Proton-Pump Inhibitor Withdrawal May Cause Rebound Acid Hyper secretion

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Proton-Pump Inhibitor Withdrawal May Cause Rebound Acid Hyper secretion

Proton-Pump Inhibitor

Proton-Pump Inhibitor

BY ABDUL SATTAR SOHRANI

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 hyper secretion (RAHS) has been demonstrated after 8 weeks of treatment with a proton-pump inhibitor (PPI),” .

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.”

Clinical Context

Treatment of acid-related symptoms and disorders with PPIs is widespread and growing rapidly. The incidence of new treatment with PPIs remains stable, but for unclear reasons, the prevalence of long-term treatment is increasing.

Dyspepsia guidelines support empiric PPI therapy for 4 weeks or more in patients with uninvestigated dyspepsia. Although continuous PPI therapy is indicated for patients with severe gastroesophageal reflux disease or as prophylaxis in those who must continue treatment with nonsteroidal anti-inflammatory drugs, up to one third of patients who begin PPI treatment refill prescriptions repeatedly without a clear indication for maintenance therapy. PPI treatment may cause physiologic changes leading to exacerbated or new acid-related symptoms once treatment is withdrawn.

Study Highlights

  • This was a randomized, double-blind, placebo-controlled trial enrolling 120 healthy volunteers.
  • The goal of this study was to assess the clinical relevance of RAHS and to determine whether long-term PPI treatment results in a need for continuous treatment, which would have significant economic and clinical implications.
  • Participants were randomly assigned to receive placebo for 12 weeks or esomeprazole 40 mg/day for 8 weeks followed by 4 weeks of placebo.
  • The GSRS was completed weekly.
  • Clinically relevant acid-related symptoms were defined as a score of more than 2 on one of the GSRS questions about heartburn, acid regurgitation, or dyspepsia.
  • GSRS scores at baseline did not differ significantly between 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).
  • In the PPI group, 44% reported at least 1 relevant, acid-related symptom at weeks 9 to 12 vs 15% in the placebo group (P < .001).
  • Symptoms in the PPI group caused mild to moderate discomfort and appeared in most subjects in the first 2 weeks after PPIs were withdrawn.
  • In contrast, symptoms in the placebo group seemed to occur at random throughout the entire study period.
  • In the PPI group, the proportion reporting dyspepsia, heartburn, or acid regurgitation was 22% at week 10, 22% at week 11, and 21% at week 12.
  • In the placebo group, the corresponding percentages were 7%, 5%, and 2%, respectively (P = .001).
  • The investigators concluded that PPI therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal, suggesting that RAHS has clinical implications.
  • Using healthy volunteers in this study prevented determining whether symptoms develop as a consequence of RAHS to the same degree in patients with dyspeptic symptoms.
  • Most subjects infected with H pylori were randomly assigned to the placebo group, which prevented determining whether the acid rebound phenomenon is clinically significant in infected subjects.

Clinical Implications

  • Among healthy volunteers, those receiving esomeprazole 40 mg/day for 8 weeks followed by 4 weeks of placebo had significantly higher GSRS scores for acid-related symptoms at week 10, week 11, and week 12 vs those receiving placebo for 12 weeks.
  • In the PPI group, 44% reported at least 1 relevant, acid-related symptom at weeks 9 to 12 vs 15% in the placebo group. The proportion reporting dyspepsia, heartburn, or acid regurgitation was also higher during the last 4 weeks of the study in the PPI group vs the placebo group.
2017-04-26T12:35:43+00:00