Background: Nonsteroidal anti-inflammatory drug (NSAID) analgesia is generally attributed to peripheral suppression of cyclooxygenase (COX) enzymes, leading to decreased products of the arachidonic acid cascade. This study evaluated the in vivo relationship between levels of prostanoids at the site of tissue injury and analgesia after systemic or local NSAID administration in a clinical model of tissue injury.
Methods: Subjects in two replicate clinical trials had one or two mandibular third molars removed and a microdialysis probe implanted at the surgical site for measurement of immunoreactive prostaglandin E(2) (PGE(2)) or immunoreactive thromboxane B(2) (TxB(2)) and pain measured concurrently. In the first study, ketorolac tromethamine (INN, ketorolac) was administered at pain onset in a 30-mg intramuscular dose, a 1-mg intramuscular dose, or a 1-mg submucosal dose at the extraction site in comparison with placebo. In the second study, subjects received either ketorolac tromethamine 30 mg by the intravenous route or placebo at pain onset.
Results: PGE(2) was detectable in the first postoperative sample, decreased over the next hour, and then increased significantly coincident with the onset of postoperative pain. Administration of 30 mg ketorolac tromethamine produced parallel decreases in pain, PGE(2) levels, and TxB(2) levels at the surgical site. Administration of 1 mg ketorolac tromethamine intramuscularly or directly at the surgical site was analgesic but without measurable effects on PGE(2) levels.
Conclusion: The temporal profile of PGE(2) and TxB(2) in the immediate postoperative period is consistent with constitutive COX-1 initially, followed by an increase in PGE(2) resulting from expression of COX-2. The temporal association between NSAID analgesia and decreased prostanoids at the site of injury is consistent with a dual COX-1/COX-2 peripheral site of action. The analgesic effects of 1 mg ketorolac tromethamine without a reduction in PGE(2) at the site of injury suggests an additional central site for NSAID analgesia.