Journal Article | Gastroenterology

July 30, 2021

Doctor. Joel E. Richter, M.D.



Gastroesophageal reflux disease (GERD) is one of the most common conditions encountered in clinical practice. It is mainly treated with proton pump inhibitors (PPIs) that suppress gastric acid production. Majority of patients respond through this regimen. However, around 10% to 40% fail to respond to standard doses of PPIs. These patients are said to have refractory GERD.


Refractory GERD is becoming commonplace in gastroenterology clinics. Mostof patients though, have normal endoscopic findings. Having less than a 50% reduction in symptoms despite the maximal 12 week-therapy with PPIs is considered a poor response. However, this is difficult to distinguish in practice since symptoms are not classic for reflux and patient’s perception of the remaining symptoms is subjective.


It is somehow complex when PPI therapy is used to define refractory GERD. Non response to once-daily PPI regimen may be enough to consider failure. Most guidelines do not recommend going beyond two doses of PPI daily although most clinicians double the PPI dose, hoping for symptom resolution. Despite this, majority of patients continue to experience reflux symptoms.




The physical and mental health-related quality of life of patients with refractory symptoms has been found to be reduced in a recent systematic review.It is imperative to distinguish patients with refractory GERD from patients who have organic or functional causes of the symptoms since not all patients who fail to respond to PPIs have GERD. Hence, a comprehensive diagnostic evaluation must be made.




The study aims to properly identify, diagnose, and treat patients with suspected reflux symptoms refractory to proton pump inhibitor therapy.




Evaluation of Symptoms and Proton Pump Inhibitor Compliance


A comprehensive history is essential in the evaluation of symptoms and compliance to PPI therapy. Persistent symptoms and aggravating factors must be thoroughly investigated. Foods, exercise, and lying down on your back usually aggravate symptoms.


A burning epigastric pain that radiates to the chest is indicative of a heartburn.An atypical burning sensation in the upper chest or throat that is unrelated to intake of food is usually experienced by patients with refractory heartburn. This is also associated with other symptoms such as dyspepsia, belching, bloating, and throat discomfort. It is also important to take note if there is regurgitation.


Clinicians must ensure that the PPI and its dose are appropriate. Furthermore, compliance must be sought before further workup is ordered. PPIs should be taken before meals to ensure maximum effect. Patients with refractory symptoms usually have lower compliance rates (46%-55%) than those who have adequate relief (84%) with PPI.


Further Investigation of Reflux Symptoms Refractory to Proton Pump Inhibitors


            Additional laboratory and imaging tests may be required to know identifiable causes of reflux symptoms refractory to PPI therapy. Differential diagnoses for refractory GERD and esophagitis include eosinophilic esophagitis, pill esophagitis, skin diseases with esophagitis such as lichen planus, acid hypersecretory conditions like Zollinger-Ellison syndrome, and genetic abnormalities in Cytochrome P450 and 2C19 metabolism.


An algorithm for the evaluation of refractory GERD has been developed as suggested by the recent guidelines from the American College of Gastroenterology (ACG).

Figure 1. Algorithm for the evaluation of refractory GERD from Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013.


Upper Gastrointestinal Endoscopy


            Endoscopy is recommended for patients presenting with esophageal symptoms to rule out non-esophageal causes. Those with primarily non-esophageal causes are referred to pulmonology, allergology, or otolaryngology for further investigation.


Majority (90%) of patients who experience refractory symptoms have normal endoscopic findings. A recent study from the U.S. Veterans found that 54% of patients who failed to respond with PPIs have normal endoscopy findings compared with 41% of patients not receiving PPIs.


Esophageal Manometry


When endoscopy turns out normal, a functional test may be warranted to gauge and monitor reflux symptoms. Esophageal manometry measureslower esophageal sphincter (LES) pressure and helps identify conditions such as achalasia and esophageal motor disorders.


Ambulatory Reflux Monitoring


Reflux testing and monitoring is done by measuring esophageal pH alone, through the use of a wireless pH capsule, or by impedance-pH. It is indicated for refractory reflux symptoms.This is done to confirm and rule out acid reflux in patients off PPI therapy. Impedance-pH testing accurately measures weak and nonacid reflux in patients on PPI therapy who have persistent symptoms despite adequate acid control.


Alternative diagnoses must be sought for patients with refractory symptoms who have normal endoscopic findings. These include achalasia, gastroparesis, eosinophilic esophagitis, rumination, aerophagia, and functional heartburn.


Treatment of Proton Pump Inhibitor Nonresponders


            The ideal management of non responders is endoscopy and/or esophageal manometry and reflux testing. However, this may not be too practical in the clinical setting. The dose of the current proton pump inhibitor can be doubled. A follow-up is scheduled to monitor for symptom response or resolution. About 25% of patients respond to doubling the dose of PPI.


Acid Suppression


Doubling the PPI dose can be done initially. Furthermore, switching of a first-generation PPI to a second-generation PPI such as esomeprazole can be instituted. About 75% of patients on twice daily dose of PPIs experience nocturnal breakthrough of gastric acid. A histamine-2 receptor antagonist (H2RA) at bedtime can be added to greatly improve night time acid control.


Reflux Inhibitors


Baclofen, a γ-aminobutyric acid type B (GABA-B) agonist used for spastic muscle disorders, is the only drug approved to inhibit transient LES relaxation. It reduces the number of postprandial acid and nonacid reflux events and decreases reflux symptoms. It is given as a 20 mg tablet taken 3 times daily.


Pain Modulators


Trazodone, tricyclic antidepressants(TCAs), and selective serotonin reuptake inhibitors (SSRIs) are used as pain modulators.They relieve esophageal pain in patients with non cardiac chest pain. The SSRI citalopram (20 mg at bedtime for 6 months) was found to be effective in patients with acid-hypersensitive esophagus and refractory reflux symptoms according to a recent randomized, placebo-controlled trial.Acupuncture and hypnotherapy are some other forms that modulate pain by decreasing visceral hypersensitivity.


Endoscopic Therapy


Two antireflux endoscopic devices are currently being used. One device delivers radio frequency energy at the gastroesophageal junction (Stretta, Mederi therapeutics). It decreases esophageal sensitivity to acid but does not reduce acid reflux. Although it is not supported by current guidelines for patients with GERD, it may be used for modulation of pain.


The other device employs transnasal incisionless fundoplication (EsophyX, Endo- Gastric Solutions). Studies using this device show relief of symptoms and normalization of acid reflux parameters in 50 % of patients, but the long-term studies on its durability are warranted.


Antireflux Surgery


Laparoscopic fundoplication is a form of antireflux surgery that is indicated in patients who have typical symptoms, those who have abnormal reflux parameters while off PPIs, and those who show partial response to PPIs. It is very effective in controlling acid and nonacid reflux.




Refractory GERD is commonly encountered in clinical practice. Patient compliance to PPIs should be thoroughly investigated before further tests are performed. Doubling the PPI dose for 6 to 8 weeks or switching PPIs should be considered first.


For those who fail to respond to standard therapy, an upper endoscopy should be suggested.  However, majority have normal results. Esophageal manometry and pH testing should be performed if endoscopic findings turn out normal. Patients must be put off PPIs for at least 1 week.


Consider alternative diagnoses for patients with normal esophageal pressures and pH. Note that more than half of the patients have functional heartburn, a visceral hypersensitivity syndrome. Treating PPI-refractory GERD–like symptoms is complex. Medical, endoscopic, or surgical treatments have to be employed although not all modalities have proven efficacy.




Richter J.E. Current Diagnosis and Management of Suspected Reflux Symptoms Refractory to Proton Pump Inhibitor Therapy. Gastroenterology & Hepatology Volume 10, Issue 9, September 2014.

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