Non steroidal antiinflammatory drugs (NSAIDs) are efficacious antiinflammatory and analgesic agents, and over recent years the role of NSAIDs in the management of acute pain has been increasingly recognised. There are many different NSAIDs currently licensed for administration to small animals. Many drugs come in both an injectable and oral preparation to allow easy administration around the time of anaesthesia, followed by oral dosing at home. The drugs are relatively cheap and are not subject to controlled drug regulations, which, compared to opioids, makes NSAIDs practically easier to dispense. NSAIDs are also perceived to be relatively safe drugs compared to opioids, which may increase their frequency of use in the perioperative period.

Using NSAIDs to provide analgesia in the perioperative period in combination with other analgesic drugs (such as opioids) also contributes to a balanced or multimodal analgesia technique. The rationale of multimodal analgesia is to achieve sufficient analgesia due to additive or synergistic effects between different analgesics; with concomitant reduction in side effects, due to resulting lower doses of analgesics and differences in side-effect profiles. Robust clinical evidence to support the benefit of multimodal analgesia incorporating NSAIDs is lacking in dogs and cats, but a few studies have suggested that a NSAID in combination with another class of drug provides better postoperative analgesia compared to the unimodal technique without a NSAID. Theoretically the practice of combining opioids and NSAIDs makes sense. Opioids tend to have a quicker onset, but shorter duration, of action then NSAIDs. Therefore given in tandem, it is easier to provide continued prolonged postoperative analgesia (up to 24 hours) without an 'analgesia gap'. However, although NSAID administration can offer many advantages in terms of improved perioperative analgesia, this class of drugs is not without side effects and must be used judiciously in the perioperative period.

Mechanisms of Therapeutic Action of NSAIDS and Side Effects

NSAIDs have antiinflammatory, anti-hyperalgesic, anti-pyretic and anti-endotoxaemic effects. They act by the inhibition of cyclo-oxygenase (COX), thus inhibiting the production of prostanoids such as prostaglandins and thromboxane A₂. Prostaglandins play an important role in the production of inflammatory pain in the periphery, and are key players in the development of primary hyperalgesia. They also facilitate the transmission of painful (noxious) stimuli in the spinal cord and higher brain centers. Therefore NSAIDs, by inhibiting the production of prostaglandins, produce analgesia through both peripheral and central effects.

The toxicity of NSAIDs is also related to their inhibition of prostaglandin production. The most important adverse effects of NSAIDs are impairment of renal function and gastrointestinal irritation and ulceration. Although all NSAIDs can have antithrombotic effects by inhibiting the production of thromboxane A₂, at therapeutic doses most NSAIDs (with the exception of aspirin) do not impair clotting mechanisms or impair bleeding time.

In the kidney locally produced prostaglandins are continually active in maintaining afferent arteriolar dilation, and during periods of hypotension and these prostaglandins assume an important role in the maintenance of normal renal haemodynamics. COX-2-derived prostaglandin (PGE₂) is released from the macula densa, which causes vasodilation in the afferent arteriole in the face of vasoconstriction produced by angiotensin II, norepinephrine and vasopressin. Blockade of this renal vasodilatory COX-2-induced PGE₂ may contribute to the decrease in glomerular filtration rate (GFR) observed after NSAID use during times of low effective circulating fluid volume. Prostaglandins in the renal cortex protect glomerular circulation in times of decreased blood volume and prostanoids regulate glomerular filtration rate, renin release and sodium excretion.

In the stomach and gastrointestinal system prostaglandins promote the secretion of protective mucus, maintain mucosal blood flow and play a role in the modulation of gastric acid secretion. A NSAID-mediated decrease in prostaglandin production through inhibition of COX can result in gastrointestinal ulceration.

How Does Anaesthesia Affect the Risk of Side Effects?

The potential for NSAIDs to modulate renal perfusion is the side effect that is probably of greatest concern when considering whether to administer a NSAID in the perioperative period. Hypotension (mean arterial blood pressure <60 mmHg) is a relatively common complication during anaesthesia in both dogs and cats and there is good evidence to suggest that NSAIDs might cause adverse effects on renal function in the presence of volume depletion or hypotension, potentially leading to fluid retention, oedema, hyperkalaemia and eventually acute renal failure. Although there are many published studies describing preoperative administration of NSAIDs to dogs and cats with no effect on renal parameters, it is important to consider that most of these studies were carried out under optimal anaesthesia conditions in young, healthy animals undergoing routine procedures. The longer-term influence of routine perioperative NSAID administration on biochemical indicators of renal function has also not been evaluated clinically in dog and cat populations. Therefore whether perioperative NSAIDs are a risk factor in the development of renal failure in dogs and cats in later life is currently unknown.

Gastrointestinal (GI) toxicity is the most common adverse class effect associated with NSAIDs. Although anaesthesia per se may not alter the risk of GI toxicity, several risk factors for GI toxicity have been identified in dogs, and these should be considered before administration in the perioperative period. Animals with a history of GI ulceration, biochemical indicators of compromised hepatic or renal function and older animals with a reduced capacity for drug clearance are all at an increased risk of GI toxicity following NSAID administration. In these cases it is sensible to carry out a cost-benefit analysis of NSAID administration in terms of analgesic requirement and the ability to provide analgesia using other classes of drugs against the potential for GI side effects.

Is it Clinically Advantageous to Give NSAIDS Preemptively?

Pre-emptive analgesia is defined as anti-nociceptive treatment that prevents the establishment of altered afferent input from injuries. The concept of pre-emptive analgesia to reduce the magnitude and duration of postoperative pain has been around for about 20 years and there are good experimental data to demonstrate that anti-nociceptive techniques applied before injury were more effective at preventing post-injury central sensitisation phenomena compared with administration after injury.

However, despite a huge number of clinical trials in human medicine, the clinical benefit of pre-emptive analgesia remains unproven. The theoretical benefits of pre-emptive analgesia support administration of NSAIDs preoperatively, but emphasis has shifted away from timing of analgesic drug administration towards use of multimodal analgesia therapies.

Conclusions and Clinical Recommendations for the Perioperative Administration of NSAIDS

Clinical evidence supports the safety of administering COX-2-sparing NSAIDs (such as carprofen and meloxicam) that are licensed for preoperative administration to healthy animals undergoing routine procedures in the perioperative period. However, in other patient groups, administration of NSAIDs preoperatively should be decided on a case-by-case basis. If in doubt about NSAID administration to an individual patient, it is better to delay administration until the animal is fully recovered from anaesthesia and provide analgesia using other classes of analgesic drugs in the intervening period. The limited benefits of pre-emptive analgesia with NSAIDs do not outweigh the risks of serious side effects, such as acute renal failure, that may occur when NSAIDs are given inappropriately.

 Only administer NSAIDs that are licensed for preoperative administration in the perioperative period.

 Only administer a NSAID preoperatively to healthy animals undergoing routine procedures when hypotension during anaesthesia is not anticipated. Renal compromise is possible if an animal becomes hypotensive during anaesthesia when any NSAID has been given. If in doubt delay NSAID administration until the animal is fully recovered from anaesthesia.

 Do not give NSAIDs to trauma or shocked patients until they are normotensive and cardiovascularly stable.

 Do not give NSAIDs to animals with pre-existing renal disease.

 Do not give NSAIDs to animals with disorders of haemostasis.

 NSAIDs are metabolised in the liver, so keep in mind that liver dysfunction may alter the half-life of NSAIDs and lead to inadvertent drug overdose. Use carefully in animals with pre-existing liver disease and monitor the animal for altered liver function (blood biochemistry testing).

 Do not combine different NSAIDs together or give NSAIDs and corticosteroids together.