See “Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy,” by Reimer C, Søndergaard B, Hilsted L, et al, on page 80.

1 Danish Medicines Agency

Medicinal product statistics in Denmark 2007. , 2 Forgacs I.

Loganayagam A. Over-prescribing proton pump inhibitors. astroenterology Reimer et al 3 Reimer C.

Søndergaard B.

Hilsted L.

et al. Proton pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Since their clinical launch 25 years ago, the use of proton-pump inhibitors has increased progressively with approximately 5% of the developed world now receiving such treatment.Several factors are likely to be contributing to the increase in usage of proton-pump inhibitors, but in this month's GReimer et alsuggest that the drugs themselves may be causing or aggravating the disease process they are used to treat. Forty-four percent of previously asymptomatic subjects experienced clinically significant heartburn, acid reflux, or dyspepsia after discontinuing a 2-month course of esomeprazole 40 mg/d compared with 15% after placebo. The authors propose that this is a clinical manifestation of the rebound acid hypersecretion arising from the trophic effects of the proton-pump inhibitor–induced hypergastrinemia on the oxyntic mucosa.

4 Gillen D.

Wirz A.A.

Neithercut W.D.

et al. Helicobacter pylori infection potentiates the inhibition of gastric acid secretion by omeprazole. 2 receptor of the parietal cell, thereby stimulating acid secretion. However, gastrin also exerts a powerful trophic effect on the enterochromaffin-like cells and the parietal cells of the oxyntic mucosa ( 5 Kuipers E.J.

Lundell L.

Klinkenberg-Knol E.

et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. , 6 Larsson H.

Carlsson E.

Mattsson H.

et al. Plasma gastrin and gastric enterochromaffin-like cell activation and proliferation studies with omeprazole and ranitidine in intact and antrectomized rats. , 7 Carlsson E.

Larsson H.

Mattsson H.

et al. Pharmacology and toxicology of omeprazole—with special reference to the effects on gastric mucosa. 7 Carlsson E.

Larsson H.

Mattsson H.

et al. Pharmacology and toxicology of omeprazole—with special reference to the effects on gastric mucosa. Figure 1 The increased gastrin concentration during proton-pump inhibitor therapy exerts trophic effects on the oxyntic mucosa causing hyperplasia and increased functional capacity of the enterochromaffin-like (ECL) cell and parietal cell. As a consequence, on discontinuing the proton-pump inhibitor there is rebound acid hypersecretion which persists for at least 2 months. Owing to their substantial elevation of intragastric pH, proton-pump inhibitor therapy produces a substantial increase in the circulating gastrin concentration.Gastrin activates the cholecystokinin-2 receptor on the enterochromaffin-like cells, causing them to release histamine, which then acts on the Hreceptor of the parietal cell, thereby stimulating acid secretion. However, gastrin also exerts a powerful trophic effect on the enterochromaffin-like cells and the parietal cells of the oxyntic mucosa ( Figure 1 ).The marked trophic effects of proton-pump inhibitor–induced hypergastrinemia caused major concerns during early animal safety tests as a proportion of female rats on long-term omeprazole developed carcinoid tumors of their oxyntic mucosa.

8 Waldum H.L.

Arnestad J.S.

Brenna E.

et al. Marked increase in gastric acid secretory capacity after omeprazole treatment. 8 Waldum H.L.

Arnestad J.S.

Brenna E.

et al. Marked increase in gastric acid secretory capacity after omeprazole treatment. 9 Gillen D.

Wirz A.A.

Ardill J.E.

et al. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. 10 Gillen D.

Wirz A.A.

McColl K.E.L. Helicobacter pylori eradication releases prolonged increased acid secretion following omeprazole treatment. In humans, proton-pump inhibitor–induced hypergastrinemia produces functional, as well as hyperplastic morphologic changes, of the oxyntic mucosa. In 1996, Waldum et alreported that at 14 days after discontinuation of a 3-month course of omeprazole 40 mg/d, gastric acid secretory capacity was increased by 50%.Our own group demonstrated that the phenomenon also occurred after 2 months treatment and was confined to Helicobacter pylori–negative subjects.This increased acid-secreting capacity persists for ≥2 months.The absence of the phenomenon in H pylori–infected subjects is probably due to the marked exacerbation of the gastritis of the oxyntic mucosa induced by proton-pump inhibitor therapy in such subjects, reducing its sensitivity to gastrin stimulation.

astroenterology , Reimer et al 3 Reimer C.

Søndergaard B.

Hilsted L.

et al. Proton pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. In their study in this issue of G, Reimer et alinvestigated whether this rebound acid hypersecretion is of clinical significance. One hundred twenty subjects without any clinically significant history of reflux symptoms were randomized in double-blind fashion to 2 months treatment with esomeprazole 40 mg/d or placebo and then during the subsequent 4 weeks all received placebo. During weeks 2, 3, and 4 posttreatment, clinically significant symptoms of heartburn, acid reflux, or dyspepsia were reported by 44% of those who had received omeprazole versus only 15% of those who had received placebo throughout (P < .001). The duration of these rebound symptoms is unclear because they were still present at the end of the monitoring period 4 weeks after discontinuing the treatment.

4 Gillen D.

Wirz A.A.

Neithercut W.D.

et al. Helicobacter pylori infection potentiates the inhibition of gastric acid secretion by omeprazole. , 9 Gillen D.

Wirz A.A.

Ardill J.E.

et al. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. , 10 Gillen D.

Wirz A.A.

McColl K.E.L. Helicobacter pylori eradication releases prolonged increased acid secretion following omeprazole treatment. 4 Gillen D.

Wirz A.A.

Neithercut W.D.

et al. Helicobacter pylori infection potentiates the inhibition of gastric acid secretion by omeprazole. , 8 Waldum H.L.

Arnestad J.S.

Brenna E.

et al. Marked increase in gastric acid secretory capacity after omeprazole treatment. , 9 Gillen D.

Wirz A.A.

Ardill J.E.

et al. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. , 10 Gillen D.

Wirz A.A.

McColl K.E.L. Helicobacter pylori eradication releases prolonged increased acid secretion following omeprazole treatment. , 11 Niklasson A.

Lindstrom L.

Simren M.

et al. Dyspeptic symptoms development after discontinuation of a proton pump inhibitor: clinical importance of acid-rebound. In patients without peptic ulcer disease, acid-related symptoms usually arise from noxious effects of acid on the esophageal squamous mucosa. A degree of gastroesophageal reflux is common in asymptomatic subjects and rebound hyperacidity increases the acidity and volume of the refluxate and thus its ability to induce damage and symptoms.The timing of onset of the symptoms at 1 week after discontinuing the proton-pump inhibitor and continuing for at least 4 weeks corresponds very closely with the pattern of acid hypersecretion demonstrated after such treatment.It is also possible that the marked suppression of intragastric acidity during proton-pump inhibitor therapy may down-regulate some of the mechanisms known to protect the esophagus from acid exposure or up-regulate mechanisms involved in perception of esophageal acid exposure.

1 Danish Medicines Agency

Medicinal product statistics in Denmark 2007. , 2 Forgacs I.

Loganayagam A. Over-prescribing proton pump inhibitors. 12 National Institute for Clinical Excellence

NICE Clinical Guideline 17 Dyspepsia-management of dyspepsia in adults in primary care. , 13 Talley N.J.

Vakil N. Guidelines for the management of dyspepsia. What are the clinical implications of this observation? Proton-pump inhibitor therapy is now being prescribed for a wide variety of upper gastrointestinal symptoms on the basis that they might be acid induced and therefore may benefit from such treatment.This increasingly liberal usage of these powerful drugs is due to a number of factors, including reduced concerns about potential side effects, reduced cost, and the lack of alternative therapies for upper gastrointestinal symptoms. This liberal employment of proton-pump inhibitor therapy has been recommended recently by many national and international guidelines based on “number needed to treat” and health economic analyses.As a consequence, a substantial proportion, if not majority, of patients now prescribed proton-pump inhibitor therapy do not have acid-related symptoms and therefore have no true indication for such therapy. The current finding that these drugs induce symptoms means that such liberal prescribing is likely to be creating the disease the drugs are designed to treat and causing patients with no previous need for such therapy to require intermittent or long-term treatment. It is likely also that treatment of mild reflux symptoms with such therapy may aggravate the underlying disease and lead to an increased requirement for long-term therapy. Studies are required to investigate whether early treatment of mild reflux disease with proton-pump inhibitor therapy results in aggravation of the natural history of the condition.

3 Reimer C.

Søndergaard B.

Hilsted L.

et al. Proton pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. 1 14 Talley N.J. Meineche-Schmidt V. Pare P. National Institute for Clinical Excellence

Efficacy of omeprazole in functional dyspepsia: double-blind, randomised, placebo-controlled trials (the Bond and Opera studies). Efforts should be pursued to try to restrict proton-pump inhibitor therapy use to those likely to derive benefit. Clearly, subjects with symptoms accompanied by endoscopic evidence of erosive esophagitis or of increased esophageal acid exposure merit treatment. If proton-pump inhibitor therapy is being considered for symptoms in patients who have not been investigated, then it should be reserved for those with clear symptoms of heartburn or acid reflux. It should be emphasized that there is very little evidence of symptomatic benefit from proton-pump inhibitor therapy in patients with epigastric discomfort that is not attributable to underlying peptic ulcer disease.

2 When using proton-pump inhibitor therapy as a diagnostic test for possible acid-related symptoms, it seems to be appropriate to implement a short course (1–2 weeks) to reduce the chance of inducing hyperacidity and associated symptoms. Further studies are required to clarify the influence of dosage and duration of treatment on both rebound acid hypersecretion and rebound symptoms.

3 2 receptor antagonists also induce rebound acid hypersecretion and induce rebound symptoms in previously asymptomatic subjects, although the duration of these is shorter than that reported after proton-pump inhibitor treatment. 15 Fullarton G.M. McLauchlan G. Macdonald A. et al. Rebound nocturnal hypersecretion after four weeks treatment with an H 2 -receptor antagonist. , 16 Fullarton G.M. Macdonald A.M.I. McColl K.E.L. Rebound hypersecretion after H 2 -antagonist withdrawal—a comparative study with nizatidine, ranitidine and famotidine. , 17 Smith A.D. Gillen D. Cochran K.M. et al. dyspepsia on withdrawal of ranitidine in previously asymptomatic volunteers. The current study also challenges the increasing tendency to adopt a “step-down” rather than “step-up” approach to the treatment of patients presenting with symptoms assumed to be from acid reflux. More effort should be made to identify contributory lifestyle factors and to utilize milder medications such as antacids or alginates. Unfortunately, Hreceptor antagonists also induce rebound acid hypersecretion and induce rebound symptoms in previously asymptomatic subjects, although the duration of these is shorter than that reported after proton-pump inhibitor treatment.

4 Patients often ask about the safety and likelihood of side effects from proton-pump inhibitory therapy. Now that rebound acid secretion has been demonstrated to induce symptoms, we are probably obliged to inform them about rebound acid hypersecretion and its potential effects. This important study by Reimer et alcertainly challenges current liberal proton-pump inhibitor prescribing habits. A number of changes in prescribing habits need to be considered, including the following.

3 Reimer C.

Søndergaard B.

Hilsted L.

et al. Proton pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. 18 Jensen R.T. CCKB/gastrin receptor antagonists: recent advances and potential uses in gastric secretory disorders. 19 Murphy M.G.

Sytnik B.

Kovacs T.O.G.

et al. The gastrin-receptor antagonist L-365,260 inhibits stimulated acid secretion in humans. 20 Nishida A.

Kobayashi-Uchida A.

Akuzawa S.

et al. Gastrin receptor antagonist YM022 prevents hypersecretion after long-term acid suppression. This study by Reimer et alalso highlights the fact that gastrin-induced hyperplasia is a clinically relevant inherent weakness in the mechanism of action of proton-pump inhibitor therapy. Although highly effective at controlling acid-related disease during therapy, the drugs may exacerbate the underlying disease process that becomes manifest upon discontinuation of the treatment. It would be better to have a drug that controlled acid and acid-related symptoms during treatment and left them no worse or even better after stopping the treatment. Gastrin receptor antagonists inhibit acid secretion, and by blocking the trophic effect of gastrin, may also reduce the stomach's acid secretory capacity.However, use of such agents may have limited efficacy as monotherapies because their acid inhibitory potency is less than proton-pump inhibitors.In animals, a combination of a proton-pump inhibitor plus a gastrin receptor antagonist has been demonstrated to effectively prevent rebound acid hypersecretion.Perhaps the demonstration of the clinical importance of rebound acid hypersecretion will rekindle interest in such treatment.

Treating gastroesophageal reflux disease with profound acid inhibition will never be ideal because acid secretion is not the primary underlying defect. Acid secretion is normal in most patients with reflux disease and acid inhibitory therapy makes it abnormally low. It is never ideal to treat 1 abnormality by creating another, as was the case for many years with management of ulcer disease before the discovery of H pylori infection. The pathophysiology of acid reflux concerns the dysfunction of the gastroesophageal barrier and research needs to refocus on ways of restoring its competence rather than merely suppressing gastric acid secretion.

Article Info Publication History Footnotes Conflicts of interest The authors disclose no conflicts. Identification DOI: https://doi.org/10.1053/j.gastro.2009.05.015 Copyright © 2009 AGA Institute. Published by Elsevier Inc. All rights reserved. ScienceDirect Access this article on ScienceDirect