Rebound Symptoms After PPI Use: Priming the Pump?

Abstract

Source: Reimer C, Sondergaard BO, Hilsted L, et al. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology. 2009;137(1):80–87; doi:10.1053/j.gastro.2009.03.058Danish investigators conducted a randomized, double-blind, placebo-controlled trial to determine the clinical relevance of rebound acid hypersecretion (RAHS) after proton pump inhibitor (PPI) use. Healthy adult volunteers without acid-related disease or symptoms were randomized to receive either 12 weeks of placebo or 8 weeks of esomeprazole 40 mg once daily followed by 4 weeks of placebo. Subjects completed the Gastrointestinal Symptom Rating Scale (GSRS), a 15-item instrument, weekly. A GSRS score of >2 for any one of three symptoms (dyspepsia, heartburn, or acid regurgitation) was defined as clinically relevant. Plasma levels of gastrin and chromogranin A (CgA) were measured at weeks 4, 8, and 12. Antacid tablets were allowed for bothersome acid-related symptoms during the study.One hundred twenty adults were enrolled with a mean age of approximately 25 years. No difference in GSRS scores between the treatment and placebo groups was seen in the first nine weeks of the study period. During weeks 10 to 12 the treatment group had significantly higher overall mean GSRS scores than placebo recipients. During weeks 9 to 12, significantly more study participants in the esomeprazole-treated group reported clinically relevant symptoms lasting one week or more than those in the placebo group (44% vs 15%). Among those with symptoms, 52% in the esomeprazole-treated group used antacids as compared to only 11% in the placebo group. At the end of the study more of those in the esomeprazole-treated group had symptoms of heartburn, acid regurgitation, or dyspepsia than those in the placebo group (20.7% vs 1.7%). The only preexisting risk factor associated with withdrawal symptoms was a history of heartburn before participating in the trial (OR 4.4; 95% CI, 1.4–13.6).Plasma gastrin levels were within normal range in both groups at weeks 0, 4, 8, and 12, but significantly higher in the esomeprazole-treated group during treatment. Plasma gastrin levels were significantly correlated with GSRS scores at week 8. Plasma chromogranin A levels peaked above the normal range and were significantly higher in the esomeprazole-treated group at both weeks 8 and 12.The authors conclude that PPI therapy induces acid-related symptoms in healthy adult volunteers after withdrawal.Drs Alexander and LeLeiko have disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.This trial suggests that isolated acid-related symptoms are experienced by a majority of healthy adults occasionally. While RAHS has been reported,1 this study reliably confirmed for the first time that new acid-related symptoms can be induced after eight weeks of therapy with a PPI. The strengths of this study include sample size, design, the use of online validated questionnaires, and the low dropout rate. Its limitations include the fact that only healthy volunteers were studied. Hence the results from this study may not be applicable to patients who are prescribed PPIs for acid-related or dyspeptic symptoms. Although there was no direct measurement of acid secretion in this study, the temporal elevation of plasma gastrin levels and of plasma chromogranin A levels (indicative of enterochromaffin cell hyperplasia causing RAHS even after stopping therapy) correlated well with the GSRS scores in the PPI group as compared to the placebo group.Although this study was done in adults, effects in children may be similar. The empiric use of PPI in infants and children for presumptive gastroesophageal reflux disease and for dyspepsia is widespread and increasing. In a recent study of the use of lansoprazole in irritable infants with presumed GERD, there was no difference between treated and placebo groups in symptom resolution, but there was an increase in serious adverse events in the PPI-treated group of infants.2 Since PPI therapy results in RAHS on withdrawal in adults, the possibility of new-onset acid-related symptoms upon withdrawal in children warrants careful selection of patients for treatment with these very potent drugs.This study drives yet another nail in the coffin of PPI inhibitors. Extrapolation of its findings to pediatric patients suggests that indiscriminate use of acid suppression treatment in children and adolescents should be discouraged. Since it is neither feasible nor appropriate to subject every symptomatic child to an invasive diagnostic procedure prior to instituting treatment, thorough history and physical examination seems to us prudent. (See Editors’ Note, AAP Grand Rounds, July 2009;22:2.)