Are there any problems with long-term use of omeprazole (proton pump inhibitor, PPI)?

Long-Term Omeprazole Use: Safety Considerations and Management

Long-term omeprazole use is generally safe when there is a clear indication, but patients should be maintained on the lowest effective dose and periodically reassessed for continued need, as observational studies suggesting serious adverse events have not been confirmed in randomized controlled trials. 1

Evidence Quality: Critical Context

The American Gastroenterological Association emphasizes that all studies reporting associations between PPIs and serious adverse events have been observational and cannot establish causality, while randomized controlled trials comparing PPIs with placebo have consistently shown no higher rate of adverse events among PPI users. 1 Many reported associations lack plausible mechanisms and are likely explained by residual confounding and analytic biases. 1

Established Risks with Higher Probability of Causality

Gastrointestinal Infections

• PPIs may increase susceptibility to gastroenteritis and other enteric infections due to reduced gastric acid barrier. 2, 1
• Increased risk of Clostridium difficile-associated diarrhea, particularly in hospitalized patients. 3
• The FDA label specifically warns about severe diarrhea caused by C. difficile infection requiring immediate medical attention. 3

Rebound Acid Hypersecretion

• Common after discontinuation of long-term PPI therapy, lasting 2-6 months, representing a physiological response to secondary hypergastrinemia. 1
• This rebound effect may necessitate continued PPI use even when the original indication has resolved. 4

Bone Fractures

• People taking multiple daily doses for ≥1 year may have increased risk of hip, wrist, or spine fractures. 3
• However, large randomized controlled trials including the COMPASS trial found no differences in fracture rates between PPI and placebo groups. 1
• The association appears strongest in patients with pre-existing risk factors (diabetes, chronic kidney disease, arthritis) and ≥2 years of use. 1

Micronutrient Deficiencies

Vitamin B12

• Large randomized trials have not shown significant differences in serum B12 levels at 5 years, though these studies had methodological limitations. 1
• Deficiencies may occur in elderly patients or those with Zollinger-Ellison Syndrome on high doses for prolonged periods. 4

Iron Deficiency

• Dose-dependent associations exist between continuous PPI use and iron deficiency, particularly after ≥1 year of use. 1
• Reduced gastric acid impairs absorption of non-heme iron. 1
• One study showed significant reductions in red blood cells and indices in patients on long-term omeprazole 40 mg. 5

Magnesium

• Meta-analysis shows 71% higher risk of hypomagnesemia with PPI use (adjusted OR: 1.71; 95% CI: 1.33,2.19). 1
• The FDA includes precautionary notices regarding anemia risk. 1

Calcium and Vitamin D

• One study reported significant declines in serum calcium and vitamin D3 levels with prolonged omeprazole use. 5

Associations with Weaker or Conflicting Evidence

Cancer Risk

• No causal relationship established in randomized controlled trials regarding PPI use and cancer risk. 1
• Japanese population-based data suggest possible association with gastric cancer, though rates were similar between PPIs and H2-receptor antagonists. 1
• Long-term use has not been convincingly proven to cause or be associated with progression of chronic gastritis, gastric atrophy, or intestinal metaplasia in the absence of H. pylori infection. 4

Enterochromaffin-Like (ECL) Cell Hyperplasia

• Demonstrated in up to 50% of children receiving PPIs for >2.5 years, though considered a benign histologic change. 2, 1
• Five-year randomized trial comparing vonoprazan and lansoprazole found infrequent and comparable proportions developing ECL hyperplasia. 1
• No cases of ECL cell carcinoids, dysplasia, or neoplasia have been found in over 3,000 patients treated long-term. 3

Cardiovascular Disease

• Long-term PPI use has been associated with increased cardiovascular risk in some observational studies. 2, 1
• However, these associations have not been confirmed in randomized controlled trials. 1

Kidney Disease

• Tubulointerstitial nephritis can occur at any time during treatment. 3
• Patients should contact their doctor if they experience decreased urination or blood in urine. 3

Respiratory Infections

• PPIs increase the risk of community-acquired pneumonia, but not hospital-acquired (nosocomial) pneumonia. 2, 4
• Infants may be at increased risk of lower respiratory tract infections. 2

Critical Management Principles

When NOT to Discontinue PPIs

Patients with the following definitive indications should continue long-term PPI therapy: 1, 6

• Barrett's esophagus
• Severe erosive esophagitis (LA Classification grade C/D)
• Eosinophilic esophagitis with PPI response
• Idiopathic pulmonary fibrosis
• High-risk NSAID/aspirin users requiring gastroprotection
• Secondary prevention of gastric/duodenal ulcers
• Esophageal strictures from GERD

When to Consider De-prescribing

• All patients without a definitive indication for chronic PPI should be considered for trial of de-prescribing. 1, 6
• Most patients on twice-daily dosing should be stepped down to once-daily PPI. 1, 6
• After symptom control, patients should be considered for step-down to the lowest effective dose. 6

Optimal Dosing Strategy

• Use omeprazole 20 mg once daily as the standard dose, taken 30-60 minutes before meals. 6
• If symptoms persist after 4-8 weeks, consider increasing to 40 mg daily or 20 mg twice daily, though twice-daily dosing is not FDA-approved. 6
• The FDA label states it is not known if omeprazole is safe and effective when used for longer than 12 months for maintenance of esophageal healing. 3

Key Clinical Pitfall

Discontinuing PPIs in patients with definite indications based on concerns about unproven risks may lead to recurrent symptoms and serious complications, including upper gastrointestinal bleeding. 1 The evidence shows that patients who discontinued PPI therapy after 12 months experienced symptom recurrence in 87.5% and histological recurrence in 100% of cases. 2

Practical Safety Monitoring

• Do not discontinue PPIs solely due to concern about potential adverse events when a valid indication exists. 1
• Periodically reassess the need for continued treatment and clearly document the indication. 6
• Take omeprazole at the lowest dose possible for the shortest time needed. 3
• Monitor for signs of kidney problems, severe diarrhea, bone fracture risk factors, and lupus-like symptoms. 3

Long-Term Safety Data

Published studies have reported PPI use for up to 11 years in small numbers of children. 2 In adults, studies of up to 6 years showed that the adverse-event profile during long-term treatment was similar to short-term treatment and comparable to H2-receptor antagonists. 7 The rate of occurrence of any specific adverse event decreased with time, and no previously unidentified adverse events occurred with long-term therapy. 7