{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:14:24Z","timestamp":1792084464285,"version":"4.4.0"},"reference-count":58,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T00:00:00Z","timestamp":1715904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Proton pump inhibitors (PPIs) are widely used in the long-term treatment of gastroesophageal reflux disease (GERD) and other upper gastrointestinal disorders, such as the healing of peptic ulcers and\/or prophylactic treatment of peptic ulcers. PPIs are also widely used as symptomatic treatment in patients with functional dyspepsia. One of the adverse effects of the long-term use of PPI is rebound acid hypersecretion (RAHS), which can occur after the withdrawal of PPI therapy due to a compensatory increase in gastric acid production. Mechanisms of the RAHS have been well established. Studies have shown that pentagastrin-stimulated acid secretion after the discontinuation of PPIs increased significantly compared to that before treatment. In healthy volunteers treated with PPIs, the latter induced gastrointestinal symptoms in 40\u201350% of subjects after the discontinuation of PPI therapy but after stopping the placebo. It is important for practicing physicians to be aware and understand the underlying mechanisms and inform patients about potential RAHS before discontinuing PPIs in order to avoid continuing unnecessary PPI therapy. This is important because RAHS may lead patients to reuptake PPIs as symptoms are incorrectly thought to originate from the recurrence of underlying conditions, such as GERD. Mechanisms of RAHS have been well established; however, clinical implications and the risk factors for RAHS are not fully understood. Further research is needed to facilitate appropriate management of RAHS in the future.<\/jats:p>","DOI":"10.3390\/ijms25105459","type":"journal-article","created":{"date-parts":[[2024,5,17]],"date-time":"2024-05-17T04:26:29Z","timestamp":1715919989000},"page":"5459","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Rebound Acid Hypersecretion after Withdrawal of Long-Term Proton Pump Inhibitor (PPI) Treatment\u2014Are PPIs Addictive?"],"prefix":"10.3390","volume":"25","author":[{"given":"Ken","family":"Namikawa","sequence":"first","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Landspitali University Hospital, 101 Reykjavik, Iceland"},{"name":"Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8392-0632","authenticated-orcid":false,"given":"Einar Stefan","family":"Bj\u00f6rnsson","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology, Department of Internal Medicine, Landspitali University Hospital, 101 Reykjavik, Iceland"},{"name":"Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1002\/pds.1969","article-title":"Marked increase in proton pump inhibitors use in Australia","volume":"19","author":"Hollingworth","year":"2010","journal-title":"Pharmacoepidemiol. Drug Saf."},{"key":"ref_2","first-page":"11","article-title":"Proton-pump inhibitors among adults: A nationwide drug-utilization study","volume":"30","author":"Lund","year":"2018","journal-title":"Therap. Adv. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1001\/jamainternmed.2015.42","article-title":"Continuous proton pump inhibitor therapy and the associated risk of recurrent Clostridium difficile infection","volume":"175","author":"McDonald","year":"2015","journal-title":"JAMA Intern. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"30130","DOI":"10.2807\/1560-7917.ES.2016.21.6.30130","article-title":"Inverse trends of Campylobacter and Salmonella in Swiss surveillance data, 1988\u20132013","volume":"21","author":"Schmutz","year":"2016","journal-title":"Euro Surveill."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1001\/jama.2013.280490","article-title":"Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency","volume":"310","author":"Lam","year":"2013","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"152","DOI":"10.5527\/wjn.v5.i2.152","article-title":"Proton-pump inhibitor-induced hypomagnesemia: Current research and proposed mechanisms","volume":"5","author":"William","year":"2016","journal-title":"World J. Nephrol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1111\/j.1365-2125.2010.03717.x","article-title":"Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes","volume":"70","author":"Furuta","year":"2010","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2070","DOI":"10.1111\/jgs.13661","article-title":"Hyperparathyroidism Associated with Long-Term Proton Pump Inhibitors Independent of Concurrent Bisphosphonate Therapy in Elderly Adults","volume":"63","author":"Hinson","year":"2015","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1136\/gutjnl-2017-315710","article-title":"Long-term proton pump inhibitor use is a risk factor of gastric cancer after treatment for Helicobacter pylori: A retrospective cohort analysis","volume":"67","author":"Niikura","year":"2018","journal-title":"Gut"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e017739","DOI":"10.1136\/bmjopen-2017-017739","article-title":"Maintenance therapy with proton pump inhibitors and risk of gastric cancer: A nationwide population-based cohort study in Sweden","volume":"7","author":"Brusselaers","year":"2017","journal-title":"BMJ Open"},{"key":"ref_11","first-page":"33","article-title":"Rat parietal cell function after prolonged inhibition of gastric acid secretion","volume":"254","author":"Larsson","year":"1988","journal-title":"Am. J. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/0016-5085(91)90258-M","article-title":"Nocturnal intragastric acidity during and after a period of dosing with either ranitidine or omeprazole","volume":"100","author":"Prewett","year":"1991","journal-title":"Gastroenterology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1136\/gut.39.5.649","article-title":"Marked increase in gastric acid secretory capacity after omeprazole treatment","volume":"39","author":"Waldum","year":"1996","journal-title":"Gut"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0016-5085(99)70118-6","article-title":"Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status","volume":"116","author":"Gillen","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1038\/ajg.2010.81","article-title":"Dyspeptic symptom development after discontinuation of a proton pump inhibitor: A double-blind placebo-controlled trial","volume":"105","author":"Niklasson","year":"2010","journal-title":"Am. J. Gastroenterol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1053\/j.gastro.2009.03.058","article-title":"Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy","volume":"137","author":"Reimer","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"398","DOI":"10.3109\/00365521.2010.537684","article-title":"Clinical and pathophysiological consequences of on-demand treatment with PPI in endoscopy-negative reflux disease. Is rebound hypersecretion of acid a problem?","volume":"46","author":"Rydning","year":"2011","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1159\/000528418","article-title":"Examination on Factors Affecting Symptom Change after Drug Withdrawal in Patients with Mild Erosive Gastroesophageal Reflux Disease Undergoing Symptom-Controlled Maintenance Therapy with Acid-Secretion Inhibition Drugs","volume":"104","author":"Tanaka","year":"2023","journal-title":"Digestion"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1023\/A:1008841022998","article-title":"Reliability and validity of the Gastrointestinal Symptom Rating Scale in patients with gastroesophageal reflux disease","volume":"7","author":"Revicki","year":"1998","journal-title":"Qual. Life Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1477-7525-6-12","article-title":"Reliability and validity of the Gastrointestinal Symptom Rating Scale (GSRS) and Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire in dyspepsia: A six-country study","volume":"6","author":"Kulich","year":"2008","journal-title":"Health Qual. Life Outcomes"},{"key":"ref_21","first-page":"1209","article-title":"Dyspepsia on withdrawal of ranitidine in previously asymptomatic volunteers","volume":"94","author":"Smith","year":"1999","journal-title":"Am. J. Gastroenterol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1097\/00004836-200109000-00007","article-title":"Does short-term treatment with proton pump inhibitors cause rebound aggravation of symptoms?","volume":"33","author":"Farup","year":"2001","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1111\/j.1365-2036.2004.02271.x","article-title":"Rebound acid hypersecretion after long-term inhibition of gastric acid secretion","volume":"21","author":"Fossmark","year":"2005","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00228-016-2150-x","article-title":"Randomised trial of the effect of a gastrin\/CCK2 receptor antagonist on esomeprazole-induced hypergastrinaemia: Evidence against rebound hyperacidity","volume":"73","author":"Boyce","year":"2017","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/j.1365-2036.1995.tb00423.x","article-title":"Patterns of 24-hour oesophageal acid exposure after acute withdrawal of acid suppression","volume":"9","author":"Orr","year":"1995","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1080\/00325481.2016.1203236","article-title":"A 14-day regimen of esomeprazole 20 mg\/day for frequent heartburn: Durability of effects, symptomatic rebound, and treatment satisfaction","volume":"128","author":"Peura","year":"2016","journal-title":"Postgrad. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.dld.2013.09.021","article-title":"The Effects of Long-term Therapy with Proton Pump Inhibitors on Meal Stimulated Gastrin","volume":"46","author":"Helgadottir","year":"2014","journal-title":"Dig. Liver Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1097\/MOG.0b013e328365efc7","article-title":"Gastric secretion","volume":"29","author":"Chu","year":"2013","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Helgadottir, H., and Bjornsson, E.S. (2019). Problems Associated with Deprescribing of Proton Pump Inhibitors. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215469"},{"key":"ref_30","first-page":"3","article-title":"Gastrin: From Physiology to Gastrointestinal Malignancies","volume":"26","author":"Duan","year":"2021","journal-title":"Function"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1136\/gut.43.2008.S35","article-title":"Acid suppression and gastric atrophy: Sifting fact from fiction","volume":"43","author":"Genta","year":"1998","journal-title":"Gut"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1136\/gut.2005.071779","article-title":"Mechanisms of increased acid secretion after eradication of Helicobacter pylori infection","volume":"55","year":"2006","journal-title":"Gut"},{"key":"ref_33","first-page":"624","article-title":"Little necessity of acid inhibition against proton pump inhibitor rebound effects and prior helicobacter pylori eradication therapy in gastric ulcer patients: A randomized prospective study","volume":"56","author":"Wada","year":"2009","journal-title":"Hepatogastroenterology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1097\/MCG.0000000000000542","article-title":"Study of Gender Differences in Proton Pump Inhibitor Dose Requirements for GERD: A Double-Blind Randomized Trial","volume":"51","author":"Helgadottir","year":"2017","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1097\/MCG.0000000000001200","article-title":"Predictors of Gastrin Elevation Following Proton Pump Inhibitor Therapy","volume":"54","author":"Lund","year":"2020","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.cgh.2011.11.021","article-title":"Maintenance of heartburn relief after step-down from twice-daily proton pump inhibitor to once-daily dexlansoprazole modified release","volume":"10","author":"Fass","year":"2012","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1136\/gut.30.4.449","article-title":"Rebound nocturnal hypersecretion after four weeks treatment with an H2 receptor antagonist","volume":"30","author":"Fullarton","year":"1989","journal-title":"Gut"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1111\/j.1365-2036.1991.tb00042.x","article-title":"Rebound hypersecretion after H2- antagonist withdrawal\u2014A comparative study with nizatidine, ranitidine and famotidine","volume":"5","author":"Fullarton","year":"1991","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_39","first-page":"355","article-title":"Marked rebound acid hypersecretion after treatment with ranitidine","volume":"91","author":"Banerjee","year":"1996","journal-title":"Am. J. Gastroenterol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.pharmthera.2005.05.005","article-title":"Potassium-competitive acid blockade: A new therapeutic strategy in acid-related diseases","volume":"108","author":"Andersson","year":"2005","journal-title":"Pharmacol. Ther."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1111\/apt.13325","article-title":"Acid-inhibitory effects of vonoprazan 20 mg compared with esomeprazole 20 mg or rabeprazole 10 mg in healthy adult male subjects: A randomized open-label cross-over study","volume":"42","author":"Sakurai","year":"2015","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.14309\/ajg.0000000000001735","article-title":"Pharmacodynamics and pharmacokinetics of the potassium-competitive acid blocker vonoprazan and the proton pump inhibitor lansoprazole in U.S. subjects","volume":"117","author":"Laine","year":"2022","journal-title":"Am. J. Gastroenterol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Kahrilas, P., Anastasiou, F., Bredenoord, A.J., El Serag, H.B., Labenz, J., Mendive, J., Savarino, E.V., Sifrim, D., Udrescu, M., and Yadlapati, R. (Dig. Dis., 2024). Proton pump inhibitors: Rational use and use-reduction. The Windsor Workshop, Dig. Dis., Epub ahead of print.","DOI":"10.1159\/000538399"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.curtheres.2005.08.012","article-title":"Effects of pantoprazole 20 mg in mild gastroesophageal reflux disease: Once-daily treatment in the acute phase, and comparison of on-demand versus continuous treatment in the long term","volume":"66","author":"Janssen","year":"2005","journal-title":"Curr. Ther. Res. Clin. Exp."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1940","DOI":"10.1111\/j.1572-0241.2003.07665.x","article-title":"Step-down from multiple- to single-dose proton pump inhibitors (PPIs): A prospective study of patients with heartburn or acid regurgitation completely relieved with PPIs","volume":"98","author":"Inadomi","year":"2003","journal-title":"Am. J. Gastroenterol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1093\/fampra\/cmu050","article-title":"Strategies for discontinuation of proton pump inhibitors: A systematic review","volume":"31","author":"Haastrup","year":"2014","journal-title":"Fam. Pract."},{"key":"ref_47","first-page":"e15022","article-title":"A Randomized Open-Label Study of Two Methods of Proton Pump Inhibitors Discontinuation","volume":"14","author":"Hendricks","year":"2021","journal-title":"Cureus"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1111\/j.1365-2036.2006.03084.x","article-title":"Discontinuation of proton pump inhibitors in patients on long-term therapy: A double-blind, placebo-controlled trial","volume":"24","author":"Abrahamsson","year":"2006","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Hojo, M., Asaoka, D., Shimada, Y., Nojiri, S., and Nagahara, A. (2022). Strategies for discontinuation of proton pump inhibitors (PPIs) in patients with long-term PPI administration: A randomized controlled trial. BMC Gastroenterol., 22.","DOI":"10.1186\/s12876-021-02086-9"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.ijpharm.2005.01.036","article-title":"Alginate rafts and their characterisation","volume":"27","author":"Hampson","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1080\/03639045.2017.1371737","article-title":"A comparative study on the raft chemical properties of various alginate antacid raft-forming products","volume":"44","author":"Dettmar","year":"2018","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"bjgpopen19X101651","DOI":"10.3399\/bjgpopen19X101651","article-title":"Sustained proton pump inhibitor deprescribing among dyspeptic patients in general practice: A return to self-management through a programme of education and alginate rescue therapy. A prospective interventional study","volume":"29","author":"Coyle","year":"2019","journal-title":"BJGP Open"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e001026","DOI":"10.1136\/bmjgast-2022-001026","article-title":"Randomised clinical trial: The use of alginates during preinvestigation proton pump inhibitor wash-out and their impact on compliance and symptom burden","volume":"10","author":"Vales","year":"2023","journal-title":"BMJ Open Gastroenterol."},{"key":"ref_54","first-page":"AT7764","article-title":"Spirulina Platensis Attenuates Rebound Dyspeptic Symptoms After Proton Pump Inhibitors\u2019 Discontinuation: Phase 2 Placebo-controlled Trial","volume":"9","author":"Gronevalt","year":"2024","journal-title":"Altern. Ther. Health Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1053\/j.gastro.2021.12.247","article-title":"AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors: Expert Review","volume":"162","author":"Targownik","year":"2022","journal-title":"Gastroenterology"},{"key":"ref_56","first-page":"354","article-title":"Deprescribing proton pump inhibitors: Evidence-based clinical practice guideline","volume":"63","author":"Farrell","year":"2017","journal-title":"Can. Fam. Physician"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Peura, D.A., Le Moigne, A., Wassel, H., and Pollack, C. (2018). Sustained efficacy following resolution of frequent heartburn with an over-the-counter regimen of esomeprazole 20 mg or placebo for 14 days: Two randomized trials. BMC Gastroenterol., 18.","DOI":"10.1186\/s12876-018-0790-2"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1053\/j.gastro.2020.09.013","article-title":"Ambulatory Reflux Monitoring Guides Proton Pump Inhibitor Discontinuation in Patients with Gastroesophageal Reflux Symptoms: A Clinical Trial","volume":"160","author":"Yadlapati","year":"2021","journal-title":"Gastroenterology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/10\/5459\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:43:47Z","timestamp":1760107427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/10\/5459"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,17]]},"references-count":58,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["ijms25105459"],"URL":"https:\/\/doi.org\/10.3390\/ijms25105459","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,17]]}}}