Reprinted from the Harvard Health publication newsletter

Are the side effects something to worry about, or much ado about nothing?

Stomach acid is natural, a valuable chemical contributor to orderly digestion. But in excess or in the wrong place, it’s a menace, inflaming and irritating the esophagus, typically causing heartburn and sometimes contributing to the development of ulcers in the stomach and the duodenum, the first part of the small intestine.

People have dealt with stomach acid–related woes in a variety of ways, proven and otherwise, for eons, but it wasn’t until the mid-1970s and the introduction of cimetidine (Tagamet) that a treatment targeted the production of stomach acid itself. Cimetidine was a huge commercial success; by some accounts, it was the first blockbuster drug. Other drugs in the same class, known as H2 blockers, quickly followed suit, including famotidine (Pepcid) and ranitidine (Zantac). Now the proton-pump inhibitor drugs (PPIs) have eclipsed the H2 blockers as the most commonly prescribed agents for problems that can be fixed — or at least ameliorated — by reducing stomach acid levels. PPIs include heavily marketed and therefore familiar brand-name drugs like Prevacid (lansoprazole), Prilosec (omeprazole), and Nexium (esomeprazole). They are prescribed to both prevent and treat ulcers in the duodenum (where most ulcers develop) and the stomach. They also counter the various problems that occur when stomach acid escapes into the esophagus, which — if it happens on a regular basis — is a condition called gastroesophageal reflux disease (GERD). In most head-to-head trials, the PPIs have proved to be superior to the H2 blockers.

Collectively, billions of dollars are spent each year on PPIs. In the United States, a year’s supply of one of the less expensive varieties, which include generic omeprazole and over-the-counter Prevacid, costs about $200. If one were to pay the full price for the more expensive PPIs, the annual cost would be at least 10 times that amount.

Reducing stomach acid levels isn’t one of medicine’s glamour jobs, but it’s yeoman’s work, so PPIs are generally considered quite a success story: safe (more on that just below), effective medications that target the source of a lot of gastrointestinal distress.

Now, though, some doubts are creeping in about PPIs. These concerns fall into two broad categories: overuse, and possible drug interactions and side effects.

Overuse

Taking a PPI makes sense if you have a chronic problem with stomach acid or the prospect of one developing. But the occasional case of mild heartburn does not need to be treated with a PPI. For that kind of spot duty, the old standbys of antacid medicine like Tums, Rolaids, and Maalox will most likely work just as well, as will any of the H2 blockers. In fact, it takes several days for PPIs to have their full effect on acid secretion, so an H2 blocker may be more effective for a mild, short-term problem with stomach acid. Yet people often take PPIs under the mistaken assumption that they are the better medication in all circumstances. The fact that omeprazole is available as a generic has narrowed the cost difference, but you’re still probably going to pay more for a PPI, and most definitely so if you are taking one of the expensive brand-name varieties.

If heartburn is the problem, there are also changes you can make that may help that don’t involve taking anything. The commercials are right: gobbling down a large meal can give you heartburn, so eating smaller meals can help tame the problem. You can also try cutting back on alcohol. And if you’re heavy, GERD and heartburn are on that very long list of problems that ease up and may even go away if you lose some weight.

Drug interactions and side effects

Initially, there was some worry that PPIs might increase the risk of developing stomach cancer. Those concerns were unfounded, but others have taken their place, partly because people often take PPIs on a daily basis for years, so the total exposure to the drug ends up being quite significant. Here’s a rundown of the some of the drug interactions and side effects that are causing concern:

Interaction with clopidogrel. Clopidogrel (sold as Ceruvin, Clopilet, and Plavix) is a drug that discourages the formation of artery-clogging blood clots and is often taken by people with heart disease to prevent heart attacks and stroke. But clopidogrel has a significant downside: it’s hard on the lining of the stomach and intestines, so it increases the risk of gastrointestinal bleeding. To keep those bleeds from happening, doctors have often prescribed a PPI with clopidogrel, especially if the patient is also taking aspirin. Like clopidogrel, aspirin makes blood clots less likely to form, and dual clopidogrel-aspirin therapy is recommended after placement of an artery-opening coronary stent. But aspirin, too, is rough on the gastrointestinal lining.

The trouble is that PPIs — and omeprazole in particular — inhibit an enzyme called CYP2C19 that’s crucial to one of the metabolic steps that activates clopidogrel and its effects. In 2009, the FDA issued a strong warning that said patients taking clopidogrel should avoid taking omeprazole (and, secondarily, the related drug Nexium) because they may cut clopidogrel’s effectiveness in half.

But whether PPIs have such a big effect on clopidogrel’s effectiveness has gotten murky lately. Two studies published in 2010, one of them a randomized controlled trial, showed no increase in heart attack or stroke among those taking a PPI with clopidogrel and a substantial benefit in the form of a reduced risk for gastrointestinal bleeds. In a letter toThe New England Journal of Medicine, FDA officials pointed to flaws in the interpretation of the randomized trial and stuck by the agency’s warning. A joint statement from the American Heart Association, the American College of Cardiology, and the American College of Gastroenterology recommended an individualized, risk-benefit approach that favors having patients take PPIs if their risk for a gastrointestinal bleed is already high (a group that includes older people, those taking warfarin, and those with a prior bleed, among others) but steers them away from taking PPIs if their risk for a gastrointestinal bleed is low. Some doctors believe a PPI prescription is advisable for people taking aspirin with clopidogrel but are more likely not to prescribe the acid-reducers for those taking just clopidogrel.

Another strategy that has been proposed but not tested is taking a PPI and clopidogrel at separate times. PPIs work best if they are taken first thing in the morning, before breakfast, and clopidogrel could be taken at night.

Fracture risk. Some studies have shown an association between PPIs and the risk of fracture — particularly hip fracture — while others have not. The FDA decided in 2010 that there was enough evidence of fracture risk to warrant a warning about it. Calcium is absorbed in the small intestine, not the stomach. But low stomach acid levels can have downstream effects, especially in the duodenum, and some research shows that one of them could be reduced absorption of calcium, which could lead to osteoporosis, weaker bones, and, consequently, a greater chance of breaking a bone. The fracture risk is probably pretty small, but it’s another reason for not taking a PPI unless necessary.

Pneumonia risk. Several studies have shown that people taking PPIs seem to be more likely to get pneumonia than those who aren’t. The association has been documented among people living in the community and hospital patients alike. Normally, stomach acid creates a fairly inhospitable environment for bacteria, but if acid levels are reduced by PPIs, the bacteria count can go up. The thinking is that in people with GERD who take PPIs, bacteria-laden stomach contents may travel up the esophagus and then get inhaled into the windpipe and lungs, where the bacteria cause pneumonia.

C. difficile risk. People typically develop Clostridium difficile infections in the hospital after taking antibiotics that have disrupted the natural bacterial ecology of the large intestine. The infections cause diarrhea but can also become a lot more serious, even life-threatening. Studies have shown a fairly strong statistical correlation between PPI use and C. difficile infection, although it’s still just a correlation and not proof of direct cause and effect. Some experimental evidence suggests that PPIs may change conditions in the gut to be more favorable to C. difficile bacteria.

Iron and B₁₂ deficiency. Stomach acid helps render the iron and vitamin B₁₂ from food into forms that are readily absorbed. So there was worry that an unintended consequence of PPIs would be deficiencies of this vitamin and mineral because of lower stomach acid levels. But research has shown that if there is any effect, it’s mild, so those concerns have been largely allayed.

The bottom line

PPIs are the most potent inhibitors of stomach acid available, and they’re a welcome addition to the medical armamentarium. But every pill — indeed, every medical intervention — is a risk-benefit balancing act. The PPI-clopidogrel interaction seems to be less important than once feared, but there are other reasons to be cautious about PPIs. You don’t need to take a PPI for the incidental case of heartburn. If you have a prescription, the reasons for it should be reviewed periodically to make sure they’re still valid; it’s common for people to take medications far longer than is necessary, and that is particularly true of the PPIs. If you need a PPI prescription — and many people do — it should be for the lowest dose that’s effective. There are differences in the chemical properties of the seven PPIs and how they are metabolized. But comparative studies haven’t yielded any clear-cut winners, so the less expensive PPIs are the best choice for most people.