The Primary Culprit: Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is one of the most common causes of peptic ulcers, second only to infection with Helicobacter pylori [1.2.2]. NSAIDs are a broad class of medications used to relieve pain and reduce inflammation, and they include many common over-the-counter and prescription drugs [1.2.1]. The risk of developing an ulcer increases with the dose and duration of NSAID use, though for some individuals, even a single low-dose aspirin daily can be enough to cause an ulcer [1.2.1].
How NSAIDs Cause Ulcers: The Mechanism
The gastrointestinal toxicity of NSAIDs is primarily related to their mechanism of action. NSAIDs work by inhibiting cyclooxygenase (COX) enzymes, which are responsible for producing prostaglandins [1.3.3]. While inhibiting the COX-2 isoenzyme provides the desired anti-inflammatory and analgesic effects, the simultaneous inhibition of the COX-1 isoenzyme is what causes harm to the stomach lining [1.3.3].
Prostaglandins produced by COX-1 play a vital protective (cytoprotective) role in the stomach [1.3.3, 1.3.7]:
- Mucus and Bicarbonate Secretion: They stimulate the secretion of a thick mucus layer and bicarbonate, which act as a physical and chemical barrier against stomach acid [1.3.2, 1.3.7].
- Maintaining Blood Flow: They help maintain adequate blood flow to the mucosal lining, which is essential for cell repair and renewal [1.3.7].
By inhibiting COX-1, NSAIDs reduce the levels of these protective prostaglandins. This leaves the stomach lining vulnerable to damage from its own acid, leading to inflammation, erosions, and eventually, the formation of an open sore, or ulcer [1.3.3]. Some NSAIDs also have a direct, topical irritant effect on the gastric mucosa, further compromising its integrity [1.3.7].
Other Contributing Medications
While NSAIDs are the most prominent drug class associated with peptic ulcers, other medications can also increase the risk, especially when taken concurrently with NSAIDs [1.4.2, 1.6.2].
- Corticosteroids: Medications like prednisone can increase the risk of developing ulcers, and this risk is significantly heightened when they are taken alongside NSAIDs [1.4.2, 1.4.4].
- Anticoagulants and Antiplatelets: Drugs such as warfarin (Coumadin) or clopidogrel (Plavix) don't cause ulcers directly but dramatically increase the risk of bleeding if an ulcer is already present or develops [1.4.1, 1.6.2].
- Selective Serotonin Reuptake Inhibitors (SSRIs): Some antidepressants in this class have been linked to an increased risk of upper GI complications, including ulcers [1.4.2].
- Bisphosphonates: Medications used to treat osteoporosis, like alendronate (Fosamax), can also contribute to ulcer formation [1.4.2].
Identifying and Managing Risk
Several factors can amplify a person's risk of developing a drug-induced peptic ulcer [1.4.1, 1.4.2, 1.4.4]. Key risk factors include:
- Age: Individuals over 65 are at a significantly higher risk [1.4.4].
- History of Peptic Ulcers: A prior ulcer is the single strongest predictor of a future one [1.4.1].
- High Doses or Multiple NSAIDs: Using high doses or more than one type of NSAID at a time increases risk [1.4.2].
- Concomitant H. pylori Infection: The presence of this bacterium has a synergistic effect, greatly increasing ulcer risk in NSAID users [1.4.6].
- Concurrent Use of Other High-Risk Drugs: As mentioned, combining NSAIDs with corticosteroids, anticoagulants, or certain SSRIs is particularly dangerous [1.4.2].
Comparison of GI Risk Among Common NSAIDs
The risk of causing gastrointestinal complications varies among different NSAIDs. This is often related to their relative selectivity for COX-1 versus COX-2 enzymes [1.3.3].
| GI Risk Category | NSAID Examples [1.3.6] |
|---|---|
| Low Risk | Ibuprofen, Celecoxib, Aceclofenac |
| Intermediate Risk | Diclofenac, Meloxicam, Naproxen |
| High Risk | Piroxicam, Ketorolac, Indomethacin |
Prevention and Treatment Strategies
For patients at high risk who must take NSAIDs, several preventive (prophylactic) strategies exist. The most effective approach is the co-prescription of a proton pump inhibitor (PPI), such as omeprazole (Prilosec) or lansoprazole [1.4.4, 1.5.4]. PPIs work by powerfully suppressing the secretion of gastric acid [1.4.4].
Other preventive measures include:
- Using the lowest effective NSAID dose for the shortest possible duration [1.5.8].
- Switching to a COX-2 selective inhibitor (e.g., celecoxib), which may be less likely to cause peptic ulcers, though cardiovascular risks must be considered [1.2.2].
- Testing for and eradicating H. pylori before starting long-term NSAID therapy, especially in high-risk patients [1.4.1].
- Using gastroprotective agents like misoprostol, although side effects like diarrhea can limit its use [1.5.3]. Double-dose H2-receptor antagonists can also be effective but are generally considered less potent than PPIs [1.5.3].
If an NSAID-induced ulcer develops, the first line of treatment is to discontinue the NSAID if possible and administer anti-ulcer therapy, typically with a PPI, to allow the ulcer to heal [1.3.8].
Conclusion
The class of drugs most responsible for inducing peptic ulcers is NSAIDs, a reality supported by extensive pharmacological research [1.2.4]. Their inhibition of the protective COX-1 enzyme in the gastric mucosa is the primary cause of injury [1.3.3]. The risk is compounded by factors like advanced age, a history of ulcers, and the concurrent use of other medications like corticosteroids and anticoagulants [1.4.4]. Fortunately, for individuals who require long-term NSAID therapy, effective preventive strategies are available. The co-administration of proton pump inhibitors stands out as the most effective and well-tolerated method for mitigating the risk of gastrointestinal damage, allowing patients to receive necessary anti-inflammatory treatment more safely [1.4.4, 1.5.4].
For more information, you can visit the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
