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Abstract Background Migraine is common in primary headaches, and with the development of social economy and the increase in living pressure, the prevalence of migraine has an upward trend. Objective To observe the clinical effect of flunarizine combined with duloxetine in the treatment of chronic migraine with comorbid depression and anxiety disorders and to provide a reference for clinical treatment. Methods A total of 118 patients with chronic migraine complicated with depression and anxiety disorder admitted to our hospital from June 2018 to August 2020 were selected and divided into two groups according to treatment methods, 59 cases in each group. The control group was treated with flunarizine combined with loxoprofen sodium, and the observation group was treated with flunarizine combined with duloxetine. The changes of electroneurophysiological indexes, tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), high sensitivity‐C reactive protein (hs‐CRP), Hamilton depression scale (HAMD) score, and Hamilton anxiety scale (HAMA) score before and after treatment in the two groups were recorded, and the total effective rate of clinical treatment in the two groups was counted. Results After treatment, TNF‐α, IL‐6, and hs‐CRP in the two groups decreased gradually (p |