PPI-Refractory GERD: an Intriguing, Probably Overestimated, Phenomenon.

Abstract

Proton-pump inhibitors (PPIs) are still a cornerstone of pharmacologic treatment for gastroesophageal reflux disease (GERD) because of their unquestionable efficacy in reducing the acid component of refluxate. However, their extensive use in the general population has revealed a subset of patients who are unsatisfied with these agents. These patients are considered unresponsive to PPIs, and this emerging phenomenon, defined as refractoriness to PPIs, may have a prevalence ranging from 10 to 40 % [1, 2]. Several drug-related variables, such as daily dosage and duration of therapy, clearly may be responsible for these numbers, and recently, it was proposed that the term PPI refractory be used only for patients unresponsive to a 12-week twice-daily course of PPI therapy [3•]. However, the greatest factor influencing PPI response likely is the type of patient to whom the drug is prescribed. It is now well established that the mechanisms underlying the symptoms in patients with GERD are related not only to esophageal acid exposure, especially in those without mucosal erosions (i.e., with nonerosive reflux disease (NERD)) who have a possibly normal but still symptomatic acid reflux (i.e., hypersensitive esophagus (HE)). In all these patients, who represent a large proportion of the GERD population, another very important mechanism for symptom occurrence is enhanced esophageal sensitivity, which also may be associated with central sensitization. We can speculate that the two mechanisms—acid exposure and hypersensitivity—each might play a different role throughout the spectrum of GERD phenotypes. Acid exposure is a predominant factor in patients with erosive disease but is less important in those without mucosal lesions; on the contrary, hypersensitivity is the major mechanism in patients without lesions and with normal reflux (Fig. 1). Despite this heterogeneous pathogenesis, however, we treat our GERD patients with drugs—PPIs—characterized by a very selective mechanism of action, i.e., the inhibition of acid secretion. It thus is reasonable to expect that the efficacy of this therapy is related directly and proportionally to the role of acid exposure in the individual patient, and this is exactly what occurs in clinical practice. A recently published paper [4••] provides an elegant summary of PPI efficacy in patients with different manifestations of GERD. The authors analyzed randomized controlled trials and evaluated the placebo effect and therapeutic gain for each patient category. Their data clearly indicate that the greatest PPI success—75 % or more—occurred in patients with esophagitis or typical reflux symptoms, such as heartburn or reflux-induced chest pain. On the contrary, patients with regurgitation as their main symptom or with laryngeal manifestations such as hoarseness or chronic cough showed a poor response to PPIs, with * Fabio Baldi fa.baldi@libero.it; fabio.baldi@unibo.it