Rebound Acid Hypersecretion Research Articles

Gastric Cancer associated with the use of Omeprazole in Adults

Introduction: proton pump inhibitors constitute a group of drugs used to suppress stomach acid secretion and whose consumption has intensified worldwide due to their consideration as the most effective gastric protectors, omeprazole being one of the most widely used. Objectives: to analyze the existence of gastric cancer risk due to long-term use of omeprazole in adults.Methods: a search for information was carried out in PubMed and Google Scholar. Search formulas were used by combining the terms: “Omeprazole”, “Cancer Gastric”, “Omeprazole and Adverse effects”, “Omeprazole and Helicobacter Pylori”. From the total number of articles identified, after the screening process, 8 articles were chosen for the present study.Results: Prolonged treatment with omeprazole can induce histological changes in the gastric mucosa, including hyperplasia, increased gastrin-producing cells, atrophic gastritis and increased colonization of Helicobacter pylori. A rebound acid hypersecretion has been observed after discontinuation of treatment, persisting for at least two months. Endocrine hyperplasia may result from suppression of acid secretion, causing hypergastrinemia and increasing the risk of malignant lesions.Conclusions: information has been compiled on the effects of prolonged use of omeprazole and its relationship with gastric carcinoma. This use is becoming more frequent, which underlines the need to investigate its long-term effects, since it may alter gastric histoarchitecture and predispose to cancer

Vonoprazan: a promising advancement in proton pump inhibitor therapy

Vonoprazan, a potent potassium-competitive acid blocker (P-CAB), has emerged as a potential therapeutic option for acid-related disorders, particularly gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD). This comprehensive review aims to provide an overview of the efficacy, safety profile, and clinical implications of vonoprazan based on current literature. Efficacy studies have demonstrated vonoprazan's superiority over proton pump inhibitors (PPIs) in achieving effective acid suppression, rapid symptom relief, and promoting mucosal healing in patients with GERD and PUD. Moreover, its long-lasting acid suppression properties offer protection against Helicobacter pylori (H. pylori) infection, presenting it as a potential alternative to traditional triple H. pylori eradication regimens. Safety evaluations reveal a favourable tolerability profile with minimal adverse effects and a lower risk of drug interactions compared to PPIs. However, concerns regarding long-term safety, such as hypomagnesemia and the potential for rebound acid hypersecretion, necessitate further investigation. Additionally, the role of vonoprazan in special populations, such as the elderly and those with renal impairment, warrants exploration. Overall, vonoprazan represents a promising advancement in acid suppression therapy, offering efficacy, safety, and potential advantages over traditional agents.

Rebound Acid Hypersecretion after Withdrawal of Long-Term Proton Pump Inhibitor (PPI) Treatment-Are PPIs Addictive?

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 40-50% 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.

A narrative review on rebound acid hypersecretion due to long-term use of proton pump inhibitors

Objectives Proton pump inhibitors (PPIs) are the most commonly used drugs to reduce hyperacidity. The usage of PPIs reduces the secretion of gastric juice; their prolonged usage results in gastric acid suppression with hypergastrinemia while their stoppage results in hypersecretion of gastric juice. This kind of paradoxical reaction is seen in the rebound effect of drugs. Dr. Samuel Hahnemann gave us the vital principles of homeopathy, the law of similitude, i.e., “similia similibus curentur” derived from the “Nature’s Law of Cure”. This also tells us that the primary action of medicine stimulates the dynamic expression of an organism (vital force), which results in the counteraction called secondary action by the organism. Material and Methods Review of literature on the effects of long-term use of PPIs and rebound hypersecretion of gastric juice due to PPIs. Results For this review article, 16 most relevant articles are selected from the search results. Thirteen systematic reviews, two randomized control trials, and one pilot study are included. Rebound acid hypersecretion (RAHS) occurs after prolonged treatment with histamine-2 blockers and PPIs, causing gastric hypoacidity and hypergastrinemia. Longer PPI durations can result in prolonged hypersecretion, with moderate hypergastrinemia and increased enterochromaffin-like (ECL) cell hyperplasia. Deprescribing PPIs is crucial to reduce RAHS and safety concerns. Long-term usage can lead to nutritional deficiencies, respiratory infections, and bone fractures. Conclusion Homeopathic remedies have shown significant results in treating symptoms caused due to gastritis, ulcers, gastroesophageal reflux disease, etc., and further research is needed to reduce RAHS caused due to the long-term use of PPIs.

Deprescribing proton pump inhibitors.

Proton pump inhibitors (PPIs) are indicated for disorders including peptic ulcer disease and gastro-oesophageal reflux disease; however, they are often used for longer and at higher doses than recommended, or for indications that are not supported by evidence. The aim of this article is to outline evidence-based approaches to deprescribing PPIs. PPIs are generally well tolerated; however, use beyond eight weeks is rarely indicated and increases the risk of adverse events. PPI deprescribing should be considered when there is no indication for long-term therapy. Evidence supports a patient-centred approach to PPI deprescribing involving stepping down the dose before ceasing or switching to pro re nata (PRN; 'as needed') use. Abrupt PPI discontinuation may result in short-term rebound acid hypersecretion that can mimic symptom return. This can be minimised with gradual dose tapering prior to discontinuation and managed with PRN treatment. Prescribers should discuss the rationale for PPI deprescribing and involve patients indeveloping the deprescribing plan.

REBOUND PHENOMENON OF PROTON PUMP INHIBITOR THERAPY

Proton pump inhibitors (PPIs) are the most potent drugs for suppressing gastric acid secretion. They are used in the treatment of acid-peptic disorders, including peptic ulcer disease, gastroesophageal reflux disease, Zollinger Ellison syndrome, in the eradication of Helicobacter pylori infection and ulcer prophylaxis. In the pharmacotherapy of these disorders, they have significantly suppressed the use of H2 blockers, like other, older groups of antisecretory drugs. Long-term PPI therapy leads to moderate hypergastrinemia (increased gastrin secretion) in 20-25% of patients. This hypergastrinemia results in rebound acid hypersecretion (RAHS) in 30-40% patients, who abruptly discontinue PPI. Most patients who abruptly discontinue PPI have symptoms of dyspepsia and gastroesophageal reflux, most commonly heartburn and a burning sensation in the esophagus. Therefore, care should be taken to properly discontinue PPI and reduce the dose of the drug before complete discontinuation. A less effective acid blocker (H2 blocker) can be switched, since H2 receptor blockers cause less pronounced hypergastrinemia and hyperplasia of enterochromaffin-like cells (ECL cells) compared to PPI.

Proton pump inhibitors and stomach neoplasm

Abstract This study aimed to explore the relationship between proton pump inhibitors (PPIs) and gastric tumors and determine the reasons behind these connections. We reviewed studies on PPIs and stomach tumors. We explored the relationship between PPIs and different types of gastric neoplasms according to the classification of gastric neoplasms. Long-term use of PPIs is associated with stomach infection, high gastrin levels, and rebound acid hypersecretion, which are directly or indirectly related to the development of gastric neoplasms. PPIs can increase the risk of gastric fundal polyps. Further evidence is needed to prove that it can increase the risk of gastric cancer.

Side Effects of Long-Term Proton Pump Inhibitor Use: A Review.

Proton pump inhibitors (PPIs) are widely used, and concerns about overuse have been raised. Therefore, side effects are important to be aware of and several suggested side effects of long-term use have been studied. In this MiniReview, we sum up the evidence of side effects related to long-term PPI treatment. Suspected side effects are mainly related to increased susceptibility to infections, secondary hypergastrinaemia, impeded absorption of micronutrients or idiosyncratic reactions. Most of the potential side effects have only been evaluated in observational studies demonstrating conflicting and weak associations with a substantial risk of confounding. However, a high probability of causality seems to be established for the side effects increased risk of gastrointestinal infections and rebound acid hypersecretion following discontinuation of treatment due to secondary hypergastrinaemia. The risk of side effects should not be a reason to withhold PPIs from patients with a true indication, and worry about poorly proven side effects should not lead to unnecessary discontinuation. The most important safety issue regarding PPI therapy is to critically evaluate the indication when initiating treatment and reconsidering the indication in long-term-treated patients.

Gastroesophageal reflux disease-related symptom recurrence in patients discontinuing proton pump inhibitors for Bravo® wireless esophageal pH monitoring study.

Patients with gastroesophageal reflux disease (GERD) are treated with proton pump inhibitors (PPIs). Those that do not achieve symptom relief, or non-responders, usually undergo esophageal pH monitoring off PPIs in order to confirm the presence of GERD. To assess the efficacy of the reverse-PPI trial in evaluating the presence of GERD or its recurrence rates, as well as to identify a correlation between the symptom recurrence rates and GERD severity determined by 48-hour Bravo® esophageal pH-monitor testing. A final total of 205 patients that underwent the 48-hour Bravo® esophageal pH-monitoring study were retrospectively included. Patients discontinued PPI usage for at least 7 days prior to testing, and completed symptom questionnaires during the 2-day test. The Bravo® test was considered positive if the percentage of time with esophageal pH <4 was >4.4%. A total of 363 patients underwent 48-hour Bravo® testing and of those patients, 205 were eligible for the study. Ninety-two patients reported symptoms as being «same/better» and 113 as being «worse» after stopping PPIs. Of the 92 patients with improved symptoms, 44 (48%) had documented acid reflux during the Bravo® study, compared with 65 of 113 (58%) patients with worsening symptoms that also complained of acid reflux. Of the 109 patients found to have confirmed GERD upon pH monitoring, 65 (59.6%) reported a worsening of symptoms, compared with 48 of 96 (50.0%) patients without GERD (p=0.043). Main symptoms stated to be worse included heartburn, chest pain, regurgitation, nausea, and belching (p<0.05). Of the 205 patients, 103 were off PPIs for 7 days. Seventy-two of them (68.9%) reported a worsening of symptoms, compared with 40 of the 102 (41.2%) patients that were off PPIs for>7 days (p=0.042) CONCLUSION: Symptom exacerbation following PPI cessation for at least 7 days correlated with acid reflux severity assessed by Bravo® testing. Patients off PPIs for 7 days had a higher likelihood of experiencing worsening symptoms, compared with those off PPIs for more than 7 days. These findings suggest that when PPIs are held for 7 days or less prior to Bravo® testing, acute worsening of upper GI symptoms due to the abrupt discontinuation of therapy may influence the Bravo® results. The etiology of this may be related to rebound acid hypersecretion and needs to be further elucidated in future studies.

Gastroesophageal reflux disease-related symptom recurrence in patients discontinuing proton pump inhibitors for Bravo wireless esophageal pH monitoring study

BackgroundPatients with gastroesophageal reflux disease (GERD) are treated with proton pump inhibitors (PPIs). Those that do not achieve symptom relief, or non-responders, usually undergo esophageal pH monitoring off PPIs in order to confirm the presence of GERD. AimsTo assess the efficacy of the reverse-PPI trial in evaluating the presence of GERD or its recurrence rates, as well as to identify a correlation between the symptom recurrence rates and GERD severity determined by 48-hour Bravo esophageal pH-monitor testing. MethodsA final total of 205 patients that underwent the 48-hour Bravo esophageal pH-monitoring study were retrospectively included. Patients discontinued PPI usage for at least 7 days prior to testing, and completed symptom questionnaires during the 2-day test. The Bravo test was considered positive if the percentage of time with esophageal pH <4 was >4.4%. ResultsA total of 363 patients underwent 48-hour Bravo testing and of those patients, 205 were eligible for the study. Ninety-two patients reported symptoms as being «same/better» and 113 as being «worse» after stopping PPIs. Of the 92 patients with improved symptoms, 44 (48%) had documented acid reflux during the Bravo study, compared with 65 of 113 (58%) patients with worsening symptoms that also complained of acid reflux. Of the 109 patients found to have confirmed GERD upon pH monitoring, 65 (59.6%) reported a worsening of symptoms, compared with 48 of 96 (50.0%) patients without GERD (p=0.043). Main symptoms stated to be worse included heartburn, chest pain, regurgitation, nausea, and belching (p<0.05). Of the 205 patients, 103 were off PPIs for 7 days. Seventy-two of them (68.9%) reported a worsening of symptoms, compared with 40 of the 102 (41.2%) patients that were off PPIs for>7 days (p=0.042) ConclusionSymptom exacerbation following PPI cessation for at least 7 days correlated with acid reflux severity assessed by Bravo testing. Patients off PPIs for 7 days had a higher likelihood of experiencing worsening symptoms, compared with those off PPIs for more than 7 days. These findings suggest that when PPIs are held for 7 days or less prior to Bravo testing, acute worsening of upper GI symptoms due to the abrupt discontinuation of therapy may influence the Bravo results. The etiology of this may be related to rebound acid hypersecretion and needs to be further elucidated in future studies.

A Prospective, Placebo-Controlled Pilot Evaluation of the Effect of Omeprazole on Serum Calcium, Magnesium, Cobalamin, Gastrin Concentrations, and Bone in Cats.

BackgroundChronic proton pump inhibitor administration has been associated with electrolyte and cobalamin deficiency, disrupted bone homeostasis, hypergastrinemia, and rebound acid hypersecretion in humans. It is unknown if this occurs in cats.ObjectivesProlonged oral omeprazole results in altered bone mineral density or content, serum calcium, magnesium, cobalamin, and gastrin concentrations in healthy cats.AnimalsSix healthy adult DSH cats.MethodsIn a within subjects, before and after design, cats received placebo followed by omeprazole (0.83–1.6 mg/kg PO q12h) for 60 days each. Analysis of serum calcium, magnesium, cobalamin, and gastrin concentrations was performed on days 0, 30, and 60. Bone density and content were evaluated on days 0 and 60 of each intervention. Continuous data were analyzed using a two‐way ANOVA (α = 0.006). On day 60 of omeprazole administration, continuous intragastric pH monitoring was performed in 2 cats to evaluate the effects of abrupt withdrawal of omeprazole.ResultsNo significant changes were detected between treatments for any variables, except serum gastrin, which was significantly higher during omeprazole treatment in comparison to placebo (P = 0.002). Evidence of gastric hyperacidity was seen in both cats in which intragastric pH monitoring was performed following cessation of omeprazole.Conclusions and Clinical ImportanceAlthough further studies with larger populations of cats will be needed to draw any definitive conclusions, these preliminary results suggest that prolonged PPI treatment results in hypergastrinemia and abrupt PPI withdrawal might result in RAH in cats.

Proton pump inhibitors overuse: only inappropriate prescriptions or further iatrogenic damage?

Proton pump inhibitors (PPIs) are the most potent drugs for reducing gastric acid secretion; so, since their release in the late 1980s, they have been recommended as the first therapeutic choice for many gastroesophageal diseases, risk reduction in or healing of non-steroidal anti-inflammatory drugs-associated ulcer disease and stress ulcer prophylaxis in intensive care unit patients. Thus PPIs account for a significant proportion of pharmaceutical health-care expenditure. Much of this high expenditure results from overuse of PPIs in account of inappropriate indications or prolongation of therapies for excessive time compared to real need. PPIs overutilization occurs in all medical care settings: in the majority of hospitalized patients with low risks for gastrointestinal bleeding, in patients healed at discharge from hospital, in outpatients in ambulatory practice. However potential adverse effects associated with PPIs therapy have been described, including enteric (especially by &lt;em&gt;Clostridium&lt;/em&gt; &lt;em&gt;difficile&lt;/em&gt; in elderly patients) and pneumonia infections, nutritional deficiencies, rebound acid hypersecretion, acute interstitial nephritis, gastric neoplasms, bone fractures. Caution is required for some coprescription, particularly with clopidogrel.

Acid suppressing therapy as a risk factor for Candida esophagitis.

Studies were reviewed from PubMed for risk factors for the development, recurrence, prevention and therapy of Candida esophagitis, and for mechanisms induced by acid-suppressing therapy potentially influencing these factors. Documented observations included greatly increased Candida populations in the mouth, esophagus, stomach, and upper small intestine induced by acid-suppressing therapy. Among patients without HIV disease, PPI consumers more frequently had developed Candida esophagitis than did non-consumers and had also developed its recurrences more frequently. Similar phenomena associated with H2 -blocker use were less intense, and the possibility of similar phenomena in patients with HIV disease apparently had not yet been examined in spite of their high frequency of this disorder. PPI-induced elimination of the gastric acid barrier is a major mechanism leading to oro-pharyngeal and esophageal candida colonization, while PPI-induced impairment of absorption of most orally administered antifungal agents may limit the prophylactic and therapeutic success of these agents. These observations suggest potential value in limiting PPI use in populations of patients with Candida infections including esophagitis, as well as in patients at risk for their development, and also suggest that post-PPI rebound acid hypersecretion may provide additional anti-Candida benefit. Studies designed to develop the risk-benefit ratios of PPI use in these patients deserve investigation with high priority appropriate for studies in patients with HIV disease.

The regulation of gastric acid secretion – clinical perspectives

The purpose of this review, based upon 40years of research, is to clear old controversies. The gastric juice is a strong acid with active enzymes (pepsin and lipase); ideal for killing swallowed microorganisms. Totally isolated rat stomach and histamine determination. Human gastric carcinomas were examined for ECL cell differentiation because tumours found in rodents after dosing with inhibitors of acid secretion were reclassified to be of ECL cell origin. The gastrin receptor is localized to the ECL cell only, where gastrin stimulates the function and growth. Drug-induced hypo-acidity induces hypergastrinaemia and ECL cell hyperplasia responsible for rebound acid hypersecretion. Every condition with long-term hypergastrinaemia disposes to ECL cell neoplasia. In man, both atrophic gastritis and gastrinoma lead to ECL cell carcinoids. Proton pump inhibitors induce hypergastrinaemia with ECL cell hyperplasia and ECL cell carcinoids that disappear when stopping treatment. The gastrin antagonist netazepide induces regression of ECL cell carcinoids due to atrophic gastritis. Human gastric carcinomas of diffuse type, particularly the signet-ring subtype, show ECL cell differentiation, suggesting involvement of gastrin in the carcinogenesis. Helicobacter pylori (Hp) causes gastritis and peptic ulcer, and when infecting the antrum only gives a slight hypergastrinaemia with acid hypersecretion predisposing to duodenal ulcer, but protecting from gastric cancer. When Hp infection spreads to oxyntic mucosa, it induces atrophy, reduced acid secretion and marked hypergastrinaemia and cancer.It is remarkable that the interaction between Hp and gastrin may explain the pathogenesis of most diseases in the upper gastrointestinal tract.

The effects of long-term therapy with proton pump inhibitors on meal stimulated gastrin

Dyspepsia develops in healthy volunteers after withdrawal of proton-pump inhibitors. This phenomenon, attributed to rebound acid hypersecretion, is thought to be mediated by reflex hypergastrinemia. To measure fasting and postprandial gastrin in patients on long-term proton-pump inhibitor treatment and correlate gastrin levels with the duration of treatment and other potential predictors. In this cross sectional study patients, with erosive esophagitis, on long-term proton-pump inhibitor treatment and healthy controls underwent gastrin measurements at baseline and four times following a meal and Helicobacter pylori status was determined. A total of 100 patients and 50 controls were studied. Pre- and postprandial gastrin levels were higher in patients (p<0.001). No significant correlation was found between the area under the gastrin-curve and the treatment duration. Female patients had significantly higher gastrin levels than males pre- and postprandial, whereas such differences was not found in the control group. Female gender was the only independent predictor of s-gastrin levels (OR 2.50 compared to males, 95% CI: 1.08-5.76, p=0.032) in the patient group. Gastrin values were higher in patients compared to controls. There was no correlation between gastrin levels and treatment duration. Female patients had significantly higher gastrin values than males.

Risk of Proton Pump Inhibitor–Induced Mild Hyponatremia in Older Adults

To the Editor: The incidence of hyponatremia, a side effect that can result from using proton pump inhibitors (PPIs), is unknown in elderly adults. A prospective clinical study of individuals with suspected drug-induced moderate hyponatremia was recently conducted; 47% of the population was being treated with PPIs, indicating that the risk of PPI-induced hyponatremia is significant in elderly adults (≥65).1 This was a retrospective study. The main objective was to determine the incidence of hyponatremia in the elderly population being treated with PPIs; other objectives were to determine the odds ratio of PPI inducing hyponatremia, the relationship between PPI dose and occurrence of hyponatremia, and risk of hyponatremia in association with other medications. The incidence of hyponatremia in individuals who had been taking PPIs for at least 1 year was compared with that in a control group of individuals who had not been exposed to PPIs. Hyponatremia risk factors, except drugs known to induce hyponatremia, were exclusion criteria. The study included individuals in a unit of a general hospital admitted during 2011. Of 302 individuals analyzed, 145 were included. Twenty-four (16.6%) had moderate hyponatremia, and 48 (33.1%) had been taking PPIs for longer than 1 year, 31.3% of whom (95% confidence interval (CI) = 18.7–46.3%) had moderate hyponatremia, versus 9.3% (95% CI = 14.3–16.9%) in the rest of the population (OR = 4.4, 95% CI = 1.8–11.1, P = .001). The relationship between dose and occurrence of hyponatremia was not significant (coefficient of determination = 0.05, P = .74). Individuals taking PPIs and tramadol had a significantly higher risk of having hyponatremia than those taking neither (OR = 7.7, 95% CI = 1.9–31.2). Table 1 describes the relationship between hyponatremia, medication use, and potentiation in association with PPIs. The results are expressed as incidence of hyponatremia and the number of affected subjects for each drug or each drug combined with PPIs. In the literature, cases of hyponatremia in conjunction with PPI use have been reported without reporting the incidence rate.2 Moreover, hyponatremia is described as a rare event in PPI product information (<0.1%).3 Between 18.7% and 46.3% of elderly PPI users had hyponatremia in the current study. This study demonstrates that the chronic use of PPIs increases the risk of hyponatremia in older adults. This could be a result of their antidiuretic activity or the potentiation of the reactive antidiuretic hormone secretion.2 The association between PPIs and tramadol also appears to potentiate the risk of hyponatremia. Risk of hyponatremia with tramadol has been described in the literature.4 This combination is frequently administered to elderly adults and requires further study. Drugs are an underestimated cause of hyponatremia in elderly adults.5 Moderate hyponatremia significantly increases morbidity, for example, by increasing the risk of falls and fractures, and increases the risk of osteoporosis. It is also a predictor of death, myocardial infarction, and longer duration of hospitalization in elderly adults.6, 7 The effectiveness of PPIs and their safety has led to their widespread use. The known potential consequences of chronic use of PPIs include hypergastrinemia, enterochromaffin-like cell hyperplasia, and parietal cell hypertrophy, which causes rebound acid hypersecretion. PPI use is also a risk factor for Clostridium difficile enteritis, pneumonia, nutritional deficiencies, and interactions with antiplatelet agents.8 Although PPI moderate hyponatremia is an unknown effect, more fractures are being reported. It may be that episodes of hyponatremia potentiate these events by causing attention deficits, with a higher incidence of falls causing fractures, which adds to the direct effect on bone remodeling.9, 10 Thus, the literature suggests a need for a benefit: risk balance assessment amended by the latest knowledge of pharmacovigilance, and the current study confirms the potential adverse effects of PPI use in the elderly population. PPIs are commonly administered to elderly adults: 33% in the current study. The extensive use of PPIs in elderly adults is often the result of a lack of therapeutic reevaluation or requests from the individual to avoid treatment interruption. PPIs must be discontinued when the risk-benefit balance becomes unfavorable. Reassessment of the prescription is useful, particularly because a recent study has shown that hyponatremia is reversible; the reduction of drugs that may induce hyponatremia was associated with significant clinical improvement.1 Future prospective studies that include follow-up laboratory results for comparisons of pre- and post-PPI therapy would be optimal and informative. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Buon, Peyro Saint Paul: acquisition of subjects and data, analysis and interpretation of data, and preparation of manuscript. Gaillard, Fedrizzi, Mosquet, Coquerel: analysis and interpretation of data, preparation of manuscript. Martin: acquisition of subjects, analysis and interpretation of data, and preparation of manuscript. Sponsor's Role: No sponsor.

Systematic review: symptoms of rebound acid hypersecretion following proton pump inhibitor treatment

Introduction. While the physiological existence of rebound acid hypersecretion (RAHS) after withdrawal of proton pump inhibitors (PPI) therapy is established, the clinical implications are less certain. It has been speculated that a clinical relevant rebound phenomenon may be responsible for difficulties in getting off acid-suppressive medication and partly explain the increase in long-term use of PPI. A number of studies addressing this issue have been published recently. The authors aimed to systematically review the existing evidence of clinically relevant symptoms caused by acid rebound following PPI treatment. Material and methods. PubMed was searched using the terms “rebound acid hypersecretion” and generic names of PPIs. Results.Five studies were included. Two studies on asymptomatic volunteers found that 44% experienced acid-related symptoms up to 4 weeks after treatment was withdrawn. Symptoms were generally mild to moderate and mainly heartburn and regurgitation. Three studies, using patients with reflux disease, found no signs of symptoms caused by acid rebound. Conclusion. Gastric acid rebound hypersecretion following PPI therapy induces reflux-like symptoms post-treatment in asymptomatic volunteers, but the significance of this in patient populations is not clear. The studies in patients with reflux disease found no evidence of symptomatic RAHS, but these studies were hampered by severe methodological weaknesses.

Proton pump inhibitors

This review summarizes adverse effects of potential proton pump inhibitors (PPIs), including nutritional deficiencies (B12 and magnesium), rebound acid hypersecretion, acute interstitial nephritis, gastric carcinoid tumor, cardiovascular risk with clopidogrel and PPI coprescription, bone fractures, enteric infections and pneumonia. An epidemiologic framework is applied to assess clinical relevance and reinforce best practice recommendations. The evidence for PPI adverse events is limited by the absence of Level 1 (randomized controlled trial) studies. The best evidence supports Clostridium difficile and bone fractures in susceptible populations. A substantial reduction in gastrointestinal bleeding risk without increase in cardiovascular events was observed in the COGENT trial when clopidogrel was coprescribed with omeprazole. The risk of pneumonia is inconsistent, and although acute interstitial nephritis, nutritional deficiencies (including B12 and hypomagnesemia), gastric carcinoid and rebound hyperacidity are biologically plausible, studies have failed to demonstrate supportive clinical relevance. Prescribe PPI for robust indications only. Strong data supporting risk of adverse events are lacking; however, exercise caution in the elderly and in patients with other risk factors for bone fractures or C. difficile infection.

Análisis crítico de un artículo: La suspensión de inhibidores de la bomba de protones induciría síntomas de reflujo

Background & Aims: Rebound acid hypersecretion (RAHS) has been demonstrated after 8 weeks of treatment with a proton-pump inhibitor (PPI). IfRAHS 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 PPIgroup 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 PPIgroup was 13 of 59 (22%) at week 10,13 of59 (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.

Overutilization of proton-pump inhibitors: what the clinician needs to know.

Proton-pump inhibitors (PPIs) remain the leading evidence-based therapy for upper gastrointestinal disorders, including gastroesophageal reflux disease, dyspepsia, and peptic ulcer disease. The effectiveness of PPIs has led to overutilization in multiple treatment arenas, exposing patients to an increasing number of potential risks. The overutilization of PPIs in ambulatory care settings is often a result of failure to re-evaluate the need for continuation of therapy, or insufficient use of on-demand and step-down therapy. PPI overutilization in the inpatient setting is often a result of inappropriate stress ulcer prophylaxis (SUP) in nonintensive care unit patients, and failure to discontinue SUP prior to hospital discharge. Potential consequences of prolonged PPI therapy include hypergastrinemia, enterochromaffin-like cell hyperplasia, and parietal cell hypertrophy, leading to rebound acid hypersecretion. PPIs have been linked via retrospective studies to increased risk of enteric infections including Clostridium difficile-associated diarrhea, community-acquired pneumonia, bone fracture, nutritional deficiencies, and interference with metabolism of antiplatelet agents. Reducing inappropriate prescribing of PPIs in the inpatient and outpatient settings can minimize potential for adverse events, and foster controllable cost expenditure.