Association of major aphthous ulcers and nicorandil

Abstract

Major aphthous ulcers are generally idiopathic but can occasionally be associated with HIV infection, Behcet’s disease, or neutropenia. We report on 16 cases of major aphthous mouth ulcers after use of nicorandil, a cardiovascular drug. The patients (nine men, seven women, median age 78 years [range 64–90]) were treated with nicorandil for angina pectoris (table). The median duration of treatment at the onset of aphthous ulcers was 12 months (range 2–36). 12 patients received 40 mg/day, and four 60 mg/day. In two patients, aphthous ulcers occurred when the dose was increased from 40 mg/day to 60 mg/day. Three patients had occasional minor aphthous stomatitis before treatment by nicorandil. The lesions, one to three in number, were typical painful major aphthous ulcers of more than 1 cm in diameter, and were located on the tongue, gingiva, or cheeks. There were no extraoral signs and laboratory investigations did not show abnormalities, white blood cell, haemoglobin, and platelet counts, erythrocyte sedimentation rates, and kidney and liver functions were normal. Histopathological assessment was done for five patients and showed non-specific ulceration. Viral, bacteriological, and fungal cultures done in three cases were negative. HIV tests done in the first three patients were negative. The median duration of each major aphthous stomatitis was 3 months (range 1–36). In the first six patients, toxic aphthous ulcers were not initially diagnosed and the patients were treated with thalidomide 25–50 mg/day (n=3) or colchicine 1 mg/day (n=3) and nicorandil was continued. Aphthous ulcers healed completely in 10–15 days in all these patients, but relapsed immediately when colchicine and thalidomide were stopped. Ulcers healed completely without scars in all 16 patients 1–3 weeks after nicorandil was discontinued. No patient relapsed during a median follow-up of 12 months (range 1–17). For ethical reasons we did not test rechallenge of nicorandil after the ulcers healed. Before this series, only two isolated cases of major aphthous ulcers induced by nicorandil were reported. Our results suggest a role for nicorandil in the onset of the major aphthous stomatitis since most of these patients had never previously had aphthous ulcers, and idiopathic major aphthous stomatitis generally begin in young patients; no other aetiology of major aphthous ulcers could be detected; the patients received many different drugs but nicorandil was the only drug common to them all; transient improvement was obtained with thalidomide or colchicine, RESEARCH LETTERS