Adverse Effects of Proton Pump Inhibitor Drugs: Clues and Conclusions

Denis M. McCarthy


Curr Opin Gastroenterol. 2010;26(6):624-631. 

In This Article

Abstract and Introduction


Purpose of review To review evidence relating to the strength of associations that have appeared in largely observational studies, between high-dose or long-term use of proton pump inhibitor drugs and certain possibly attributable side-effects, which emerge from studies confounded by other variables. In retrospective studies not designed to assess safety, evidence of causality is generally lacking.
Recent findings The associations of fractures of hip, wrist, forearm and other sites appear weak and only slightly higher than the risks in control populations matched for age. They may increase with drug exposure, but probably do so only in individuals in whom other risk factors are also operational (smoking, alcohol, poor nutrition, steroids, etc.). The risks of Clostridium difficile colitis, other enteric infections, small bowel bacterial overgrowth and possibly spontaneous bacterial peritonitis also appear increased. Impaired gastric secretion may adversely affect the absorption of various nutrients, but their clinical impact is ill defined. Potentially more important are the consequences of hypergastrinemia, including rebound hypersecretion of acid, and possible development of various cancers, including carcinoid tumors. Effects of other drugs, including clopidogrel, on metabolism are reviewed, but clouded by uncertainties.
Summary The safety of long-term PPI administration needs serious prospective study.


The widespread use of proton pump inhibitor drugs (PPIs) world wide for almost two decades is gradually increasing concern among physicians and the public that their benefits may be attended by a variety of risks that until recently have received little attention. Based largely on observational studies, a number of adverse drug reactions (ADRs) have emerged as likely or possibly associated with PPI therapy. Such ADRs are either uncommon in incidence, or associated only with prolonged use or high doses of the drugs. Not all these ADRs are class effects, although often erroneously treated as such, and some may occur only in subpopulations, susceptible because of age, genetics, comorbidity or environmental factors such as Helicobacter pylori infection or cotherapy with other agents.

The incidences of minor adverse events, identified in premarketing clinical trials, are typically of the order of 1–5% and include headache, diarrhea, constipation, nausea and rash, with little difference between products and with only minor differences from those seen with H2-receptor antagonists (H2RAs) or placebo. These effects of therapy will not be discussed here except to say that the short-term use of the drugs in recommended doses is generally well tolerated, even in children, the fetus, the pregnant and the elderly, with only rare exceptions. Nonetheless, from studies not designed to determine drug safety systematically, a number of associated ADRs have emerged and are the focus of this brief commentary. Due to limitations of space, this review will not attempt to discuss all relevant studies or provide detailed bibliographic references: for more information on specific points, the interested reader is referred to other recent reviews.[1,2•–4•]

The available literature mainly identifies associations of PPI therapy, often weak, and frequently accompanied by unsupported speculations as to the mechanisms that underlie them. However, such observational data, despite the listed imperfections, are often later borne out by the results of randomized controlled trials (RCTs), and prove to have furnished valuable clues to important effects, unrecognized prior to extensive postmarketing use. That these suspected ADRs are unproven in no way justifies the belief that PPI therapy is completely well tolerated. Most prominent among associations of ADRs with long-term PPI therapy are concerns about the risks of bone fractures, increased susceptibility to infections and effects of altered gastric function.