Side effects and contraindications of omeprazole

Omeprazole is usually well tolerated, and that is precisely why it is often taken for years without review. However, prolonged acid suppression has consequences, and some adverse reactions, though rare, require attention. The editors have divided the effects into short-term and long-term, separately assessing how strong the evidence is for each of them.

Common short-term side effects

The most common adverse reactions listed in the prescribing information for omeprazole are headache, abdominal pain, diarrhea or constipation, nausea, flatulence. They occur in a small proportion of patients and, as a rule, are mild, often resolving on their own or after adjusting the regimen of intake.

Some of these symptoms are explained by a change in the environment in the stomach and intestine: reduced acidity affects the digestion of proteins and the composition of the microbiota. In clinical studies the frequency of many such complaints on omeprazole was comparable to placebo, which complicates assessing the true contribution of the drug.

Less often described are dizziness, sleep disturbances, itching and rashes, dry mouth, peripheral edema. Very rarely hypersensitivity reactions occur — from urticaria to anaphylaxis — as well as severe skin reactions, at the appearance of which the drug should be stopped immediately and medical help sought.

The FDA and EMA regulatory documents also mention cutaneous and systemic lupus erythematosus associated with PPIs. This is a rare effect, but it is important: if a rash appears on sun-exposed areas of the skin, especially with joint pain, it is worth informing the doctor.

Consequences of long-term use

The main concerns are related to many months and many years of use. An expert review by the American Gastroenterological Association (Freedberg et al., 2017) lists associations of PPIs with vitamin B12 deficiency, hypomagnesemia, fractures, intestinal infections, pneumonia, chronic kidney disease and dementia, while emphasizing that most of these data are observational.

The most biologically grounded effects are those that follow directly from acid suppression. Vitamin B12 deficiency is related to impaired release of it from food proteins: the study by Lam et al. (2013) found an association between taking PPIs for more than two years and B12 deficiency. Reduced absorption of non-heme iron can deepen iron deficiency.

Hypomagnesemia is a rare but serious effect that can manifest as seizures, arrhythmias and tetany. In 2011 the FDA issued a separate warning about this and recommended monitoring magnesium in patients who take PPIs for a long time, especially together with diuretics or digoxin.

Clostridioides difficile infection is another risk associated with reduction of the acid barrier and changes in the microbiota. Meta-analyses, in particular Kwok et al. (2012), showed an increased risk of this infection in people who take acid-suppressing agents, especially in combination with antibiotics.

What the randomized data showed

The most substantial test of the long-term safety of PPIs was provided by the COMPASS trial: within it more than 17 thousand patients were randomized to pantoprazole or placebo and followed for an average of about three years. Moayyedi et al. (2019) found no statistically significant increase in most of the anticipated side effects, with the exception of a possible increase in intestinal infections.

These data are reassuring regarding associations such as dementia, chronic kidney disease or fractures that had previously been found in observational studies. At the same time COMPASS lasted several years, so it could not assess the most distant consequences of many years of use.

Observational studies have an important limitation — so-called "confounding by indication": people with more diseases are more often prescribed PPIs, and it is precisely these diseases, and not the drug, that may explain the worse outcomes. The works of Lazarus et al. (2016) on the kidneys and Gomm et al. (2016) on dementia should be interpreted with exactly this caveat.

The practical conclusion of the guidelines is the same: do not be afraid of PPIs when they are really needed, but also do not take them without indications. Regular review of therapy and discontinuation when there is no need are the best way to minimize the risks.

Rare but serious reactions

Acute tubulointerstitial nephritis is a rare immune reaction that can develop at any time during PPI use. It manifests as worsening kidney function, sometimes with fever, rash, changes in the urine test, but often runs with few symptoms. This effect is included in the prescribing information, and if it is suspected the drug is discontinued.

Cases of severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), drug-induced hepatitis, and changes in blood counts (leukopenia, thrombocytopenia) have also been described. They are isolated, but worth knowing about: atypical symptoms during use are a reason to see a doctor.

With long-term use of PPIs, fundic gland polyps of the stomach are found more often. For the most part they are benign and do not require treatment, but endoscopists pay attention to them. An increase in gastrin is an expected physiological consequence, which in humans is not unambiguously linked with tumors, unlike the data from studies in rodents.

Another problem is the masking of symptoms. Omeprazole can temporarily relieve pain and heartburn in stomach cancer, delaying diagnosis. Therefore in older people or those with alarm signs, doctors recommend examination before long-term therapy.

Contraindications and caution

An absolute contraindication is hypersensitivity to omeprazole, other benzimidazole derivatives or the components of the drug. According to the prescribing information, omeprazole should not be used together with nelfinavir (an antiretroviral agent), whose concentration is significantly reduced.

• Alarm symptoms— weight loss, dysphagia, vomiting of blood, melena, anemia: examination first.
• Severe liver failure— a dose adjustment may be needed at the doctor's discretion.
• Osteoporosis and high fracture risk— weigh the duration of therapy.
• Taking digoxin, diuretics— monitoring of magnesium.
• Clopidogrel, methotrexate in high doses— possible interactions.
• Pregnancy and breastfeeding— only after assessment by a doctor.

It should also be remembered that omeprazole affects the results of some tests: chromogranin A, gastrin, tests for Helicobacter pylori. Before such examinations, the doctor may ask you to temporarily stop taking it.

For people who take omeprazole for a long time, the editors advise discussing with a doctor once a year whether there is still an indication and whether the dose can be reduced or switched to "as needed" use, as proposed by the AGA update on deprescribing (2022).

Editorial conclusions

The short-term side effects of omeprazole are usually mild. The main questions arise with long-term use: deficiency of B12 and iron, hypomagnesemia, intestinal infections, and also rare immune reactions such as interstitial nephritis.

Many high-profile associations — with dementia, kidney diseases, fractures — are based on observational data and were not confirmed in the randomized COMPASS trial. The best prevention is clear indications and regular review of therapy.

We also recommend the materials "Tests during the use of omeprazole", "Omeprazole: what clinical studies show" and "Myths about omeprazole".

References

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2. Moayyedi P, Eikelboom JW, Bosch J, et al. Safety of proton pump inhibitors based on a large, multi-year, randomized trial of patients receiving rivaroxaban or aspirin. Gastroenterology. 2019;157(3):682–691.
3. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435–2442.
4. Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. 2012;107(7):1011–1019.
5. Lazarus B, Chen Y, Wilson FP, et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med. 2016;176(2):238–246.
6. Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol. 2016;73(4):410–416.
7. Targownik LE, Fisher DA, Saini SD. AGA clinical practice update on de-prescribing of proton pump inhibitors: expert review. Gastroenterology. 2022;162(4):1334–1342.