title: Lack of beneficial effect for preemptive analgesia in postoperative pain control: verifying the efficacy of preemptive analgesia with N-methyl-D-aspartate receptor antagonists in a modified animal model of postoperative pain.
abstract: BACKGROUND
  In previous animal studies, preemptive treatments with N-methyl-d-aspartate (NMDA) antagonists were ineffective at preventing incision-induced allodynia. It is very likely that the model was not clinically relevant for testing treatment effects on postoperative pain. The beneficial effects of preemptive treatment can be verified only by treatments with a pharmacologically proven effect in a specific pain type or animal model. We previously showed that NMDA receptor antagonists effectively alleviate enhanced mechanical hyperalgesia after plantar incision in adult rats that had been given an intraplantar injection of carrageenan as neonates. Here, using this modified model, we tested the efficacy of preemptive treatment with the NMDA antagonist MK-801.
  
  
  METHODS
  We injected rat pups subcutaneously with 0.25% carrageenan or saline in the plantar surface of one hindpaw on postnatal day 1. On postnatal day 50, rats were killed and the ipsilateral side of the lumbar spinal cords were harvested for biochemical analysis of the expression of NR2A and NR2B at baseline, 2 hours, 4 hours, 8 hours, and 24 hours after plantar incision (n = 5 per group for each time point). For pharmacological study, rats were allocated into one of the following groups: 1 intrathecal injection of 40 nmol MK-801 15 minutes before plantar incision, 1 intrathecal injection 30 minutes after plantar incision, or 2 injections of 20 nmol or 40 nmol given at 15 minutes and 60 minutes after plantar incision (n = 10 per group for neonatally saline-treated and 12 for carrageenan-treated rats). Paw withdrawal thresholds were measured with von Frey filaments, and weight-bearing percentages were measured hourly after plantar incision.
  
  
  RESULTS
  Expressions of NMDA receptor subunits NR2A and NR2B were increased maximally 4 hours postoperatively and were significantly greater in carrageenan-treated rats than in saline-treated rats. Tests of pain sensitivity showed that MK-801 significantly alleviated the incision-induced mechanical hyperalgesia and increased weight-bearing percentage on the injured paw in carrageenan-treated rats. However, preincisional treatment was not superior to postincisional treatment as assessed during the 6-hour postoperative observation period. Groups with 2 successive postoperative injections exhibited prolonged analgesic effects. Only the group that received 2 postoperative injections and increased total dosage had improved analgesic indices.
  
  
  CONCLUSIONS
  Under conditions of proven analgesic action of an NMDA antagonist, we demonstrated that preincisional treatment is not more beneficial than postincisional treatment for postoperative pain relief in the modified animal model. Increasing the duration of administration and/or total dosage had an incremental analgesic effect in comparison with a single injection.
authors.affiliation: Department of Anesthesiology, Taipei Veterans General Hospital, No. 201, Shih-Pai Rd., Sec. 2, Taipei 112, Taiwan, ROC.
authors.forename: Wen-Kuei
authors.initials: WK
authors.lastname: Chang
authors.forename: Yuan-Xiang
authors.initials: YX
authors.lastname: Tao
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Chuang
authors.forename: Pin-Tarng
authors.initials: PT
authors.lastname: Chen
authors.forename: Kowk-Hon
authors.initials: KH
authors.lastname: Chan
authors.forename: Ya-Chun
authors.initials: YC
authors.lastname: Chu
mesh_terms: D000698:Analgesia / Q000379:methods; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D005260:Female; D008297:Male; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D010149:Postoperative Pain / Q000503:physiopathology / Q000517:prevention & control*; D011247:Pregnancy; D011300:Preoperative Care / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: D018691:Excitatory Amino Acid Antagonists; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate