less on day 4 in the curcumin using group when compared with Group A. Also, the pain score reduced significantly on day 7 in curcumin-using patients when compared with amlexanox. (P = 0.012). Our findings were in line with those of a previous randomized clinical trial where curcumin performed comparatively better than the placebo in a 2-week intervention. Previous studies had evaluated curcumin and 1% triamcinolone acetonide and both the groups performed equally well in treating RAS., However in our study, curcumin performed better in reducing the erythema and significant pain relief was noted on day 7 among the Group B participants.
In our study, there was a 37% reduction in pain on day 3 in Group A and a 42% reduction in pain in Group B. On day 5, there was a 46% reduction in pain in Group A participants and a 60% reduction in pain in Group B. On day 7, there was 88% pain reduction in group A and 98% pain reduction in Group B participants.
Many studies have evaluated the anti-inflammatory properties of curcumin and report that curcumin acts through the inhibition of phospholipase, lipidase, and cyclo-oxygenase-2. It also effectively reduces the levels of cytokines namely Interleukin (IL)-2, Tumor Necrosis Factor (TNF)-alpha, IL-6, and IL-1 beta. Further light has been shed on the pathways involved in the process wherein it is hypothesized that curcumin may stimulate cortisol secretion, which in turn reduces the levels of cytokinins. This could explain the possible pain control achieved by using curcumin in RAS.
When the size of the ulcers was measured, both groups showed a decrease in the size from day 1 to day 7. Although there was no significance, the group that used amlexanox performed well in reducing the ulcer size with a mean size of 3.2 ± 1.19 on day 1, 2.63 ± 1.49 on day 3, and 1.0 ± 0.85 (mm) on day 7. The results were consistent with those of various studies that used amlexanox where the application of amlexanox in the pre-ulcerative stage reduced the ulcer size significantly by the third day itself., Curcumin showed a mean ulcer size of 3.88 ± 1.25 on day 1, 2.71 ± 1.98 on day 3, and 1.25 ± 1.49 on day 7. There was no statistical significance in either group. Our results were contrary to those of earlier studies, which state that there was a significant decrease in the size of the lesion when curcumin was used.
A few challenges in using curcumin for oral use are that the drug has to be in contact with the oral mucosa for longer periods for any significant effect. Various studies have shown the poor bioavailability of curcumin due to its poor absorption, rapid metabolism, chemical instability, and rapid systemic elimination. However, the ionic environment in the oral cavity, the adhesion properties of the oral mucosa, and the low soluble property of curcumin in an aqueous medium prevent the retardation of the agent in the oral environment. This explains the reason for its better efficacy in the oral cavity despite its lower bioavailability.
Major concerns revolve around the use of corticosteroids and immunomodulatory drugs for RAS as there is an increase in the frequency of episodes, an increase in severity of ulcers, and also reported adverse effects. However, curcumin has been evaluated for its safety and is reported safe even at high doses (12 g/day). It was found to be well tolerated even in our study and can be considered as a viable alternative in the management of RAS.,
Also, with the increased use of topical corticosteroids such as triamcinolone acetonide, there is an increased risk of opportunistic fungal infections. This issue can be sorted out with curcumin as it has been studied for its anti-fungal nature in various studies. Cytokines along with inducible nitric oxide synthase (INOS) produce nitric oxide that is believed to kill microorganisms. A slow-release formulation of curcumin in concentrations ranging from 0.1% to 15%, preferably 1% to 10% is found to be effective for oral ulcers.
Moreover, curcumin was found to be significantly effective in the reduction of recurrence rates when the participants were reviewed on days 30, 60, 90, and 180. Only 4.16% (1 participant) reported recurrence on day 30 in Group B, 29.16% (7 participants) on day 60, 37.5% (9 participants) on day 90, and 50% (12 participants) reported recurrence at the end period of 6 months [Figure 3]. These results were very satisfactory when compared to the participants who used amlexanox, where a predominant number of 22 participants (92%) reported recurrence at the end of 6 months. Our results were similar to previous studies where the healing of RAS was satisfactory in participants who used curcumin., This long-term follow-up enabled us in evaluating the healing benefits of curcumin in RAS as the objective of treating RAS is not only in reducing the symptoms but also in preventing the recurrence of this perennial oral condition.
Various drug therapies have been tried for the management of RAS and, amlexanox was found to have better efficacy in most of the studies. In our study, we wanted to look for a potent herbal alternative with high efficacy, safety, and better symptomatic relief. Curcumin-based oral gels are herbal preparations that have fewer side effects and safety even at high doses. They reduce the size and erythema of the ulcer and the associated pain. Recurrence of RAS minor is very less and so it can be a better alternative to the existing therapeutic options. However, a limitation of the present study is the small sample size. Further long-term studies should be conducted with a larger sample size to evaluate the effectiveness of curcumin in the management of all clinical variants of RAS. Also, comparative studies evaluating curcumin and other conventional therapies will help in determining its effectiveness.
| Conclusion|| |
The present study suggests that curcumin can be used as a potential substitute to other drug therapies in the management of RAS minor as it is effective in reducing erythema, pain, and also recurrence of ulcers. Similar herbal alternatives with reduced adverse effects have to be considered in such recurrent oral diseases for a better prognosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]