Do PPIs have long-term side effects?

Nexium and the other proton-pump inhibitors are great at reducing stomach acid, but that might have some unintended consequences.

 Madison Avenue has given stomach acid a bad name, but it's really kind of a bum rap. Dip into any physiology textbook, and you'll find that stomach acid serves several constructive purposes. Pepsin, an enzyme that is essential to the preliminary digestion of protein, needs an acidic environment in the stomach to be effective. The strongly acidic hydrochloric acid pumped out by cells in the lining of the stomach also plays a direct role in the early digestion of some foods. And stomach acidity is a built-in barrier to infection: many bacteria and other pathogenic fellow travelers don't make it out of the stomach alive because of the low pH levels they encounter there.

Long-term use

Yet millions of us spend billions of dollars each year on products and medications designed to lessen or get rid of stomach acid. The old standbys, antacids like Maalox and Mylanta, have been supplanted in many cases by drugs that go to the source, acting on the cells that produce the hydrochloric acid, rather than just neutralizing the acid. Starting in the late 1970s, histamine2-receptor (H2) blockers like cimetidine (Tagamet), famotidine (Pepcid), and ranitidine (Zantac) came on the market. They were followed by the proton-pump inhibitors, or PPIs, which include esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec). The PPIs are increasingly the acid reducers of choice because they're far more effective than the H2 blockers. They're also quite a bit more expensive; for example, the over-the-counter version of Prilosec is about twice as expensive as the over-the-counter versions of Pepcid and Zantac.

People take acid-reducing medication for several reasons. PPIs are part of the "triple therapy" used to treat Helicobacter pylori, the bacteria that cause ulcers in the stomach and the upper part of the small intestine (the duodenum). Typically, though, that treatment lasts just one or two weeks. Long-term use of a nonsteroidal anti-inflammatory drug (NSAID) often comes with a long-term acid-reducing prescription. Randomized trials have shown that timely use of PPIs can protect people from getting the ulcers that can develop as a result of NSAID use. Whether PPIs ought to be routinely prescribed with the low doses of aspirin (aspirin is an NSAID) taken to prevent heart attack and strokes is unclear, although some findings suggest that it might be a good idea, and some doctors recommend it for people who are likely to have NSAID-related gut problems.

But the main use of acid reducers is to treat gastroesophageal reflux disease, or GERD, a condition characterized by stomach acid backing up into the esophagus from the stomach. We've all had occasional bouts of reflux and the heartburn pain that it causes. But GERD can be a serious, chronic problem that can lead to terribly painful inflammation of the esophagus (esophagitis), ulceration and bleeding of esophageal tissue, and, in rare instances, esophageal cancer. People with GERD might take an H2 blocker or PPI indefinitely: several studies have shown that in many cases it comes back unless people stay on maintenance therapy.

Like every medication, PPIs occasionally cause side effects, including nausea and headaches. Doctors are aware that PPIs can, in a roundabout way, promote an abundance of gastrin, an important stomach hormone. Too much gastrin could conceivably cause a number of problems, including a rebound effect of extra-heavy stomach acid secretion if people stop taking PPIs. PPIs may interfere with the metabolism of clopidogrel (Plavix). But by and large, PPIs have been viewed as safe medications with few drawbacks.

Yet some patients — and doctors and researchers — have wondered whether suppressing a natural process like stomach acid secretion for long periods might have unintended consequences. A number of studies suggest that there may, in fact, be a few things to worry about. But don't jump the gun: this is an area of research that's still taking shape, and we shouldn't lose sight of the benefits of acid suppression for some people.

PPI-associated pneumonia

Obviously the respiratory and digestive tracts are quite separate, but they share a common beginning in the mouth and the back of the throat before forking into two separate "tubes" — the cartilage-encased trachea in the front of the neck and the slender, muscular esophagus that goes to the stomach (see illustration). Given the shared plumbing and cramped quarters, it's amazing that things don't go down the wrong way more often. The epiglottis, which covers the opening of the trachea when we swallow, is a big help in that regard. But, especially when we are lying flat while asleep, small amounts of stomach contents tend to travel up the esophagus and get into the trachea. Aspiration, as it is called, occurs even in people with perfectly healthy respiratory and digestive systems.

Bacteria are more likely to proliferate in the less acidic environment created by PPIs, so in people who take these medications, this little bit of aspiration may be more likely to carry bacteria into the lungs, where they can cause pneumonia. This is a recognized problem among hospitalized patients, whose defense mechanisms against respiratory illness are often impaired (a reduced cough reflex, for example). But several studies have suggested that relatively healthy people outside the hospital might also be at risk for PPI-associated pneumonia. In 2007, Danish researchers reported results showing that current PPI use was associated with a 50% increase of pneumonia. They found no such association for the less-potent H2 blockers. Studies have gone the other way: in 2008, University of Pennsylvania researchers did not find an association between pneumonia and long-term PPI use after crunching data culled from a large British database of patient records. Their analysis showed that newcomers to PPIs — people who had started taking the pills in the previous 30 days — did have more pneumonia than people not taking PPIs, but that's probably for reasons unrelated to acid suppression and PPIs.

How reducing stomach acid can lead to infections

A connection to C. difficile

Clostridium difficile is a bacterium capable of causing life-threatening cases of diarrhea (10 bowel movements a day) and conditions like colitis, an inflammation of the lining of the colon. Growing numbers of people are coming down with C. difficile infections, and virulent "supergerm" strains have become a scary problem.

The conventional wisdom says the main risk factors for C. difficile infection are old age and use of antibiotics that disrupt the natural ecology of the gut. But in the past several years, a number of studies have identified a possible connection to PPIs — either by themselves or in combination with antibiotics. Using the same database as the University of Pennsylvania researchers, a group at McGill University in Montreal found an association between PPI use and C. difficile infection among people not in the hospital — the so-called community-acquired cases. And a well-designed case-control study of hospitalized patients published in the September 2008 American Journal of Gastroenterology found that people with diarrhea related to C. difficile were over three times more likely to be taking PPIs than people without a C. difficile infection.

People get infected with C. difficile by swallowing it. By making the stomach less acidic, PPIs may leave the door ajar to infections that wouldn't have taken hold had the acid levels been normal — a pH of 4 or less. One wrinkle in the plot is that C. difficile is transmitted by way of acid-resistant spores, although researchers say the higher pH levels may still affect the life cycle of the spores in such a way as to encourage infection.

Bad for bone — and your B12 levels?

By lowering stomach acid levels, PPIs might affect the body's absorption of calcium, which in turn could lead to osteoporosis and fractures. The University of Pennsylvania group that did not find a connection between PPIs and pneumonia did find a link between long-term use of PPIs and hip fractures. Their results also suggested that the risk increased the longer people were taking PPIs, which is the kind of dose-response relationship that researchers look for when deciding whether a correlation might indicate a causal relationship. In 2008, University of Manitoba researchers reported that continuous use of PPIs for five years resulted in excess risk of hip fractures. At seven years, there was an association with all kinds of osteoporosis-related fractures.

PPIs may also affect vitamin B12 levels because the body can't absorb the vitamin without stomach acid to uncouple the vitamin from protein in food. Many doctors monitor the B12 levels of their patients taking PPIs. In its pill form, B12 doesn't need stomach acid to be absorbed, so some people on long-term PPI therapy may take vitamin B12 pills — or a multivitamin that includes B12.

Time to take a step back

PPIs are a real advance, and millions of people have benefited from their ability to squelch the production of stomach acid that causes heartburn and contributes to NSAID-related ulcers and other serious conditions. But they've also been heavily marketed, especially Nexium as that appealing "little purple pill."

Now that studies are beginning to show that PPIs could — the jury's out still — cause some problems, it may be a good time to step back and ask whether we've been reaching for that PPI bottle too often and too soon. Occasional reflux can be treated effectively with the old-fashioned antacids. Some people find that only certain foods (chocolate, coffee, fatty food) trigger GERD-related heartburn, so they learn to avoid them. A chewing gum habit increases the production of saliva that can soothe an irritated esophagus and wash stomach acid back down into the stomach. And if the problem is nighttime heartburn, elevating the head of the bed can help.

People who need heavy-duty stomach acid suppression should still take a PPI but, working with your doctor, be sure that you're one of them before getting into a long-term relationship with this medication.