NSAIDs and GI mucosal integrity: what holds up?

The debate over nonsteroidal anti-inflammatory drugs (NSAIDs) and the level of gastrointestinal (GI) side effects is not new, but has recently been intensified by the finding that horses with small intestinal strangulating obstruction treated with flunixin meglumine have delayed recovery of mucosal integrity. Although this would seem to be a logical extension of what we already know about NSAIDs and GI function, it has taken the equine community somewhat by surprise because of the wellknown association between colic and administration of flunixin meglumine. Importantly, flunixin is simply representative of a class of drugs that inhibit cyclooxygenase (COX), also including phenylbutazone. However, flunixin has been repeatedly tested because of its frequent use in colic patients. To date, there have been preclinical trials examining the effects of NSAIDs on strangulated bowel, and at least one clinical trial with the same goal. The question ‘what holds up’ indicates an appraisal of the evidence is needed, so that sensible recommendations can be made.

Some important background – how do NSAIDs work?

The mechanism of action of the NSAIDs used in equine practice is inhibition of COX activity, thereby preventing production of prostaglandins. The recent discovery of multiple isoforms of COX has revolutionised the field of NSAID pharmaceutical development, leading to a number of drugs that are preferential for one of the COX isoforms. Of the 2 COX isoforms, COX1 is constitutively expressed, or continuously produced at steady levels, in most tissues. For this reason, COX-1 has been credited with synthesising prostanoids involved in physiological organ function, whereas COX-2 is typically up-regulated by inflammatory stimuli such as endotoxin, and has therefore been the target of selective drugs aimed at inhibiting inflammation without disrupting normal organ function. Until relatively recently, only nonselective equine NSAIDs have been available on the market, including flunixin and phenylbutazone. However, now that we have a preferential COX-2 inhibitor (meloxicam) and a selective COX-2 inhibitor (firocoxib) available on the market, a full appraisal of NSAIDs in horses should include all classes of these drugs. […]