What are the side effects of Proton Pump Inhibitors (PPIs)?

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Last updated: April 24, 2025View editorial policy

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From the Guidelines

Proton pump inhibitors (PPIs) can cause several side effects, but the most recent and highest quality study suggests that the benefits of PPIs outweigh the risks for most patients 1.

Common Side Effects of PPIs

  • Headache
  • Nausea
  • Abdominal pain
  • Flatulence
  • Diarrhea
  • Constipation These side effects typically resolve on their own and affect about 1-10% of users.

Serious Concerns with Long-term PPI Use

  • Increased risk of vitamin B12 and magnesium deficiencies
  • Bone fractures due to reduced calcium absorption
  • Increased susceptibility to certain infections like C. difficile and pneumonia
  • Kidney problems including chronic kidney disease
  • Potential increased dementia risk PPIs may also interact with certain medications like clopidogrel, reducing their effectiveness.

Recommendations for PPI Use

  • Patients with an indication for chronic PPI use who take twice-daily dosing should be considered for step down to once-daily PPI 1.
  • Double-dose PPIs have not been studied in any RCT and are not US Food and Drug Administration–approved.
  • Higher-dose PPIs increase the costs of care and have been more strongly associated with certain complications.

Managing PPI Side Effects

If experiencing troublesome side effects, don't stop taking PPIs abruptly but consult your healthcare provider who may adjust your dosage, switch to another medication class like H2 blockers, or implement a tapering schedule to prevent acid rebound. The most recent study suggests that de-prescribing of PPIs should be done under the supervision of a healthcare provider to minimize potential harm 1.

From the FDA Drug Label

Omeprazole delayed-release capsules can cause serious side effects, including: • A type of kidney problem (tubulointerstitial nephritis). • Diarrhea. • Bone fractures. • Certain types of lupus erythematosus. Omeprazole delayed-release capsules can have other serious side effects.

The possible side effects of omeprazole delayed-release capsules include:

  • Kidney problems: tubulointerstitial nephritis
  • Diarrhea: may be caused by an infection (Clostridium difficile) in the intestines
  • Bone fractures: people who take multiple daily doses of PPI medicines for a long period of time (a year or longer) may have an increased risk of fractures of the hip, wrist, or spine
  • Lupus erythematosus: certain types of lupus erythematosus or worsening of the lupus they already have These side effects are reported in the drug label of omeprazole delayed-release capsules 2 and 2.

From the Research

PPI Side Effects

  • The current evidence suggests that proton pump inhibitors (PPIs) are generally considered safe, but there are some potential side effects associated with their long-term use 3, 4.
  • Some of the reported side effects include:
    • Enteric infections, such as Clostridium difficile 3, 4, 5, 6
    • Osteoporosis-related fractures 5, 6
    • Micronutrient deficiencies, such as vitamin B12, magnesium, and iron 5, 6
    • Acid rebound after abrupt discontinuation of PPIs 5
    • Potential increased risk of kidney disease, especially in the elderly with long-term PPI use and pre-existing kidney disease 5, 6
    • Reports of dementia, pneumonia, myocardial infarction, and stroke, although the causal association is still subject to validation 5
  • It is essential to note that the quality of the evidence underlying most of these associations is very low and cannot ascribe cause and effect 3.
  • The key to mitigating adverse effects is the rational use of PPIs at the lowest effective dose and in the shortest possible duration 4, 5.
  • Higher-quality data is needed to better understand PPI-associated risks of adverse effects 6.

References

Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

Research

Proton pump inhibitors: misconceptions and proper prescribing practice.

Current opinion in gastroenterology, 2020

Research

SAFETY OF LONG-TERM PROTON PUMP INHIBITORS: FACTS AND MYTHS.

Arquivos de gastroenterologia, 2022

Research

Proton pump inhibitors: Understanding the associated risks and benefits of long-term use.

American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 2023

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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