The Purple Pill Problem: PPIs and Serious Side Effects

For the 10 to 20 million Americans who experience GERD, commonly called acid reflux, proton pump inhibitors (PPIs) like Nexium, Prilosec and Prevacid, can relieve their symptoms  of heartburn, chest pain and a hoarse throat. Increasingly, however, studies and clinicians are warning about the serious side effects of long-term use of PPIs, which can range from colon infections to pneumonia, an irregular heartbeat to muscle spasms, bone loss to seizures. Some patients also find that they quickly become dependent on these medications, using them for years rather than for the 8- to 12-week period usually recommended.

Robert Kuttner learned how easy it was to become dependent on a daily PPI the hard way. After suffering frequent bouts of heartburn, he changed his diet and began taking Prilosec. But his symptoms worsened, so he followed his doctor’s advice and took increasingly higher doses of the drug for longer and longer periods. This cycle continued for 7 years, until he stopped taking Prilosec. He felt better within just a few weeks.

“As I learned, this stuff can create a dependency,” says Kuttner, co-editor of The American Prospect magazine. “It creates a rebound effect, and then you need more and more of it.”

Prilosec, Nexium, Prevacid, Protonix and other brands of PPIs are among the most prescribed and most purchased drugs in the US. Between July 2013 and June 2014, Nexium — “the Purple Pill,” as the ads called it — was the 3rd most prescribed drug with 18,656,464 prescriptions written. It was also the 3rd top seller, with $6.3 billion in sales in the same one-year period. Over-the-counter PPIs, also big sellers, include Nexium OTC, Prevacid 24HR, Prilosec OTC and Zegerid OTC. But widespread use of PPIs doesn’t mean they are risk-free.

Kuttner’s experience underscores what more and more medical studies indicate and what clinicians are warning: PPIs can lead to worrisome health problems, especially if taken for a  year or longer.

Higher Doses and Prolonged Use Bring Problems

Andrew Chan, MD, a gastroenterologist at Massachusetts General Hospital, says that in general, most of the harmful side effects of PPIs are linked to higher doses and prolonged use of the drugs.

“You really want to encourage patients to take the lowest effective dose that manages symptoms effectively, for the shortest possible duration,” says Dr. Chan, an associate professor at Harvard Medical School and a co-author of one of the studies that found a connection between regular PPI use and bone fracture.

This research, published in the BMJ, involved 79,899 women who answered questionnaires about PPI use over an 8-year period.

Postmenopausal women who took PPIs for at least 2 years had a 35% higher risk of hip fracture compared with postmenopausal women who did not use the drugs, according to the study. Participants who were current or former smokers had an even greater risk: They were 50% more likely to sustain a hip fracture.

One theory behind PPIs’ negative effect on bone strength centers on the notion that because the drugs lower stomach acid, they may hamper the body’s absorption of calcium — a mineral vital to bone health.

GERD Symptoms and Treatment Options

Commonly called acid reflux, GERD is a chronic condition in which stomach acid or bile backs up — or refluxes — from the stomach into the esophagus. This happens because the lower esophageal sphincter (LES), a muscle that acts as a valve between the stomach and esophagus by opening temporarily to allow food and liquid to flow into the stomach, weakens over time or relaxes abnormally.

Symptoms include heartburn, a bitter taste in the mouth, chest pain, a dry, persistent cough, hoarseness, and a sensation of a lump in the throat. If untreated, GERD can damage the lining of the esophagus and lead to complications such as bleeding, ulcers, respiratory problems, scarring that causes swallowing difficulties, and in some cases, Barrett’s esophagus, a precancerous condition, which in turn can lead to cancer of the esophagus.

When it comes to treating patients diagnosed with GERD, physicians often turn to PPIs, which work by reducing the secretion of acid in the stomach. They are available in both prescription and over-the-counter (OTC) forms. In addition to being used to treat GERD, they are prescribed for other disorders, including ulcers and inflammation of the esophagus.

PPIs can relieve GERD symptoms, allowing the lining of the esophagus to heal. Proponents of the drugs note that they generally have a record of safety and effectiveness. Detractors, however, point to their long list of side effects, which run the gamut from nausea and headaches to bone fractures and seizures.

FDA Issues Safety Warnings

In fact, the FDA has issued several safety warnings about the use of prescription-strength PPIs and lower-dose OTC forms of the medicine. According to the federal agency, PPIs may lead to low levels of magnesium in the blood (hypomagnesemia), especially if taken for more than one year. Hypomagnesemia can cause muscle spasms, irregular heartbeat and seizures. The drugs may also be linked to greater risk of C. difficile-associated diarrhea, according to a 2012 FDA warning.

A recent Mayo Clinic study published in the journal Microbiome points to a possible reason for this increased risk of infection with Clostridium difficile bacterium that causes severe diarrhea. Though the study was done with a small sample, the results showed that PPIs disrupted healthy “gut microbiome” (bacteria), and found that the problems were reversible with cessation of PPI use.

“Evidence has been mounting for years that long-term use of proton pump inhibitors poses increased risks for a variety of associated complications, but we have never really understood why,” says John DiBaise, M.D., a Mayo Clinic gastroenterologist and senior author of the study. “What this study does for the first time is demonstrate a plausible explanation for these associated conditions.”

Use of PPIs for long periods of time has also been associated with pneumonia,  fractures of the hip, wrist and spine, and iron and vitamin B12 deficiencies, according to the FDA, the National Digestive Diseases Information Clearinghouse (NDDIC) and several medical studies.

Other research, including the 2009 Danish study mentioned above, has also shown that PPI use may lead to “rebound acid hypersecretion” — the problem that Kuttner describes. According to the study, “PPI therapy for 8 weeks induces acid-related symptoms in healthy volunteers after withdrawal.”

While no measures have been consistently shown to prevent or minimize side effects, Dr. Chan says, certain steps may help. For example, PPI users can lower their risk of hip fracture by boosting their calcium intake and staying physically active.

Drug Interactions

PPI labels now carry warnings about possible interactions with certain drugs, including methotrexate, which is used to treat psoriasis, rheumatoid arthritis and some cancers. Nexium and Prilosec labels will include an interaction warning about clopidogrel, which prevents blood clots.

PPIs may interact with the above drugs and other medicines by affecting how they are metabolized by the body or interfering with their absorption. As a result, the effectiveness of the other medication, such as the blood thinner clopidogrel, may be decreased.

Before you head to the pharmacy to fill your PPI prescription, tell your doctor about all the medicines and supplements you take. Other drugs and supplements that may interact with PPIs include:

  • other blood thinners, such as warfarin
  • diazepam (anxiety medication)
  • digoxin (heart medicine)
  • ketoconazole and other antifungal drugs
  • phenytoin (a seizure drug)
  • tacrolimus (immune system medicine)
  • prescription antiretroviral drugs (for HIV infection)
  • medicines and supplements containing iron
  • St. John’s wort

Each PPI can cause side effects that fall into the “less serious” category, according to the Physicians’ Desk Reference and other medical sources. These include headache, nausea, constipation, gas, mild diarrhea and insomnia. Be sure to tell your doctor if you experience these, or any other, side effects.

What Are the Options?

Before relying on PPIs to prevent or lessen GERD symptoms, Dr. Chan says, people should make lifestyle changes, such as losing weight, avoiding foods that trigger or aggravate symptoms, refrain from smoking and minimize alcohol intake. Other lifestyle changes include these simple strategies:

  • Don’t lie down for two to three hours after eating.
  • For pain relief, avoid aspirin, ibuprofen (Advil, Motrin), or naproxen (Aleve, Naprosyn). Take acetaminophen (Tylenol) instead.
  • Drink plenty of water when you take any medicine. If you are prescribed a new medicine, ask your doctor if it will worsen your acid reflux symptoms.
  • Raise the head of your bed by about 6 inches by placing wood or cement blocks under the legs at the head of the bed. Plastic risers are also available online, and are typically advertised as a way to increase storage space under your bed. Be sure to look for sturdy risers that can support your weight and your bed’s weight.
  • Avoid tight waistbands, belts and other clothing that fits snugly around your waist.

“Sometimes there isn’t any other option than to take these medications,” says Dr. Chan, noting that the best candidates for PPI therapy are patients who have adjusted their lifestyles but continue to experience GERD symptoms on a regular basis.

Physicians typically recommend avoiding a long list of foods and beverages thought to cause or worsen GERD symptoms by boosting stomach acid production, irritating the esophageal lining or relaxing the LES. They include fried, fatty or spicy foods, tomatoes, tomato sauce, citrus fruits and juices, garlic, onion, chocolate, mint, coffee, carbonated drinks and alcohol. See MedShadow’s story Food as Medicine: GERD.

But not everything on that “foods to avoid” list is a problem for every patient, says Dr. Chan, who recommends using the guidelines as a starting point.

“I generally ask patients to keep a food diary and record their symptoms to see if there are any particular foods that are associated with their symptoms, then work to eliminate those foods and see if that makes a difference.”

Coffee, butter and cream are the main culprits for him, Kuttner says. “As long as I watch my diet and take a low dose of Pepcid (an antacid called an H2 blocker), I’m fine.”

Some GERD sufferers also find relief by chewing licorice root extract tablets  before meals. DGL — deglycyrrhizinated licorice — products are the safest to use because they do not contain glycyrrhizin, a compound that in high amounts can cause serious side effects, including high blood pressure, headaches, fatigue and reduced potassium levels.

DGL, which usually is taken within 20 minutes of a meal, is a demulcent — it helps protect the esophagus from acid reflux by coating the esophageal lining.

To be safe, consult your doctor before trying DGL, especially if you have high blood pressure or take diuretics, corticosteroids or other drugs that decrease the body’s potassium levels. If taken with those medicines, licorice can cause dangerously low potassium levels.

If you have been diagnosed with GERD, consider trying behavior and lifestyle changes first to see if you feel better. If not, talk to your doctor about your options. You may discover that you can keep your symptoms in check by taking an OTC antacid as needed — a safer alternative to a PPI drug, whose risks may outweigh the benefits.

For more information

Combatting Acid Reflux May Bring Host of Ills (The New York Times)
How Your Reflux Medication Affects Your Health (U.S. News and World Report)
Side-effect risk to millions who take unnecessary stomach drugs (Daily Mail)

Additional Resources

Understanding Heartburn and Reflux Disease (American Gastrological Association)
National Institute of Diabetes and Digestive and Kidney Diseases
Gastroesophageal reflux disease (University of Maryland Medical Center’s Complementary and Alternative Medicine Guide)
Gastroesophageal Reflux Diseasease (The Society of Thoracic Surgeons)
Practice Guide: GERD (University of Michigan)


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