Introduction

Gastroesophageal reflux (GER) is one of the most prevalent gastrointestinal diseases worldwide, with estimates ranging from 10 % to 20 % in Western populations and a growing trend in emerging countries¹. Although most cases respond satisfactorily to lifestyle modifications combined with proton-pump inhibitors (PPIs), up to 40 % of patients remain symptomatic after eight to twelve weeks of correct PPI use, characterizing treatment-resistant gastroesophageal reflux (TR-GER)². Therapeutic resistance is multifactorial. Pathophysiological studies show that many patients labeled as refractory actually have weak or non-acid reflux, esophageal hypersensitivity or functional brain-esophagus axis disorders, conditions in which acid suppression alone is insufficient³.

Diagnostic errors such as mistaking eosinophilic esophagitis, achalasia or severe dysmotility for GER and low adherence to medication significantly contribute to persistent symptoms⁴. Parallel to elucidating these mechanisms, the last decade has witnessed the advent of high-resolution diagnostic technologies that precisely characterize reflux nature and esophageal motor behavior. Twenty-four-hour multichannel intraluminal impedance-pH monitoring detects reflux episodes regardless of pH and temporally correlates them with patient-reported symptoms⁵.

High-resolution esophageal manometry provides detailed parameters of peristalsis and lower esophageal sphincter (LES) pressure, allowing identification of specific motor disorder sub-phenotypes. These advances have shaped new assessment algorithms based on objective patient stratification. Therapeutically, the arsenal for TR-GER has expanded considerably. Beyond dose adjustment and split dosing of PPIs, several pharmacologic classes have been incorporated into treatment algorithms: nocturnal H₂-receptor antagonists (“breakthrough acid” strategy), prokinetics that accelerate gastric emptying and reduce transient LES relaxations and central neuromodulators that modulate esophageal pain perception⁶. Consequently, constructing evidence-based clinical protocols to guide decision-making and deliver personalized, mechanism-targeted care has become imperative.

Objectives

This article aims to provide a comprehensive review of recent literature on TR-GER, describing the judicious use of complementary tests and targeted selection of therapeutic alternatives. The economic impact of TR-GER on health systems and the emerging role of minimally invasive endoscopic interventions as a bridge or alternative to classic ant reflux surgery are also discussed.

Materials and Methods

A literature review was conducted using the PubMed, SciELO, Google Scholar and ScienceDirect databases.

Discussion

Discussion of TR-GER management must begin by recognizing that not every refractory patient truly has persistent pathologic reflux. In prospective series employing impedance-pH monitoring in symptomatic individuals on PPIs, only one-third showed a positive correlation between reflux episodes and symptoms². This underscores the importance of systematic evaluation, starting with confirming adherence and optimizing PPI dosing administering the drug 30 minutes before the first meal and, if necessary, in a double dose. Those with genuine pharmacologic failure are candidates for stepped therapy. An initial step includes double-dose or immediate-release PPIs combined with nocturnal H₂ antagonists, a strategy that reduces “breakthrough acid” in up to 70 % of cases⁶.

If symptoms persist, adding a prokinetic such as domperidone or prucalopridemay be useful, especially in patients with delayed gastric emptying. Recent meta-analyses show a significant reduction in total acid exposure time when prokinetics are combined with PPIs⁷. Patients with negative pH monitoring and a high symptom index fit the hypersensitive esophagus profile; in these cases, low-dose tricyclic antidepressants or serotonin-noradrenaline reuptake inhibitors reduce pain scores by more than 50 %. When severe motor disorders such as failed peristalsis or absent contractions are documented, procedures that increase LES pressure should be avoided, prioritizing pharmacologic therapies or corrective motility surgery.

Endoscopic interventions have emerged as an intermediate option between pharmacotherapy and surgery. Radiofrequency (Stretta) produces collagen remodeling and increases basal LES tone; randomized trials demonstrate a sustained 2.5-point symptom score reduction after 48 months, with low complication rates⁸. Transoral incisionless fundoplication (TIF) creates a 270° valve endoscopically, yielding symptom relief comparable to laparoscopic fundoplication at three-year follow-up. Antireflux surgery remains the gold standard for patients with documented acid reflux and partial PPI response. Laparoscopic Nissen fundoplication achieves satisfaction rates exceeding 85 % at ten years⁹, although complications such as dysphagia and gas-bloat syndrome must be considered. Magnetic sphincter augmentation (LINX®) offers a promising alternative, preserving physiologic gastric anatomy and being reversible.

A dimension still under-explored in TR-GER involves duodenogastroesophageal reflux, rich in bile acids. Conventional pH monitoring detects only acid reflux; thus, alkaline events may remain hidden, causing persistent inflammation¹⁰. Studies using alkaline impedance-pH monitoring show that up to 20 % of refractory patients exhibit prolonged bile exposure. In such cases, adding sucralfate or ursodeoxycholic acid and, if unsuccessful, definitive surgery may be beneficial. Finally, lifestyle measures remain essential. Ten-percent weight loss reduces reflux frequency by 32 %, an effect potentiated by a Mediterranean diet¹¹. Head-of-bed elevation, avoiding meals three hours before bedtime and smoking cessation complete the recommended non-pharmacologic approach⁴.

Conclusion

TR-GER requires precise diagnosis, individualized therapy and active patient participation. Apparent PPI failure may stem from non-adherence, motor disorders or visceral hypersensitivity; therefore, tests such as impedance-pH monitoring and high-resolution manometry are mandatory before advanced therapies³. A stepped algorithm includes pharmacologic adjustments, neuromodulation, endoscopic procedures (Stretta, TIF) and laparoscopic antireflux surgery, with magnetic devices as an emerging alternative⁹.

Future prospects include drugs that modulate transient LES relaxations, bile reflux inhibitors and remote esophageal pH sensors. Although technology advances, lifestyle measures remain a fundamental pillar. Weight loss, a Mediterranean diet, smoking cessation and correct PPI intake timing reduce recurrence and complications¹¹.

Multidisciplinary programs integrating gastroenterologists, surgeons, nutritionists and psychologists shorten the time to definitive diagnosis and improve patient satisfaction. Public health policies focusing on obesity and sedentary behavior may reduce the incidence of symptomatic GER and, consequently, TR-GER. By combining robust science, appropriate technology and health education, the challenge of TR-GER can be transformed into an opportunity for person-centered care, promoting durable symptom relief and restoration of quality of life^12-15.

References

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