Mode of action of peripheral analgesics

Peripheral analgesics amount to more than 95% of the analgesic market. The most important drugs of this group, salicylates, p-aminophenol derivatives, and nonacidic pyrazoles, have been used in therapy for about 100 years, their mode of action remaining unclear until today. This brief review gives a survey on the current knowledge of the therapeutic mechanisms and the molecular causes of the effects and the most important side effects of peripheral analgesics. At present, two theories cannot be rejected on the basis of current knowledge. The first and very popular concept postulates that peripheral analgesics act by inhibiting the formation of arachidonic acid metabolites. The alternative hypothesis relates the effects of the salicylates and related drugs to inhibition of various cell functions by unspecific, concentration-dependent incorporation of drug molecules in the cellular membrane. These two concepts are discussed, and the importance of the physiochemical characteristics and the pharmacokinetic behaviour of peripheral analgesics for the understanding of their effects and side effects is pointed out.