NONSTEROIDAL ANTIINFLAMMATORY DRUGS IN PERISURGICAL PAIN MANAGEMENT -MECHANISMS OF ACTION AND RATIONALE FOR OPTIMUM USE

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a group of agents wi th similar actions but diverse chemical structures. Aspirin (acetylsal icylic acid) and sodium salicylate were the first drugs of this type t o be used clinically. However, over the past 3 decades there has been a dramatic increase in the number of NSAIDs available for the treatmen t of postoperative pain. Tissue injury, such as occurs with surgical i ntervention, is associated with the release of numerous inflammatory m ediators including prostaglandins. Prostaglandins derived from the ara chidonic acid cascade are implicated in the production of inflammatory pain, and in sensitising nociceptors to the actions-of other mediator s. They are synthesised from arachidonic acid via the endoperoxide bio synthesis pathway, the initial step of which is catalysed by the enzym e cyclooxygenase. Two forms of the cyclo-oxygenase enzyme (COX-1 and C OX-2) have been characterised. COX-1 is important in circumstances whe re prostaglandins have a protective effect such as gastric mucus produ ction and renal blood flow maintenance. NSAIDs inhibit the synthesis o f prostaglandins at 1 or more points in the endoperoxide pathway. Thre e mechanisms of inhibition of the biosynthetic enzymes have been propo sed: (i) rapid, reversible competitive inhibition; (ii) irreversible, time-dependent inhibition; and (iii) rapid, reversible noncompetitive (free radical trapping) inhibition. In addition, there is evidence tha t NSAIDs have a central antinociceptive mechanism of action that augme nts the peripheral effect. This may involve inhibition of central nerv ous system prostaglandins or inhibition of excitatory amino acids or b radykinins. There is considerable variability in the pain relief obtai ned from NSAIDs. Such variability in drug response may be explained in terms of differences between agents with respect to either pharmacody namic actions or pharmacokinetic parameters or a combination of both. Stereoisomerism, where preparations exist as racemic mixtures and wher e only 1 enantiomer is active, may also be important. However, chiral inversion from inactive to active enantiomer may occur and may be rapi d or slow. NSAIDs have numerous adverse effects. Gastrointestinal dist urbances including ulceration are the commonest adverse responses to N SAIDs and carry the greatest risk of death. Also significant are renal impairment and an increased risk of postoperative haemorrhage. Asthma and allergic reactions are uncommon. The choice of NSAID should be ma de on a rational basis. For short term perioperative use it is advisab le to favour drugs with good safety profiles, which an available in a range of formulations. It is important to review therapy regularly, ch anging to an alternative NSAID if there is poor response to treatment. NSAIDs should not be used in patients with known contraindications to their use. Disparity between clinical effect and plasma concentration of some NSAIDs may be due to a complex, time-dependent concentration- effect relationship. Dosage of NSAIDs should be tailored to individual patient response, based on clinical assessment. Oral mandatory dosage regimens and intravenous (or even intramuscular) infusions may result in steady state therapeutic plasma concentrations of NSAIDs and there fore provide consistent analgesia. Finally, there seems to be little b enefit from preoperative administration of NSAIDs, indeed haemorrhagic complications may be more likely.