Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to control acute and chronic pain in veterinary patients. The presence and activity of two isoforms of the cyclooxygenase (COX) enzyme, a constitutive COX-1 and an inducible COX-2, have been investigated intensely since the early 1990s. COX-1 is present under basal conditions in many cells including platelets, mucosal cells in the GI tract, endothelial cells, and the renal medullary collecting ducts and interstitium. The COX-2 isoform is present in low concentrations under basal conditions in monocytes, macrophages, smooth muscle cells, fibroblasts, and chondrocytes. Despite widespread use, ongoing research to introduce new drugs, and efforts to improve the safety and efficacy of existing drugs, side effects such as gastrointestinal (GI) irritation, renal and hepatic toxicity, interference with hemostasis, and reproductive problems persist. Remarkably, the true incidence of NSAID-associated side-effects in companion animals is still unknown. Many of the adverse side-effects of the non-selective NSAIDs (drugs which inhibit both COX-1 and COX-2 isoforms) have been attributed to inhibition of the constitutive COX-1. As a result, over the past decade many COX-1 sparing drugs have been developed and introduced into clinical use. NSAIDs produce analgesia and toxic side-effects primarily by inhibiting a key enzyme in the arachidonic acid (AA) pathway, ceasing the production of prostaglandins, most notably prostaglandin E2 (PGE2). The AA pathway is initiated by damage to cell membranes, resulting in the release of prostanoids, which signal inflammation and pain, as well as perform physiologic functions on target tissues. The anti-inflammatory effects of NSAIDs are not solely limited to their function as cyclooxygenase inhibitors. A number of studies have shown that NSAIDs are capable of inhibiting proinflammatory transcription factors, which are independent of cyclooxygenase and prostaglandin activity.

With the testing and marketing of several efficacious NSAIDs over the last decade, veterinarians are more and more comfortable using these drugs. New discoveries about inflammatory mediators and their interactions in the inflammatory cascade, as well as new data on the biochemical mediators associated with osteoarthritis, have led to increased use of NSAIDs. It is now recognized that there are at least three different COX enzymes (COX-1, COX-2, and a COX-1 variant called COX-3) which are active in the metabolism of arachidonic acid, and certain NSAIDs may have selectivity in their actions against these isoenzymes. Furthermore, there is data to support that the ratio of COX and lipoxygenase (LOX) inhibition may be important in the improved gastrointestinal safety seen in dogs, and a dual COX/LOX inhibitor has been introduced to the market. However, these drugs are not a panacea with 100% efficacy and 0.0% adverse effects. In this lecture we will focus on everything from the basic pharmacology of these drugs to some of the tougher, unanswerable questions about potential dosing variations that might be considered due to hepatic or renal insufficiency. We will also touch on multimodal therapeutic ideas with NSAIDs as a component of the therapeutic protocol.

Although their sites of action are still unclear, NSAIDs appear to produce analgesia at both central and peripheral levels. They inhibit the peripheral COX-2 enzyme to block the formation of prostaglandins such as PGE2 and PGI2 which function to dilate arterioles and sensitize peripheral nociceptor terminals to the actions of mediators such as histamine and bradykinin to produce localized pain and hypersensitivity. The PGE2 produced by COX-2 plays a pivotal role in sustaining acute pain sensation by increasing the level of cyclic AMP within nociceptors, thus decreasing their threshold of activation. In addition to peripheral pain perception, COX-2 mediated prostaglandins such as PGE2 are involved in spinal nociception and central analgesia. COX-2 is expressed in the brain and spinal cord, and is upregulated in response to traumatic injury and peripheral inflammation. The actions of COX-2 are thought to contribute to neuronal plasticity and central sensitization. The anti-inflammatory effects of NSAIDs are not solely limited to their function as cyclooxygenase inhibitors. A number of studies have shown that NSAIDs are capable of inhibiting proinflammatory transcription factors, which are independent of cyclooxygenase and prostaglandin activity. Aspirin, sodium salicylate, rofecoxib, and ibuprofen have all been shown to mediate some of their anti-inflammatory effects via inhibition of the transcription factor, nuclear factor-kappa B (NF-KB). Briefly, NF-KB is located in the cytoplasm of the cell in an inactive complex with the inhibitory subunit, KB. Upon activation of the cell, the KB subunit is degraded and NF-KB translocates into the nucleus where it interacts with DNA KB binding sites, resulting in transcription of numerous proinflammatory genes. In addition, aspirin and sodium salicylate have also been shown to inhibit another important transcription factor in the immune response, activating protein-1 (AP-1) but again its mechanism of inhibition is unknown. This inhibition of proinflammmatory transcription factors is not a feature of all NSAIDs. NF-KB and AP-1 are key factors in the inflammatory and immune reaction, which make them important targets for modulation of the immune response. Understanding these pathways may help the efficacy of NSAID choice in treatment for certain diseases. For instance in both rheumatoid and osteoarthritis the inflammatory response not only elicits pain, but also is a stimulus for degredation of the cartilage, bone and the other tissues of the joint. Both NF-KB and AP-1 are known to up-regulate some matrix metalloproteinases, which appear to play a significant role in the degradation of cartilage and bone in arthritis. Also, these other mechanisms of NSAID action may be important in understanding the adverse effects associated with NSAID use.