Clinical and laboratory investigations about preemptive analgesia

最近的证据表明，给药的时机通过减少伤害性输入引起的神经系统敏感化来影响止痛药的疗效。术后疼痛的强度可以通过预先给药，如局部麻醉药或阿片类药物来减轻，这导致了超前止痛的概念。然而，这一概念仍存在争议。本研究旨在阐明超前镇痛在临床和实验室研究中的依据。1)90例腹部手术患者随机分为3组：全麻组30例，全麻组30例，全麻术前20min硬膜外镇痛组30例，硬膜外镇痛组30例。术后立即硬膜外注入0.225%布比卡因和0.0005%芬太尼混合液5毫升，行…术后4、24 h，3组视觉模拟评分和Prince-Henry评分均明显低于1组和2组。2)41例患者随机分为两组：硬膜外组21例，硬膜外注射芬太尼0.2 mg；静脉组20例，静脉注射芬太尼0.2 mg。术后疼痛按上述方法处理。术后24、48h，硬膜外组的Prince-Henry评分明显低于静脉组。实验研究：戊巴比妥钠麻醉后，将150亩1的5%福尔马林溶液注入右后足底。分别于1~2周前、治疗前15min、治疗早期5min或福尔马林试验后60min(治疗后期)经导管将芬太尼(0.01、0.01、0.1或0.5mg10 MU1)注入蛛网膜下腔。福尔马林试验前10min、试验后5min或试验后60min鞘内注射利多卡因(0.3或0.75 mg/15亩1)。福尔马林实验结束2 h后，用戊巴比妥钠再次麻醉大鼠，并经心内注入4%多聚甲醛。腰椎膨大处的脊髓被摘除并后固定。横切面切取50 mm冰冻切片，与多克隆抗c-Fos抗血清反应。用链霉亲和素-生物素-辣根过氧化物酶方法显示c-Fos免疫反应核。在注射福尔马林的同侧L4和L5脊髓的Lawinae I和II，以及L4和L5脊髓的V和VI层内，观察到大量的c-Fos免疫反应阳性神经元。芬太尼或利多卡因预处理显著减少c-Fos阳性神经元，并呈剂量依赖关系。芬太尼对第V层和第VI层c-Fos阳性神经元的减少明显大于第I层和第II层。芬太尼或利多卡因处理后早期也观察到c-Fos阳性神经元的减少，但显著低于预先处理后的减少。我们的实验室研究结果表明，在福尔马林注射前或注射后立即鞘内注射芬太尼或利多卡因可抑制脊髓c-Fos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，有强烈的抑制作用。在伤害性刺激前给予阿片类药物或局麻药的抗伤害性治疗比在伤害性刺激后给予的治疗更有效地抑制c-Fos的表达。我们的临床研究结果表明，当手术中对中枢神经系统的伤害性刺激被硬膜外局部麻醉剂或阿片类药物阻断时，术后持续硬膜外镇痛是有效的。这些证据支持超前镇痛的概念。较少

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