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Year : 2021  |  Volume : 8  |  Issue : 4  |  Page : 89-93

A comparative study of amlexanox and tetracyclines in the management of recurrent aphthous stomatitis

1 Senior Lecturer, Department of Oral Medicine and Radiology, Kothiwal Dental College, Moradabad, Uttar Pradesh, India
2 Senior Lecturer, Department of Oral Medicine and Radiology, Hazaribag College of Dental Sciences and Hospital, Godda, India
3 Private Practitioner, Oral Pathology and Microbiology, Godda, India
4 Senior Research Fellow, PGIMER, Chandigarh, India
5 Senior Lecturer, Department of Conservative Dentistry and Endodontics, Hazaribag College of Dental Sciences and Hospital, Hazaribagh, Jharkhand, India
6 Assistant Professor, SMBT Institute of Dental Sciences and Research, Dhamangaom Nandi Hills, Nasik, Maharastra, India

Date of Submission29-Sep-2021
Date of Acceptance26-Oct-2021
Date of Web Publication23-Dec-2021

Correspondence Address:
Dr. Mohd Zeeshan
Department of Oral Medicine and Radiology, Kothiwal Dental College, Moradabad, Uttar Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpcdr.ijpcdr_34_21

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Background: Although there are many drugs which are used for topical therapy in recurrent aphthous stomatitis (RAS) patients, there are few clinical trials that have used tetracycline and amlexanox.
Aim and Objectives: To evaluated the therapeutic efficacy of topical tetracycline and amlexanox.
Materials and Methods: Here in this study we divided the RAS patients into two groups in each group alternative selection was done. Patients of 1st Group received topical application of tetracycline crushed tablets with denture adhesive and few drops of saline solution on each alternative day visit. Same as Group 2nd subject received amlexanox. Treatment response was assessed by measuring pain reduction, photographic record, ulcer duration, and adhesive retention time.
Results: Amlexanox oral paste show more efficacy in comparision of topical tetracycline in the treatment of recurrent minor aphthous ulcers.
Conculsion: Amlexanox is more effective in comparison of tetracycline.

Keywords: Amlexanox, recurrent aphthous ulcer, tetracycline

How to cite this article:
Zeeshan M, Srishti, Kumari S, Pothamsetty Y, Verma K, Dubey T. A comparative study of amlexanox and tetracyclines in the management of recurrent aphthous stomatitis. Int J Prev Clin Dent Res 2021;8:89-93

How to cite this URL:
Zeeshan M, Srishti, Kumari S, Pothamsetty Y, Verma K, Dubey T. A comparative study of amlexanox and tetracyclines in the management of recurrent aphthous stomatitis. Int J Prev Clin Dent Res [serial online] 2021 [cited 2022 Aug 17];8:89-93. Available from: https://www.ijpcdr.org/text.asp?2021/8/4/89/333545

  Introduction Top

Recurrent aphthous ulcers (RAUs) are currently one of the most common oral disorders and are known to affect 20% of the population at sometimes in their lives.[1] Aphtae (Greek aphtai, burn), Hippocrates (460-370BC) was the first to use the term aphthai, he used this term to describe all disorders affecting the mouth.[2],[3] Recurrent aphthous stomatitis (RAS) is an inflammatory condition of unknown etiology characterized by painful, recurrent, single, or multiple ulcerations of the oral mucosa.[1] several factors such as local trauma, immunodeficiency, genetic background, allergic agents, nutrition deficiency, hormonal changes in women, physical or psychic stress, chemical irritants, and infective agents have been proposed.[4] Popularly referred to as mouth ulcers or canker sores, aphthous ulcers are round or oval with a yellow or grey floor surrounded by an erythematous halo of inflamed mucosa. They can cause considerable pain and may interfere with eating, talking, and swallowing.[4] The duration of the ulcers is usually 7–10 days.[1]

The primary disorder appears to be the result of activation of the cell-mediated immune system.[5] Patient with recurrent aphthous ulcerations may have increased number of cytotoxic CD8+ and decreased number of helper CD4+ cells in peripheral blood.[5] Due to the uncertain etiology and unpredictable course of the disease, the primary goals of therapy are to control the pain of ulcer, promote ulcer healing, and prevent recurrence.[6]

Treatment for oral aphthous can be included antibacterial, anti-inflammatory and analgesic, mouth rinse, immunomodulatory, hormones, and CO2 laser.[4] Despite the many therapeutic options available for the management of RAS, no treatment is specific and definitive.[1] Systemic and topical tetracycline regimens have been used for several decades in the treatment of RAS[1] and since 1996 amelexanox is used for the treatment of RAS due to its anti-inflammatory property.

  Materials and Methods Top

A randomized, controlled study was conducted in the Department of Oral Medicine and Radiology, Kothiwal Dental College and Research Center, Moradabad, U. P., India. The study group comprised 30 subjects of either sex above the age of 16 years. Diagnosis of RAS was made on the basis of natural history and clinical features.

Inclusion criteria

  1. Physically healthy patients with a history of duration of ulcers for more than 24 h and not exceeding 72 h
  2. Symptoms that are pain and burning sensation secondary to oral aphthous ulcers and with the characteristic clinical features of recurrent minor oral aphthous ulcers were included in the study.[1]

Exclusion criteria

  1. Pregnant and lactating women, patients with any other coexisting oral mucosal diseases, hematologic abnormalities, end-stage renal disease[1]
  2. History of hypersensitivity to tetracycline[1]
  3. Those taking any other medications for RAS were excluded from the study.[1]

Patients who are participated were explained the need and design of the study, benefits of the pharmacologic therapy, possible adverse effects, and possibility of recurrent rate of the drugs used in the study. Only those patients who gave a signed informed consent on an institutionally approved document participated. All procedures performed in the study were conducted in accordance with the ethics standards given in 1964 Declaration of Helsinki, as revised in 2013. The study proposal was submitted for approval and clearance was obtained from the ethical committee of our institution. A written informed consent was obtained from each participant. Drugs used for the study included Tetracycline capsules (Restecline 500 mg, contains tetracycline hydrochloride 500 mg) manufactured by Abbott and Amlexanox (Lexanox oral paste 5%, contains amlexanox 50 mg with preservatives of sodium methylparaben I. P. 1.8 mg and sodium propylparaben I. P. 0.2 mg) manufactured by Macleods.

The initial appointment consisted of collecting the demographic data, general history, a history of patient's past experiences with the lesions, and a clinical examination. Under adequate illumination, a pair of sterile mouth mirror was used to examine the lesion. A diagnosis of aphthous ulcer was made if it occurred in the nonkeratinized mucosa as a shallow crater form ulcer covered by a whitish-yellow pseudo-membrane and presented with a round, regular border with a surrounding erythematous halo.[1]

On clinical examination, pain intensity using a visual analog scale (VAS) of 0–10 (with 1 mm division, where “0” is no pain and “10” is worst possible pain), number of ulcers, size of each ulcer, and the duration of each ulcer (the day of onset of the first prodromal symptom of each ulcer) were recorded in which 7 major, 19 minor, and 4 herpetiform.

The 30 patients included in the study were divided into two groups, Group A and Group B. Every alternate patient was allocated to each group. In Group A, 15 patients received powdered tetracycline topically whereas, in group B, 15 patients received paste of amlexanox topically.

After complete clinical examination of the ulcer, pretreatment photographs were taken before the start of treatment [Figure 1]a and [Figure 2]a. The ulcer and the mucosa surrounding the ulcer were dried thoroughly. Cotton rolls were placed for isolation near the salivary duct openings. The tetracycline capsule is opened and powder was taken out on the glass slap. An appropriate amount of the medicament, roughly corresponding to the size of the ulcer was mixed with the 2–3 drops of normal saline with the help of stainless steel cement spatula. Then the final mixture was placed over the ulcer using a plastic instrument whereas Amlexanox is already in ointment form it is directly apply to the lesions. After topically applying the medicament or the tetracycline and amlexanox over the ulcer, the patient was asked to refrain from eating or drinking for 1 h.
Figure 1: a) pretreatment photographs showing ulcer on the tongue. b) post treatment photographs showing complete healed ulcer on the tongue

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Figure 2: a) pretreatment photographs showing ulcer on the floor of the mouth. b) post treatment photographs showing complete healed ulcer on the floor of the mouth

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A single application of the tetracycline or amlexanox was done during the patient's initial visit and procedure of application was explained to patients for further application of 3 times in a day. Every patient was recalled after alternate days following the treatment procedure. A pain scale sheet to record the daily status of the patient was given at the initial visit. The patients were instructed to self-evaluate the pain scale sheet on the day after treatment and daily after that for 10 days. The size was measured with help of periodontal probe and scale. Every alternate visit till the 10th day, the patients were asked to return the pain scale, and the size was record. Patients were questioned about any adverse effects following drug therapy. The patients were also asked to record the adhesive retention time in the oral cavity and mark the day when the ulcer healed by looking at the mirror and using the pain scale sheet provided to the patient. Posttreatment follow-up involved the evaluation of patient on the relief day. The pain scale sheet was collected from the patient and post-treatment photographs were taken for comparing with the baseline [Figure 1]b and [Figure 2]b. Response to the drug therapy was assessed on the basis of pre-vs post treatment scores.

  Results Top

A total of 30 patients with minor RAS were enrolled in this study. They were randomly divided into two groups, tetracycline group (n = 15) and amlexanox group (n = 15) and patients of both groups were clinically evaluated and later compared the topical efficacy of 5% amlexanox oral paste and topical tetracycline in the treatment of recurrent minor aphthous ulcers.

As we seen in the [Table 1], the size of ulcer (mm) was recorded 1st visit for all the patients. Following the application of tetracycline paste and amlexanox, the patients were recalled on the 3rd and the 5th day, and the ulcer size was again recorded. The amlexanox group had a statistically significant improvement between the 1st and 5th day (1.65 ± 0.51–0.93 ± 1.29) when compared with that of the tetracycline controlled group (3.58 ± 2.03–1.92 ± 1.80). At the day 7 visit, the amlexanox group maintained a significantly greater effectiveness between the 3rd day and the 7th day (2.93 ± 2.29–1.70 ± 1.79), when compared with that of the tetracycline group (3.92 ± 1.80–3.42 ± 1.70). At day 7 visit, compared with those of the placebo group, the amlexanox group maintained a significantly greater efficacy index (P < 0.001**), the “improvement” rate (85% vs. 44%), and “marked improvement” rate (52% vs. 4%).
Table 1: Comparison of ulcer size and pain score between two groups criteria size of ulcer (mm)

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  Discussion Top

RAS is a common oral disorder affecting 5%–66% of examined adult patient groups.[1] Although many exacerbating factors have been identified, the cause as yet remains unknown.[1] The patient of RAS presents with painful, recurring ulcers of the oral cavity. Diagnosis of RAS rests on features: A history of recurrent ulcers since childhood or adolescence and presence of typical multiple round or ovoid ulcers on examination.[3] They can cause considerable pain and may interfere with eating, talking, and swallowing.[4]

Aphthous ulcers can be classified into three different types: Minor, major, and herpetiform. Minor mouth ulcers are by far the most common representing ulcers (an estimated 80%–87% of all aphthous). They have a diameter of <1 cm, usually occur on the nonkeratinized oral mucosa, have a good prognosis, and generally do not persist for >2 weeks (spontaneous healing within 7–10 days is usual). Major aphthous, also termed Sutton disease, constitute an estimated 10%–15% of all aphthous, are larger (>1 cm in diameter), and involve deeper ulceration that heals slowly over weeks or months, often with scarring. Herpetiform ulcers constitute only 5%–10% of all aphthous, consist of clusters of multiple pinpoint-type ulcers that are 1–3 mm in diameter and the whole cycle may take only few days (3–4 days), but the new crops may develop during this time with the cycle pattern of these ulcers reach about 1 month.[4]

Although most cases of RAS are idiopathic, a careful history taking and physical examination are essential to rule out any secondary cause. A number of systemic conditions can give rise to oral ulcerations resembling RAS. They are Crohn's disease, Ulcerative Colitis, Gluten-Sensitive Enteropathy, Behcet's syndrome, Reiters syndrome, Sweet's syndrome, cyclic neutropenia, nutritional deficiencies, and drugs like Nicorandril.[3]

Various pathogenic factors have been implicated in the causation of RAS. Interstitial collagenases matrix metalloproteinase-1 (MMP-1 and MMP-8) are enzymes that are able to degrade the main oral mucosal collagen Types I and III. It has been suggested that interstitial collagenases MMP-8 and MMP-1 play a role in tissue destruction events in RAU. Tetracyclines have been shown to inhibit prostaglandin production, suppress leukocyte activities, and inhibit collagenase and gelatinase activities as well as the oxidative activation of their latent forms. As there is no specific management for RAS,[1] this study was undertaken to examine pain reduction in RAS following topical application of tetracycline, an inhibitor of MMPs.

For the treatment of RAU, topical medications have played a crucial role in reducing ulcer pain and accelerating ulcer healing[6] Amlexanox has recently been found to have a significant role in the management of minor aphthous ulcers. The present study aimed at evaluating the potential of this drug in reducing the size of the ulcer, pain, erythema, and exudation.

Both groups had a reduction in the VAS scores throughout the treatment period. This indicates that both amlexanox and the tetracycline could bring about a reduction in the pain associated with ulceration. However, on comparing the two groups, the patients on amlexanox had a statistically lower (P < 0.001) VAS values than the tetracycline group. This indicates that amlexanox has a significant therapeutic effect. This was in accordance with studies conducted previously by Meng et al., Liu et al., Greer et al., and Khandwala et al.[6]

Even though both the groups showed improvement in erythema and exudation associated with RAU, there was significant lower scores (P < 0.001) among amlexanox group when compared to the tetracycline group. Similar observations were reported by Liu et al., Greer et al., Khandwala et al., and Meng et al.[6]

A study by Bhat S et al. proposed that the treatment effect is caused by inhibition of histamines and leukotrienes in the development of an aphthous ulcer in the oral mucosa; although the exact working mechanism is still unclear.[4] Scully was of the opinion that the cyclic nature of RAU makes it difficult to conduct a well-designed prospective double-blind controlled clinical study. Some patients of RAU have mild outbreaks, whereas others have severe and longer episodes. Some patients have fewer ulcers, whereas others present with larger or combination of small and large ulcers. In some, the severity and frequency of outbreaks ease with the passing of years; in others, it worsens. All these factors contribute for the inconsistency in the vast literature on the treatment of RAU.[6]

We found that there was some effect for pain relief and healing in the placebo group as well. Three possible reasons have been proposed to explain this phenomenon. First, the cellulose recipients may have formed a protective film to cover the ulcer and therefore, produced some curative effect. Second, minor aphthous ulcers are a self-limiting disease, which can get relief without any treatment. Finally, stress factors have been known as etiologic factors, and subjects of the tetracycline group might be consoled by the feeling of “being treated” in the trial.[7],[8],[9],[10],[11],[12]

In the present study, 30 patients on 5% amlexanox oral paste were followed up for 6 months. It showed some improvement in the recurrence of ulcers up to the 3rd month, but it slowly started increasing thereafter. No such follow-up studies on 5% amlexanox oral paste have been reported in the previous literature. Only one article mentions about the role of 5% amlexanox in decreasing the recurrence of ulcers.[6] Nearly 5% amlexanox oral paste was well tolerated during the study with negligible adverse effects. Few patients complained of a transient “stinging” sensation that was mild in severity, metallic taste in the oral cavity soon after application of the paste, and “cooling” sensation at the application site.

  Conclusion Top

Due to the unknown etiology of RAS, most of the treatments are therapeutic. Literature shows that aphthous ulcers are best treated with 5% amlexanox as it decreases healing time and pain and prevents recurrences if applied in the prodromal stage. The effectiveness of treatment, however, is not clinically significant since pain relief and healing time are accelerated by only 1.3 and 1.6 days, respectively, and since a vehicle also reduces pain. Amlexanox is more effective in comparison of tetracycline.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Porter SR, Hegarty A, Kaliakatsou A, Hodgson TA, Scully C. Recurrent aphthous stomatitis. Clin Dermatol. 2000;18:569-578.  Back to cited text no. 1
Riera Matute G, Riera Alonso E. Recurrent aphthous stomatitis in rheumatology. Reumatol Clin 2011;7:323-8.  Back to cited text no. 2
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. 3
Bhat S, Sujatha D. A clinical evaluation of 5% amlexanox oral paste in the treatment of minor recurrent aphthous ulcers and comparison with the placebo paste: A randomized, vehicle controlled, parallel, single center clinical trial. Indian J Dent Res 2013;24:593-8.  Back to cited text no. 4
[PUBMED]  [Full text]  
Gaphor SM. Different treatment modilities of RAU. J Baghdad Coll Dent 2009;21:86-8.  Back to cited text no. 5
El-Meguid Mostafa AA, El-MoneamIbrahem MA. Management of aphthous ulceration with topical quercetin. Cairo Dent J 2009;25:9-15.  Back to cited text no. 6
Abbasi F, Raoof M, Khatami R, Shadman N, BorjianBoroojeni F, Nazari F. Effectiveness of Amlexanox and Adcortyl for the treatment of recurrent aphthous ulcers. J Clin Exp Dent. 2016;8:e368-72.  Back to cited text no. 7
Jiang XW, Zhang Y, Zhang H, Lu K, Yang SK, Sun GL. Doubleblind, randomized, controlled clinical trial of the effects of diosmectite and basic fibroblast growth factor paste on the treatment of minor recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116:570-5.  Back to cited text no. 8
Abbasi F, Raoof M, Khatami R, Shadman N, BorjianBoroojeni F, Nazari F. Effectiveness of Amlexanox and Adcortyl for the treatment of recurrent aphthous ulcers. J Clin Exp Dent. 2016;8:e368-72.  Back to cited text no. 9
Akintoye S, Greenberg MS. Recurrent Aphthous Stomatitis. Dent Clin North Am. 2014;58:281-97.  Back to cited text no. 10
Ofluoglu D, Ergun S, Warnakulasuriya S, NamdarPekiner F, Tanyeri H. An evaluation of the efficacy of a topical gel with Triester Glycerol Oxide (tgo) in the treatment of minor recurrent aphthous stomatitis in a Yurkish cohort: A randomized, double-blind, placebocontrolled clinical trial. Med Oral Patol Oral Cir Bucal. 2017;22:e159-66.  Back to cited text no. 11
Akintoye S, Greenberg MS. Recurrent Aphthous Stomatitis. DentClin North Am. 2014;58:281-97.  Back to cited text no. 12


  [Figure 1], [Figure 2]

  [Table 1]


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