Amitriptyline for the Treatment of Extra-esophageal Symptoms in Proton Pump Inhibitor-refractory Patients With Suspected Gastroesophageal Reflux Disease.

Background/Aims: Gastroesophageal reflux disease (GERD) is a chronic, heterogeneous condition that impairs quality of life. Extra-esophageal symptoms (eg, globus sensation, chronic cough, hoarseness, wheezing) often persist despite proton pump inhibitor (PPI) therapy. Tricyclic antidepressants are recommended for such refractory cases, but supporting evidence is limited. This study aims to evaluate the efficacy of low-dose amitriptyline in treating extra-esophageal GERD symptoms. Methods: We conducted a single-center, single-blind, randomized, controlled crossover pilot trial. Forty patients with both typical GERD symptoms and one or more atypical symptom unresponsive to ≥ 4 weeks of PPI therapy were randomized to receive either lansoprazole 30 mg daily plus amitriptyline 10 mg at bedtime or lansoprazole alone for 4 weeks, followed by crossover to the alternate regimen. The primary outcome was symptom improvement assessed by numeric rating scale. Secondary outcome included changes in quality of life (QoL) measured by the 36-item Short Form survey. Results: All 40 patients completed the trial. Overall, 75% reported symptom improvement: 65% in the amitriptyline group vs 85% in the PPI group ( Conclusions: Adding low-dose amitriptyline to PPI therapy did not offer a short-term advantage over PPI alone. Both treatments improved symptoms and QoL. Given the challenging nature of GERD's extra-esophageal manifestations and mixed evidence for neuromodulator therapy, further studies are needed to identify patient subgroups that may benefit from adjunctive neuromodulator therapy.