BACKGROUND: Gabapentin and baclofen are recommended for the treatment of chronic refractory cough (CRC). We investigated the efficacy of flupentixol/melitracen in patients unresponsive to these neuromodulators.METHODS: A total of 101 patients with CRC who failed to respond to gabapentin and baclofen were recruited, and treated with flupentixol/melitracen. The prevalence of cough resolution and changes in the Cough Symptom Score (CSS), cough thresholds to capsaicin, Hull Airway Reflux Questionnaire (HARQ), Leicester Cough Questionnaire (LCQ), Generalized Anxiety Disorder-7, Hamilton Anxiety Rating Scale, Patient Health Questionnaire-9, and Hamilton Depression Rating Scale-24 were evaluated after treatment.RESULTS: Ninety-eight patients (97.0%) completed the study. The overall successful cough resolution rate was 62.4% (63/101). Cough resolution was accompanied by an obvious decrease in the CSS and HARQ score and a remarkable increase in cough thresholds to capsaicin challenge and LCQ score, whereas anxiety and depression scores did not change significantly. The prevalence of adverse effects (e.g., insomnia and dizziness) was 21.8%. The prevalence of cough recurrence within 2 weeks after treatment cessation was 17.8%.CONCLUSION: Flupentixol/melitracen may be an efficacious option for CRC unresponsive to other neuromodulators.