Clinical and laboratory investigations about preemptive analgesia

最近的证据表明，镇痛药物的施用时间通过减少由伤害性输入引起的神经系统的敏化来影响其疗效。术后疼痛的强度可以通过预先使用局部麻醉剂或阿片类药物来减轻，这导致了先发制人镇痛的概念。然而，这个概念仍然存在争议。本研究的目的是在临床和实验室调查中阐明先发制人镇痛的证据。临床研究：1)将90例腹部下切术患者分为3组：1组30例单纯全麻，2组30例术前20 min全麻下硬膜外镇痛，3组30例术前硬膜外镇痛加全麻。术后立即硬膜外注射0.225%布比卡因和0.0005%芬太尼的混合物5 ml，并以2.1 ml/h的速度连续输注相同的混合物，持续24 h。术后4和24 h， 3组的视觉模拟评分和Prince-Henry评分明显低于1和2组。2) 41例患者分为两组：硬膜外组21例，单次给予0.2 mg芬太尼；静脉组20例，单次给予0.2 mg芬太尼。术后疼痛处理方法同上。术后24、48 h硬膜外组Prince-Henry评分明显低于静脉内组。实验室研究：戊巴比妥麻醉后，右后爪足底表面皮下注射5%福尔马林溶液150 μ 1。芬太尼（0.001、0.01、0.1或0.5 μ g / 10 μ 1）分别于1-2周前、治疗前15分钟、治疗后早期、治疗后60分钟或福尔马林试验后注射。利多卡因（0.3或0.75 mg / 15 μ 1）于福尔马林试验前10分钟、后5分钟或后60分钟鞘内注射。福尔马林试验结束2 h后，用戊巴比妥再次麻醉大鼠，经心灌注4%多聚甲醛。腰椎肿大处的脊髓切除后固定。横切50 μ m冰冻切片，与多克隆抗c- fos抗血清反应。采用链亲和素-生物素-辣根过氧化物酶法观察c-Fos免疫反应核。与注射福尔马林的后爪同侧，在L4和L5脊髓I、II和V、VI层可见大量c-Fos样免疫反应（c-Fos LI）神经元。芬太尼或利多卡因预处理显著降低剂量依赖性c-Fos LI神经元。芬太尼对c-Fos - LI神经元的减少在V、VI层明显大于I、II层。在芬太尼或利多卡因治疗后早期也观察到显着降低，尽管其明显低于预处理后的降低。然而，在芬太尼或利多卡因治疗后，没有发现减少。我们的实验室研究结果表明，在注射福尔马林之前或之后立即在鞘内注射芬太尼或利多卡因可抑制脊髓中c-Fos的表达。与福尔马林感染后立即给药相比，芬太尼或利多卡因在福尔马林感染前给药具有很强的抑制作用。在有害刺激前给予阿片类药物或局部麻醉剂的抗痛觉性治疗比在有害刺激后给予治疗更有效地抑制c-Fos表达。我们的临床研究结果表明，当手术中对中枢神经系统的有害刺激被硬膜外局麻药或阿片类药物阻断时，术后持续硬膜外镇痛是有效的。这些证据将支持先发制人镇痛的概念。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