Last Updated November 9, 2020
Proton Pump Inhibitors (PPIs) are drugs first developed in the mid-1970s which are designed to limit the production of digestive acid by blocking a key enzyme in the stomach wall. Specifically, PPIs stop certain cells in the stomach lining from pumping or producing acid. Since first gaining approval by the U.S. Food and Drug Administration (FDA), PPIs such as omeprazole and esomeprazole have experienced extreme popularity both in their prescription and over-the-counter (OTC) formats with patients. Prilosec (omeprazole) generated over $26 billion for AstraZeneca before falling “off-patent” – only to be replaced with Prilosec (esomeprazole) which generated another $48 billion in sales for the company.
Without a doubt, PPIs have been a huge commercial success and millions have used them as part of a comprehensive strategy to combat peptic ulcer disease, non-ulcer dyspepsia, and Gastroesophageal Reflux Disease (GERD) among other digestive afflictions. However, PPIs also come with a range of possible side effects: some common, others not so common. Furthermore, recent studies regarding the long-term use of PPIs have suggested possible adverse side-effects which have the potential to be life-altering or worse.
More Common Side Effects
Documented side effects for PPIs include the following:
- Headache
- Nausea
- Stomach Pain
- Gas
- Constipation
- Diarrhea
- Rash
- Vomiting
- Constipation
- Fever
- Cold or Flu-like Symptoms
Other Possible Serious Side Effects
Acute Interstitial Nephritis, Chronic Kidney Disease, and End-Stage Renal Disease
Recent reporting and studies have raised concerns about a possible association between PPI use and acute injury to the kidneys. In particular, several case reports have suggested a link between PPIs and the development of Acute Interstitial Nephritis (AIN). AIN is a kidney disorder in which the spaces between the kidney tubules become inflamed and swollen. Symptoms of AIN associated with PPI use include:
- Malaise
- Fever
- Nausea
- Lethargy
- Weight Loss
If left unchecked, AIN can progress to Chronic Kidney Disease (CKD), a condition that encompasses the gradual loss of kidney function. Unfortunately, the symptoms of CKD are not always readily apparent for sufferers and may not become obvious until kidney function has already been substantially impaired. While the onset of CKD is gradual, its effects are serious and it brings a substantially increased risk of death from cardiovascular events.
Long-term suffering with CKD can regrettably lead toward End-Stage Renal Disease (ESRD) otherwise known as complete renal failure. ESRD occurs when a person’s kidneys are no longer able to function properly. ESRD treatment options require either frequent dialysis or a kidney transplant for the patient to survive.
Note: in 2014 the FDA required prescription PPIs to carry warnings on their labels concerning the risk of AIN.
Hypomagnesemia
Hypomagnesemia, otherwise known as magnesium deficiency, is a condition where this important element’s presence in the blood is lower than normal. Magnesium is critical to the operation of the heart, lungs, and kidneys among other critical organs, and is of central function to the body’s metabolism. In 2011, the FDA issued a safety warning concerning the association between PPI use and magnesium deficiency and recommended monitoring of magnesium levels in patients who have been on PPIs for a long duration.
Clostridium Difficile Associated Diarrhea
In 2012, the FDA issued a safety communication concerning increased risk from PPIs and Clostridium Difficile Associated Diarrhea (CDAD). Clostridium difficile is a bacteria that can cause serious diarrhea that does not improve. After reviewing reports from the FDA’s Adverse Event Reporting System (AERS), the agency noted that many reports of patients undergoing treatment with PPIs and who manifested CDAD suggested the possibility of a linkage. It should be noted that most of the reporting involved elderly patients who were also taking doses of broad-spectrum antibiotics or had other conditions that may predispose them to CDAD. However, the FDA could not rule out the role of PPIs in the development of CDAD.
Small Intestine Bacterial Overgrowth
Small Intestine Bacterial Overgrowth (SIBO) is a condition where there is an abnormal increase in the bacterial population of the small intestine. SIBO can occur as a result of surgery or disease and can cause diarrhea, weight loss, and malnutrition. The Mayo Clinic recently reported that PPI use may also carry an increased-risk for SIBO in patients.
Cancer Risk from Long Term Use
There are no definitive research or medical links between PPI use and cancer. However, two studies conducted in 2017 and 2018 included data and conclusions that support further research into any potential relationship between PPIs and gastric cancer. Specifically, researchers at the University of Hong Kong and others in Sweden conducted similar studies examining the relationship between PPIs and H. Pylori infections in the gastrointestinal system. H. Pylori are bacteria that live in the digestive tract and cause ulcers and increase the risk of stomach or esophageal cancer. It is theorized that long-term PPI use can contribute to an increased level of H. Pylori in the digestive tract and possibly, therefore, the increased risk. Although the two research studies arrived at the same conclusion, their findings are not without controversy and have been contradicted by researchers elsewhere.
Heart Attack Risk
In June 2015, the Stanford Medicine journal reported on a data-mining study carried out at Stanford Medical School linking PPIs with an elevated risk of a heart attack. Although researchers were quick to point out that their study did not illustrate a causative link between PPIs and heart attack risk, they stated that the report combed through the health records of nearly 3 million people and found indications that PPI use was associated with a roughly 20% increase in the rate of a subsequent heart-attack in all adult PPI users.
Risk of Fractures of the Hip, Wrist and Spine
The FDA issued a drug safety communication for all PPIs in May 2010, revising the labeling to include safety information about the possibility of increased risk of fractures to the hip, wrist, and spine. The FDA’s decision came on the heels of its own reviews of several studies that reported an increased risk of fractures with PPI use. In fact, the FDA said that some studies found that those of the greatest risk of fracture were those who received high doses of PPIs or used them for a year or more.
Dementia and Cognitive Decline
The Harvard Medical School published an article in 2016 highlighting the findings of a study that shed light on the potential for dementia and cognitive decline with long-term PPI use. Specifically, a 2015 study published in the neurology Journal of the American Medical Association (JAMA) showed a possible association between chronic use of PPIs and dementia risk. Experts compared prescription PPI intake and diagnosis of dementia among approximately 74,000 adults ages 75 and older.
All of the participants in the study were dementia-free at the time that the study commenced. However, follow-up interviews eight years later seemed to indicate that chronic PPI users had a 44% rate of increased risk for dementia. Men were at a slightly higher risk than women and occasional users of PPIs had a much lower risk.
The article publishers and researchers are quick to point out that the study does not mean PPI users will automatically get dementia. It only points to a “statistical association” and the need for ongoing research and discussion about the potential for linkage.
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Tracy Everhart
Tracy Everhart is the Editor for Drug Law Journal. A highly-trained and certified medical professional, Tracy is also an accomplished medical writer. After spending years on the front lines of the medical profession, Tracy now devotes her expertise and skills to researching and reporting on new drugs and devices that enter the market, as well as their side-effects and the real-life stories involved. Prior to joining Drug Law Journal, Tracy wrote for benchmark online healthcare resources focused on families and, in particular, women’s health issues. Tracy holds post-graduate degrees from both the American College of Healthcare Sciences and the Yale School of Nursing. She is also a graduate of both Hampshire College, where she studied microbiology and the University of South Carolina school of nursing.
