Re: Gastroesophageal reflux disease and functional dyspepsia. Authors reply

We thank Dr Seldon for his thoughtful letter and for raising the possibility of rebound acid hypersecretion (RAHS) following proton-pump inhibitor (PPI) withdrawal. We agree that judicious prescribing and deprescribing of PPIs deserve emphasis in primary care, and we welcome the opportunity to clarify our recommendations.

The randomized control trial[1] cited by Dr Seldon reported acid-related symptoms in approximately 44% of healthy volunteers after 8 weeks of PPI therapy, raising concern for RAHS. There are limited studies that support similar outcomes, with many methodological weaknesses limiting the clinical relevance of the findings. We note that Niklasson and colleagues[2] is the only study to produce similar results, with 44% of the PPI group in healthy volunteers developing dyspepsia after withdrawal. However, subsequent studies have shown contrasting findings, as noted below.

First, Reimer and colleagues[1] treated patients for 8 weeks, which is the upper end of the recommended 4- to 8-week trial of PPI therapy; thus, in patients in whom PPI is appropriately trialed and deprescribed, RAHS is of lower clinical concern. Moreover, while Niklasson and colleagues saw similar rates of symptoms after PPI withdrawal, these symptoms resolved by the third week after discontinuation, much sooner than reported by Reimer and colleagues.[1] Therefore, in patients who may experience RAHS, this is not a chronic symptom. Moreover, Reimer and colleagues used not objective measurements but rather symptom questionnaires; accordingly, the correlation between symptoms and rebound acid secretion was inferred, rather than demonstrated. Finally, both studies used healthy volunteers, limiting our ability to extrapolate the findings to patients with GERD, where symptom recurrence after PPI withdrawal may be the natural history of their underlying GERD rather than a rebound acid secretion phenomenon.

Several studies cite contrasting evidence, supporting safe prescribing and deprescribing of PPI therapy. An RCT by Boyce and colleagues[3] treated healthy volunteers with PPI for 4 weeks and found that gastrin and chromogranin A levels returned to baseline within 2 or 3 days of PPI withdrawal, with no reported rebound dyspepsia. A systematic review by Lødrup and colleagues[4] found only two studies that supported RAHS—Reimer and colleagues[1] and Niklasson and colleagues,[2] as discussed above. The authors also noted that given the lack of objective measurements, RAHS was inferred; therefore, the clinical significance of the mild to modest self-reported symptoms is unclear. Notably, Lødrup and colleagues also found that while RAHS induced symptoms in healthy volunteers, studies in patients with pre-existing reflux disease did not demonstrate any additional symptom burden attributable to RAHS.[4] Both the American College of Gastroenterology (ACG) and the American Gastroenterological Association (AGA), in their respective guidelines,[5,6] recognize RAHS as a physiologic phenomenon but note that strong evidence for the clinical significance of this is currently lacking. Moreover, there are no studies that have used true pH-impedance monitoring to demonstrate true reflux: Niklasson and colleagues measured gastrin and chromogranin A levels; thus, their demonstrated correlation is indirect.[2] Therefore, given the present body of evidence, there is no direct correlation between postwithdrawal symptoms and true acid hypersecretion, and symptoms may represent esophageal hypersensitivity, functional heartburn, or recurrent GERD.

Guidelines from the ACG and AGA[5-7] recommend a duration of 4 to 8 weeks as an adequate trial of PPI therapy. Regarding the use of shorter durations in uncomplicated GERD, while symptomatic relief often begins within days, mucosal healing in patients with unrecognized erosive esophagitis or reflux-related gastritis requires an appropriate treatment duration of 4 to 8 weeks. This also allows for assessment of durable clinical response. Truncating therapy at less than 2 weeks risks undertreatment of erosive disease and a falsely negative therapeutic trial, prompting unnecessary investigation or premature escalation to invasive testing such as endoscopy.

While we continue to recommend a trial of 4 to 8 weeks of therapy, we do endorse Dr Seldon’s broader point: PPIs are commonly overprescribed and underdeprescribed. For patients continued on PPI therapy beyond 8 weeks, if clinically appropriate, a gradual taper and step-down to the lowest effective dose—including on-demand or intermittent use in non-erosive reflux disease—should be considered to mitigate the potential risk of rebound symptoms. As per the AGA’s GERD management guidelines,[8] in patients with objectively unproven GERD who have required PPI use for 12 months, we recommend esophageal reflux testing to clarify the indication for prolonged PPI use. This is consistent with all the recommendations in our article. The 2022 AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors[7] provides a practical framework that we would recommend to readers interested in this area.

We thank Dr Seldon for prompting this discussion and agree that further high-quality data on RAHS risk stratification and withdrawal protocols would benefit the field.
—Estello Nap Hill, MD
—Gunisha Kalra, MD
—Sarvee Moosavi, MD, FRCPC, EdM, AGAF

This letter was submitted in response to “Re: Gastroesophageal reflux disease and functional dyspepsia.”

References

1.    Reimer C, Søndergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009;137:80-87.

2.    Niklasson A, Lindström L, Simrén M, et al. Dyspeptic symptom development after discontinuation of a proton pump inhibitor: A double-blind placebo-controlled trial. Am J Gastroenterol 2010;105:1531-1537. https://doi.org/10.1038/ajg.2010.81.

3.    Boyce M, van den Berg F, Mitchell T, et al. Randomised trial of the effect of a gastrin/CCK2 receptor antagonist on esomeprazole-induced hypergastrinaemia: Evidence against rebound hyperacidity. Eur J Clin Pharmacol 2017;73:129-139. https://doi.org/10.1007/s00228-016-2150-x.

4.    Lødrup AB, Reimer C, Bytzer P. Systematic review: Symptoms of rebound acid hypersecretion following proton pump inhibitor treatment. Scand J Gastroenterol 2013;48:515-522. https://doi.org/10.3109/00365521.2012.746395.

5.    Katz PO, Dunbar KB, Schnoll-Sussman FH, et al. ACG clinical guideline for the diagnosis and management of gastroesophageal reflux disease. Am Gastroenterol 2022;117:27-56. https://doi.org/10.14309/ajg.0000000000001538.

6.    Yadlapati R, Gyawali CP, Pandolfino JE, et al. AGA clinical practice update on the personalized approach to the evaluation and management of GERD: Expert review. Clin Gastroenterol Hepatol 2022;20:984-994. https://doi.org/10.1016/j.cgh.2022.01.025.

7.    Targownik LE, Fisher DA, Saini SD. AGA clinical practice update on de-prescribing of proton pump inhibitors: Expert review. Gastroenterology 2022;162:1334-1342. https://doi.org/10.1053/j.gastro.2021.12.247.

8.    Chen JW, Vela MF, Peterson KA, Carlson DA. AGA clinical practice update on the diagnosis and management of extraesophageal gastroesophageal reflux disease: Expert review. Clin Gastroenterol Hepatol 2023;21:1414-1421.e3. https://doi.org/10.1016/j.cgh.2023.01.040.