Review of proton pump inhibitors for the initial treatment of heartburn: Is there a dose ceiling effect?

Abstract

Proton pump inhibitors (PPIs) are widely used in clinical practice. However, concerns have been expressed about their long-term use, particularly with regard to bone health, Clostridium difficile infections, and drug interactions with platelet aggregation inhibitors. There has been limited guidance for clinicians concerning appropriate dose selection of PPIs for the initial treatment of heartburn. This review explored whether published clinical trials provide evidence of a ceiling above which higher PPI doses do not provide additional clinical benefit over the lowest approved dose. All articles of randomized, controlled clinical trials in nonerosive gastroesophageal reflux disease (GERD) in which the effects of two or more doses of the same PPI on symptomatic relief of heartburn were quantified as a study endpoint were identified and analyzed through PubMed searches up to the end of September 2010. The majority of trials evaluated provided no evidence that higher PPI doses were superior to the lowest approved dose for the initial treatment of heartburn. There were no clinically relevant findings with respect to dose dependence and safety outcomes in these studies. Efficacy outcomes from the trials suggest there may be a dose ceiling effect and highlight the need for further research on the use of the lowest effective PPI doses as an appropriate strategy in the initial treatment of uncomplicated heartburn. Observational studies and some meta-analyses have suggested that long-term PPI pharmacotherapy might be associated with safety concerns, which necessitate the periodic evaluation of therapeutic benefit in terms of symptom resolution and regimen tolerability. However, evidence to date suggests that use of the lowest effective dose for the indication is not associated with significant adverse events, particularly in the short term. Clinical practice suggests that patients requiring long-term treatment should be maintained on the lowest dose necessary to control symptoms, and monitored for potentially confounding factors that may lead to safety concerns.

25 Years of Proton Pump Inhibitors: A Comprehensive Review

“…With few exceptions, such as severe grades of esophagitis, half the healing dose of a PPI is often adequate for maintenance 66. Therefore we suggest that the lowest dose of PPI necessary to control symptoms should be the goal of long-term treatment.…”

Non-GCs Drug-Induced Osteoporosis

“…PPIs are among the most frequently recommended treatments worldwide in clinical practice. Although the majority of patients handle PPIs well overall, there is growing concern over a possible link between PPI use and an increased risk of bone fracture [11,12]. Indeed, the correlation between PPI medication and the incidence of fracture has been documented in numerous observational studies [13][14][15].…”

Evidence-based treatment of frequent heartburn: The benefits and limitations of over-the-counter medications

“…While relative healing rates for erosive esophagitis can be correlated with the duration for which intragastric pH is maintained >4 (Bell, Burget, Howden, Wilkinson, & Hunt, 1992;Miner et al, 2003), there is no similar correlation for control of gastric pH > 4.0 and complete resolution of frequent heartburn. This is because of an apparent "dose ceiling effect" that occurs at a PPI dose of 20 mg (Kushner & Peura, 2011). For complete resolution of frequent heartburn, PPI doses less than or equal to 20 mg show a dose-response, while PPI doses greater than or equal to 20 mg fail to show a consistent dose-response.…”

“…In contrast, clinical evidence supports that there is a lack of dose–response for PPI doses greater than or equal to 20 mg in patients with frequent heartburn but without esophageal erosions, which represent the majority (70%) of the OTC frequent heartburn population (Kushner & Peura, ). Three clinical studies, published together, assessed the efficacy of esomeprazole 40 mg and esomeprazole 20 mg versus omeprazole 20 mg, in a total of 2645 patients with frequent heartburn (without erosive esophagitis; Armstrong et al., ).…”