Introduction: Gastroesophageal reflux disease (GERD) affects one in eight people in Colombia. Its characteristic symptoms are heartburn and regurgitation. The cornerstone of treatment is proton pump inhibitors (PPIs) with a clinical response of 58%-80%. In non-responders 75%-90% have a superimposed functional disorder and could be treated by adding visceral neuromodulators such as amitriptyline. Objective: To evaluate the impact of optimizing treatment in patients with GERD when there is no response to esomeprazole (ESO). Materials and methods: Prospective study in patients with no clinical response (> 2 episodes of reflux/week) treated with ESO half an hour before meals and simultaneously recommendations for weight loss if BMI> 25, stop smoking, stress control and finally increased the dose of ESO to 40 mg on an empty stomach and before dinner. When all the above was done and symptoms persisted, amitriptyline 12.5 mg was added overnight. Every 12 weeks the response was evaluated. Results: 149 patients were included. Optimizing treatment, 111 patients had a clinical response without using amitriptyline (74.5%; 95% CI 67.2%-81.4%). In 22 amitriptyline was added (14.8%), responding 15 patients, 68.2% (95% CI 47.04%-89.32%). A relationship was found between PPI compliance and clinical response (p <0.0001). Conclusion: In patients with GERD and non-response to PPI (ESO), sequential optimization achieved cumulative improvement in symptom control in 86% (95% CI 78.6% -90.4%) of patients, avoiding costly esophageal studies. Key Words: Optimize treatment, PPI, neuromodulator, compliance, clinical response.