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Long Term Use of Proton Pump Inhibitors (PPIs)

By: Luke Schilling

Is there potential harm associated with using PPIs long-term?  This is a question that researchers have been studying for over a decade, and the results aren’t clear-cut.  PPIs have been on the US market since the late 1980s by prescription and since the early 2000s over the counter.  They have long been considered some of the safest drugs for gastrologists to prescribe, but that doesn’t mean there aren’t some potential risks with long term use.

What are PPIs used to treat?

PPIs can be prescribed for a number of conditions including, but not limited to:

  • Healing of erosive esophagitis (EE)
  • Maintenance of healed EE
  • Treatment of gastrointestinal reflux disease (GERD)
  • Risk reduction for gastric ulcer (GU) associated with non-steroidal anti-inflammatory drugs (NSAIDs)
  • pylori eradication to reduce the risk of duodenal ulcer (DU) reoccurrence, combined with antibiotics
  • Pathological hypersecretory conditions, including Zollinger-Ellison (ZE) syndrome
  • Short-term treatment and maintenance of DUs
  • PPIs are also available over the counter and are used for the treatment of frequent heartburn

How should I treat heartburn over the counter (OTC)?

There are three classes of medications over the counter that can be used for heartburn:

  • Antacids
  • Histamine Antagonists (H2 Blockers)
  • Proton pump inhibitors (PPIs)

If your heartburn is associated with certain foods, like greasy or spicy foods, an antacid like Tums or Rolaids might be all you need to neutralize the stomach acid and relieve your symptoms of occasional heartburn.  If antacids don’t work, an H2 blocker like famotidine (Pepcid) or ranitidine (Zantac) would be a good next step to try.  If you have heartburn more two times or more a week and you have already tried the first two classes of medications, the last class to try is a PPI like lansoprazole (Prevacid) or omeprazole (Prilosec).  If none of these over the counter medications relieve your symptoms, or your symptoms last longer than two weeks, you should see your doctor.FullSizeRender

What are some potential risks for using PPIs long term?

Vitamin and Mineral Absorption

Some studies have shown that there may be a link between long term use of PPIs and mineral malabsorption.  Some minerals like iron, calcium, magnesium are better absorbed in an acidic environment.  Since PPIs lower the amount of acid in the stomach, their absorption may be reduced, but studies have shown mixed results and lack strong evidence that this is a concern.  Stomach acid helps absorb vitamin B12 from food, so theoretically, PPIs may reduce its absorption.  However, studies show conflicting results.  If a doctor puts you on a PPI long term it is important that routine blood work is done to monitor for any vitamin or mineral deficiencies.


Patients on PPIs may be at an increased risk for certain infections.  The hypothesis for the mechanism of action is that stomach acid is a defense mechanism against certain bacteria and when a PPI is on board, infections are more likely to occur.  The American College of Gastroenterology warns of increased risk of C. difficile (or “C diff”) and Community Acquired Pneumonia (CAP) for patients taking PPIs.  Other infections that have been linked to PPI use are traveler’s diarrhea, small intestinal bacterial overgrowth, spontaneous bacterial peritonitis, and interstitial nephritis.  More studies are needed to establish a definite relationship, but your doctor should be aware of the increased risk, especially if you are more prone to getting infections already.

Drug Interactions

PPIs may interact with two commonly prescribed medications:

  • Plavix (clopidogrel)
  • Trexall (methotrexate)

Clopidogrel is metabolized by enzyme classes CYP2C19 and CYP3A4 in your body to become its active form which helps prevent blood clots from forming.  PPIs also use the same enzymes to be metabolized, so PPIs may reduce the effectiveness of clopidogrel.  However, studies have shown very little effect on clinical outcomes for patients.

Methotrexate is most commonly prescribed for rheumatoid arthritis, but can also be used for psoriasis or certain cancers.  Using both a PPI and methotrexate together may decrease the elimination of methotrexate from your body, leading to methotrexate toxicity.  If you are taking a PPI and your doctor wants to start methotrexate, switching to an H2 blocker might be the best option, seeing as there is no interaction between H2 blockers and methotrexate.


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