Analgesic activity of diflunisal [MK-647; 5-(2,4-difluorophenyl)salicylic acid] in rats with hyperalgesia induced by Freund's adjuvant

A method is described for testing analgesia for narcotic or nonnarcotic drugs in rats injected with Freund's adjuvant in the tail, by manipulation of the tail the day after injection, or of the feet after the development of adjuvant arthritis. The method is responsive to a behavioral depressant or an anti-inflammatory steroid. Diflunisal (MK-647; 5-(2,4-difluorophenyl)salicylic acid] exhibited activity in this assay after oral administration with potency about 25 times greater than that of aspirin, about 3 times that of glafenine and twice that of zomepirac. The onset of activity was within a 1/2 hour for narcotic analgesics but required about an hour for non-narcotic compounds. With the latter, the peak of activity was not attained until 2 to 4 hr, depending on the compound. The peak for diflunisal was delayed until the 3rd or 4th hour, but the onset of action was more prompt and the duration greater as the dose was increased. [14C]Diflunisal was concentrated to some extent in the inflamed tissue after adjuvant injection. Peak levels both in plasma and tissue appeared about 2 hr before peak analgesic effect. Repeated administration of large doses produced neither tolerance nor sensitization to the analgesic action of diflunisal. Naloxone and naltrexone did not antagonize the action of the compound, but when morphine and diflunisal were given together, the overall effect was enhanced.