Key messages
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Compared to a placebo (dummy or inactive treatment), proton pump inhibitors probably reduce the development of new ulcers. They also slightly decrease symptoms of dyspepsia (indigestion). They may reduce ulcer complications and probably slightly improve quality of life. They may have little to no harmful effects, but the evidence is very uncertain.
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Compared to histamine 2-receptor antagonists (also known as H2-blockers; medications that help reduce stomach acid), proton pump inhibitors may increase the development of new ulcers. The evidence for this comparison came from only one study.
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Compared to misoprostol (medication that helps protect the stomach lining from damage), proton pump inhibitors may increase the development of new ulcers and may have fewer harmful effects, but the evidence is very uncertain. The evidence for this comparison came from only one study.
What are non-steroidal anti-inflammatory drugs, ulcers, dyspepsia, and proton pump inhibitors?
Non-steroidal anti-inflammatory drugs are commonly used medications to reduce pain and inflammation (the body's response to an injury or illness). Using non-steroidal anti-inflammatory drugs for a long time can cause ulcers, which are lesions (sores) in the stomach lining or the small intestine that cause pain and serious complications. One complication is dyspepsia (indigestion or discomfort in the upper abdomen (tummy)). Proton pump inhibitors are medications that reduce the production of acid in the gastric juice (which aids digestion of food), protecting the stomach from damage caused by non-steroidal anti-inflammatory drugs.
What did we want to find out?
We wanted to determine if proton pump inhibitors are effective in preventing dyspepsia and ulcers in people who use non-steroidal anti-inflammatory drugs for four weeks or longer. We sought information on the occurrence of ulcers, symptoms of dyspepsia, harmful effects, ulcer complications, and quality of life.
What did we do?
We searched for studies up to October 2023. We included studies comparing proton pump inhibitors with placebo (dummy or inactive treatment), histamine 2-receptor antagonists (also known as H2-blockers; medications that help reduce stomach acid), misoprostol (medication that helps protect the stomach lining from damage), or sucralfate (medication that treats and prevents ulcers in the stomach and the intestines) in adults and children who used non-steroidal anti-inflammatory drugs for at least four weeks.
What did we find?
We found 12 studies that involved 8760 adults using non-steroidal anti-inflammatory drugs. The largest study included 2426 people, and the smallest study included 26 people. People received one of the following proton pump inhibitors by mouth: esomeprazole, lansoprazole, omeprazole, and pantoprazole, but most studies used esomeprazole. Ten studies compared proton pump inhibitors versus placebo, one study compared proton pump inhibitors versus misoprostol versus placebo, and one study compared proton pump inhibitors versus the H2-blocker, famotidine. Studies lasted around six months; only one lasted 12 months or more. Pharmaceutical companies funded seven studies.
Main results
Compared with placebo, proton pump inhibitors slightly reduce the symptoms of dyspepsia. Proton pump inhibitors probably reduce the development of new ulcers compared with placebo (there were 36 new ulcers per 1000 people with proton pump inhibitors and 119 new ulcers per 1000 people with placebo). Proton pump inhibitors may reduce ulcer complications compared with placebo (there were 4 complications per 1000 people with proton pump inhibitors and 11 complications per 1000 people with placebo). Proton pump inhibitors probably slightly improve quality of life.
Proton pump inhibitors may increase new ulcers compared with H2-blockers (there were 154 new ulcers per 1000 people with proton pump inhibitors and 77 new ulcers per 1000 people with H2-blockers).
Proton pump inhibitors may increase new ulcers compared to misoprostol, but the evidence is very uncertain. Proton pump inhibitors may have fewer harmful effects compared to misoprostol, but the evidence is very uncertain.
We found no studies comparing proton pump inhibitors and sucralfate.
What are the limitations of evidence?
Except for the comparison of proton pump inhibitors versus placebo on the formation of new ulcers and quality of life, we have moderate to little confidence in the evidence. The studies were very small, they did not report the measures we were interested in, the comparison included only one study, and there was variation between studies in the results (some studies found benefits whereas others found harms).
How up to date is this review?
The evidence is up to date to 23 October 2023.
Compared with placebo, PPIs may have no effect on the presence of global symptoms of dyspepsia and probably result in a slight reduction in global symptoms of dyspepsia scales. PPI probably reduces incident ulcers and may have little to no effect on adverse events. PPIs may reduce ulcer complications and probably slightly increase quality of life.
Compared with histamine 2-receptor antagonists, PPIs may increase incident ulcers. The evidence for this comparison came from only one study.
Compared with misoprostol, PPIs may increase incident ulcers and may reduce adverse events, but the evidence is very uncertain. The evidence for this comparison came from only one study.
The certainty of the evidence for most outcomes and comparisons was low or very low, except for global symptoms of dyspepsia measured as a continuous outcome, incident ulcer, and quality of life in the comparison of PPI versus placebo.
Further research is needed to assess the effect of PPIs compared to other active treatments such as sucralfate, misoprostol, or histamine 2-receptor antagonists. Well-designed and reported studies focussing on patient-important outcomes and addressing the methodological limitations found in the present included studies would be informative. These could include different baseline ulcer risks, ages, and types of NSAIDs. Long-term follow-up would be beneficial.
To assess the effects of proton pump inhibitors on the prevention of dyspepsia and ulcers in people with chronic consumption of non-steroidal anti-inflammatory drugs.
We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid), and two trial registers up to 23 October 2023, as well as reference checking, citation searching, and contact with study authors to identify additional studies.
This Cochrane review had no dedicated funding.
Protocol (2022): doi.org/10.1002/14651858.CD014585.