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Gut. 2007 April; 56(4): 593–594.
PMCID: PMC1856855

Proton pump inhibitor‐therapy refractory gastro‐oesophageal reflux disease patients, who are they?

In a recent version of Gut, Mainie and colleagues report on patients with persistent symptoms despite acid suppressive therapy.1 This is often presented as a considerable problem and impedance seems useful in the evaluation of these patients. The importance of the phenomenon of proton pump inhibitor(PPI)‐refractory symptoms is also stressed in studies in which the need for a new anti‐reflux drug is propagated. However, we think some caution is appropriate when speaking of PPI‐refractory gastro‐oesophageal reflux disease (GORD) symptoms, in particular when it is decided that new reflux‐inhibiting drugs are warranted to treat the “PPI‐resistant reflux symptoms”.

Firstly, the term PPI‐resistant GORD is often used for patients that are not fully investigated, particularly with regard to the question whether their symptoms truly originate from reflux of gastric contents. Indeed, what are judged “reflux symptoms” does not necessarily imply that these are due to GORD, as they may also occur in conditions such as functional heartburn and functional dyspepsia. Reduction of reflux episodes with a new drug will not result in symptom reduction in these latter patients.

Secondly, when one has ascertained that a patient's symptoms are indeed caused by gastro‐oesophageal reflux, it is pivotal to treat the patient for a sufficient period of time. The effect of a PPI on acid secretion is within days but due to acid‐induced oesophageal hypersensitivity the number of responders seems to increase for up to 8 or even 12 weeks of acid suppressive treatment.2,3 Compliance to drug intake may be an issue when symptoms do not resolve immediately after onset of therapy. When symptoms persist even after a sufficiently long treatment period, either the drug does not adequately inhibit acid secretion and a higher dose is required, or the symptoms are induced by weak levels of acid (above pH 4), or the non‐acid component of the reflux in which the only option would be a reduction of reflux episodes (by pharmacotherapeutical or surgical means).4 These patients are the ones that can be identified by impedance monitoring as Mainie et al. show in their study. These are also the patients that would benefit from a future reflux‐reducing drug.

We conclude that a critical approach is required when symptoms do not respond adequately to PPI therapy in suspected GORD patients. The true number of PPI‐refractory GORD patients is likely to be overestimated.


Competing interest: None.


1. Mainie I, Tutuian R, Shay S. et al Acid and non‐acid reflux in patients with persistent symptoms despite acid suppressive therapy. A multicenter study using combined ambulatory impedance‐pH monitoring. Gut 2006. 551398–1402.1402 [PMC free article] [PubMed]
2. Heading R C, Bardhan K D, Sander P. et al Application of the complete remission concept: many patients with GERD are incompletely treated by a standard proton pump inhibitor (PPI) regime. Gut 2006. 55(suppl 5)A62
3. Marrero J M, de Caestecker J S, Maxwell J D. Effect of famotidine on oesophageal sensitivity in gastro‐oesophageal reflux disease. Gut 1994. 35447–450.450 [PMC free article] [PubMed]
4. Vela M F, Tutuian R, Katz P O. et al Baclofen decreases acid and non‐acid post‐prandial gastro‐oesophageal reflux measured by combined multichannel intraluminal impedance and pH. Aliment Pharmacol Ther 2003. 17243–251.251 [PubMed]

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