Research article

Role of rebamipide in the treatment of recurrent aphthous – A systematic review Reshma Thirunavakarasu, Sreedevi Dharman*

ABSTRACT

Background: Recurrent aphthous is a recurrent inflammatory condition characterized by painful, multiple in the . Rebamipide is a gastroprotective agent which is used to treat many inflammatory . A number of clinical trials were done using rebamipide on recurrent aphthous ulcers (RAUs). Thus, this systematic review aimed to analyze the existing literature on the role of rebamipide in the treatment of RAU. Materials and Methods: The following electronic databases were searched, namely, PubMed (Mesh), Cochrane Library, and Wiley online library using keywords rebamipide and RAU. The articles were screened on the basis of title and abstract. Full text was then procured for the relevant articles which fulfilled the inclusion criteria. For each study, the following data were extracted: Authors, study design, description of participants (sample size, mean age), length of study, drug dosage, and main outcome. Results: The initial search yielded a total of 31 studies, of which 25 articles were excluded. The full texts of the remaining six articles were found and thoroughly read and assessed. Rebamipide has shown to have a reduction in the score, ulcer count, ulcer size, and faster healing for RAU in all the six articles. Rebamipide has proven to be more superior when compared to other drugs with no side effects and minimal recurrence. Conclusion: This systematic review has proven the demand for future clinical trials to assess the use of rebamipide in treating RAU. Based on the above six articles, rebamipide has proven to benefit patients who are suffering from RAU. Further, clinical trials should be conducted with a larger sample size for better understanding about the drug, rebamipide. KEY WORDS: Efficacy, Management, Rebamipide, Recurrent aphthous ulcer, Treatment

INTRODUCTION which is tumor factor.[4,5] RAU lesions are often referred to as “canker” sores and are amongst Recurrent (RAS) or recurrent the most common oral ulcerative lesions.[2,6-8] More aphthous ulcer (RAU) is a condition characterized by than 10 million people per year in India are affected multiple recurrent small, round, or ovoid ulcers with with RAUs.[9] RAU can be classified based on size circumscribed margins, erythematous haloes, and and number. It is divided into three different clinical [1,2] yellow or gray floor. They are a kind of lesion in the variations which are minor recurrent aphthous oral mucosa which causes sudden and painful stomatitis, major RAS (MaRAS), and herpetiform loss of the normal tissue in the mucosa. The specific ulcers. The most common form of RAU is said to be the cause of RAU is unknown;[3] however, there are minor aphthous ulcer as it accounts for approximately several factors which are believed to be responsible 70–90% of RAU cases.[6] RAS is often mistaken for for the pathogenesis of the . Those factors include food , genetic factors, hormonal varicella-zoster (); however, it changes (), , anxiety, smoking can be differentiated based on the clinical presentation cessation, chemical products, and microorganisms. (extraoral and intraoral distribution pattern) and other [10] Another factor that was found to cause RAU lesion burning symptoms. The basic goals for the management of patients Access this article online with RAU are to shorten the duration of ulcer, to provide relief from pain, and to increase the disease- Website: jprsolutions.info ISSN: 0975-7619 free periods. Once these goals are accomplished,

Department of and Radiology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, Tamil Nadu, India

*Corresponding author: Dr. Sreedevi Dharman, Department of Oral Medicine and Radiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, 162, Poonamallee High Road, Chennai, - 600 077, Tamil Nadu, India. Phone: +91-9841009003. E-mail: [email protected] Received on: 09-06-2019; Revised on: 24-07-2019; Accepted on: 12-08-2019

146 Drug Invention Today | Vol 11 • Special Issue 1 • 2019 Reshma Thirunavakarasu and Sreedevi Dharman the next goal is to lessen the frequency as well as Outcome measure the severity of the disease[6] There have been varied Pain scores, ulcer count, and ulcer size were measured types of treatment modalities which have been tried as the primary outcome of the study. Secondary over the years for RAU such as vitamins, antivirals, outcome comprised the complete resolution of RAU , , and topical and oral or any instances of recurrence after therapy. steroid. Antibiotics ( and ), anti-inflammatory agents (topical and systemic Search Strategy ), immune modulators (thalidomide), The following electronic databases were searched, pain-relieving agents ( and benzocaine), namely, Pub Med (Mesh), Cochrane Library, and zinc, Vitamin B complex, and Vitamin C; however, Wiley online library using keywords rebamipide none of these regimens have been able to provide an and RAU. The articles were screened on the basis of effective cure for RAU.[11-15] title and abstract. Full text was then procured for the relevant articles which fulfilled the inclusion criteria. Rebamipide is a mucoprotective agent, aids in Only articles published in the English language were enhancing preservation of existing epithelial cells and considered for this review [Table 1 and Figure 1]. replacement of lost tissues through a multifactorial mode of action. It increases the expression of Data Extraction epidermal growth factors and endothelial growth For each study, the following data were extracted: factor (EGF) receptors causing angiogenesis and Authors, study design, description of participants increases the production of granulation tissue and (sample size, mean age), length of study, drug dosage, [11] epithelization of ulcer healing. Oxygen radicals and main outcome. will be decreased, blood flow will be increased and production of protective prostaglandins in ulcer Methodological Quality Assessment [1] mucosa which accelerates the process of healing; The following criteria were used to assess the this drug has also been used for stomatitis, Behcet’s methodological quality of the RCTs: Randomization, disease, an inflammatory disease involving chronic explanation of sequence generation for randomization, recurrent oral aphthous ulcers (aphthae), , skin explanation for allocation concealment, blindness lesions, and genital ulcers. It has ulcer healing and methods, sample size calculation, evaluating for ulcer protective functions. Other systemic therapies comparability of baseline data, intentional to treat include potassium penicillin G, corticosteroids, and analysis, and patient follow-up after the final treatment. immunosuppresses.[16] This drug is recommended for Risk of bias – These were categorized according to a long-term treatment for RAU.[1] the following, low risk of bias (bias less likely to seriously alter the results), if all criteria were met; This systematic review aims to study the various moderate risk of bias (bias that raises some ambiguity clinical trials done to evaluate the efficacy of about the results), if one or more criteria were partly rebamipide in the treatment of RAU. met; and high risk of bias (bias that seriously weakens acceptance of the results), if one or more criteria were MATERIALS AND METHODS not met [Tables 2 and 3]. Research Question RESULTS The present systematic review was conducted to address the following participants, intervention, Literature Search and Study Selection control, and outcomes question. “Is rebamipide The initial search yielded a total of 31 studies, of which effective in the management of RAU?” 18 articles were excluded from the study. Thus, a total of 13 articles were remained after the initial screening. Eligibility Criteria Inclusion criteria A randomized blinded study on human clinical trials where rebamipide was used in the treatment of RAU alone was included in the study.

Exclusion criteria In vitro studies, animal studies, experimental studies, case reports, case series, and literature reviews were excluded from the study. All irrelevant studies were excluded and the reasons for their exclusion were noted. Figure 1: Flowchart showing search strategy

Drug Invention Today | Vol 11 • Special Issue 1 • 2019 147 Reshma Thirunavakarasu and Sreedevi Dharman =0.75) <0.05), P P <0.01) P <0.05) P 0.006, no new ulcers, P= <0.05). Rebamipide reported P week). 6% of patients had nd =0.91), number of ulcer ( P <0.05). Recurrence was only seen in P Outcome No statistical significance, mean size ( Reduction in number of ulcer and pain 65% versus 35% in placebo ( Ulcer completely disappeared ( score) ulcer pain reduced to 0 (VAS ( 4/30 patients in 2 months 90% of patients with significant decrease absence of Total score (10–13). VAS in lesion (2 recurrence Rebamipide provided faster healing than ( with decreased number of recurrence Rebamipide showed improved in oral ulcer count, 70% in decreased pain score ( daily daily daily daily daily daily 3 times 3 times 3 times 3 times 3 times 3 times 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg Drug dosage Not stated weeks 12–24 60 days 4 weeks 6 months 16 weeks Length of study years years 19–75 15–55 >15 years Not stated Not stated 34.1 years Mean age: Age group

60 (four groups) (20 – amlexanox, 20 – rebamipide, 10 – placebo, 10 – sugar tablets) Sample size 100 (50 – rebamipide+50 ) 35 (16 – placebo and 19 – Rebamipide) 60 (30 – rebamipide and 30 – placebo) 100 54 (37 – rebamipide and 14 – placebo) Type of study Type Clinical trial Randomized, double ‑ blinded, placebo ‑ controlled study Single ‑ blinded, placebo ‑ controlled study Non ‑ randomized prospective study Single ‑ blinded, randomized, placebo ‑ controlled trial Single ‑ center, double ‑ blinded, placebo ‑ controlled study [9] [17] . [18] . [20] [19] . ., et al et al et al et al [1] Singh Authors Devi Ramesh D N S V Matsuda Jadhav K. Dr. Kesavalingam Abou ‑ Raya potential useful Evaluation of the efficacy of topical Evaluation of the efficacy amlexanox oral paste and rebamipide tablets in the management of recurrent aphthous ulcer 1: Characteristic of included studies Table Article title of rebamipide and levamisole in Efficacy the treatment of patients with recurrent aphthous ulcer of rebamipide as adjunctive Efficacy therapy in the treatment of recurrent aphthous ulcer in patients with Behcet’s disease of rebamipide evaluate the efficacy To on clinical resolution and recurrence of minor recurrent aphthous stomatitis of prospective study on efficacy A rebamipide in recurrent aphthous stomatitis A Rebamipide: therapeutic addition in the treatment of disease recurrent oral ulcer in Behcet’s analog scale Visual VAS:

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Table 2: Risk of bias – major criteria Study Sample justified Baseline comparison I/E criteria Method error Devi et al.[1] Yes No Yes No Matsuda et al.[17] Yes Yes Yes No Jadhav et al.[18] Yes Yes Yes No Kesavalingam et al.[9] Yes No Yes No Singh et al.[19] Yes Yes Yes No Abou‑Raya et al.[20] Yes Yes Yes No

Table 3: Risk of bias – minor criteria Study Randomization Allocation concealment Assessor blinded Dropouts Withdrawals Devi et al.[1] Yes Yes No No No Matsuda et al.[17] Yes Yes Yes No No Jadhav et al.[18] Yes Yes No No No Kesavalingam et al.[9] No No No No Yes Singh et al.[19] Yes Yes No No No Abou‑Raya et al.[20] Yes Yes Yes No No

The initial screening was done based on the titles and decrease in the rebamipide group. Jadhav et al. found the abstract. Of the 13 articles remained, 7 articles that the mean VAS score for ulcer pain was 2 at day were excluded as they were found to be irrelevant, all 0 and was reduced to 0 at day 7 in the study group.[18] review or novels. The full texts of the remaining six articles were found and thoroughly read and assessed. Ulcer size Dr. Aarti Singh conducted a study whether the local General Characteristic of the Included Studies application of amlexanox and oral administration of General characteristics of the remaining six articles rebamipide are effective in reducing the ulcer size; were studied and tabulated in Table 1. The studies however, it was evident that rebamipide appeared to were clinical trials which use the drug rebamipide be superior in promoting rapid healing compared to to test its efficacy in treating RAU. A study by amlexanox. As both these drugs help in promoting Devi et al.[1] and Singh et al.[19] used rebamipide rapid healing, it was found that the difference was along with another drug, levamisole/amlexanox, and not statistically significant (P < 0.05).[19] A study by compared the outcomes. Other remaining drugs used Jadhav et al. showed that the mean ulcer size was rebamipide along with a placebo. The age group of the 4 mm at day 0, and at day 7, it was found to have participants ranged from 15 to 75 years. The duration completely disappeared (size 0 mm).[18] A comparative of the studied varies from 3 weeks to 3 months. study was done between rebamipide and levamisole, it was found that the results were not statistically Clinical Parameter significant. The mean size of ulcers was found to be The outcomes that were measured in each study insignificant (P = 0.91). Devi found in her study that were determined. The objective outcomes included rebamipide was well tolerated and was useful for the pain score, ulcer count, ulcer size, and presence or treatment of RAU.[1] absence of recurrence. Pain score was done using visual analog scale (VAS). All the studies measured Ulcer count these parameters to determine the efficacy of the Matsuda et al.[17] concluded that rebamipide is well drug used. tolerated and improves the aphthae count. It was stated that of the 35 patients in his study, the rebamipide Study Outcome group showed a higher efficacy rate than the placebo Pain scores group in terms of aphthae count. Devi et al. found Kesavalingam had conducted a study on 64 patients that the mean number of ulcer was not statistically with a history of recurrent oral painful ulcers for significant (P = 0.75); however, the efficacy of more than 3 times. A VAS score of 10 was recorded rebamipide was almost the same as levamisole. It by 42% of the patients and other patients recorded was shown that the aphthae count was should be VAS score of 4–9. The outcome was that 90% of the lesser after a 3-month follow-up.[1] Sheshaprasad patients had a significant decrease in VAS scoring and Pai conducted a study which showed that when from 10 to 3 in 1 week.[9] Matsuda et al.[17] conducted compared the efficacy of rebamipide and a control a study and found that the pain score for patients group, placebo, on patient with Behcet’s disease, the taking rebamipide and placebo decreased to the same aphthae count continuously decreases throughout extent for the first 3 months of treatment; however, it the treatment in the rebamipide group; however, it was increased in patients in the placebo group but a increases in the placebo group.[4]

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Recurrence Besides, consuming drugs for the management of the A study by Kesavalingam et al. found that in 6% of disease, removal or eliminating the causative factors the patients, there was a recurrence of the disease such as diet should be managed. Patients are told to within the study period of 6 months.[9] Devi et al.[1] avoid hard food such as hard toasted bread, all types have done the current study with a 3-month follow-up of nuts such as walnut, hazelnut, as well as chocolates and it showed that there was a lesser frequency of with nuts, acidic foods or drinks (fruit juices, citric occurrence. It also showed that rebamipide was useful fruits, and tomatoes), salty meals, strong spicy food in the treatment and prevention of frequently RAUs not which are pepper, capsicum, and curry, and alcoholic restricted to Behcet’s disease. Rebamipide has shown and carbonated beverages. General measures should greater potential in preventing the recurrence of RAU also be taken such as to avoid teeth cleaning products when compared to amlexanox. A reason for this could and containing sodium lauryl sulfate.[22] be due to the fact that the method of administration of rebamipide is by systemic administration which Various clinical trials have been conducted to test the causes the effect to be long lasting. Patients under efficacy of rebamipide in comparison with other drugs the rebamipide group have reported with decreased or with a placebo. This is to determine whether or not number of recurrence as compared to the patients rebamipide plays a significant role in the treatment treated with amlexanox.[19] of RAU. One study was conducted to compare the efficacy of two different drugs which are rebamipide DISCUSSION and levamisole. A total of 100 patients participated in this study and they were assigned randomly into two There have been various studies which have been groups. This clinical trial shows that rebamipide is done to determine the efficacy of rebamipide used for effective in treating RAU as it reduces pain, number, treating patients with RAU. There are a few aspects size, and frequency. However, a literature shows that in which were checked on these patients, aphthae aphthous ulcers are best treated with levamisole as it count, pain score, size of the ulcers, healing rate of decreases healing time, pain, number, size and prevent the ulcer, and the chances of recurrence. These studies recurrence.[1] Both drugs are said to be superior in are clinical trials conducted on humans that have RAU their own way in treating RAS. This study shows no along with an underlying disease or simply have RAU. clinical significance between the two drugs.

Table 1 shows the characteristic of included studies. One study was done to compare rebamipide and All of these articles were studied and their findings amlexanox along with placebo. Group 1 patients were tabulated and recorded. As previously mentioned, were treated with 5% amlexanox oral paste, rebamipide has a mucoprotective action which Group 2 patients were treated with rebamipide 100 mg accelerated the gastric ulcer healing which increases tablets, Group 3 patients were treated with orabase the prostaglandins in the gastric mucosa through (placebo), and Group 4 were treated with sugar tablets upregulation of cyclooxygenase-2 protein and EGF (placebo). Patients in Groups 3 and 4 were the control and EGF receptors. EGF and prostaglandins E2 are groups and they were given no other . It present in biological fluids which include saliva. They was found that topical application of amlexanox was play a role in the maintenance of the epithelial barrier effective in relieving pain, and in the early stages, it and in healing of damaged mucosa. It was suggested was better than the placebo group; however, it showed that a decrease in EGF and in the moderate improvement in the ulcer size. When saliva might be associated with ulcer formation in compared to rebamipide, it was found to be more recurrent aphthous stomatitis. Thus, Rebamipide plays effective in reducing the ulcer size when compared to an important role in stimulating mucus secretion, the placebo group. Faster healing (reduction of ulcer inactivate and scavenge free radicals.[11] size) was seen more evidently in the rebamipide group compared to the topical application of amlexanox. When testing out a drug on a particular disease or Rebamipide has shown to have lesser number of condition, the of the disease are to patients reporting back with recurrence compared to be assessed before and after administration of the drug. amlexanox. As mentioned before, the aspects discuss and observed for RAS are pain score, ulcer size, ulcer count, and Placebo groups are used in studies for comparison recurrence. The treatment for RAU is symptomatic purposes or for a control group. Out of the six studies and based mainly on empirical basis.[21] The goal for which were found, three of the studies have used a the management of this disease is by relieving pain, placebo. This is to show how effect rebamipide is diminishing functional disability, inhibition of the in treating RAU. Matsuda et al.[17] found that, in his acute inflammatory reaction and frequency, reduce study, the rate of moderate or marked improvement ulcer number and size, increase disease-free period, and in aphthae count and pain was 36% (5 of 14 subjects) reducing the degree of severity of the recurrence.[21,22] in the placebo group and 65% (11 of 17 subjects) in

150 Drug Invention Today | Vol 11 • Special Issue 1 • 2019 Reshma Thirunavakarasu and Sreedevi Dharman the rebamipide group. With this, we can see that the 9. Sivakumar V. A prospective study on efficacy of rebamipide drug, rebamipide, shows to have an effect in RAS in recurrent aphthous stomatitis. IOSR J Dent Med Sci 2017;16:44-5. whether placebo does almost little or no effect in RAS. 10. Namrata M, Abilasha R. Recurrent aphthous stomatitis. Int J It was also found that the pain score increases in the Orofac Biol 2017;1:43-7. placebo group but decreased in the rebamipide group. 11. Kudur MH, Hulmani M. Rebamipide: A Novel agent in the A study was done, rebamipide showed a statistically treatment of recurrent aphthous ulcer and behcet’s syndrome. Indian J Dermatol 2013;58:352-4. significant higher efficacy rate than placebo in terms 12. Barrons RW. Treatment strategies for recurrent oral aphthous of clinical resolution. ulcers. Am J Health Syst Pharm 2001;58:41-50. 13. Femiano F, Gombos F, Scully C. Recurrent aphthous stomatitis unresponsive to topical corticosteroids: A study of the CONCLUSION comparative therapeutic effects of systemic and systemic sulodexide. Int J Dermatol 2003;42:394-7. This systematic review has proven the demand for 14. Muzio Ll, della Vella A, Mignogna MD, Pannone G, Bucci P, future clinical trials to assess the use of rebamipide Bucci E, et al. The treatment of oral aphthous ulceration or in treating RAU. Based on the above six articles, erosive with topical clobetasolpropiopnated rebamipide has proven to benefit patients who are in three preparations: A clnical and pilot study on 54 patients. J Oral Pathol Med 2001;30:611-7. suffering from RAU. Further, clinical trials should 15. Piskin S, Sayan C, Durukan N, Senol M. Serum iron, ferritin, be conducted with a larger sample size for better folic acid, and levels in recurrent aphthous understanding about the drug, rebamipide. There are stomatitis. J Eur Acad Dermatol Venereol 2002;16:66-7. not enough evidence to support the effectiveness of 16. Vaishnavi V. Management of recurrent apthous stomatitis a review. Res J Pharm Tech 2014;7:1193-5. using rebamipide in treating RAU. 17. Matsuda T, Ohno S, Hirohata S, Miyanaga Y, Ujihara H, Inaba G, et al. Efficacy of rebamipide as adjunctive therapy REFERENCES in the treatment of recurrent oral aphthous ulcers in patients with Behçet’s disease: A randomised, double-blind, placebo- 1. Devi MK, Ramesh DN, Koppal S, Byatnal AR, Rukmangada T, controlled study. Drugs R D 2003;4:19-28. Byatnal AA, et al. Efficacy of rebamipide and levamisole 18. Jadhav A, Marathe S, Mhapuskar A, Jadhav S, Thopte S, in the treatment of patients with recurrent aphthous ulcer a Vhatakar P. To evaluate the efficacy of rebamipide on clinical comparative study. J Clin Diagn Res 2014;8:ZC119-22. resolution and recurrence of minor recurrent aphthous 2. Jurge S, Kuffer R, Scully C, Porter SR. Mucosal disease stomatitis. Int J Dent Health Sci 2015;2:781-97. series. Number VI. Recurrent aphthous stomatitis. Oral Dis 19. Singh A, Adil HA, Umarji HR. Evaluation of the efficacy 2006;12:1-21. of topical amlexanox oral paste and rebamipide tablets in 3. Quijano D, Rodríguez M. Topical corticosteroids in recurrent the management of recurrent aphthous ulcers. Int J Curr Res aphthous stomatitis. Systematic review. Acta Otorrinolaringol 2018;10:71105-8. Esp 2008;59:298-307. 20. Abou-Raya A, Abou-Raya S, Sallam N. OP0183 rebamipide: 4. Sheshaprasad R, Pai A. A comprehensive review of therapeutic A potential useful therapeutic addition in the treatment of agents in the treatment of recurrent apthous ulcer and oral ulcer recurrent oral ulcers in Behçet’s disease. Ann Rheum Dis in behcets syndrome. Indian J Physiol Pharmacol 2018;5:48-59. 2013;71 Suppl 3:116-7. 5. Preeti L, Magesh K, Rajkumar K, Karthik R. Recurrent 21. Altenburg A, Abdel-Naser MB, Seeber H, Abdallah M, Zouboulis aphthous stomatitis. J Oral Maxillofac Pathol 2011;15:252-6. CC. Practical aspects of management of recurrent aphthous 6. Sabbagh AH, Felemban MF. Therapeutic management of stomatitis. J Eur Acad Dermatol Venereol 2007;21:1019-26. recurrent aphthous stomatitis: A review of the growing 22. Scully C, Gorsky M, Lozada-Nur F. The diagnosis and knowledge. Ann Int Med Dent Res 2016;2:DE01-9. management of recurrent aphthous stomatitis: A consensus 7. Cugadasan V. Management of recurrent ulcers of the approach. J Am Dent Assoc 2003;134:200-7. current concepts. Singapore Med J 1987;28:56-60. 8. Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Source of support: Nil; Conflict of interest: None Declared Dent Clin North Am 2005;49:31-47, 7-8.

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