Proton Pump Inhibitor (PPI) Side Effects

Most short-term side effects of proton pump inhibitors are gastrointestinal. Patients report symptoms such as nausea, diarrhea, flatulence and constipation. Some patients may also experience headaches and dizziness.

Furthermore, the prescribing information for a popular PPI medication, Prilosec, warns of a potential interaction with clopidogrel, a heart disease medication. This interaction may diminish the efficacy of clopidogrel.

“As a pharmacist, I’ve seen many patients struggle with side effects from short-term PPI use,” Sazan Sylejmani, pharmacy manager at Westmont Pharmacy in Westmont, Ill., told Drugwatch. “My advice is to take the lowest effective dose for the shortest time necessary.”

A 2021 study published in the British Journal of Clinical Pharmacology showed that PPIs have a mild connection to an increased short-term risk of death from cardiovascular complications such as heart disease. A review in BMC Medicine from the same year also showed a 16% increased risk of stroke associated with regular PPI use.

Additionally, a 2020 study in the Annals of Gastroenterology highlights the increased risk of pneumonia with PPI use.

While there were initial concerns about a connection between PPIs and Alzheimer’s disease, a 2022 review in the British Journal of Pharmacology showed “no clear evidence for an association between PPI intake and the risk of dementia.”

The U.S. Food & Drug Administration has issued warnings regarding several uncommon, but severe, adverse reactions related to PPI usage.

CDAD Warnings

In 2012, the FDA issued a safety communication about the link between PPIs and an increased risk of developing Clostridium difficile-associated diarrhea (CDAD). C. difficile is a bacterium that can cause persistent diarrhea.

Research published in Infectious Diseases and Therapy in January 2024 also showed that hospitalized patients were more likely to develop C. difficile infection after taking PPI or H2 receptor agonists, such as Pepcid and Zantac, for 10-14 days.

Regarding why this happens, a 2024 preprint article on BioRxiv suggests that the increased infection rate may be due to altered pH levels in gastrointestinal systems caused by PPIs. Because preprint articles have not undergone peer review, we do not know if this idea holds merit yet.

Patients taking proton pump inhibitors who have CDAD symptoms should immediately contact a health care provider regarding their symptoms. They may recommend additional fluid intake to avoid dehydration.

Bone Fracture Risk

The FDA issued communications between 2010 and 2011, alerting the public of potential links between PPIs and the risk of bone fracture. In 2010, the FDA revised the labels on PPIs to include warnings regarding the risk of bone fracture and osteoporosis.

However, in 2011, the FDA removed this revision on over-the-counter PPIs. The administration determined that people who adhere to the package instructions for these PPIs, which usually call for a dosage regime of less than two weeks, are unlikely to experience significant bone-related issues.

The FDA advised health care providers to be aware of the risks of bone fracture when recommending or prescribing PPIs for a duration longer than two weeks.

Severe side effects of proton pump inhibitors include an increased risk of Clostridium difficile-associated diarrhea, bone fracture, stomach cancer, kidney injury and stroke.

The FDA requires that PPI labels contain several additional warnings for potentially serious side effects. These side effects are uncommon, but patients should still be aware of them.

These issues can appear after a single use of PPIs but are more likely to develop after prolonged treatment. Talk to your doctor before beginning a course of PPIs if you are concerned about any vitamin deficiencies, bone fractures or kidney problems.

Gastric and Esophageal Cancer

Recent research points to a correlation between PPI usage and gastric cancer. In 2023, Frontiers in Pharmacology published a meta-analysis of 24 studies that found a significant increase in gastric cancer, also known as stomach cancer, diagnoses among patients taking PPIs. Patients who used PPIs long-term were especially at risk.

Researchers have also linked proton pump inhibitors to esophageal cancer. A 2022 case-control study published in Pharmaceuticals looked at data from over 4,000 patients in South Korea. It showed higher rates of esophageal cancer among participants who had previously taken PPIs or H2-receptor antagonists.

A Swedish study published in Cancer Epidemiology in 2021 evaluated participants for their risk of gastric and esophageal cancer while on PPIs and after discontinuing the drug.

The research team found that PPI users were 7-10 times more likely than non-users to develop gastric and esophageal cancer during their first year of taking PPIs. The risk remained elevated for all patients after the first year, ranging from a 24% to 202% increased risk compared to the general population.

Kidney Injury and Disease

A significant body of research demonstrates a relationship between PPI usage and “silent” kidney damage.

The Journal of Clinical Medicine published a 2023 analysis of 10 observational studies looking at 6.8 million people with a range of comorbidities. The results overwhelmingly supported the claim that PPIs taken for an extensive period can cause kidney issues. The study authors recommend continuous monitoring of at-risk patients to help ensure early detection in case of kidney dysfunction.

This builds upon earlier analysis of the FDA adverse event reporting system reported in 2021 in Scientific Reports. The analysis found that kidney disease most commonly occurred within the first year of use. Earlier studies found a correlation between PPI use and chronic kidney disease and kidney failure, also known as end-stage renal disease.

If you have concerns about the side effects of PPIs, alternatives are available. Antacids are a popular choice for mild and non-recurring symptoms of heartburn or acid reflux. Many are available over the counter in a variety of forms, such as dissolvable tablets, liquids and capsules.

While antacids can be effective in alleviating heartburn and other symptoms of gastroesophageal reflux disease (GERD), they are generally not used for long-term treatments.

Doctors sometimes recommend lifestyle changes as a potential solution for navigating gastrointestinal issues. For example, they may suggest avoiding fatty, spicy or acidic foods that can cause heartburn and trigger other GERD-related symptoms.

“From a registered dietitian’s perspective, proton pump inhibitors, commonly prescribed for acid reflux, can significantly impact nutrient absorption, particularly magnesium, calcium, and vitamin B12,” Trista Best, a registered dietician at Balance One Supplements, told Drugwatch.

“To mitigate these effects, it’s crucial for patients on PPIs to monitor their nutrient levels regularly. Incorporating nutrient-rich foods like leafy greens, dairy products, and lean meats can help counteract deficiencies.”

Some home remedies, such as drinking low-fat milk or eating ginger, may help reduce GERD flare-ups. Some people also find relief by drinking warm water with honey and a bit of lemon.

If you wish to alleviate gastrointestinal symptoms, talk to your doctor to help you identify the root cause of your symptoms. Together, you can seek a treatment that minimizes the risk of side effects.

If you are currently on PPI and wish to switch to alternative treatments, it’s important not to quit abruptly.

Ending Proton Pump Inhibitor Intake

It is rarely advisable to abruptly end your PPI intake, especially if you’ve been using it long-term. Doing so can cause rebound hyperacidity, which is when the stomach produces more acid after ending a medication.

When you want to stop taking PPIs, your doctor can help you prepare a taper-off plan. This typically involves taking decreasing amounts of medication over a period of weeks or months, giving your body time to readjust. The exact time it will take to taper off PPIs depends on your biology, as well as your use duration and dosage of the PPIs you’ve been taking.

Editor Lindsay Donaldson contributed to this article.