The Basis for the Decreased Response to Proton Pump Inhibitors

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The Basis for the Decreased Response to Proton Pump Inhibitors
Background: The reason why heartburn in gastro-oesophageal reflux disease subjects without oesophagitis is less responsive to proton pump inhibitors than heartburn in those with erosive oesophagitis is not known.
Methods: Gastric and oesophageal pH were determined in 26 subjects with gastro-oesophageal reflux disease at baseline and on days 1, 2 and 8 of treatment with 20 mg omeprazole or 20 mg rabeprazole in a randomized, two-way cross-over fashion. The presence or absence of erosive oesophagitis at baseline was documented by upper gastrointestinal endoscopy.
Results: At a given value of the integrated gastric acidity during treatment with a proton pump inhibitor, the probability of pathological oesophageal reflux was significantly higher in subjects with no oesophagitis than in those with erosive oesophagitis. This occurred because the post-prandial gastric acidity in subjects with no oesophagitis showed a decreased response to the antisecretory agent.
Conclusions: Compared with gastro-oesophageal reflux disease subjects with erosive oesophagitis, those with no oesophagitis are relatively refractory to the pharmacodynamic effects of proton pump inhibitors on the post-prandial integrated gastric acidity.

In patients with gastro-oesophageal reflux disease (GERD), the inhibition of gastric acid secretion with a proton pump inhibitor is the mainstay of treatment of oesophageal pathology and symptoms. These drugs decrease oesophageal as well as gastric acidity and reduce the frequency and severity of heartburn. We and others have reported that GERD subjects with erosive oesophagitis have higher values of oesophageal acid exposure than GERD subjects without erosive oesophagitis. On the other hand, heartburn in subjects without erosive oesophagitis is less responsive to proton pump inhibitors than heartburn in subjects with erosive oesophagitis. In the present study, we examined the relationship between oesophageal reflux and gastric acidity in an attempt to establish a basis for the reduced responsiveness to proton pump inhibitors in GERD subjects without erosive oesophagitis — a group that would be expected to have an increased responsiveness to proton pump inhibitors because of their lower oesophageal acidity.

One reason for the lack of information regarding the relationship between the effect of antisecretory treatment on gastric acid secretion or gastric acidity and the effect on other features in GERD has been the lack of suitably precise analytical techniques. Previously, we have described techniques using recordings of gastric and oesophageal pH that can quantify acidity over time. A previous paper illustrated how these approaches can be used to demonstrate the extent to which gastric acidity has to be decreased to prevent pathological oesophageal reflux in GERD subjects who are being treated with a proton pump inhibitor.

In the present study, we analysed data from 24-h recordings of oesophageal and gastric pH during treatment with a proton pump inhibitor to examine possible relationships between gastric and oesophageal acidity in GERD subjects stratified on the basis of whether or not they had erosive oesophagitis. We found that, at a given value of the integrated gastric acidity during treatment with a proton pump inhibitor, GERD subjects with no oesophagitis were significantly more likely to experience pathological oesophageal reflux than those with erosive oesophagitis.

Previously, we have found the following: (i) subjects with GERD have increased meal-stimulated gastric acid secretion; (ii) the post-prandial integrated gastric acidity between 09.00 and 22.00 h is a good surrogate measure for meal-stimulated gastric acid secretion; and (iii) post-prandial, but not nocturnal, integrated gastric acidity is significantly increased in GERD subjects. In view of these findings, we examined whether GERD subjects with no erosive oesophagitis were refractory to the pharmacodynamic effects of proton pump inhibitors on the post-prandial gastric acidity, nocturnal gastric acidity or both. We found that the reduced response to proton pump inhibitors in GERD subjects with no oesophagitis occurred primarily with regard to the post-prandial integrated gastric acidity.

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