By inhibiting
prostaglandin synthesis, non-steroidal anti-inflammatory drugs (
NSAIDs) cause mucosal damage, ulceration and
ulcer complication throughout the gastrointestinal tract. The recognition that there are two
cyclo-oxygenase enzymes, one predominating at sites of
inflammation (COX-2) and one constitutively expressed in the gastrointestinal tract (COX-1), has led to the important therapeutic development of
COX-2 inhibitors. COX-2 is phylogenetically more primitive that COX-1 and, while very similar, has critical differences, particularly the existence of a small pocket half way down the active
enzyme site. A number of drugs achieve selectivity by binding to this pocket, including presumptively
rofecoxib and
celecoxib. Others, such as
meloxicam, may inhibit COX-2 by different mechanisms. Truly selective
COX-2 inhibitors have been shown to have no effect on gastric mucosal
prostaglandin synthesis, to cause no acute injury, and no chronic ulceration compared to placebo.
Rofecoxib has, in a prospective systematic evaluation involving 8076 patients, been shown to reduce clinically significant
ulcers,
ulcer complications and gastrointestinal
bleeding significantly compared to
naproxen. Outcomes data for
celecoxib have also been published although differences from the combined comparator agents (
diclofenac and
ibuprofen) did not reach statistical significance. Use of
aspirin in the class study has shown that the benefits of
COX-2 inhibitors may be reduced by
aspirin use. The VIGOR study has raised the possibility that some
NSAIDs, particularly
naproxen, may protect against
vascular disease compared to
COX-2 inhibitors (or placebo).