Prevalence and Clinical Characteristics of Refractoriness to Optimal Proton Pump Inhibitor Therapy in Non-erosive Reflux Disease

Mentore Ribolsi; Michele Cicala; Patrizia Zentilin; Matteo Neri; Aurelio Mauro; Konstantinos Efthymakis; Tommasangelo Petitti; Vincenzo Savarino; Roberto Penagini


Aliment Pharmacol Ther. 2018;48(10):1074-1081. 

In This Article

Abstract and Introduction


Background: The real size of the gastro-oesophageal reflux disease (GERD) population not responding to proton pump inhibitor (PPI) therapy has still not been fully elucidated. Causes of PPI refractoriness include incorrect diagnosis and lack of adherence to therapy, in terms of incorrect dosage and timing.

Aims: To evaluate the prevalence of refractoriness to optimal PPI therapy and the contribution of non-erosive reflux disease (NERD), reflux hypersensitivity, and functional heartburn, to PPI refractoriness. The association of functional GI symptoms in non-responders was evaluated.

Methods: Frequency and severity of GERD symptoms (heartburn, regurgitation, chest pain), dysphagia, belching, epigastric pain, postprandial distress, irritable bowel syndrome (IBS), globus, and ear nose and throat (ENT) symptoms were evaluated in patients previously classified as non-responders. Patients with at least one of the oesophageal symptoms with a frequency ≥3/week were treated with esomeprazole 40 mg once daily for 8 weeks and then re-evaluated. Non-responders (patients with oesophageal symptoms ≥3 times per week) underwent 24 hour multichannel intraluminal impedance-pH monitoring.

Results: Of 573 consecutive patients, 92 with oesophageal symptoms and classified as PPI-refractory underwent the esomeprazole trial; 60 did not respond. IBS, epigastric pain, and post-prandial distress episodes were associated with a poor response on multivariate analysis. NERD, reflux hypersensitivity, and functional heartburn patients constituted 32%, 42%, and 26%, respectively of the PPI-refractory group.

Conclusions: True refractoriness in patients with GERD symptoms attending a secondary care setting is lower than previously reported. Following a careful history and optimal PPI dosing, the rate of refractoriness was 20%. True NERD constitutes only a third of the PPI-refractory group.


Gastro-oesophageal reflux disease (GERD) is a common disorder affecting up to 20% of adults in Western countries.[1–3] Proton pump inhibitors (PPIs) represent the mainstay of treatment both for healing erosive oesophagitis and symptom relief. Although acid suppressive therapies have improved in efficacy over the last few decades, several studies have shown that a relevant proportion of patients with GERD symptoms (19%–44%) reports either partial or complete lack of response of symptoms to a standard PPI dose.[4–9] The management of refractory GERD patients is both a common and challenging task in routine clinical practice. Moreover, refractory GERD symptoms are associated not only with a significant decrease in all physical and mental domains of health-related quality of life questionnaires but also with a significant increase in healthcare costs, due to repeated diagnostic procedures, medical consultations, and drug prescriptions.[10]

Various mechanisms involved in PPI refractoriness, in patients with GERD symptoms, have been proposed, such as peculiar patterns of reflux events, oesophageal hypersensitivity to physiological reflux (reflux hypersensitivity), mutations of cytochrome p450, and presence of functional heartburn, a condition which does not fall into the GERD spectrum.[11–16,8] It has been reported that beside the reflux pattern, assessed by 24–hour impedance-pH monitoring, the absence of oesophagitis, concomitant presence of functional disorders, and a body mass index (BMI) ≤25 are associated with PPI failure.[17]

In a proportion of non-responder GERD patients, the main cause of PPI refractoriness might be the lack of adherence to therapy, in terms of incorrect dosage and timing. Recently it has been shown that, in GERD patients, adherence to the prescribed PPI was achieved in only 55% of patients after 1 month, and 30% of patients 6 months after prescription. Moreover, the lowest levels of compliance were observed in non-erosive reflux disease (NERD) patients.[18] In a study focusing on patients with persistent GERD symptoms despite prolonged PPI treatment, the drug was appropriately administered in the fasting state, before breakfast, in less than 46% of them.[19]

To our knowledge, in most clinical studies focused on refractory GERD patients, either prospective or retrospective, adherence to PPI therapy was not checked and it might be, in part, involved in partial or nonresponse to PPIs. Moreover, several studies have evaluated patients with typical, oesophageal symptoms, more specific of GERD with those presenting with atypical and extra-oesophageal symptoms refractory to PPIs; few investigations were focused on selected groups of NERD patients with oesophageal symptoms only.

Therefore, the real size of the GERD population not responding to an adequate PPI course has not been fully elucidated. Indeed, the largest series report a very high proportion of patients with symptoms refractory to PPIs, but with very different figures according to the various settings, much higher (up to 45%) in community-based and practitioner surveys, probably due to a less strict classification of patients and with several methodological limitations. Limitations in assessing the real PPI resistance include: (a) inconsistencies in the literature of the definitions used of partial and nonresponse, (b) the type of symptoms included in this definition, (c) the absence, in many studies, of baseline frequency and severity scores for heartburn and regurgitation, assessed by structured questionnaires, and (d) incorrect classification and inclusion of patients with functional heartburn, eosinophilic oesophagitis, and major motor oesophageal disorders.

The present study was therefore aimed at evaluating the real prevalence of refractoriness to an optimal PPI therapy in patients with oesophageal GERD symptoms and with a previous diagnosis of nonresponder, non-erosive, reflux disease. Moreover, the association of concomitant GI symptoms in patients with/without an optimal response was also evaluated. Finally, our study was aimed at evaluating the contribution of NERD, reflux hypersensitivity (RH), and functional heartburn (FH) to the refractory group.