Reported Side Effects and Complications of Long-term Proton Pump Inhibitor Use

Dissecting the Evidence

David A. Johnson; Edward C. Oldfield IV


Clin Gastroenterol Hepatol. 2013;11(5):458-464. 

In This Article


Proton pump inhibitors (PPIs) are medications that are ubiquitous in a gastroenterologist's practice. This class of medication has been available for commercial use for nearly 25 years and this class of acid-reduction agents has supplanted the use of histamine-2–receptor antagonists (H2RA) for patients with moderate to severe gastric acid–related diseases as well as for prophylaxis of upper gastrointestinal (GI) injury (eg, with nonsteroidal anti-inflammatory drugs). The success of these drugs, with sales totaling approximately $13.6 billion worldwide in 2009,[1] is not just a result of their potency and effectiveness in improving symptoms and complications of acid-peptic diseases. Their safety among pharmacologic agents has been unparalleled as one of the safest classes of medications that gastroenterologists deal with, however, despite this there have been emerging concerns with reports of potential adverse effects associated with use of PPIs. In the United States, such reports have led the Food and Drug Administration (FDA) to issue a number of broad-based product warnings, including all of the available PPI drugs either for prescription or over-the-counter purchase. The pathogenesis of these proposed associations is not clear in most cases and the evidence base to support a clear association for harm is extremely variable. These potential interactions have ranged from alteration of absorption of vitamins and minerals, metabolic effects on bone density, alteration of pharmacokinetics/pharmacodynamics and related drug interactions, or alterations of intended effect, infection risk, and hypersensitivity response with consequent organ damage. This review examines the proposed scientific basis for the adverse events and the evidence base surrounding these controversies, and provides the authors' bottom-line recommendations for clinical practice.