Inhibition of synovial plasma extravasation by preemptive administration of an antiinflammatory irrigation solution in the rat knee

Inflammation and hyperalgesia during surgical procedures are caused by the local release of multiple inflammatory mediators. We used a rat knee joint model of acute inflammation (synovial plasma extravasation) to determine wh ether preemptive intraarticular irrigation of the antiinflammatory drugs ke toprofen, amitriptyline, or oxymetazoline, alone or in combination, can red uce inflammatory soup-induced plasma extravasation. These three drugs were selected because of their abilities to collectively inhibit the inflammator y effects of biogenic amines, eicosanoid production, and the release of neu ropeptides from C-fiber terminals. Synovial perfusion of each one of the th ree drugs 10 min before, and then in combination with, the inflammatory sou p (bradykinin, 5-hydroxytryptamine, and mustard oil) did not reduce plasma extravasation. Similarly, two-drug combinations did not significantly reduc e inflammatory soup-induced plasma extravasation. The combination of all th ree drugs (amitriptyline, ketoprofen, and oxymetazoline) produced a dramati c inhibition of plasma extravasation and was more effective than any of the two-drug combinations. A comparison between the preemptive (10 min before inflammatory soup perfusion) and postinflammatory administration (10 min af ter inflammatory soup perfusion) showed that the postinflammatory administr ation of the three-drug solution lost all ability to inhibit inflammatory s oup-induced plasma extravasation. We conclude that acute synovial inflammat ion, which is induced and maintained by multiple mediators, can be substant ially inhibited only by the preemptive administration of a drug combination that targets multiple inflammatory mediators.