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 with similar actions but diverse chemical structures. Aspirin (acetylsalicylic acid) and sodium salicylate were the first drugs of this type to be used clinically. However, over the past 3 decades there has been a dramatic increase in the number of NSAIDs available for the treatment of postoperative pain. Tissue injury, such as occurs with surgical intervention, is associated with the release of numerous inflammatory mediators including prostaglandins. Prostaglandins derived from the arachidonic acid cascade are implicated in the production of inflammatory pain, and in sensitising nociceptors to the actions-of other mediators. They are synthesised from arachidonic acid via the endoperoxide biosynthesis pathway, the initial step of which is catalysed by the enzyme cyclooxygenase. Two forms of the cyclo-oxygenase enzyme (COX-1 and COX-2) have been characterised. COX-1 is important in circumstances where prostaglandins have a protective effect such as gastric mucus production and renal blood flow maintenance. NSAIDs inhibit the synthesis of prostaglandins at 1 or more points in the endoperoxide pathway. Three mechanisms of inhibition of the biosynthetic enzymes have been proposed: (i) rapid, reversible competitive inhibition; (ii) irreversible, time-dependent inhibition; and (iii) rapid, reversible noncompetitive (free radical trapping) inhibition. In addition, there is evidence that NSAIDs have a central antinociceptive mechanism of action that augments the peripheral effect. This may involve inhibition of central nervous system prostaglandins or inhibition of excitatory amino acids or bradykinins. There is considerable variability in the pain relief obtained from NSAIDs. Such variability in drug response may be explained in terms of differences between agents with respect to either pharmacodynamic actions or pharmacokinetic parameters or a combination of both. Stereoisomerism, where preparations exist as racemic mixtures and where only 1 enantiomer is active, may also be important. However, chiral inversion from inactive to active enantiomer may occur and may be rapid or slow. NSAIDs have numerous adverse effects. Gastrointestinal disturbances including ulceration are the commonest adverse responses to NSAIDs 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 made on a rational basis. For short term perioperative use it is advisable to favour drugs with good safety profiles, which an available in a range of formulations. It is important to review therapy regularly, changing 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 therefore provide consistent analgesia. Finally, there seems to be little benefit from preoperative administration of NSAIDs, indeed haemorrhagic complications may be more likely.