Optimal management of severe symptomatic gastroesophageal reflux disease

J Intern Med. 2021 Feb;289(2):162-178. doi: 10.1111/joim.13148. Epub 2020 Jul 21.


Gastroesophageal reflux disease (GERD) is a common disorder, and empirical proton pump inhibitor (PPI) treatment is often the first step of management; however, up to 40% of patients remain symptomatic despite PPI treatment. Refractory reflux refers to continued symptoms despite an adequate trial of PPI, and management remains challenging. The differential diagnosis is important; other oesophageal (e.g. eosinophilic oesophagitis) and gastroduodenal disorders (e.g. functional dyspepsia) should be ruled out, as this changes management. A combination of clinical assessment, endoscopic evaluation and in selected cases oesophageal function testing can help characterize patients with refractory reflux symptoms into oesophageal phenotypes so appropriate therapy can be more optimally targeted. Medical options then may include adding a H2 receptor antagonist, alginates, baclofen or antidepressant therapy, and there is emerging evidence for bile acid sequestrants and diaphragmatic breathing. The demonstration of a temporal association of symptoms with reflux events on pH-impedance testing (reflux hypersensitivity) serves to focus the management on modulating oesophageal perception and reducing the reflux burden, or identifies those with no obvious pathophysiologic abnormalities (functional heartburn). Anti-reflux surgery based on randomized controlled trial evidence has a role in reflux hypersensitivity or continued pathological acid reflux despite PPI in carefully considered, fully worked up cases that have failed medical therapy; approximately two of three cases will respond but there is a small risk of complications. In patients with persistent volume reflux despite medical therapy, given the lack of alternatives, anti-reflux surgery is a consideration. Promising newer approaches include endoscopic techniques. This review aims to summarize current diagnostic approaches and critically evaluates the evidence for the efficacy of available treatments.

Keywords: functional dyspepsia; functional heartburn; fundoplication; gastroesophageal reflux disease; prokinetic; proton pump inhibitors; reflux hypersensitivity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alginates / therapeutic use
  • Antidepressive Agents / therapeutic use
  • Baclofen / therapeutic use
  • Bile Acids and Salts / metabolism
  • Breathing Exercises
  • Diagnosis, Differential
  • Endoscopy, Gastrointestinal
  • Gastroesophageal Reflux / diagnosis*
  • Gastroesophageal Reflux / drug therapy*
  • Gastroesophageal Reflux / physiopathology
  • Gastrointestinal Agents / therapeutic use
  • Histamine H2 Antagonists / therapeutic use
  • Humans
  • Hydrogen-Ion Concentration
  • Muscle Relaxants, Central / therapeutic use
  • Phenotype
  • Proton Pump Inhibitors / therapeutic use


  • Alginates
  • Antidepressive Agents
  • Bile Acids and Salts
  • Gastrointestinal Agents
  • Histamine H2 Antagonists
  • Muscle Relaxants, Central
  • Proton Pump Inhibitors
  • Baclofen