In 2008 americans spent more than $14 billion on heartburn treatments called proton pump inhibitors—such as Nexium, Prevacid and Protonix—making them second only to lipid regulators as the best-selling drug class in the country. But recent research suggests that the popularity of these drugs in part results from unnecessary prescriptions that may be putting millions of people at risk. Long-term use has been linked to withdrawal symptoms, an increased risk of bacterial infection, hip fracture and even possibly nutritional deficiencies.

Proton pump inhibitors, or PPIs, work just as their name implies: they block an enzyme system in the stomach’s cells essential for pumping out acid. Although they are meant to treat only gastroesophageal reflux and peptic ulcer disease, “a number of people who have gastrointestinal symptoms that are not due to acid are given PPIs,” perhaps because of misdiagnoses or because “the physician didn’t have any better alternative,” says Colin W. Howden, a gastroenterologist at the Northwestern University School of Medicine.

Doctors also give PPIs to hospital patients who have serious injuries to prevent gastrointestinal bleeding and stress ulcers. But not only are such prescriptions questionable—only one intensive care patient is saved from serious bleeding for every 900 treated—they are also frequently given to patients who do not need them, despite the fact that the American Society of Health System Pharmacists released guidelines in 1999 delineating who specifically to treat. “This spilled out into, ‘Let’s do this for all or most of our hospitalized patients,’ ” explains Joel Heidelbaugh, an associate professor of family medicine at the University of Michigan at Ann Arbor. He co-authored a 2006 study reporting that his university’s health system annually spends about $110,000 on unnecessary PPI prescriptions. A more recent 2009 study published in the American Journal of Medicine concluded that up to 60 percent of PPI prescriptions for hospitalized patients are unnecessary.

Bizarrely, Heidelbaugh has also found that people admitted to hospitals for gastrointestinal symptoms are less likely to be put on PPIs than people admitted for other problems, such as rheumatological disorders.* And approximately one third of patients who start taking the drugs refill their prescriptions without needing to. “We know that people are put on them and left on them; we know it costs something; and we know it’s not without risk,” Heidelbaugh says.

Indeed, multiple studies suggest that long-term use of PPIs can cause problems. A 2006 study in the Journal of the American Medical Association reported that people taking long-term, high-dose proton pump inhibitors are 2.65 times as likely as controls to experience hip fractures, possibly because the drugs inhibit calcium absorption. By increasing the pH of the stomach, PPIs also boost the risk of infection: studies published in JAMA in 2004 and 2005 reported that subjects on acid-suppressing drugs are nearly twice as likely to develop pneumonia, and nearly three times as likely to acquire a potentially deadly infection from the bacterium Clostridium difficile, as unmedicated subjects (although the overall risk is low). And in March researchers reported in Clinical Gastroenterology and Hepatology that half the subjects taking PPIs at an Italian hospital, compared with only 6 percent of healthy subjects not taking the drugs, suffered from an infection of the small intestine caused by bacteria from the colon. The condition can trigger diarrhea and impede nutrient absorption.

Most worrisome, long-term use of PPIs may cause the very symptoms the drugs are designed to treat. In a 2009 study published in Gastroenterology, researchers split 120 healthy patients into two groups. Half received a placebo for 12 weeks, while the other half received a PPI for eight weeks, followed by a placebo for the last four weeks. At the end of the trial, 22 percent of subjects who had taken the drugs reported suffering from heartburn and acid reflux, compared with only 2 percent of those who had never taken the drugs.

Howden points out that because the trial was conducted in healthy subjects, knowing whether PPIs would worsen symptoms in patients with existing acid problems is impossible. But “there is no reason to believe that this should not be the case,” says trial co-author Peter Bytzer, a professor of medicine at the University of Copenhagen in Denmark. “I would even anticipate that the effects might be more pronounced in patients who already suffer from heartburn.” And if that’s true, then no wonder PPIs are so popular, he says: they may well be addictive.

Currently no national move exists to curb PPI overuse, but “there are many efforts, mostly specific to institutions, to raise awareness about this issue and to try to limit nonjudicious PPI use,” Heidelbaugh says. The Carolinas Medical Center in Charlotte, N.C., saved about $100,000 in annual drug costs after setting such guidelines, and a similar move by St. Paul’s Hospital in Vancouver cut daily medication costs nearly in half without worsening clinical outcomes.

*Clarification (6/23/10): This statistic refers to PPIs given for stress ulcer prophylaxsis.