How do Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) cause gastric perforation?

From the Guidelines

NSAIDs cause gastric perforation primarily by inhibiting cyclooxygenase (COX) enzymes, which disrupts the production of protective prostaglandins in the stomach lining, leading to direct mucosal damage and impaired healing of the gastric lining, as reported in the 2008 study by the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents 1. The mechanism of gastric perforation involves the inhibition of COX enzymes, which reduces the production of protective prostaglandins, resulting in decreased protective mucus and bicarbonate production, while gastric acid secretion continues unabated. This leads to direct mucosal damage and impaired healing of the gastric lining. Some key points to consider:

• The risk of perforation increases with higher doses, longer duration of use, and in patients with risk factors such as advanced age, history of peptic ulcer disease, concurrent use of corticosteroids or anticoagulants, and Helicobacter pylori infection, as noted in the 2008 study 1.
• To reduce this risk, patients should take NSAIDs with food, use the lowest effective dose for the shortest duration possible, and consider gastroprotective agents like proton pump inhibitors (such as omeprazole 20mg daily) when NSAID use is necessary, as suggested in the 2006 study by the Clinical Gastroenterology and Hepatology journal 1.
• For high-risk patients, alternative pain management strategies or COX-2 selective inhibitors (like celecoxib) may be safer options, though they still carry some risk of gastrointestinal complications, as reported in the 2004 study by the Alimentary Pharmacology and Therapeutics journal 1. It is essential to weigh the benefits and risks of NSAID use and consider alternative treatment options, especially for high-risk patients, to minimize the risk of gastric perforation and other gastrointestinal complications.

From the FDA Drug Label

NSAIDs, including celecoxib cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with celecoxib capsules. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3 to 6 months, and in about 2% to 4% of patients treated for one year.

NSAIDs cause gastric perforation by irreversibly inhibiting COX-1 enzymes, which are essential for maintaining the protective lining of the stomach. This inhibition leads to a decrease in the production of prostaglandins, which are crucial for protecting the stomach lining from acid damage. As a result, the stomach lining becomes more susceptible to ulceration and perforation.

• Risk factors for NSAID-induced gastric perforation include a prior history of peptic ulcer disease, concomitant use of oral corticosteroids or anticoagulants, older age, and poor general health status 2.
• The concurrent use of aspirin with NSAIDs, such as celecoxib, increases the risk of serious gastrointestinal events, including gastric perforation 2.
• To minimize the risk of gastric perforation, it is essential to use the lowest effective dose of NSAIDs for the shortest possible duration and to monitor patients closely for signs of gastrointestinal adverse events 2.

From the Research

Mechanisms of NSAID-Induced Gastric Perforation

• NSAIDs cause gastrointestinal damage by two independent mechanisms: a topical effect and a systemic effect mediated by cyclooxygenase (COX) inhibition with a reduction in prostaglandin synthesis 3.
• The topical effect is pH and pKa related, and the systemic effect leads to a reduction in prostaglandin synthesis, which impairs mucosal defense mechanisms against damage by acid and pepsin 4.
• NSAIDs interact with phospholipids and uncouple mitochondrial oxidative phosphorylation, initiating biochemical changes that impair the function of the gastrointestinal barrier, leading to increased intestinal permeability and low-grade inflammation 5.

Pathogenesis of NSAID-Induced Gastric Injury

• NSAID-induced gastric injury is principally attributable to impairment of mucosal defense mechanisms against damage by acid and pepsin, mediated largely by prostaglandins 4.
• The mechanism by which nonaspirin NSAIDs cause gastrointestinal damage is uncertain, but all are known to inhibit prostaglandin synthesis, which could contribute to their toxicity 6.
• NSAIDs can cause gastric mucosal damage by penetrating the protective mucous and bicarbonate layers and damaging the epithelial lining cells, allowing gastric acid to pour through the breached defenses 6.

Complications of NSAID-Induced Gastric Perforation

• NSAID-induced gastric lesions can lead to complications such as bleeding, protein loss, stricture formation, and perforation 5.
• Gastric perforation is a serious complication of NSAID-induced gastric injury, and patients receiving these drugs must be closely monitored for signs of gastric injury 4.
• Limiting NSAID use or co-administration with proton pump inhibitors (PPIs) can reduce dyspepsia, peptic ulcer disease, and rates of complications, including gastrointestinal bleeding and perforation 7.