Patients with refractory reflux symptoms: What do they have and how should they be managed?

Neurogastroenterol Motil. 2015 Sep;27(9):1195-201. doi: 10.1111/nmo.12644.


With the widespread use of proton pump inhibitors (PPIs), the frontier of treating reflux disease has shifted from refractory esophagitis to PPI-refractory symptoms. However, symptoms are inherently less specific than mucosal disease and, as noted by Herregods et al. in their contribution appearing in this issue of Neurogastroenterology and Motility, patients with refractory gastroesophageal reflux disease (GERD) symptoms often do not have GERD. This review discusses potential etiologies for PPI-refractory symptoms. Three major concepts are explored: subendoscopic esophagitis, weakly acidic reflux events, and alternative explanations for persistent symptoms. With respect to subendoscopic esophagitis and unsuppressed reflux, ample evidence exists that these are present in PPI-refractory patients. The problem is that these findings are also often present in substantial numbers of individuals with a satisfactory response to PPI therapy. Hence, the emphasis shifts to determinants of symptom perception. The major conclusion of the review is that psychogenic factors such as hyperalgesia, allodynia, hypervigilance, and heightened anxiety are the most plausible explanations as the dominant determinants of PPI-refractory symptoms.

Keywords: esophagus; functional disease; reflux disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Esophagitis / complications
  • Esophagitis / diagnosis
  • Gastroesophageal Reflux / complications
  • Gastroesophageal Reflux / diagnosis*
  • Gastroesophageal Reflux / drug therapy*
  • Humans
  • Proton Pump Inhibitors / therapeutic use*
  • Symptom Assessment
  • Treatment Outcome


  • Proton Pump Inhibitors