Management of Gastroesophageal Reflux Disease that does not Respond Well to Proton Pump Inhibitors

Tiberiu Hershcovici and Ronnie Fass


Curr Opin Gastroenterol. 2010;26(4):367-378. 

In This Article

Abstract and Introduction


Purpose of review Patients with gastroesophageal reflux disease (GERD) who are not responding to proton pump inhibitors (PPIs) given once daily are very common. These therapy-resistant patients have become the new face of GERD in clinical practice in the last decade and presently pose a significant therapeutic challenge to the practicing physician. We reviewed newly accumulated information about the management of PPI failure that has been published over the past 2 years.
Recent findings There are diverse mechanisms that contribute to the failure of PPI treatment in GERD patients and they are not limited to residual reflux. Some of the causes of PPI failure may coincide in the same patient. Upper endoscopy appears to have limited diagnostic value. In contrast, esophageal impedance with pH testing on therapy appears to provide the most insightful information about the subsequent management of these patients. Commonly, doubling the PPI dose or switching to another PPI will be offered to patients who failed PPI once daily. Failure of such therapeutic strategies is commonly followed by assessment for residual reflux. There is growing information about the potential value of compounds that can reduce transient lower esophageal sphincter relaxations. Esophageal pain modulators are commonly offered to patients with functional heartburn, although supportive clinical studies are still missing.
Summary Management of refractory GERD patients remains an important clinical challenge. Recent studies have cemented the value of impedance-pH testing in pursuing proper treatment. Presently, the most promising therapeutic development for this patient population is transient lower esophageal sphincter relaxation reducers.


It has been estimated that between 10 and 40% of patients with GERD fail to respond symptomatically, either partially or completely, to a standard-dose proton pump inhibitor (PPI).[1,2] During a period of only 7 years (1997–2004), there was an increase by almost 50% in the usage of at least double-dose PPI in patients with GERD.[3] In a recent US survey of 617 GERD patients taking PPIs, 71% used PPIs once a day, 22.2% twice a day and 6.8% more than twice a day or on as-needed basis.[4] Approximately 42.1% of all patients supplemented their prescription PPIs with other antireflux therapies, including over-the-counter antacids and H2-receptor antagonists (H2RAs). Although more than 85% of the patients still experienced GERD-related symptoms, 72.8% claimed to be satisfied or very satisfied with their PPI treatment.

In the 2000 Gallup Study of Consumers' Use of Stomach Relief Products, 36% reported taking nonprescription medication in addition to a prescription medication for GERD (Fig. 1).[2] Of those, 56% stated that they used their prescription medication daily but still needed to supplement with nonprescription medication for breakthrough symptoms. Interestingly, 28% stated that only the combination of prescription and nonprescription medications relieved their symptoms, and 24% reported that the prescription medication worked better in the long run, but the nonprescription medication was faster acting.

Figure 1.

Reported type of medications used in the past 30 days in 1009 patients that were surveyed
The box shows the common explanations given by patients with GERD for adding a nonprescription drug to a prescription drug. GERD, gastroesophageal reflux disease. Reproduced from [2].

Failure of PPI treatment to resolve GERD-related symptoms has become the most common presentation of GERD in gastrointestinal practice. Whereas cost analysis of PPI failure has yet to be carried out, it is likely an expensive clinical problem due to repeated utilization of healthcare resources such as clinic visits, diagnostic tests, and prescription medications.

Most of the GERD patients who are not responsive to PPIs are from the nonerosive reflux disease (NERD) and functional heartburn groups, primarily due to the high frequency of these groups in the heartburn patient population (up to 70%) and their known low response rate to PPI once daily.[3,5] In contrast, patients with erosive esophagitis, who account for 30–40% of the total GERD population, have a symptom response rate significantly higher than what has been reported in patients with NERD (pooled symptomatic response rate to PPI once daily at 4 weeks is 56%).[3,6••]

The Rome III Committee for Functional Esophageal Disorders redefined the functional heartburn group, and consequently NERD, by primarily incorporating the hypersensitive esophagus group and those patients with negative symptom association who are responsive to PPI treatment back into the NERD group (Fig. 2).[7] Presently, functional heartburn is recognized as one of the most important conditions that contributes to PPI failure among patients with heartburn.

Figure 2.

A diagnostic algorithm of NERD and functional heartburn based on Rome III criteria
NERD, nonerosive reflux disease.