Clinical and laboratory investigations about preemptive analgesia

最近的证据表明，镇痛药物的给药时机通过减少由伤害性输入诱导的神经系统的敏化来影响其功效。术后疼痛的强度可以通过预先给药如局部麻醉剂或阿片类药物来降低，从而产生了超前镇痛的概念。然而，这一概念仍有争议。本研究的目的是阐明超前镇痛在临床和实验室研究中的证据。临床研究：1）90例接受腹部手术的患者被分为三组：第1组30例单纯全麻，第2组30例全麻结束前20 min硬膜外镇痛，第3组30例，术前硬膜外镇痛加全麻。手术后立即注入0.225%布比卡因和0.0005%芬太尼混合液5 ml， ...更多信息 以2.1ml/h的速率连续输注相同的混合物24小时。术后4 h和24 h，第3组的视觉模拟评分和M-H评分显著低于第1组和第2组。2）41例患者分为两组：硬膜外组21例，硬膜外注射芬太尼0.2mg;静脉组20例，静脉注射芬太尼0.2mg。术后疼痛采用上述相同方法进行管理。术后24和48 h硬膜外组的M-H评分明显低于静脉组。实验室检查：戊巴比妥钠麻醉后，右后足跖面皮下注射5%福尔马林溶液150 μ l。通过1-2周前、治疗前15分钟（治疗前）、治疗后5分钟（治疗后早期）或福尔马林试验后60分钟（治疗后后期）放置的导管向蛛网膜下腔注射芬太尼（0.001、0.01、0.1或0.5 μ g/10 μ l）。利多卡因（0.3或0.75mg/15 μ l）在福尔马林试验前10 min、后5 min或后60 min鞘内注射。福尔马林试验后2 h，用戊巴比妥再次麻醉大鼠，并经心灌注4%多聚甲醛。切除腰椎膨大处的脊髓并进行后固定。将50 μ m冰冻切片在横切面上切下，并与多克隆抗c-Fos抗血清反应。采用链霉亲和素-生物素-辣根过氧化物酶法观察c-Fos免疫反应阳性细胞核。大量c-Fos样免疫反应（c-Fos LI）神经元观察到lawinae I和II，和层V和VI的L4和L5脊髓，同侧福尔马林注射后爪。芬太尼或利多卡因预处理后，c-Fos阳性神经元数量明显减少，且呈剂量依赖性。芬太尼对c-Fos阳性神经元的抑制作用在第五层和第六层明显大于第一层和第二层。然而，没有发现减少后的后处理与芬太尼或利多卡因。我们的实验室调查结果表明，芬太尼或利多卡因鞘内注射前或后立即福尔马林注射抑制c-Fos在脊髓中的表达。芬太尼或利多卡因在福尔马林感染前给药时，与福尔马林感染后立即给药相比，具有强烈的抑制作用。在伤害性刺激之前给予阿片类药物或局部麻醉剂的抗伤害性治疗在抑制c-Fos表达方面比在伤害性刺激之后给予的治疗更有效。我们的临床研究结果表明，连续硬膜外镇痛手术后是有效的，当伤害性刺激的中枢神经系统在手术中被硬膜外局麻药或阿片类药物阻断。这些证据支持超前镇痛的概念。少

Recent evidence has suggested that the timing of administration of analgesic drugs influences their efficacy by reducing the sensitization of the nervous system induced by nociceptive inputs. The intensity of postoperative pain may be reduced by preadministration of drugs like local anesthetics or opioids leading to the concept of preemptive analgesia. However, this concept is still debated. The purpose of this study is to clarify the evidence of preemptive analgesia in clinical and laboratory investigations.Clinical investigation : 1)Ninety patients undergoing abdominal hypterctomy were allocated to three groups : 30 patients of group 1 with general anesthesia alone, 30 patients of group 2 with epidural analgesia 20 min before the end of surgery under general anesthesia, and 30 patients of group 3 with epidural analgesia plus general anesthesia before surgery. Immediately after surtery, 5 ml of the mixture of 0.225% bupivacaine and 0.0005% fentanyl was injected epidurally and followed … More with continuous infusion of the same mixture at the rate of 2.1 ml/h over 24 h. Visual analogue score and Prince-Henry score were significantly less in group 3 than in groups 1 and 2 at 4 and 24 h after surgery. 2)Forty-one patients were divided into two groups : 21 patients of an epidural group received 0.2 mg of fentanyl epidually and 20 patients of an intravenous group received 0.2 mg of fentanyl intravenously. Postoperative pain was managed with the same method above. Prince-Henry score was significantly less in the epidural group than in the intravenous group at 24 and 48 h after surgery.Laboratory investigation : After pentobarbital anesthesia, 150 mu 1 of 5% formalin solution was injected subcutaneously into the plantar surface of the right hindpaw. Fentanyl (0.001,0.01,0.1 or 0.5 mu g in 10 mu1) was injected in the subarchnoid space through the catheter placed 1-2 weeks ago, 15 min before (pretreatment), 5 min after (early posttreatment) or 60 min after formalin test (later posttreatment). Lidocain (0.3 or 0.75 mg in 15 mu 1) was also injected intrathecally 10 min before, 5 min after or 60 min after formalin test. Two h later from formalin test, the rats were re-anesthetized with pentobarbital and perfused transcardially with 4% paraformaldehyde. The spinal cord at the lumbar enlargement was removed and post-fixed. Fifty mu m frozen sections were cut in the transverse plane and reacted with polyclonal anti-c-Fos antiserum. The streptavidin-biotin-horseradish peroxidase method was employed to visualize the c-Fos immunoreactive nuclei. Numerous c-Fos like immunoreactive (c-Fos LI) neurons were observed in lawinae I and II,and laminae V and VI of the L4 AND L5 spinal cord, ipsilateral to the formalin-injected hindpaw. Pretreatment with fentanyl or lidocaine decreased significantly dose-dependently c-Fos LI neurons. The reduction of c-Fos LI neurons by fentanyl was significantly greater in laminae V and VI than in laminae I and II.The significant reduction was also observed follwing early posttreatment with fentanyl or lidocaine, although it was significantly less than the reduction following pretreatment. However, no reduction was found following later posttreatment with fentanyl or lidocaine.Our results of laboratory investigation demonstrated that fentanyl or lidocaine administered intrathecally before or immediately after formalin injection suppresses c-Fos expression in the spinal cord. Fentanyl or lidocaine suppressed strongly when it administered before formalin infection, compared with it administered immediately after formalin. An antinociceptive treatment with opioids or local anesthetics given before noxious stimuli is more effective in the suppression of c-Fos expression than the treatment given after noxious stimuli. Our results of clinical investigations suggested that continuous epidural analgesia after surgery is effective when noxious stimuli to the central nervous system during surgery are blocked by epidural local anesthetics or opioids. These evidence would support the concept of preemptive analgesia. Less