What Drugs Cause Ulcers in the Stomach? An Overview of Medications and Risk Factors

October 10, 2025 •

4 min read

According to the Mayo Clinic, long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is a common cause of peptic ulcers, accounting for up to 24% of cases. While H. pylori infection is the most frequent cause, it is crucial to understand what drugs cause ulcers in the stomach, as certain medications significantly increase your risk by disrupting the body’s natural protective mechanisms.

Quick Summary

Certain medications, especially long-term, high-dose nonsteroidal anti-inflammatory drugs (NSAIDs), damage the stomach lining and cause ulcers. Other implicated drugs include corticosteroids, bisphosphonates, SSRIs, and potassium chloride, often with increased risk when combined. Awareness of these medication-induced risks is crucial for prevention.

Key Points

NSAIDs are the primary cause: Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, are the most common medication class causing ulcers, particularly with long-term, high-dose use.
Inhibition of protective prostaglandins: NSAIDs cause ulcers by blocking the COX-1 enzyme, which leads to a reduction in protective prostaglandins and leaves the stomach lining vulnerable to acid.
Corticosteroids increase risk with NSAIDs: While steroids alone have a low ulcer risk, combining them with NSAIDs creates a synergistic, high-risk effect and impairs mucosal healing.
SSRIs and bleeding risk: Selective Serotonin Reuptake Inhibitors (SSRIs) are associated with an increased risk of gastrointestinal bleeding, a risk that is amplified when combined with NSAIDs.
Bisphosphonates cause direct irritation: Oral bisphosphonates can cause esophageal irritation and ulcers through direct contact if proper administration instructions are not followed.
Protective strategies are available: Risk can be minimized by using the lowest effective dose, taking medication with food, and co-administering gastroprotective agents like Proton Pump Inhibitors (PPIs).
Prioritize risk assessment: It is crucial for patients and doctors to assess individual risk factors, including age, H. pylori status, and concurrent medication use, before starting long-term ulcer-causing medications.

Your stomach and duodenum (the first part of your small intestine) are protected by a thick mucosal lining that shields them from damaging digestive acids. This protective layer is maintained by prostaglandins, hormone-like substances produced by the body. When certain medications disrupt prostaglandin production or cause direct irritation, this protective layer weakens, leaving the lining vulnerable to acid erosion and the development of painful peptic ulcers.

The Primary Culprits: Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs are among the most common medications in the world, used to relieve pain, reduce inflammation, and lower fever. However, they are also the leading cause of drug-induced peptic ulcers. This class includes well-known over-the-counter and prescription medications such as:

Aspirin
Ibuprofen (Advil, Motrin)
Naproxen sodium (Aleve)
Indomethacin
Ketorolac

Mechanism of Action

NSAIDs cause ulcers primarily by inhibiting the cyclooxygenase (COX) enzyme, specifically COX-1. While inhibiting the COX-2 enzyme provides pain relief, inhibiting COX-1 has a negative effect on the stomach. Here’s how it works:

Prostaglandin Suppression: COX-1 produces prostaglandins that are essential for maintaining the stomach's protective mucus and bicarbonate layer, regulating blood flow to the stomach lining, and promoting cellular repair.
Impaired Protection: By blocking COX-1, NSAIDs significantly reduce these protective prostaglandins, weakening the mucosal barrier.
Acid Damage: The stomach lining, now unprotected, becomes susceptible to damage from gastric acids, which can lead to erosions and eventually, a full-blown ulcer.

Other Medications That Increase Ulcer Risk

While NSAIDs are the most common cause, several other drugs can also contribute to the formation of ulcers, especially when used in combination or by individuals with existing risk factors.

Corticosteroids

Often used to treat inflammatory conditions like asthma and arthritis, corticosteroids pose a significant ulcer risk, particularly when used with NSAIDs. While steroids alone are not highly ulcerogenic, their combination with NSAIDs has a synergistic, highly damaging effect on the gastrointestinal mucosa. Corticosteroids may also impair the body’s ability to heal wounds, which can delay the repair of existing mucosal damage.

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are a class of antidepressants that have been associated with an increased risk of gastrointestinal bleeding. This risk is heightened when SSRIs are taken with NSAIDs. One proposed mechanism is that SSRIs can affect platelet function by decreasing the serotonin available for platelet aggregation, thereby increasing the risk of bleeding from a pre-existing erosion or ulcer.

Bisphosphonates

Oral bisphosphonates (like alendronate, ibandronate) are used to treat and prevent osteoporosis. They can cause severe irritation and ulcers in the esophagus if they get lodged or are not cleared quickly. Patients are typically instructed to take these medications with a full glass of water and remain upright for at least 30 to 60 minutes to prevent esophageal irritation.

Potassium Chloride

High-concentration potassium chloride tablets, especially slow-release formulations, can cause localized hyperosmolarity and tissue injury in the gastrointestinal tract. If a tablet lingers in the esophagus or intestine, it can cause severe chemical injury, leading to ulcers and even strictures. Patients with slow gastrointestinal motility are at higher risk.

Chemotherapy Drugs

Some chemotherapy agents can cause mucositis, a painful inflammation and ulceration of the mucous membranes lining the digestive tract, from the mouth to the anus. This occurs because these drugs target rapidly dividing cells, including the healthy cells of the gastrointestinal mucosa. Common culprits include 5-fluorouracil (5-FU) and methotrexate.

Comparison of Drug-Induced Ulcer Risk


Drug Class	Examples	Mechanism of Ulceration	Risk Level (Alone)	Synergistic Risk Factors
NSAIDs	Ibuprofen, Naproxen, Aspirin	Inhibits protective prostaglandins via COX-1 inhibition.	High, especially with high dose/long term use.	Age >65, prior ulcer, H. pylori infection, corticosteroids, SSRIs, anticoagulants.
Corticosteroids	Prednisone	Impairs mucosal healing.	Low, unless high dose/long term.	NSAID co-administration dramatically increases risk.
SSRIs	Sertraline, Paroxetine	Inhibits platelet aggregation, increases gastric acid.	Low-Moderate.	NSAID co-administration significantly increases bleeding risk.
Bisphosphonates	Alendronate	Direct mucosal irritation of the esophagus.	Low, if taken correctly.	Incorrect administration (not staying upright).

Mitigating Risk: Prevention and Management

For individuals who must take medications that pose a risk of ulcer formation, there are several preventive measures that can be taken in consultation with a healthcare provider:

Use the Lowest Effective Dose: Use the lowest possible dose of NSAIDs for the shortest duration necessary.
Consider a COX-2 Inhibitor: Selective COX-2 inhibitors were designed to have fewer gastrointestinal side effects than non-selective NSAIDs by sparing the protective COX-1 pathway. However, they carry different cardiovascular risks.
Use Gastroprotective Agents: Taking a proton pump inhibitor (PPI) along with an NSAID is an effective strategy, especially for high-risk patients. Other options include H2-receptor antagonists or misoprostol, a synthetic prostaglandin.
Test for H. pylori: Since H. pylori infection synergizes with NSAID use to increase ulcer risk, testing for and eradicating the bacteria before starting long-term NSAID therapy is recommended.
Take with Food: Taking NSAIDs and oral potassium chloride with food can help protect the stomach lining.
Follow Administration Instructions: For bisphosphonates, always take with a full glass of water and remain upright to prevent esophageal irritation.
Avoid Smoking and Excessive Alcohol: Both smoking and excessive alcohol consumption irritate the stomach lining and increase the risk of ulceration, particularly with other risk factors present.

Conclusion

While many people associate stomach ulcers with the H. pylori bacteria, a significant number of cases are caused by medications. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common culprits, but other drugs such as corticosteroids, SSRIs, bisphosphonates, and potassium chloride can also increase your risk. Understanding the specific mechanisms and risk factors is the first step toward prevention. For long-term medication use, especially in high-risk groups, prophylactic measures are often necessary to protect the gastric mucosa and prevent serious complications. Always consult a healthcare professional to discuss your individual risk profile and determine the best strategy for managing your medication safely.

For more information on digestive diseases and peptic ulcers, refer to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Frequently Asked Questions

While all NSAIDs carry a risk, studies show that certain non-selective NSAIDs have a higher risk. High-risk NSAIDs include indomethacin, piroxicam, and ketorolac, while ibuprofen and selective COX-2 inhibitors are generally considered lower risk.

Yes, even low-dose aspirin, often taken for cardiovascular prevention, can cause ulcers and bleeding. The risk is lower than with high-dose use but is still significant, especially with long-term use and other risk factors.

The presence of H. pylori infection significantly increases the risk of ulcer development in patients taking NSAIDs, creating a synergistic effect. Screening for and eradicating H. pylori is a recommended preventive strategy before initiating long-term NSAID therapy.

Taking medication with food can help protect the stomach lining from some direct irritation, but it does not eliminate the risk, especially with long-term NSAID use. For higher-risk situations, additional gastroprotective agents like a PPI or H2-receptor blocker may be necessary.

Symptoms can include dull or burning stomach pain, bloating, heartburn, nausea, and vomiting. However, ulcers can also be asymptomatic and only discovered when a complication like bleeding occurs. If you experience persistent symptoms or signs of bleeding (black, tarry stools; vomiting blood), you should contact a doctor.

Yes. While NSAIDs are the most common cause, other medications like oral bisphosphonates, potassium chloride tablets, corticosteroids, and some chemotherapy drugs have also been linked to ulcers or mucosal damage.

Yes, acetaminophen (Tylenol) is often a safer alternative for pain relief as it does not affect the stomach lining in the same way as NSAIDs. For individuals with a high ulcer risk who need an NSAID, a doctor might recommend a selective COX-2 inhibitor or co-administration with a PPI.