Treatment Strategies for Recurrent Oral Aphthous Ulcers


Am J Health Syst Pharm. 2001;58(1) 

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First introduced into the European market in 1957 as a sedative, thalidomide's use was halted in 1961 after it was linked to a rare congenital birth defect known as phocomelia.[43] Interest in thalidomide was renewed in 1980 after it was used successfully to treat erythema nodosum leprosum. This finding led to the study of thalidomide for various dermatologic disorders and exploration of thalidomide's anti-inflammatory and immunomodulatory properties.

In a study of healthy male volunteers, thalidomide demonstrated the ability to decrease the ratio of circulating helper T cells to suppressor T cells.[44] Thalidomide has also been found to inhibit the production of various cytokines as a result of its effects on T lymphocytes, monocytes, and polymorphonuclear cells. In vitro studies showed that thalidomide selectively inhibits the production of tumor necrosis factor (TNF- ), a cytokine that plays a central role in regulating immune and inflammatory responses to infection. Patients with erythema nodosum leprosum have elevated TNF- levels, which are highest during the lepra reactions.[43] Elevated TNF- has also been observed both locally and systemically in patients with RAU.[45,46] However, a recent study found that thalidomide actually increased circulating TNF- levels in HIV-seropositive patients with aphthous ulcers.[46] Whether it involves a generalized or specific cytokine regulatory pathway, thalidomide's exact mechanism of action in treating RAU remains unknown.

Three double-blind, placebo-controlled trials investigated the use of thalidomide for oral aphthous ulcers in patients with advanced HIV disease,[40] Behçet's syndrome,[41] or a history of severe RAU.[42] All the trials excluded patients taking medications that may alter immunocompetency,[40,41,42] and one trial excluded Behçet's syndrome and inflammatory bowel disease as alternative causes of RAU.[42]

In HIV-seropositive patients, aphthous ulcers were completely or partially resolved in 55% and 34%, respectively, of thalidomide-treated patients.[40] Complete and partial resolution rates for the placebo recipients were 7% and 18%, respectively. The thalidomide-treated patients had diminished pain, an improved ability to eat, and an average weight gain of four pounds in four weeks (compared with no weight gain in the placebo group). In patients with severe RAU, thalidomide treatment resulted in complete resolution of aphthae in 48% of patients (versus 9% of placebo recipients), significant reductions in the number of buccal aphthae, and improved function.[42] A total of 22% of patients with Behçet's syndrome who received thalidomide had complete resolution of oral ulcers, compared with none of the placebo recipients.[41] Thalidomide also reduced the number of minor oral and genital ulcers and the frequency of uveitis episodes that are commonly associated with Behçet's syndrome. Thalidomide was effective at dosages of 100 and 300 mg/day. Complete responses were seen as early as 3.5-6 weeks after the start of therapy.[40,41,42] The effects of thalidomide are suppressive, not disease modifying.[41,42] Once thalidomide was discontinued, the average duration of remission was 20 days.[42]

In the three trials, adverse effects of thalidomide resulted in the discontinuation or interruption of therapy in 6-26% of patients. The adverse events most frequently associated with thalidomide were neurosensory, gastrointestinal (GI), and cutaneous. Rash occurred in 24% and 32% of patients with Behçet's syndrome and HIV disease, respectively.[40,41] Constipation was the most common GI event, occurring in up to 65% of thalidomide-treated patients. Neurosensory effects included somnolence (24-87% of patients), headaches (up to 39%), and polyneuropathy (0- 6%). In a recent review of thalidomide use for dermatologic conditions, the frequency of peripheral neuropathy ranged from 21% to 50%.[43] The frequency may vary with the patient population studied, ranging from less than 1% in patients with erythema nodosum leprosum to greater than 70% in patients with prurigo nodularis.[43]


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