Pain can be protective, but through the stress response it may also contribute significantly to patient morbidity and even
mortality. Undermanaged acute (peri-operative or post-trauma) pain can slow or even prevent recovery, and chronic pain is
not merely acute pain of extended duration. Rather, it is a maladaptive state whereby the discomfort transcends the original
injury or stimulus, and becomes instead an innate feature of the central nervous system. Many modalities may be employed to
minimize both acute and chronic pain, but it is clear that non-steroidal anti-inflammatory drugs will likely remain the most
commonly used tool in the toolbox. They are highly effective, commonly available, licensed for use in dogs, and generally
quite safe...but at the same time do carry the potential for adverse effects that might range from the mild to the catastrophic.
The primary mode of action is to inhibit cyclooxygenase 2 (COX2), the enzyme that is expressed at site of inflammation and
results in the production of pro-inflammatory and vasoactive prostaglandins. Also, through poorly understood mechanisms, likely
by modulating multiple gene expression pathways, it may inhibit central perception of pain. Several superior products are
now labeled for use in dogs (and some in cats), making them among the most popular of pain management medications in veterinary
medicine. All seem to be effective, and head to head studies now emerging may help to reveal objective differences if they
are present. The main limitation of all NSAID's revolves around the potential for adverse effects, since both COX 1 and COX
2 enzymes may be constitutive, that is, consistently present and crucial to the production of cyto-protective prostaglandins
(COX1 especially in the GI tract and renal tubules, COX2 in the renal tubules). Thus the primary adverse effects of non-selective
NSAID's may include GI erosion/ulceration and nephrotoxicity. COX1-sparing NSAIDS should have a dramatically diminished GI
toxicity profile, but will maintain their risk for nephrotoxicity. Rarely and on an idiosyncratic basis, hepatoxicity may
occur. The GI and renal adverse effects can be expected to occur most commonly in higher risk patients, e.g.: hypovolemia,
hypotension (including anesthetic procedures especially those not supported by intravenous fluids), pre-existing GI or renal
disease, overusage, and the inappropriate combination with other NSAID's or corticosteroids. Notable in this last category
is client use of aspirin in their pets, which may be unbeknownst to the clinician unless specifically queried in a thorough
history. Unique to aspirin, this NSAID produces a cyto-protective lipoxin through the COX pathway; thus when COX is inhibited
through the use of another, concurrently-given NSAID, the potential for GI toxicity is considerably enhanced. The relative
roles and molecular dynamics of COX1, COX2, and a possible new variant COX3, is still being elucidated and the "final word"
on the optimal COX-selective or –sparing effect in order to maximize effectiveness and to limit toxicity, is yet to be heard.
Acetaminophen may elicit some of its analgesic effects by inhibiting the COX3 variant, and recent studies suggest that it
may also inhibit COX2-mediated production of PGE2. Lipooxygenase also metabolizes arachadonic acid, but instead of prostaglandins
the byproducts are leukotrienes, which are potent attractors of PMN's and promote their adherence to endothelium. One commercial
veterinary NSAID, tepoxalin, inhibits LOX as well as balanced COX enzymes. In any use of NSAID's, the potential for adverse
effects needs to be made clear to pet owners, and for any extended use, regular metabolic monitoring should be performed.