The dual-injury hypothesis suggests that both NSAID-mediated direct acidic damage and the suppression of prostaglandin synthesis are necessary to induce gastric damage.

Initially, the acidic properties of NSAIDs induce topical mucosal injury to the gastroduodenum. The active hepatic metabolites of NSAIDs and the NSAID-related decrease in gastric mucosal prostaglandins indirectly contribute to cause gastroduodenal mucosal injury.When the hepatic metabolites in the bile are secreted into the duodenum, they cause mucosal damage to the stomach by duodenogastric reflux and to the small intestine by antegrade passage through the GI tract.

Prostaglandins maintain an intact gastric mucosal barrier by increasing secretion of mucus and bicarbonate, maintaining mucosal blood flow, and decreasing acid secretion.[29] Suppression of prostaglandin synthesis can occur systemically with both oral and parenteral NSAID therapy.[26] The antiplatelet activity of some NSAIDs in low doses may cause bleeding from preexisting ulcers.[30]

Researchers have discovered that 2 isoforms of the enzyme prostaglandin synthase or cyclooxygenase (COX) exist and that NSAIDs inhibit both isoforms.[31] The isoform COX-1 produces protective prostaglandins in the stomach and the isoform COX-2 is inducible at sites of inflammation.[31,32]Researchers developed a new type of NSAID that specifically inhibits COX-2 while sparing COX-1.[31] In theory, selective COX-2 inhibitors should provide the analgesic and anti-inflammatory effects of older NSAIDs with a reduced risk of GI injury.[25] However, within a few months of marketing, physicians reported a case of NSAID-associated gastropathy with celecoxib (a COX-2 inhibitor).[32]

When NSAIDs irritate the gastric mucosa, they weaken the resistance to acid, causing gastritis, ulcers, bleeding, or perforation.[15] The damage ranges from superficial injury to single or multiple ulcers, some of which may bleed. The clinical signs and symptoms of NSAID-induced gastropathy include dyspepsia, diarrhea, and nausea and vomiting.[29] Since these do not always correlate with the severity of the mucosal damage,[29] patients, especially the elderly, need to understand the prudent use of NSAIDs to prevent serious complications.[26]

Elderly patients are especially at risk for NSAID-induced gastroduodenal mucosal injury because of their multiple medical conditions and polypharmacy. Risk factors include concomitant corticosteroid or anticoagulant therapy, high doses of NSAIDs, and long-term NSAID therapy.[5] Patients with a history of peptic ulcer disease, Helicobacter pylori infection, or gastritis are also at risk.[15]

The various NSAIDs differ with regard to their risk of inducing upper GI bleeding and/or perforation.[33,34] Commonly prescribed NSAIDs such as ibuprofen and diclofenac appear to have the lowest relative risk.[33] Sulindac, aspirin, naproxen, and indomethacin have an intermediate relative risk, and piroxicam has the highest relative risk.[33] A reason for these differences may be related to dose.[34]Continue Reading