Proton Pump Inhibitors: Dangerous and Habit-Forming Heartburn Drugs

Robert Kuttner, co-editor of The American Prospect magazine, had experienced a few bouts of mild heartburn, when a particularly severe episode sent him to the emergency room. After his doctor prescribed PRILOSEC (omeprazole), a common heartburn therapy, he thought that this would resolve his condition.

He never imagined that this drug, intended to treat his symptoms, would actually make them worse and that he would become dependent for years on ever-increasing doses of the medication in a dangerous cycle ending only after he stopped taking PRILOSEC and switched to other safer therapies.

This story is likely all too common among patients placed on a widely used class of medications known as proton pump inhibitors (PPIs) — PRILOSEC being the most widely prescribed — which suppress stomach acid and are used to treat conditions such as heartburn and other, more severe illnesses. The drugs traditionally have been considered largely harmless by patients and physicians alike. Yet PPIs have been increasingly associated with a range of dangerous, and sometimes fatal, side effects and can even cause, as in Kuttner’s case, long-term dependence.

In August 2011, Public Citizen filed a petition with the Food and Drug Administration (FDA) to put black box warnings on all PPIs to warn doctors and patients of these life-threatening side effects and to remind doctors that there are many safer alternatives for conditions such as acid reflux that often work just as well. (To read the petition, visit www.citizen.org/petition-asking-fda-to-add-warnings-to-ppis.) The petition was co-signed by Kuttner and Dr. Helge Waldum, a physician-researcher and author of 135 scientific papers, among them the first study showing that patients could become dependent on PPIs.

The absence of prominently displayed risk information in PPI labels is likely a key contributor to the vast amount of overuse of the drugs, as doctors may not be aware that such serious risks exist and thus resort to PPIs as a first option for even mild cases of heartburn. Most patients on the drugs do not have a documented need for the therapy, and many more could easily be switched to safer options.

PPIs available in the U.S.

There are currently eight different prescription PPI medications and three over-the-counter PPI medications available on the U.S. market. (See the table.)

Some of the FDA-approved uses for prescription PPIs are treatment of gastric ulcers and erosive esophagitis, as well as prevention of upper gastrointestinal bleeding, commonly seen with nonsteroidal anti-inflammatory drug (NSAID) use. One of the most common conditions for which PPIs are prescribed is gastroesophageal reflux disease (GERD), or heartburn.

Many people have experienced GERD at some point in their lives, and for some, it is so severe that they seek out, and often need, medication for relief. But for most, the symptoms are mild and fluctuate with lifestyle or diet, and minor modifications to either could alleviate symptoms. Yet studies show that many of these people are placed on PPIs unnecessarily — and once they’re on, they may have a hard time getting off the drugs.

History and popularity of PPIs

PPIs first emerged on the scene in the 1980s, at a time when patients often medicated for heartburn on an as-needed basis, using safer antacid therapies or modifying their daily routines in ways that often worked to relieve symptoms, such as raising the head of the bed or avoiding certain foods in excess. The need for long-term, once-daily acid-suppressing therapy was relatively uncommon and reserved for severe cases of acid reflux. Histamine-2 receptor antagonists (H2As), such as cimetidine (TAGAMET) and ranitidine (ZANTAC), were the drugs of choice for quelling excessive acid production in these cases. These drugs work by suppressing acid production in the stomach, but not as profoundly as do PPIs. They therefore carry a lower risk for serious adverse effects.

However, following their introduction in the U.S., PPIs rapidly rose in popularity over the next two decades. This was due in part to their considerable effectiveness for certain serious conditions, such as peptic ulcer disease, but much more so to their widespread inappropriate use for indications for which there is no evidence of benefit and their (incorrectly) perceived lack of side effects. PPI use increased more than eight-fold from 1995 to 2006, and in 2009, there were 119 million prescriptions filled for the medications in the U.S.

Contributing to this explosion in PPI use were massive promotional campaigns and a disturbing trend of older PPIs being repackaged in new, slightly tweaked but otherwise identical forms.

NEXIUM (esomeprazole) is a poster child of this trend. NEXIUM, the so-called “purple pill,” was simply a reformulation, functionally identical to a previously approved drug, PRILOSEC (omeprazole), with a patent expiring around the time of NEXIUM’s introduction. In 2001, drug manufacturer AstraZeneca released NEXIUM amid a large-scale promotional campaign, with a half-billion dollars spent on marketing in just the first year. In response, sales predictably climbed to astronomical levels. By 2009, NEXIUM was easily the top-selling PPI and ranked second in both retail sales ($5 billion) and number of prescriptions filled (26.5 million) among all brand-name drugs in the country.

This trend of repackaging older PPIs in slightly modified (and much more expensive) forms continued with the recent approval of DEXILANT (dexlansoprazole, which is a reformulation of PREVACID, or lansoprazole, now available in a cheaper, generic form). NEXIUM and DEXILANT are prime examples of the decreased innovation seen in the pharmaceutical industry in recent years, and of the desperate — and wildly successful — attempts of the industry to get doctors to prescribe, and patients to use, exorbitantly priced drugs that are essentially identical to older, cheaper versions.

Relief at a high cost

Due in large part to these promotional campaigns, PPI sales have skyrocketed. But what are the costs of such widespread use? And do these costs outweigh the benefits?

The economic cost of PPI use is high enough, with $13.6 billion spent on the drugs in one year alone (2009), making them the third highest-selling class of drugs in the country. By contrast, safer H2A therapies are not even among the 15 top-selling drug classes, not to mention the lower prices of antacids and the safest of all options: diet and lifestyle changes.

Unfortunately, this higher spending on PPIs does not confer any increase in safety or, in most cases, effectiveness.

Dangerous side effects

PPIs are so named because of the mechanism they use to shut off the production of stomach acid, which they do very well. So well, in fact, that a multitude of side effects can occur, in part as a result of this shutdown of one of the body’s most basic functions. As Dr. Waldum observed in his statement in support of our petition, many scientists and physicians “dismiss the alteration by PPIs of central biological functions [of stomach acid] and believe that some of these basic functions can be removed without adverse consequences.”

This perception has now been refuted by an increasing body of research showing that PPIs do, in fact, have unintended consequences. The drugs cause a wide range of side effects, and although some of these are already included in the labels, none (including those that are life-threatening) are displayed prominently as black box warnings. Thus, physicians who routinely prescribe PPIs as initial therapy for GERD may not be aware of these serious risks when deciding whether to start patients on the drugs.

Furthermore, new side effects surface frequently. In just the past year and a half, the FDA has released two safety alerts warning that PPI use was associated with potentially fatal side effects: osteoporotic fractures (of the hip, spine and wrist) and severe magnesium deficiency. These are just two of many serious adverse reactions that have been associated with PPI therapy. The major side effects of PPI therapy documented in our petition include:

• Bone fracture. In 2010, the FDA announced that it was requiring a change in prescription and over-the-counter labeling of PPIs to include safety information warning patients about the risk of hip, spine and wrist fractures after using PPIs for a year or more. This announcement came after a review by the FDA of seven large studies showing that the drugs were linked with a higher rate of these serious fractures in women with osteoporosis. A few months later, the labels of all PPIs were changed to reflect this new information, although no (more prominent) black box warning in the labels was required. Women with osteoporosis are already at high risk for fractures, especially hip fractures, which are often fatal. This risk should be seriously considered by these women before starting long-term therapy.

• Infection. PPIs increase the risk for certain serious, and often fatal, infections, such as pneumonia and a severe type of diarrhea known as Clostridium difficile, which is normally seen only in severely ill patients or those on antibiotics. Maintaining normal amounts of stomach acid is important in preventing harmful bacteria from colonizing the intestinal lining. As PPIs work by largely eliminating this acid, bacteria can thrive and cause infections in the intestines or even the lungs. There is currently only limited risk information on Clostridium difficile infection and no information at all on pneumonia risk in PPI product labels.

• Magnesium deficiency. In March 2011, the FDA released a safety alert warning that long-term use of PPIs may cause severe magnesium deficiency. Magnesium is an essential electrolyte, and a decrease in levels can be life-threatening, causing dangerous heart-rhythm disorders and seizures. Certain patients, especially the elderly, may be taking other medicines that decrease magnesium levels (such as diuretics for high blood pressure) or medications (e.g., digoxin) that can prove fatal in the presence of low magnesium. Patients on long-term PPI therapy, especially those taking these other medications, should have magnesium levels checked both before starting therapy and periodically throughout treatment.

• Drug-drug interactions. In 2009, the FDA released a warning saying that taking omeprazole, one of the oldest and most popular PPIs, could diminish the effectiveness of another widely used drug to prevent heart attacks and strokes, clopidogrel (PLAVIX). The warning was based on multiple studies that showed increased rates of heart attacks in patients who took both medicines compared to those who took only PLAVIX. The FDA restricted its warning solely to omeprazole, even though studies have shown that other PPIs could also be implicated in this interaction. PPIs have also been shown to reduce levels of the immune suppressants methotrexate (FOLEX, TREXALL) and mycophenolate mofetil (CELLCEPT), potentially reducing their effectiveness in treating cancer and preventing organ transplant rejection, respectively. Patients taking any of these medications should talk with their doctors before starting (or continuing) PPI therapy.

• Vitamin B12 deficiency. Vitamin B12 is an essential vitamin needed for nerve signaling and production of blood cells, among other functions. PPIs may cause vitamin B12 deficiency, leading to anemia or serious neurological dysfunction. Elderly patients and others (such as vegans) at risk for low B12 levels may need to reconsider PPI therapy with their doctors or at least monitor B12 levels before and during treatment.

• Acute interstitial nephritis. The risk for a serious kidney disease known as acute interstitial nephritis (AIN) may be increased with long-term use of PPIs. In 60 case reports describing AIN after PPI use, one-third of patients required steroid therapy, and three were placed on dialysis (one permanently). Although it’s unclear whether the PPI use actually caused the kidney disorder, patients with existing kidney disease should talk with their doctors about this potential side effect before starting PPI therapy.

PPIs may be habit-forming, causing the condition they are supposed to treat

The previously mentioned serious side effects are all the more likely to occur given that people tend to use PPIs for much longer than originally intended. When first developed, the drugs were designed for short-term relief of GERD, and on almost all PPIs, the recommended therapy for uncomplicated heartburn is only four to eight weeks. However, recent studies have shown that patients are increasingly staying on the drugs for years, in part because these seemingly innocuous medications may be habit-forming.

Research shows that after using PPIs for a month or more, patients who stop taking the drugs make even more stomach acid than they did before they started, a phenomenon known as rebound acid hypersecretion, which causes acid reflux symptoms to return at an even greater intensity than before therapy. The symptoms prompt patients to begin taking the PPI again, creating a long-term dependence on the medication. This is particularly worrisome for the large number of patients who did not even need the drugs in the first place. In other words, PPIs actually cause the symptoms they are intended to treat — even in previously healthy patients.

Kuttner’s story is a case in point. After years of unsuccessfully trying to control his symptoms with ever-higher doses of a PPI, the reflux resolved only after a physician tapered him off the drug to safer therapies. Now largely symptom-free, Kuttner said:

“My experience certainly seems to confirm the pattern of PPI medication causing — or in my case, seriously aggravating — the condition that it supposedly treats. In my case, the PPI seemed to have primed my system to produce increasing amounts of acid so that over time I was more prone to more attacks triggered by ever more minor departures from a very low fat diet. The ever increasing amounts of PPI helped only temporarily and required dependence on even higher doses, and so on, over several cycles. Only getting off the PPI reversed what seemed to be a chronic and progressive condition.” [emphasis in original]

For too many patients, serious risks come with no benefit

As previously mentioned, one of the main reasons for the rapid rise in popularity of PPIs has been their widespread inappropriate use for indications for which there is no evidence of benefit. For most patients, this overutilization of PPIs has serious adverse consequences but not many benefits when compared to alternative heartburn therapies. Here we outline four key reasons for the massive overuse of PPIs. (See recommendations on how to treat heartburn symptoms without resorting to this risky therapy.)

• Inappropriate prescribing. PPIs are meant to be taken for serious conditions (e.g., peptic ulcer disease and rare diseases where stomach acid secretion is greatly increased) and to protect against the harmful effects of NSAIDs on the stomach lining. For these conditions, they have been proven to be of benefit. But patients taking PPIs for these reasons are a minority. Studies have shown that one-half to two-thirds of all patients on PPIs do not, in fact, have an appropriate indication for treatment, and many become dependent on the drugs, taking them much longer than indicated for mild cases of heartburn.

• Unnecessarily high doses and daily therapy. Another problem, even in patients for whom PPIs are indicated, is the use of unnecessarily high doses. Most patients on PPIs are prescribed high doses to be taken on a daily basis, but these high doses are often neither necessary nor more effective than lower doses. Multiple studies have confirmed that lower doses (often only half the dose recommended in the label) and less frequent use (every other day) are in many cases just as effective as higher doses, and put patients at a lower risk for some of the serious side effects mentioned above. On-demand therapy (where PPIs are not taken regularly, only when symptoms arise) is also effective for many patients.

• PPIs as the first choice for GERD. In this age of overreliance on medications for almost every minor condition, it is not surprising that PPIs are often thought of as the first option in treating heartburn. Even the professional association of gastroenterologists (the American Gastroenterological Association) has recommended that PPIs be used as initial therapy for GERD. However, as shown above, there are many safer alternatives that are often just as effective as, and much cheaper than, daily-dose PPI therapy. In fact, studies show that most patients wouldn’t even need PPI therapy were they to follow the “step-up” regimen for treating heartburn outlined at the end of this article. The regimen starts with lifestyle changes and progresses gradually to more intense therapy, with PPIs indicated only if these other treatments fail to relieve symptoms.

• PPIs unnecessarily started during hospitalization. Estimates vary, but anywhere from 20 to 70 percent of patients admitted to the hospital will be unnecessarily started on a PPI. This has become common practice in hospitals, where starting a PPI is as easy as checking a box on the admission checklist. And many, if not most, of these patients are continued on the drugs for no apparent reason after discharge. In one study, up to half of all hospitalized patients inappropriately placed on acid-suppressing drug therapy (most commonly PPIs) were still on the drugs six months after being sent home.

Summary: PPIs are helpful for some but unnecessary and risky for most

PPIs are now one of the most widely used classes of prescription drugs, with an estimated 1 out of every 20 people in the developed world currently taking one of these medications. However, given that the majority of this use is probably inappropriate, with minimal or no benefit to the patient, and that new, life-threatening risks with long-term therapy are frequently emerging, it is time for the medical community to re-evaluate the role of PPIs in everyday practice.

As a critical first step, FDA-approved black box warnings are needed, so doctors and patients can be made aware, in a clear and prominent manner, of the risks of PPI treatment in order to make an informed decision on whether to start therapy, especially in cases where there exist much safer and less expensive alternatives (e.g., in the case of heartburn). PPIs may indeed prove to be the only treatment option for many patients but should not be the first option for mild cases of heartburn.

PPIs were never intended to be taken for such long periods of time for minor symptoms, and people had been dealing with heartburn safely and effectively for decades prior to the arrival of PPIs on the market. This key point has gone by the wayside as doctors and patients increasingly rely on quick fixes for symptoms such as heartburn, which often require only minor changes in everyday habits.

The overreliance on PPIs has needlessly exposed millions of people to serious harms, and many did not even need the drugs to begin with.

With this risk information in mind, patients considering PPI therapy — and those already taking the drugs — for heartburn should raise these safety concerns with their doctors and ask about the safer, just as effective, options.

PPIs Available in the U.S.

 * VIMOVO is a combination of the PPI esomeprazole and the nonsteriodal anti-inflammatory drug (NSAID) naproxen)