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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 30  |  Issue : 3  |  Page : 235-240

Comparative evaluation of the efficacy of topical amlexanox 5% oral paste and triamcinolone acetonide 0.1% oral paste in the treatment of Recurrent Aphthous Stomatitis (RAS)


Department of Oral Medicine and Radiology, Rishi Raj College of Dental Sciences and Research Centre, Bhopal, Madhya Pradesh, India

Date of Submission18-Jan-2018
Date of Acceptance17-Feb-2018
Date of Web Publication18-Oct-2018

Correspondence Address:
Dr. K Shrivastava
Department of Oral Medicine and Radiology, Rishi Raj College of Dental Sciences and Research Centre, Bhopal - 462 026, Madhya Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaomr.jiaomr_40_18

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   Abstract 


Background: A double-blind randomized control trial was conducted to compare the clinical efficacy of topical triamcinolone acetonide 0.1% and amlexanox 5% in recurrent apthous stomatitis (minor). Materials and Methods: Forty adult patients were assessed for erythema, ulcer size, pain scores, and ulcer healing on three evaluation visits within 24 h of ulcer formation, third day, and fifth day. All participants were monitored for compliance with treatment protocols of four times daily application of calibrated quantity of medication. Results and Discussion: Ninety percent of controls when compared with 65% of the participants in the amlexanox group showed complete improvement of peri-ulcer erythema. Pain reduction was marked from the first to the fifth day (F = 15.249, P = 0.000). The control participants showed 90% reduction in pain in comparison to 70% in the amlexanox group. The mean ulcer size was shown to reduce from the first to fifth day in both groups (F = 18.611, P = 0.000). Completely healed ulcers were seen in 70% of the participants in the control group compared with 75% of the participants in the amlexanox group. Conclusion: The data suggest that the clinical efficacy of topical amlexanox 5% is comparable to topical 0.1% triamcinolone acetonide and may be considered a substitute except in pain control, which was marginally less for the treatment for recurrent apthous stomatitis (minor).

Keywords: Amlexanox, aphthous ulcer, triamcinolone acetonide


How to cite this article:
Shrivastava K, Naidu G, Deshpande A, Handa H, Raghuvanshi V, Gupta M. Comparative evaluation of the efficacy of topical amlexanox 5% oral paste and triamcinolone acetonide 0.1% oral paste in the treatment of Recurrent Aphthous Stomatitis (RAS). J Indian Acad Oral Med Radiol 2018;30:235-40

How to cite this URL:
Shrivastava K, Naidu G, Deshpande A, Handa H, Raghuvanshi V, Gupta M. Comparative evaluation of the efficacy of topical amlexanox 5% oral paste and triamcinolone acetonide 0.1% oral paste in the treatment of Recurrent Aphthous Stomatitis (RAS). J Indian Acad Oral Med Radiol [serial online] 2018 [cited 2019 Mar 19];30:235-40. Available from: http://www.jiaomr.in/text.asp?2018/30/3/235/243656




   Introduction Top


Oral ulcerations, most often recurrent apthous stomatitis (RAS), have plagued mankind since antiquity and perplexed clinicians since the beginnings of organized medicines. RAS is prevalent in 5%–25% of the population presenting frequently between the second to fourth decades of life.[1] Of the three subtypes of RAS, RAS major (MaRAS), RAS herpetiform (He RAS), and RAS minor (MiRAS), the most common MiRAS accounts for 75%–85%.[2]

Since definitive etiology is unknown, the diagnosis is entirely based on history and clinical criteria and no laboratory procedures exist to confirm the diagnosis. The comorbid factors strongly associated with RAS include trauma, genetic predisposition, allergy, T-cell-mediated immunological dysfunction, nutritional deficiency hormones, psychological stress, and infections ranging from viral to bacterial.[3],[4]

During their course, they can significantly interfere with eating and speaking affecting quality of life.[4] Treatment consists of therapeutic measures to suppress the symptoms rather than bringing about a definitive cure. The therapeutic choice depends on the severity of the disease, including the frequency of ulcer recurrence, the number of ulcers present, their location and duration, and the level of associated orofacial pain.[5] A number of researched treatment modalities exist which include the use of nutritional supplements, topical agents, antibiotics, immunomodulators, corticosteroids, and other noncategorized pharmacotherapeutic agents with varying degrees of effectiveness or side effects.[6]

Amlexanox is a topical anti-inflammatory, antiallergic drug. It has been developed as a 5% topical oral paste for the treatment of patients with RAS. It is currently the only clinically proven product approved by the US Food and Drug Administration for the treatment of aphthous ulcers.[7]

It inhibits the formation and release of histamines and leukotrienes from mast cells, neutrophils, and mononuclear cells thus reducing the inflammatory symptomatology of the RAS, taking into account the outcomes of clinical trials on the action of topical 5% amlexanox on RAS done by various researchers. This study was designed because studies in RAS comparing the efficacy of mild potency topical steroids such as triamcinolone acetonide 0.1% and amlexanox 5% have not yet been reported. Furthermore, the clinical efficacy of amelxanox 5% was not evaluated thus far in the Indian context. We hypothesized that 5% amlexanox was as effective as triamcinolone acetonide 0.1% for the treatment of minor RAS.

Oral formulations for high-potency corticosteroids do not exist in the Indian market. The only available oral formulation included triamcinolone acetonide which also happens to be the most commonly prescribed medication for the treatment of recurrent apthous ulcers besides topical analgesics and anesthetic preparations with or without antiseptics.


   Materials and Methods Top


The study was planned as a double-blinded randomized clinical trial comparing experimental drug (topical amlexanox 5%) to a standard drug (topical triamcinolone acetonide 0.1%). The participants and the evaluating investigator were blinded to the nature of medication dispensed. The ethical clearance for the study was obtained from the independent institutional ethics committee.

A total of 60 adult participants reporting to the outpatient clinics of the Department of Oral Medicine and Radiology and Department of Otorhinolaryngology were enrolled into the study. We included patients >18 and <45 years of age of either sex with an history of recurrent aphthous stomatitis minor with at least two previous episodes with healing within 7 days. Patients who had one to three minor aphthous ulcer of less than 48 h duration in an easily accessible area of mouth for paste application were selected and only participants with active ulcers not in the prodromal phase were evaluated. The exclusion criteria consisted of patients <18 and >45 years of age; pregnant or lactating ladies; history of smoked or chewed tobacco, areca, and alcohol consumption; history of ulcers that are a manifestation of a systemic disease process such as ulcerative colitis, Crohn's disease, Behcet's syndrome or anemia, mucosal disease, or allergic etiology such as those resulting from the use of drugs or food substances; any concurrent clinical conditions that could pose a health risk to the participant involved with the study; history of dental surgery within past 2 weeks; and use of orthodontic appliances or complete denture wearer. Patients on the following medications during the study and for an indicated times before study entry were excluded: systemic corticosteroids, oral retinoids, immunomodulatory agents, nonsteroidal anti-inflammatory drugs, oral antihistamines, systemic antibiotics including any preparation or medication directly applied to the ulcer, and finally allergy to any of the constituents of amlexanox oral paste.

After obtaining an informed consent, the enrolled participants were randomly assigned into two groups of 30 each, control [Figure 1]a and experimental groups [Figure 2]a. The drugs were dispensed in coded tubes A (topical triamcinolone acetonide 0.1%) and B (topical amlexanox 5%). The participants were instructed to apply a “dab” of the paste on the ulcers four times a day for a minimum of 10 min, repeated for the duration of the study or until the investigator determines that the ulcers have healed whichever occurs first. Patient compliance was evaluated by checking the preweighed dispensed tubes again after the treatment and a diary maintained by patient recording time and date of every application.
Figure 1: (a) Clinical photograph showing lesion on Day 1 in the control group (b) Clinical photograph showing completely healed lesion in Control group on day 5 of evaluation

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Figure 2: (a) Clinical photograph showing lesion on Day 1 in the case group (b) Clinical photograph showing almost healed lesion in Case group on day 5 of evaluation

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Three evaluations were conducted on the first visit, third day, and the fifth day. If healing was delayed, then participants were shifted to control drug (0.1% triamcinolone acetonide) and followed up till healing. Further follow-up was advised after 2 weeks. In our study, only one ulcer was selected for analysis and for patients with more than one ulcer the most recent ulcer was selected.

Ulcer size

Ulcer size was measured by the investigators with a calibrated dental probe with millimeter markings. Two measurements approximately 90 degrees from each other were obtained and the cross-sectional areas of the ulcers were calculated by a simple multiple of the two measurements [Figure 3]a and [Figure 3]b.
Figure 3: (a and b) Picture showing ulcer size evaluation

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Erythema

Erythema improvement was measured on a categorical scale assigning numbers for each category (worse, same, mild, moderate, marked, and complete improvement) [Table 1].
Table 1: Erythema Score scale used in the ulcer evaluation

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Pain

Pain was evaluated by the patient before the first drug application (day 1) and at each evaluation thereafter by a 100-mm Visual Analog Scale (VAS), with the following associated notations: no pain (origin), pain with rough aggravation, pain with moderate aggravation, pain with slight aggravation, constant pain, and severe pain. Aggravation was anything that moves or touches the ulcer and that pain associated with gentle touching was greater than with rough handling.

Healing

Participants were evaluated at the fifth day treated as healed, partially healed, or not healed on the evaluation day. Participants with unhealed ulcers will be counted as “unhealed” at the evaluation day, but for those who presented with healed ulcers the time to healing will be assigned to the midpoint back to the previous day's evaluation (e.g., four if days 3 and 5 are evaluated) [Figure 3]b and [Figure 2]b.


   Statistical Methods Top


All data were as coded and analyzed using IBM SAS SPSS version 19 (International Business Machine Statistical Analyzing System Software package used for statistical analysis, USA). All categorical data between experimental and control groups were compared using Pearson's Chi-square test or Fisher's exact test; while independent t-test of Levennes was used to compare noncategorical data. Intragroup comparison of evaluation on first, third, and fifth days for noncategorical data was performed by repeated measure analysis of variance and for categorical data by McNemar's Chi-square test. Correlation between variables was done using Pearson's coefficient and Spearman's Rho test. The level of significance was set at P ≤ 0.05 at 95% confidence interval.


   Results Top


In all, 40 of 60 participants completed the study protocol (22 male and 18 female). No statistically differences were found in baseline demographic and ulcer characteristics between the treatment groups [Table 2] and [Table 3].
Table 2: Details of the previous episodes of ulcers

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Table 3: The comparision of pain score between the two groups

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Erythema

The erythema was shown to decrease from third day to fifth day in both the groups. This decrease was found to be statistically insignificant (χ2 = 5.140a, P = 0.273).

Pain

The mean pain score was shown to reduce from first day to fifth day in both the groups, control group (where it reduced from 5.8 to 1.1) and for experimental group (5.8 to 2.2) as shown in [Graph 1] and [Table 3]. This was found to be statistically significant (F = 15.249, P = 0.000).



Ulcer size

[Table 4] summarizes the average ulcer size on the first, third, and fifth days of assessment. The mean ulcer size was shown to reduce from first day to fifth day in both the groups, control groups (where it reduced from 4.105 to 1.24 mm) and experimental group (from 3.95 to 1.72 mm). This was found to be statistically significant (F = 18.611, P = 0.000) and shown in [Graph 2].
Table 4: The comparison of ulcer size between the two groups

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Healing

On the fifth day of trial, the ulcers were assessed for healing in the control and the experimental group, 14 (70%) of the participants in the control group when compared with 15 (75%) in the experimental group presented with healed ulcers. This difference was not statistically significant (χ2 = 3.034a, P = 0.219). Further two participants in the experimental group presented with unhealed ulcers while none of the participants in the control group presented with unhealed ulcers [Graph 3].



Adverse reactions

None of the participants in the control group presented with any allergy to any of the constituents of triamcinolone oral paste. However, two participants in the experimental group presented with increase in erythema and pain which could be due to an adverse reaction to the constituents of the amlexanox oral paste.


   Discussion Top


RAS is a disease of the oral mucosa characterized by recurrent, painful, single, or multiple well-demarcated ulceration with peripheral red halo where healing takes place with or without scarring. In the adult population, the first ulceration appears before the age of 30 years in 60%–85% of patients.[8] There is no curative therapy to prevent the recurrence of ulcers, and all available treatment modalities can only reduce the frequency or severity of the lesions. The primary treatment goal for RAS is to reduce inflammation and duration of ulcer and to promote healing. 5% Amlexanox as a topical medication has been proven to target this goal with minimum side effects. It reduces mast cell degranulation thereby reducing the inflammatory symptoms of RAS.

An evidence-based study of the literature for the best treatment for aphthous ulcers concluded that the best treatment for Mi RAS is 5% amlexanox due to its triple action in the form of preventing recurrence, decreasing healing time, and pain reduction mainly when used from prodromal stage till healing completes for four times a day with statistically significant results.[9]

The average age of the participants included in the study was 27.5 years when compared with a range of 25–48 years in the literature. A total of 40 participants completed the trial, of which 22 were males and 18 were females with a male-to-female ratio of 1.1:0.9. Previous studies have shown a slight female predilection ranging from 1:1.3,[10] 2:3,[11] 1:2,[12] and 1:2.5.[13] One study from India reported a male predilection with a ratio of 4.5:1.[14]

Peri-ulcer erythema was a predominant feature at baseline in all participants enrolled in the trial. About 85% of the control participants and 90% of the experimental participants presented with mild to moderate erythema on the first day of evaluation. On the third day of evaluation, 55% of the control participants and 65% of the experimental did not show any change in erythema. Significant improvement in the erythema was noted in the participants on the fifth day of evaluation; 90% of control when compared with 65% of experimental participants showed complete improvement of erythema. However, two participants on amlexanox (5%) presented with mild to moderate erythema, and in one participant the erythema worsened. Although the difference in erythema did not appear to be statistically significant between the two groups, participants on triamcinolone acetonide 0.1% seemed to fare better toward the final day of evaluation. An earlier trial using amlexanox[15] demonstrated complete resolution of erythema by the fourth day. Similarly, vehicle controlled trials[12],[13] have also showed similar results in the past. However a few recent trials[14] did not show any improvement till the ninth day and sixth day, respectively.

The second stage of RAS presents with ulcer formation accompanied with a, erythematous halo and pain. The rate of decrease in ulcer size depends on the onset of treatment. The average ulcer size of all the participants included in the study at baseline was 4 mm. On the third day of evaluation, there was a 25% reduction in size of ulcer in both groups. By the fifth day, there was a 75% reduction in size in control group in comparison to a 60% reduction in the experimental group. However, this difference in ulcer size reduction was not statistically significant as reported earlier.[11] Previous trials[8],[12],[13],[15] have reported marked reduction in the ulcer size by the third day when compared with a placebo. Application of amlexanox in these studies began in the preulcerative stage itself (average of 2 days before ulcer formation) continuing in to 3 days in the ulcerative stage. In hindsight, amlexanox 5% shows significant improvement only by the fourth or fifth day of application in most studies. Recent trials[14] did not find improvement till the sixth day when compared with healing by lignocaine 2%.

The average pain score at baseline was 5.8 as recorded by a 100-mm VAS scale in all the participants at the time of presentation. There was approximately 45% reduction in pain on the third day in both the groups. By the fifth day, control participants showed 90% reduction in pain, whereas experimental participants showed a 70% reduction in pain. This difference in pain perceived was found to be statistically significant when evaluated on third and fifth days. These findings were similar to previous placebo trials[8],[12],[13],[14],[15] where a marked pain reduction in the amlexanox-treated groups was noted within 2–3 days of evaluation. Another trial used 0.2% hyaluronic acid and reported immediate pain relief on application regardless of the stage of ulceration. Recently, aloe vera 2% oral gel[15] demonstrated pain relief only after 4 days compared with lignocaine 2% in a trial.

In the present trial, all the participants in the control group presented with either partially or completely healed ulcers when compared with 90% of the participants in the experimental group, and this difference was not statistically significant. Previous placebo-controlled trials[12],[13],[15] have demonstrated complete healing of the ulcer in the 5% amlexanox-treated group within 4–6 days of the start of the treatment. More recently,[14] a significant difference in healing between amlexanox- and lignocaine-treated control groups has been reported. Overall, noticeable ulcer healing in the amlexanox-treated groups takes place with marked resolution seen by fifth to sixth days of the trials.


   Conclusion Top


The above clinical trial demonstrates the comparable clinical efficacy of 5% amlexanox oral paste in decreasing erythema, ulcer size, pain, and healing time of recurrent apthous ulcers (minor) and can be considered as a substitute to topical corticosteroid preparations in these participants, except in pain control. Follow-up for recurrence of ulcers and prevention of further episodes are areas which can be explored with further long-term studies, with a larger sample size with an emphasis on the improvement in quality of life after treatment. Episodes of adverse reaction or poor response to the oral paste were recorded in our study which should be documented and compared to similar reports if any elsewhere.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Vincent SD, Lilly GE. Clinical, historic, and therapeutic features of aphthous stomatitis: literature review and open clinical trial employing steroids. Oral Surg Oral Med Oral Pathol 1992;74:79-86.  Back to cited text no. 1
    
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Scully C, Gorsky M, Lozada-Nur F. The diagnosis and management of recurrent aphthous stomatitis: A consensus approach. J Am Dent Assoc 2003;134:200-7.  Back to cited text no. 2
    
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Mimura MA, Hirota SK, Sugaya NN, Sanches JA Jr, Migliari MA. Systemic treatment in severe cases of recurrent aphthous stomatitis – An open trial. Clinics 2009;64:193-8.  Back to cited text no. 5
    
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Barrons RW. Treatment strategies for recurrent oral aphthous ulcers. Am J Health Syst Pharm 2001;58:41-50.  Back to cited text no. 6
    
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Rennie JS, Reade PC, Hay KD, Scully C. Recurrent aphthous stomatitis – Review. Br Dent J 1985;159:361-7.  Back to cited text no. 8
    
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Zain RB. Classification, epidemiology and etiology of oral recurrent aphthous ulceration/stomatitis. Ann Dent Univ Malaya 1999;6:34-7.  Back to cited text no. 9
    
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Khandwala A, Van Inwegen RG, Alfano MC. 5% Amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:222-30.  Back to cited text no. 10
    
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Murray B, McGuinness N, Biagioni P, Hyland P, Lamey PJ. A comparative study of the efficacy of Aphtheal™ in the management of recurrent minor aphthous ulceration J Oral Pathol Med 2005;34:413-9.  Back to cited text no. 11
    
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Murray B, McGuinness N, Biagioni P, Hyland P, Lamey PJ. The efficacy of amelxanox OraDisc™ on the prevention of recurrent minor aphthous ulceration. J Oral Pathol Med 2006;35:117-22.  Back to cited text no. 12
    
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Rodrıguez, M Rubio JA, Sanchez R. Effectiveness of two oral pastes for the treatment of recurrent aphthous stomatitis. Oral Dis 2007;13:490-4.  Back to cited text no. 13
    
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Katti G, Darshan DD. Amlexanox in the treatment of recurrent minor aphthous ulcers. Int J Dent Clin 2011:3:23-6.  Back to cited text no. 14
    
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Robert O, Greer JR, James EL, Timothy J, Khandawala A. A double-blind study of topically applied 5% amlexanox in the treatment of aphthous ulcers. J Oral Maxillofac Surg 1993;51:243-8.  Back to cited text no. 15
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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