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Background Recent progress in chronic cough management includes controlling cough triggers and hypersensitivity using antitussives. Therefore, we investigated the effects and safety outcomes of antitussives, codeine and levodropropizine, in patients with chronic cough. Methods We conducted an open-label, randomized comparative trial with newly referred patients with chronic cough. Patients were orally administered codeine (60 mg/day) and levodropropizine (180 mg/day) for 2 weeks. Cough severity, including the visual analog scale (VAS), Cough Symptom Score (CSS), Leicester Cough Questionnaire (LCQ), and safety for each treatment were assessed. The primary outcome was VAS score changes before and after 2 weeks of treatment. Results Among the 88 participants, 45 and 43 in the codeine and levodropropizine groups, respectively, were included in the analysis. Changes in the VAS score were higher in the codeine group than in the levodropropizine group (35.11 ± 20.74 vs. 19.77 ± 24.83, P = 0.002). Patients administered codeine also had improved CSS (2.96 ± 2.35 vs. 1.26 ± 1.89, P < 0.001) and LCQ (3.28 ± 3.36 vs. 1.61 ± 3.53, P = 0.025) than those administered levodropropizine. Treatment-related adverse events, including drowsiness, constipation, and headaches, were more frequent in the codeine group than in the levodropropizine group. However, no significant differences existed in the adverse events leading to discontinuation. Conclusion Codeine is an effective and generally well-tolerated antitussive for chronic cough. However, it may induce side effects in some patients. Individual responses and adverse events should be carefully monitored when codeine is used to treat chronic cough.

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