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Effects of the 2‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐proprionic acid/kainate antagonist LY293558 on spontaneous and evoked postoperative pain
Author(s) -
Gilron Ian,
Max Mitchell B.,
Lee Gloria,
Booher Susan L.,
Sang Christine N.,
Chappell Amy S.,
Dionne Raymond A.
Publication year - 2000
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2000.108677
Subject(s) - ketorolac tromethamine , anesthesia , kainate receptor , placebo , ketorolac , medicine , antagonist , analgesic , ampa receptor , nmda receptor , receptor , alternative medicine , pathology
Background Previous studies suggest that 2‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐proprionic acid (AMPA)/kainate antagonists reduce experimentally induced pain. There have been no studies of AMPA/kainate antagonists in clinical pain. Methods Analgesic efficacy of intravenous LY293558 (0.4 or 1.2 mg/kg) was compared with that of intravenous ketorolac tromethamine (INN, ketorolac; 30 mg) and placebo in a randomized, double‐blind, parallel‐group study after oral surgery (n = 70). Study drugs were administered at the onset of moderate pain; pain intensity and relief were measured for 240 minutes. Results High‐dose LY293558 and ketorolac tromethamine were superior to placebo (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 placebo (−162 ± 50). High‐dose LY293558 was superior to placebo at individual time points (45 to 240 minutes) for pain evoked by mouth opening but not for spontaneous pain. The spontaneous summed pain intensity difference over 240 minutes (SPID240 ± SEM) was highest for ketorolac tromethamine (303 ± 84), intermediate for high‐dose LY293558 (−51 ± 40) and low‐dose LY293558 (−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 reduces clinical pain. Tests of evoked pain may be more sensitive to certain analgesics than those of spontaneous pain. The evaluation of evoked pain as an outcome measure in analgesic trials may identify potentially useful compounds otherwise missed if only spontaneous pain is evaluated. Clinical Pharmacology & Therapeutics (2000) 68 , 320–327; doi: 10.1067/mcp.2000.108677