The substance P receptor antagonist CP-99,994 reduces acute postoperative pain.
BACKGROUND
Animal studies suggest that substance P, a peptide that preferentially activates the neurokinin-1 (NK1) receptor, is involved in pain transmission, with particular importance in pain after inflammation.


METHODS
The analgesic efficacy of CP-99,994, a NK1 receptor antagonist, was compared with ibuprofen and placebo in 78 subjects undergoing third molar extraction. The initial 60 subjects randomly received 1 of 3 possible treatments in a double-blind fashion before oral surgery: 750 microg/kg CP-99,994 infused intravenously over 5 hours on a tapering regimen starting 2 hours before surgery, 600 mg oral ibuprofen 30 minutes before surgery, or placebo. In a second study, 18 subjects were randomized to the same regimens starting 30 minutes before surgery to maximize the amount of CP-99,994 circulating during pain onset.


RESULTS
In the first study, ibuprofen significantly reduced pain, as measured by visual analog scale, from 90 to 240 minutes postoperatively compared with placebo. CP-99,994 produced analgesia that was significant at 90 minutes (P < 0.01 compared with placebo), but not at subsequent time points. In the second study, ibuprofen and, to a lesser extent, CP-99,994 significantly suppressed pain in comparison to placebo at 60, 90, and 120 minutes (P < 0.05). The incidence of side effects was similar across groups.


CONCLUSIONS
This replicate demonstration that a NK1 receptor blocker relieves clinical pain supports the hypothesis that substance P contributes to the generation of pain in humans. The reduction in postoperative pain at doses not producing side effects suggests that NK1 antagonists may be clinically useful.
Dionne
R A
RA
Pain and Neurosensory Mechanisms Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892-1258, USA.
Max
M B
MB
Gordon
S M
SM
Parada
S
S
Sang
C
C
Gracely
R H
RH
Sethna
N F
NF
MacLean
D B
DB
D000208:Acute Disease; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D004311:Double-Blind Method; D006801:Humans; D064729:Neurokinin-1 Receptor Antagonists; D010147:Pain Measurement; D010149:Postoperative Pain / Q000188:drug therapy* / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014081:Tooth Extraction / Q000009:adverse effects*; D016896:Treatment Outcome
D000700:Analgesics; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; C080755:3-(2-methoxybenzylamino)-2-phenylpiperidine