Efficacy of topical erythropoietin gel and mouthwash for recurrent aphthous stomatitis in a randomized clinical trial

Erythropoietin (EPO) has anti-inflammatory, antioxidant, and wound-healing properties that could be valuable in managing Recurrent Aphthous Stomatitis (RAS). This study aimed to evaluate its clinical effectiveness in either gel in orabase or mouthwash, on pain reduction, ulcer healing, recurrence rates, and salivary IL-2 level in patients with RAS. In this randomized clinical trial, 60 patients with RAS were equally divided into 3 groups: EPO oral gel, EPO mouthwash, or a placebo. Ulcer size, the Pain Visual Analog Scale (P-VAS), and salivary IL-2 levels were evaluated at baseline, day 3, and day 7. When compared to a placebo, both EPO formulations significantly decreased pain, ulcer size, and salivary IL-2 levels (p < 0.001). With nearly total pain relief, significant ulcer healing, and the lowest post-treatment IL-2 concentration, the EPO gel group showed the greatest improvement. In comparison to mouthwash and a placebo, patients treated with EPO gel also had noticeably longer recurrence-free intervals (median 5 months). No negative effects noted. These findings suggest that EPO gel is a therapeutic option for RAS that is both safe and effective, with the potential to modify the disease in addition to relieving symptoms.Trial registration: The study was registered at Clinical Trials.gov (NCT06923605) on 11/4/2025.