Gastroenterology

Gastroenterology

Volume 137, Issue 1, July 2009, Pages 80-87.e1
Gastroenterology

Clinical—Alimentary Tract
Proton-Pump Inhibitor Therapy Induces Acid-Related Symptoms in Healthy Volunteers After Withdrawal of Therapy

https://doi.org/10.1053/j.gastro.2009.03.058Get rights and content

Background & Aims

Rebound acid hypersecretion (RAHS) has been demonstrated after 8 weeks of treatment with a proton-pump inhibitor (PPI). If RAHS induces acid-related symptoms, this might lead to PPI dependency and thus have important implications.

Methods

A randomized, double-blind, placebo-controlled trial with 120 healthy volunteers was conducted. Participants were randomized to 12 weeks of placebo or 8 weeks of esomeprazole 40 mg/d followed by 4 weeks with placebo. The Gastrointestinal Symptom Rating Scale (GSRS) was filled out weekly. A score of >2 on 1 of the questions regarding heartburn, acid regurgitation, or dyspepsia was defined as a clinically relevant acid-related symptom.

Results

There were no significant differences between groups in GSRS scores at baseline. GSRS scores for acid-related symptoms were significantly higher in the PPI group 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). Forty-four percent (26/59) of those randomized to PPI reported ≥1 relevant, acid-related symptom in weeks 9–12 compared with 15% (9/59; P < .001) in the placebo group. The proportion reporting dyspepsia, heartburn, or acid regurgitation in the PPI group was 13 of 59 (22%) at week 10, 13 of 59 (22%) at week 11, and 12 of 58 (21%) at week 12. Corresponding figures in the placebo group were 7% at week 10 (P = .034), 5% at week 11 (P = .013), and 2% at week 12 (P = .001).

Conclusions

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

Section snippets

Participants

A randomized, double-blind, placebo-controlled trial was conducted between September 2007 and March 2008 at Køge University Hospital, Denmark. Healthy volunteers without acid-related disease or symptoms were chosen as our study population to establish that the symptoms observed were actually symptoms caused by the acid rebound phenomenon and not relapse of symptoms of underlying disease after discontinuation of treatment.

We advertised for healthy volunteers in student papers, on a student web

Results

Supplementary Figure 1 shows the trial profile. Table 1 shows study participants' baseline demographic and other characteristics. The PPI group was comparable to the placebo group in terms of age, gender, body mass index, smoking, alcohol habits, GSRS and SF-36 scores, previous acid-related symptoms ever, P-gastrin, and P-CgA levels. A significantly higher proportion or participants (13% vs 2%; P = .02) in the placebo group was H pylori positive.

Compliance, defined as intake of >90% of

Discussion

The results of our study indicate and support the hypothesis that the RAHS is clinically significant. Treatment with a PPI (esomeprazole 40 mg once daily) for 8 weeks induces acid-related symptoms like heartburn, acid regurgitation, and dyspepsia once treatment is withdrawn. The symptoms observed in our trial caused mild to moderate discomfort and appeared for the majority of subjects in the first 2 weeks after withdrawal of PPI. The observation that >40% of healthy volunteers, who have never

Conclusion

Acid inhibition with a PPI for 8 weeks induces acid-related symptoms in a significant proportion of asymptomatic subjects when therapy is withdrawn. 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. These results justify the speculation that PPI dependency could be 1 of the explanations for the rapidly and continuously increasing use of PPIs.

Acknowledgments

The authors thank Jane Lancaster for expert technical assistance on gastrin and CgA analyses.

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    Conflicts of interest The authors disclose the following: Peter Bytzer has consulted for and received honoraria and research funding from manufacturers of proton-pump inhibitors (AstraZeneca, Wyeth, Nycomed, Eisai). Bo Søndergaard has received honoraria from Wyeth. The remaining authors disclose no conflicts.

    Funding The study received funding through the Danish Medical Research Council, Københavns Amts Research Foundation and Region Sjællands Research Foundation. The medication and placebo was provided by AstraZeneca.

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