Prior to discussing the advantages and disadvantages of the products currently licensed for veterinary use in the UK it is essential to understand the mechanisms of action of non-steroidal antiinflammatory drugs (NSAIDs).

Mode of Action

These agents reduce inflammation and provide analgesia primarily through inhibition of inflammatory cytokine synthesis. When tissues are damaged, mediators are released that activate nociceptors and primary afferent neurons leading to the sensation of pain. Cyclo-oxygenase (COX) is responsible for converting one of these mediators, arachidonic acid, into prostaglandins (PG) and thromboxane A2. Lipoxygenase (LOX) is responsible for converting arachidonic acid into leukotrienes (LTs). PG and LT sensitise pain receptors lowering the threshold needed for activation.

Thromboxane A2 is intimately involved in platelet activation but its role in the pain pathway is not believed to be significant. Some NSAIDs also seem to have central effects. PG synthesis can also occur in the brain, and the central action is believed to be due to blocking these pathways but this process is still not clearly understood.

Most NSAIDs inhibit the COX side of the inflammatory pathway. There are two COX enzyme isoforms, COX-1 and COX-2. It was originally thought that COX-1 was solely responsible for basal prostaglandin production for normal homeostasis, e.g., maintenance of gastrointestinal blood flow and mucus production and renal perfusion. It was also thought that COX-2 was only involved in the production of prostaglandins in the inflammatory response. At this point the available NSAIDs were non-selective and inhibited both COX isoforms and it was suspected that the side effects seen, i.e., gastrointestinal ulceration and renal failure were due to the suppression of COX-1. Attempts have since been made to produce products which are COX-2 selective and therefore do not inhibit the 'housekeeping' prostaglandins of COX-1. Recent research has shown that things are not quite as clear cut as this and it has been found that COX-1 may have a part to play in the inflammatory response process and that COX-2 may in fact have certain constitutive roles within the body. Therefore it can be assumed that COX-2 selective NSAIDs may not be such potent anti-inflammatory agents as those that inhibit both forms of COX. There is however evidence that highly selective COX-2 NSAIDs are less likely to induce gastrointestinal side effects.

Many commercially available NSAIDs currently on the veterinary market appear to be more selective for COX-2 but still have some inhibitory effects over COX-1 with varying selectivity.

Due to the apparent reduction of renal perfusion caused by these drugs there are very few that are licensed for perioperative use. Carprofen and meloxicam are currently available for perioperative use in dogs and cats. Carprofen has been shown to be a poor inhibitor of COX and meloxicam has undergone extensive toxicity testing and has been shown to have a relatively high selectivity for COX-2.

Carprofen

This drug is licensed in cats (injectable) and dogs (tablets and injectable) including perioperative use. The mode of action of this drug is still not fully understood although it is thought to be a poor inhibitor of COX with the COX inhibition that it does have being COX-2 selective. The therapeutic safety level of this drug appears high and it produces good anti-inflammatory and analgesic effects both peri- and postoperatively and for chronic use (in the dog). Renal toxicity is not common with this drug; however, gastrointestinal effects have been observed. Cases of hepatic failure have been noted in North America (mainly Labrador Retrievers) but further substantiation is required.

Meloxicam

This drug is licensed in dogs and cats both peri- and postoperatively and is available in injectable and oral syrup forms for both species. Meloxicam is a relative COX-2 selective inhibitor. It provides good anti-inflammatory and analgesic effects and, as with carprofen, has the advantage that it can be administered preemptively.

Flunixin

Flunixin is licensed in dogs, cats and small mammals but not for perioperative use. This drug is a non-selective potent COX inhibitor and should not be administered preoperatively due to the risk of acute renal failure seen with the reduced renal perfusion caused by this agent. Other side effects include gastrointestinal signs, i.e., vomiting and malaena, haemorrhagic diarrhoea. This drug is also shown to have antiendotoxaemic actions at lower doses than produce anti-inflammatory effects and has been used in horses with colic. It is no longer recommended for small animal use.

Aspirin

Aspirin binds irreversibly to COX within platelets for the life of the platelet, inhibiting thromboxane A2, hence its use in the prevention of thrombi formation.

Tolfenamic Acid

Tolfenamic acid is a COX inhibitor that preferentially inhibits COX-2.

Firocoxib

Firocoxib is a COX-1 sparing COX-2 inhibitor. The clinical relevance of this action has not been established, but the theory is that it will cause fewer side effects due to not affecting COX-1.

Tepoxalin

Tepoxalin inhibits both COX and LOX, and is supposed to have wider gastrointestinal and renal safety margins. A theory is that blocking COX may cause a shunt to the LOX side of the pathway causing an increase in LTs and thus increasing inflammation, making COX/LOX inhibitors more potent anti-inflammatories. However, the relationship between COX and LOX and the safety and efficacy of this drug in dogs are not yet formally established.

Drug Interactions

All NSAIDs should be avoided in patients receiving treatment with corticosteroids as the risk of gastrointestinal ulceration is greatly increased.

In human medicine convulsions have been documented when NSAIDs have been administered with fluoroquinolones; however, this has not been documented in the veterinary sector.

It has been shown that concomitant use of NSAIDs and diuretics may increase the risk of nephrotoxicity.

It is also thought that this group of agents may antagonise the hypotensive effects of antihypertensives, e.g., beta-blockers.

Conclusion

There are many NSAIDs currently on the market and, while there is no doubt that they provide an important adjunct to multimodal pain relief in small animals, each drug should be examined on its own merit paying particular attention to documented side effects. Many of these agents have been shown in research studies to provide pain relief equivalent to some opiate agents and this should be noted.

It is likely that different animals will have a different NSAID that will best suit their needs.

The author feels that until further research shows the exact pathways and mechanisms of selective COX inhibition then the potential side effects should be respected and these drugs should be used with caution in patients with renal or hepatic insufficiency, bleeding disorders or gastrointestinal ulceration.

References

1.  Flecknall P, Waterman-Pearson A. Pain management in animals. London: WB Saunders, 2000.

2.  McKelvey D, Hollingshead KW. Veterinary anesthesia and analgesia (third edition). St Louis: Mosby, 2003.

3.  Muir W, Hubbell J, et al. Handbook of veterinary anesthesia (fourth edition). St Louis: Mosby, 2007.

4.  Lumb W, Jones E, et al. Lumb & Jones' veterinary anesthesia (third edition). Philadelphia: Lippincott Williams & Wilkins, 1996.

5.  Welsh E. Anaesthesia for veterinary nurses. Oxford: Blackwell Publishing, 2003.