Combination Use of Proton Pump Inhibitors and H2 Blockers: Is This Appropriate?

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Proton pump inhibitors (PPIs) and histamine H2 antagonists (H2 blockers) are the most common medications prescribed for the treatment of gastroesophageal reflux disease (GERD) or peptic ulcer disease (PUD). The treatment usually begins with antacids or over-the-counter H2 blockers for mild symptoms. Then steps up to PPIs or higher dose of H2 blockers for moderate to severe symptoms. Occasionally, PPI and H2 blocker may be combined to treat certain patients. This article will discuss the appropriateness of combination therapy and its associated risk.

Hospice patients are predisposed to PUD due to many risk factors including the age-related change in gastric mucosal defense, serious illness and long-term use of NSAID. The majority of patients are managed clinically with a once daily dose of a PPI. The unofficial use of twice daily dosing of PPI or the addition of a nighttime H2 blocker to the daytime PPI therapy may be required for optimal control in a subset of patients such as those with Barrett’s esophagus or extra-esophageal disease (1).

PPIs and H2 blockers have overlapping mechanisms of actions, which ultimately suppress gastric acid secretion, but at different stages of production. When used together, the extensive acid suppression therapy may decrease the absorption of certain nutrients (i.e. vitamin B12, iron and calcium), which are dependent upon an acidic environment to be absorbed in the stomach. There is also a significant risk of hip fractures with long-term PPI treatment. This risk theoretically may be further increased with the combination therapy due to impaired calcium absorption. Combination therapy may also increase the risk of gastrointestinal infections. A recent meta-analysis evaluated Clostridium difficle (C.diff) infections in patients receiving PPIs and found an association between PPI use and an increased risk of C diff (2). H2 blockers have been showed to carry a lower risk for gastrointestinal infection compared to PPIs. However, when both PPIs and H2 blockers are used together, the further reduction of gastric acid may allow for bacteria to multiply in the digestive system and the risk of infection may be increased.

In general, long-term combination therapy does not offer any additional benefit for the management of GERD and may only be appropriate in a particular subset of patients (i.e. Barrett’s esophagus or extra-esophageal disease). Practitioners are encouraged to re-evaluate patient’s condition and consider discontinuation if patient no longer exhibits symptoms or has no indication for continued use. Since PPIs provide superior acid suppression, healing rates and symptom relief compared to H2 blockers, our recommendation is to discontinue H2 blockers over PPIs. If it is determined PPI is no longer indicated for a patient, it should be tapered to avoid rebound acid reflux. For patients who require long-term PPI therapy, the lowest effective dose should be considered.


  1. Katz PO, Tutuian R. Histamine Receptor Antagonists, Proton Pump Inhibitors and their combination in the treatment of gastroesophageal reflux disease. Best Pract & Res Clin Gastroenterol 2001;15(3):371-84.
  2. Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. The American journal of gastroenterology 2012 Jul;107(7):1011–9.

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