THE SUBSTANCE-P RECEPTOR ANTAGONIST CP-99,994 REDUCES ACUTE POSTOPERATIVE PAIN

Background: Animal studies suggest that substance P, a peptide that pr eferentially activates the neurokinin-1 (NK1) receptor, is involved in pain transmission, with particular importance in pain after inflammat ion. Methods: The analgesic efficacy of CP-99,994, a NK1 receptor anta gonist, was compared with ibuprofen and placebo in 78 subjects undergo ing third molar extraction. The initial 60 subjects randomly received 1 of 3 possible treatments in a double-blind fashion before oral surge ry: 750 mu g/kg CP-99,994 infused intravenously over 5 hours on a tape ring regimen starting 2 hours before surgery, 600 mg oral ibuprofen 30 minutes before surgery, or placebo. In a second study, 18 subjects we re randomized to the same regimens starting 30 minutes before surgery to maximize the amount of CP-99,994 circulating during pain onset. Res ults: In the first study, ibuprofen significantly reduced pain, as mea sured by visual analog scale, from 90 to 240 minutes postoperatively c ompared with placebo, CP-99,994 produced analgesia that was significan t at 90 minutes (P < 0.01 compared with placebo), but not at subsequen t time points. In the second study, ibuprofen and, to a lesser extent, CP-99,994 significantly suppressed pain in comparison to placebo at 6 0, 90, and 120 minutes (P < 0.05). The incidence of side effects was s imilar across groups, Conclusions: This replicate demonstration that a NK1 receptor blocker relieves clinical pain supports the hypothesis t hat substance P contributes to the generation of pain in humans. The r eduction in postoperative pain at doses not producing side effects sug gests that NK1 antagonists may be clinically useful.