Archief Roodbont

July 6, 2009 — Proton-pump inhibitor (PPI) therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal, according to the results of a randomized, double-blind, placebo-controlled trial reported in the July issue of Gastroenterology.

"Rebound acid hypersecretion (RAHS) has been demonstrated after 8 weeks of treatment with a proton-pump inhibitor (PPI)," write Christina Reimer, from Køge University Hospital, Copenhagen University in Copenhagen, Denmark, and colleagues. "If RAHS induces acid-related symptoms, this might lead to PPI dependency and thus have important implications."

PPIs Induce Acid-Related Symptoms

In this study, 120 healthy volunteers were randomized to receive placebo for 12 weeks or esomeprazole 40 mg/day for 8 weeks followed by 4 weeks of placebo. Clinically relevant acid-related symptoms were defined as a score of 2 or higher on one of the questions regarding heartburn, acid regurgitation, or dyspepsia on the Gastrointestinal Symptom Rating Scale (GSRS), which was completed weekly.

At baseline, GSRS scores were statistically similar in both groups. Compared with the placebo group, the PPI group had significantly higher GSRS scores for acid-related symptoms at week 10 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .023), week 11 (1.4 ± 1.4 vs 1.2 ± 0.9; P = .009), and week 12 (1.3 ± 1.2 vs 1.0 ± 0.3; P = .001).

Of volunteers receiving PPI, 44% (26/59) reported at least 1 relevant, acid-related symptom in weeks 9 to 12, as did 15% (9/59; P < .001) in the placebo group. In the PPI group, the proportion reporting dyspepsia, heartburn, or acid regurgitation was 13 (22%) of 59 at week 10, 13 (22%) of 59 at week 11, and 12 (21%) of 58 at week 12 vs 7% (P = .034), 5%, and 2% (P = .001), respectively.

"PPI therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal," the study authors write. "This study indicates unrecognized aspects of PPI withdrawal and supports the hypothesis that RAHS has clinical implications."

Limitations of this study include the use of healthy volunteers, which prevents determining whether symptoms develop as a consequence of RAHS to the same degree in patients with dyspeptic symptoms. In addition, the randomly skewed assignment of most subjects infected with Helicobacter pylori to the placebo group prevented determining whether the acid rebound phenomenon is clinically significant in infected subjects.

"We find it highly likely that the symptoms observed in this trial are caused by RAHS and that this phenomenon is equally relevant in patients treated long term with PPIs," the study authors conclude. "These results justify the speculation that PPI dependency could be 1 of the explanations for the rapidly and continuously increasing use of PPIs."

Inform Patients of Potential Risks

In an accompanying editorial, Kenneth E. L. McColl, MD, and Derek Gillen, MD, from the University of Glasgow Gardiner Institute, Glasgow, United Kingdom, note that findings from this study challenge current liberal PPI prescribing patterns and suggest changes in prescribing habits that should be considered.

"More effort should be made to identify contributory lifestyle factors and to utilize milder medications such as antacids or alginates," Drs. McColl and Gillen write. "Patients often ask about the safety and likelihood of side effects from [PPI] 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."

The Danish Medical Research Council, Københavns Amts Research Foundation, and Region Sjællands Research Foundation supported this study. AstraZeneca provided the medication and placebo. Two of the study authors have disclosed relevant financial relationships with AstraZeneca, Nycomed, Eisai, and/or Wyeth. Drs. Mccoll and Gillen have disclosed no relevant financial relationships.

Gastroenterology. 2009;137:20-39, 80-87.