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Efficacy of Rebamipide as Adjunctive Therapy in the Treatment of Recurrent Oral Aphthous Ulcers in Patients with Behçet’s Disease

A Randomised, Double-Blind, Placebo-Controlled Study


Background: Behçet’s disease (BD) is a recurrent inflammatory disease involving chronic recurrent oral aphthous ulcers (aphthae), uveitis, skin lesions and genital ulcers. We prospectively investigated the efficacy of rebamipide, a gastroprotective drug, against oral aphthous ulcers in BD patients.

Methods: In a multicentre, double-blind, placebo-controlled study, 35 patients with BD, having as the main symptom oral aphthosis, were randomised to receive rebamipide 300 mg/day or placebo for 12 to 24 weeks between August 1994 and December 1996. Oral aphthosis must have occurred within 4 weeks prior to enrolment and must have been visible for at least 7 days during that time. Oral aphthae count and pain scores were recorded daily in a diary by the patients themselves. Monthly aphthae count and pain scores were defined as the sum of aphthae count and pain scores for a month, respectively. Investigators rated the global improvement in aphthae count and pain using a 6-point scale. The rate of change in monthly aphthae count and pain scores in the first 3 and last 3 months of treatment were assessed in patients with more severe symptoms whose aphthae count and pain score were >28 at baseline (trial entry).

Results: The rate of moderate or marked improvement in aphthae count and pain was 36% (5 of 14 subjects) in the placebo group and 65% (11 of 17 subjects) in the rebamipide group. During months 2 to 6 of treatment, aphthae count tended to increase and reached a peak at month 4 in the placebo group but decreased in the rebamipide group. Pain score decreased to the same extent in both groups for the first 3 months of treatment; however, in the fourth to sixth months of treatment, the pain score tended to increase in the placebo group but decreased in the rebamipide group. In patients with a monthly aphthae pain score >28 at baseline, pain and count scores decreased throughout the 6 months of rebamipide treatment but increased during the last 3 months of treatment in the placebo group (p < 0.01 for the between-group comparisons).

Conclusions: Rebamipide is well tolerated and improves the aphthae count and pain score in BD patients. It may therefore be useful in the treatment and prevention of frequently recurrent oral aphthous ulcers (not restricted to BD). Administration of rebamipide is not cumbersome, and it does not cause any discomfort, which corticosteroid ointments for example may do; furthermore, there are no specific adverse drug reactions. Rebamipide is therefore recommended as a long-term treatment for recurrent oral aphthous ulcers.

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The authors would like to thank Prof. Shinichi Kawai of the Institute of Medical Science, St Marianna University School of Medicine, for performing the duties of controller (assignment of the investigational drug, preservation of blindness, methods for processing the data, etc.) in this study. In honour of the memory of Prof. Tsuyoshi Sakane (deceased) of St Marianna University School of Medicine, the authors would like to acknowledge his extensive contribution to the performance of the study.

This study was funded by Otsuka Pharmaceutical Co. Ltd, Osaka, Japan.

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Correspondence to Dr Takahide Matsuda.

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Matsuda, T., Ohno, S., Hirohata, S. et al. Efficacy of Rebamipide as Adjunctive Therapy in the Treatment of Recurrent Oral Aphthous Ulcers in Patients with Behçet’s Disease. Drugs in R&D 4, 19–28 (2003). https://doi.org/10.2165/00126839-200304010-00002

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  • Pain Score
  • Gastric Ulcer
  • Rebamipide
  • Genital Ulcer
  • Recurrent Aphthous Stomatitis