Clinical Effects of Indomethacin and Additive Clinical Effect of Indomethacin During Salicylate Maintenance Therapy

Studies on the therapeutic effect of nonsteroidal anti-inflammatory agents in relation to doses or plasma concentrations have been relatively rare. We have investigated the clinical effects of indomethacin in daily doses of 45, 75 and 105 mg compared with placebo. The treatments were given double blind in two-week periods to eight rheumatic patients. There was a statistically significant therapeutic effect on parameters related to pain but no effect was detected on the activity of the disease by technetium scintigraphy. There was no clear association between dose or plasma concentration of indomethacin and therapeutic response in the actual patients with the dose range used. In a subsequent study ASA was given double blind in daily doses of 2 and 4.5 g in two three-week periods to twelve rheumatic patients. Placebo and indomethacin were given as suppositories at night and the clinical effect was evaluated by articular index and subjects rating of morning stiffness and pain. Prostaglandin release from platelets was assessed by a RIA method. It was found that both doses of ASA suppressed the PGF2alpha release totally. Indomethacin had a significant additive effect during 2 g ASA therapy as estimated by articular index and subjective ratings of pain and morning stiffness. On the 4.5 g ASA dose there was a significant improvement only for articular index. Thus the release of PGF2alpha cannot be used as a measure of antirheumatic effect and the clinical practice to combine these drugs seems justified. As the dose of ASA was increased from 2 to 4.5 g daily the total salicylate concentration increased up to 5 times. The unbound and pharmacologically active concentration increased up to 24 times. This disproportionality reflects the combined effect of capacity limited metabolism and capacity limited protein binding of salicylate.