epithelial growth factor receptor by membrane-bound transforming growth factor α in vitro is actually increased in gastric and colonic mucosa of aged rats,61 suggesting that the relative lack of activity may not be due to intrinsic inactivation. Mucosal blood flow plays an essential role in maintaining gastric mucosal integrity. In rats, aging is associated with a decrease in basal gastric blood flow associated with impaired healing of acid-induced mucosal lesions.56, 62 Impaired healing of gastric ulcers has also been associated with underlying impairment in sensory neuron function in several aging models.63 Peptic ulcer disease (H pylori induced and NSAID inducedGeriatric patients are the heaviest users of NSAIDs, primarily for treatment of osteoarthritis pain and degenerative joint disease. There is overwhelming evidence that geriatric patients have an increased risk of complications such as ulceration, stricturing, and bleeding from use of nonselective NSAID cyclooxygenase (COX)-1 inhibitors. Surveys of physicians in the United Kingdom indicate that 38% of patients prescribed NSAIDs are hospitalized, and 4% die.64 In response to the risks of using nonselective NSAIDs, interest focused on the use of more selective COX-2 inhibitors. Risk of ulceration during 8 weeks of treatment was decreased by use of more selective COX-2 inhibitors by approximately 50% in a trial of etoricoxib versus nonselective NSAIDs such as ibuprofen.65 COX-2 inhibitors are prescribed more frequently than nonselective NSAIDs to elderly patients with musculoskeletal disease who have had GI complications, with a 47% decrease in the use of concomitant gastroprotective agents such as proton pump inhibitors.66 Some studies have attributed cost savings to the use of COX-2 inhibitors. In a large, randomized survey of 6118 NSAID users in Switzerland, 294 had adverse effects from NSAIDs, primarily COX-1.67 Costs of treatment and lost time from work were $7425.70 million (in US dollars), with 91% of costs attributed to the use of COX-1 agents. The investigators concluded that COX-2 inhibitors were 25 times more cost-effective. In the United States, costs of COX-2 inhibitors are much higher and use does not result in lower treatment costs.68 Treatment with COX-2 inhibitors has recently been limited due to concerns that their use may increase the risk of cardiovascular complications. The risk seems to be greater in patients on high doses of COX-2 inhibitors. In studies of younger patients (mean age, 64.7 years), both misoprostol (200 μg 4 times a day) and lansoprazole (15–30 mg once a day) have been shown to significantly reduce the risk of gastric ulceration at 4, 8, and 12 weeks in patients taking NSAIDs daily.69 Other studies of newer prophylactic agents, such as nitric oxide–donating COX inhibitors, show minimal efficacy at preventing ulcer formation and have not included geriatric-aged patients in sufficient numbers to determine whether these agents could be used successfully in geriatric patients.70 GI Bleeding Acute GI bleeding is a fairly common problem in the elderly and can occur from any portion of the GI tract. However, studies of older patients indicate that 75% of GI bleeding can be attributed to upper sources (esophagus, stomach, small bowel), with approximately 50% due to NSAID use and 50% due to peptic ulcers. Approximately 20%–25% of bleeding is from the lower tract (terminal ileum, colon, rectum). Patients are usually older (mean age, 71 years vs 65 years for upper GI tract