Are Proton Pump Inhibitors (PPIs) Safe for Long-Term Use?

For many people, acid reflux—where stomach acid flows back into the esophagus, causing symptoms like heartburn—happens occasionally after eating certain foods or overindulging. Often, taking an antacid medication, such as Tums® or Rolaids®, provides relief.

But an estimated 20% of people in the United States have a severe form of acid reflux called gastroesophageal reflux disease (GERD), in which the backflow is more frequent and, over time, can damage the esophagus.

People with GERD may rely on a proton pump inhibitor (PPI), a type of medication that lowers stomach acid production; common ones include omeprazole (Prilosec®), lansoprazole (Prevacid®), and esomeprazole (Nexium®). Although some can take PPIs for as little as two weeks to feel better, those with serious forms of GERD may need to be on PPIs indefinitely.

PPIs are generally considered safe, but concerns about long-term use have been raised over the years—especially as they have been widely used and sometimes, overused, doctors say. Research has associated these medications with an increased risk of fracture, cardiovascular disease, dementia, chronic kidney disease, vitamin and mineral deficiencies, and infection.

So far, all studies linking PPIs to these issues have been observational—in other words, they do not actually prove cause and effect but only an association, whereby patients with these conditions also happened to be taking PPIs. Nonetheless, this body of research has raised concerns among prescribers and patients about the long-term safety of PPIs.

"Reading about these health effects in the media understandably makes people question PPIs and, in some cases, stop taking them on their own," says William Ravich, MD, a Yale Medicine gastroenterologist. This is worrisome, Dr. Ravich says, because it might cause symptoms and esophageal damage that had been under control to worsen. “Each patient needs to weigh the risks and benefits of taking a PPI with their medical provider,” he says. “And if the PPI was originally prescribed by a gastroenterologist, it would be best to discuss the pros and cons with them or another gastroenterologist.”

People with severe forms of GERD might not be able to manage their symptoms without the use of PPIs, which are the most effective medication for many patients, Dr. Ravich adds. “So, it’s important when discussing potential side effects to not ‘throw the baby out with the bath water,’ so to speak,” he says.

Below, we talk more with Dr. Ravich about GERD and PPIs, including how lifestyle modifications may help.

The esophagus is the tube that carries food from your mouth to your stomach where acidic digestive juices break it into nutrients. In someone with GERD, the sphincter muscle at the end of the esophagus, which protects against reflux, doesn’t close properly.

As a result, some of the food and stomach acid can leak back, or reflux, into the esophagus and irritate it, causing heartburn or the taste of acid or bile in your mouth. That’s because the stomach has a protective lining that shields it from the acid, but the esophagus does not. If left untreated, GERD can develop into esophagitis, the medical term to describe chronic, or long-term, inflammation of and damage to the esophagus from stomach acid.

Typically, GERD is diagnosed based on a patient’s symptoms, and a medication, such as a PPI, may be prescribed to see if it helps. If someone doesn’t respond to medication or if symptoms are severe, the physician may do an upper endoscopy, during which a thin tube equipped with a tiny camera and light is passed into the esophagus and stomach to confirm the diagnosis or rule out other issues, such as cancer or ulcers.

Many people have reflux symptoms, but they don’t all need to undergo an endoscopy, Dr. Ravich says. The decision on whether or not to perform one depends mostly on clinical judgment, he adds, but he says that it is more likely to occur if symptoms are more severe and/or not controlled with medication.

But symptoms don’t always match disease severity. Someone can have severe esophagitis and the esophagus is damaged, but they don’t present with terrible symptoms, he notes. And it’s important to know if someone has esophagitis because, if not treated, it can progress to a condition called Barrett’s esophagus in which there are precancerous changes in the esophagus lining that can lead to esophageal cancer.

Other symptoms, such as difficulty swallowing, or laboratory findings, such as anemia, can point toward someone having esophagitis without also experiencing severe symptoms, he adds. “So, it’s important to discuss this with your doctor or gastroenterologist,” he says.

Proton pumps are enzymes in the stomach lining responsible for producing acid that aids in digestion. PPIs target and slow this enzyme activity, significantly reducing acid production. The decrease in acid makes the reflux less acidic and, therefore, less irritating to the esophagus. This helps the esophagus heal and brings relief from symptoms, such as heartburn, regurgitation, and reflux-related chest pain.

Before the late 1970s, there were few treatments for reflux, and even fewer were effective for severe disease, Dr. Ravich says. The available medications were antacids, including Tums, Mylanta®, and Rolaids, which neutralize acid but don’t decrease acid secretion.

“Some of the antacids are good neutralizers and work immediately, but an hour later, you might need another dose, and you often have to take seven doses of antacids a day to control acid throughout the day,” Dr. Ravich says. “Plus, diarrhea is a common side effect of heavy antacid use. And for severe esophagitis, antacids are just not effective.”

A class of drugs called H2 blockers was introduced in 1978. They reduce the amount of acid the stomach produces by blocking how stomach cells respond to histamine, which normally stimulates acid release. H2 blocker medications include Pepcid Complete® and Pepcid AC®.

H2 blockers were initially considered miracle drugs until PPIs came around. “And then PPIs were the new miracle drug because they were about 90% effective, compared to H2 blockers, which were about 70% effective,” Dr. Ravich says.

For people who experience occasional acid reflux, an antacid is most likely an effective treatment. If symptoms are frequent or more severe, an H2 blocker or PPI may be recommended, Dr. Ravich says.

There is also a distinction between who should take over-the-counter (OTC) PPIs and who should get them by prescription. (Although not all PPIs are available over the counter, those that are contain the same medication as the prescription version but in varying strengths.)

OTC PPIs are often recommended for people with frequent heartburn (occurring two or more days a week) for whom antacid medications or H2s don’t provide relief. Prescription PPIs are intended for people with GERD and esophagitis. And if someone’s GERD or esophagitis is severe, it may require long-term or indefinite use of PPIs to keep symptoms in check.

PPIs are not meant for immediate relief as they can require one to four days to take full effect. The Food and Drug Administration (FDA) advises that over-the-counter PPIs be limited to a 14-day course up to three times a year.

PPIs are considered safe for short-term use, but risks from longer-term use have been raised in numerous observational studies.

Some of the concerns associated with long-term use include a higher risk of fracture because of interference with calcium absorption, an increased risk of certain infections (including pneumonia and C. difficile), and nutritional deficiencies (including magnesium, iron, and vitamin B12). All of these are presumed to be related to the effects of decreased stomach acid production.

In recent years, there have been observational studies about a potential increased risk of dementia, kidney disease, and heart disease, but those findings have been inconsistent, notes Dr. Ravich.

“It’s important to note—and something that may not have been reported—that many of the studies linking PPI use to cardiovascular disease, dementia, and kidney disease weren’t focused on PPIs, but rather on other issues with patients who happened to be on PPIs. In retrospect, the statistics suggest that perhaps the apparent association between these problems and PPIs were most likely coincidental, rather than causally related,” Dr. Ravich says.

Given the widespread use of PPIs—often for indications that don’t call for them—the American Gastroenterology Association in 2022 put forth new guidelines on de-prescribing them. The association wants to make sure that both the right people are taking PPIs and that they don’t suddenly stop taking them because of fears of side effects that might not warrant discontinuation given the severity of their disease.

“When patients have these PPI fears after reading about the risks in the media, they don’t necessarily come back to their gastroenterologist and say, ‘I'd like to come off my PPI. Is that a good idea?’ Instead, they go off it, and they could experience a rebound of symptoms, sometimes worse than prior to being on the PPI. Or, a year later, I find out that a person who desperately needed to be on the drug has not been taking it.”

Instead of discontinuing the use of PPIs on their own, Dr. Ravich recommends that patients work with a GI specialist to see if they can get by on a weaker dose or augment the PPI with an H2 blocker.

Before starting any medication for acid reflux, Dr. Ravich advises looking at your diet and habits. For example, caffeine, especially coffee, stimulates acid production, he says.

“Unfortunately, even decaffeinated coffee appears to produce as much acid as caffeinated coffee. I tell people to limit their cola drinking and cut down their coffee to, at most, one cup a day if they are having reflux,” Dr. Ravich says. “Fatty foods, including fried foods and processed foods, also have an effect on reflux, as can chocolate. Obesity can also have an effect.”

Lying down after a meal or even reclining in a chair can also make reflux worse, Dr. Ravich says. “A lot of these things are habits that can be difficult to break, but you can try. However, even if you stop all of them, that probably won’t be sufficient to control reflux in patients with severe symptoms or esophageal damage,” he says.

“The bottom line is that many people have good control of their disease with PPIs, and then they stay on them indefinitely because it’s a chronic disease,” Dr. Ravich says. “There was an early hope in reflux disease that, if you can control it, maybe it would control the disease enough so you wouldn't need as much medication. But we now know that is probably not true. That’s why PPIs are so helpful.”