Effects of the 2-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain

Background: Previous studies suggest that 2-amino-3-hydroxy-5-methyl-4-isox azole-proprionic acid (AMPA)/kainate antagonists reduce experimentally indu ced pain. There have been no studies of AMPA/kainate antagonists in clinica l pain. Methods: Analgesic efficacy of intravenous LY293558 (0.4 or 1.2 mg/kg) was compared with that of intravenous ketorolac tromethamine (INN, ketorolac; 3 0 mg) and placebo in a randomized, double-blind, parallel-group study after oral surgery (n = 70). Study drugs were administered at the onset of moder ate pain; pain intensity and relief were measured for 240 minutes. Results: High-dose LY293558 and ketorolac tromethamine were superior to pla cebo (P < .05) for pain evoked by mouth opening and one of several measures of spontaneous pain: SPID240 +/- SEM for pain evoked by mouth opening was highest for ketorolac tromethamine (151 +/- 58), intermediate for high-dose LY293558 (-45 +/- 35), and least for low-dose LY293558 (-151 +/- 39) and p lacebo (-162 +/- 50). High-dose LY293558 was superior to placebo at individ ual time points (45 to 240 minutes) for pain evoked by mouth opening but no t for spontaneous pain. The spontaneous summed pain intensity difference ov er 240 minutes (SPID240 +/- SEM) was highest for ketorolac tromethamine (30 3 +/- 84), intermediate for high-dose LY293558 (-51 +/- 40) and low-dose LY 293558 (-96 +/- 45), and least for placebo (-180 +/- 24), LY293558 was well tolerated, with dose-dependent and reversible side effects including hazy vision in 20% of patients and sedation in 15%. Conclusions: This is the first evidence that an AMPA/kainate antagonist red uces clinical pain. Tests of evoked pain may be more sensitive to certain a nalgesics than those of spontaneous pain. The evaluation of evoked pain as an outcome measure in analgesic trials may identify potentially useful comp ounds otherwise missed if only spontaneous pain is evaluated.