Efficacy and safety of neuromodulators combined with proton pump inhibitors for non-erosive reflux disease: A randomized clinical trial

Abstract

BACKGROUND

Treatment with proton pump inhibitors in non-erosive reflux disease (NERD) remains unsatisfactory, imposing a considerable burden due to persistent symptoms, impaired quality of life, and recurrent healthcare use. Because the pathogenesis of NERD often involves a complex interplay among acid reflux, esophageal hypersensitivity, and altered gut-brain interactions, the potential value of early adjunctive neuromodulation in treatment-naive patients remains uncertain.

AIM

To investigate the efficacy, safety, and cost-effectiveness of low-dose flupentixol-melitracen (FM) combined with lansoprazole (LPZ) as an initial regimen for patients with NERD.

METHODS

Patients with NERD were randomly assigned to 2 groups for 2 weeks of initial treatment with 30 mg LPZ plus 10.5 mg FM once daily (FM + LPZ) or 30 mg LPZ plus placebo. NERD was diagnosed based on typical reflux symptoms, gastroesophageal reflux disease questionnaire score, and the absence of mucosal erosions on endoscopy. Twenty-four-hour pH-impedance monitoring was not performed. During the subsequent 10-week on-demand treatment period, patients were advised to take the assigned initial treatment dose for 3 consecutive days if symptoms recurred. The primary endpoint was the percentage of patients achieving adequate relief on day 14. Secondary endpoints included health-related quality of life, psychological condition, sleep quality, and cost-effectiveness, which were evaluated at weeks 2 and 12. Treatment satisfaction and adherence were also assessed.

RESULTS

From April 25 to September 5, 2025, 164 patients were included in the intent-to-treat (ITT) population, and 154 were included in the per-protocol population. Combination therapy demonstrated superior efficacy in the ITT population at week 2 (86.6% vs 62.2%; P < 0.001). Significant differences were observed in most secondary endpoints. The cost-effectiveness ratio was lower in the FM + LPZ group than in the LPZ plus placebo group (47.5 vs 95.2). The incidence of adverse events did not differ between the groups.

CONCLUSION

Compared with placebo plus LPZ, combination therapy with FM and LPZ as an initial treatment regimen showed better therapeutic efficacy and a lower economic burden for patients with NERD during the 12-week study period.

Keywords: Non-erosive reflux disease; Neuromodulator; Lansoprazole; Flupentixol-melitracen; Symptom relief; Proton pump inhibitors

Core Tip: This randomized, double-blind, placebo-controlled trial evaluated the efficacy, safety and cost-effectiveness of low-dose flupentixol-melitracen combined with lansoprazole as an initial regimen for non-erosive reflux disease. The findings demonstrate that combining short-term, low-dose neuromodulation with a proton pump inhibitor as initial therapy in treatment-naive patients provides rapid, cost-effective symptom relief during the 12-week study period. This early-intervention strategy may help reduce symptom burden and offer a potential alternative to standard proton pump inhibitor monotherapy for patients with non-erosive reflux disease.