Relative Contributions of Humoral and Nerve Nociceptive Inputs to Postoperative Central Sensitisation and Pain: Interaction of Extended Perioperative COX-2 Inhibition and Local Anaesthetic Blockade for Breast Malignancy Surgery

Study on the effect of the interaction of cyclooxygenase-2 (COX-2) inhibition (started preoperatively and continued 5 days into the postoperative period) and extended local anaesthetic blockade via paravertebral block on postoperative central sensitisation after breast surgery for malignancy.BackgroundPersistent pain is a challenging clinical problem after breast cancer treatment. After surgery, inflammatory pain and nociceptive input from nerve injury induce central sensitization which may play a role in the genesis of persistent pain. Using quantitative sensory testing, we tested the hypothesis that adding COX-2 inhibition to standard treatment reduces hyperalgesia after breast cancer surgery. A secondary hypothesis was that patients developing persistent pain would exhibit more postoperative hyperalgesia.Methods138 women scheduled for lumpectomy/mastectomy under general anesthesia with paravertebral block were randomized to COX-2 inhibition (2x40mg parecoxib on day of surgery, thereafter 2x200mg celecoxib/day until day five) or placebo. Preoperatively and 1, 5, 15 days and 1, 3, 6, 12 months postoperatively, we determined electric and pressure pain tolerance thresholds in dermatomes C6/T4/L1 and a 100mm VAS score for pain. We calculated the sum of pain tolerance thresholds and analyzed change in these versus preoperatively using mixed models analysis with factor medication. To assess hyperalgesia in persistent pain patients we performed an additional analysis on patients reporting VAS>30 at 12 months.Results48 COX-2 inhibition and 46 placebo patients were analyzed in a modified intention to treat analysis. Contrary to our primary hypothesis, change in the sum of tolerance thresholds in the COX-2 inhibition group was not different versus placebo. COX-2 inhibition had an effect on pain on movement at postoperative day 5 (p<0.01). Consistent with our secondary hypothesis, change in sum of pressure pain tolerance thresholds in 11 patients that developed persistent pain was negative versus patients without pain (p<0.01) from day 5 to 1 year postoperatively.ConclusionsPerioperative COX-2 inhibition has limited value in preventing sensitization and persistent pain after breast cancer surgery. Central sensitization may play a role in the genesis of persistent postsurgical pain.

围手术期环氧合酶-2（cyclooxygenase-2, COX-2）抑制（术前启动并持续至术后5天）联合经椎旁阻滞延长局部麻醉阻滞对恶性乳腺肿瘤术后中枢敏化的影响研究

背景：乳腺癌治疗后持续性疼痛是极具挑战性的临床难题。术后，炎性疼痛与神经损伤引发的伤害性刺激可诱导中枢敏化，该过程或参与持续性疼痛的发生发展。本研究采用定量感觉测试（quantitative sensory testing）验证假说：在标准治疗基础上加用环氧合酶-2抑制可减轻乳腺癌术后痛觉过敏。次要假说为：出现持续性疼痛的患者术后会表现出更显著的痛觉过敏。

方法：本研究纳入138例拟在全身麻醉联合椎旁阻滞下行保乳切除术/乳房切除术的女性患者，将其随机分为环氧合酶-2抑制组与安慰剂组。其中环氧合酶-2抑制组患者术中予帕瑞昔布40mg，每日2次；术后予塞来昔布200mg，每日2次，持续至术后第5天。分别于术前、术后1天、5天、15天及1、3、6、12个月，检测患者C6、T4、L1皮节的电痛阈与压力痛阈，并采用100mm视觉模拟评分法（Visual Analogue Scale, VAS）评估疼痛程度。计算痛阈总和，并采用以用药方案为因素的混合效应模型，分析各时间点痛阈相对于术前的变化情况。为评估持续性疼痛患者的痛觉过敏情况，本研究对术后12个月时VAS评分＞30的患者进行了额外分析。

结果：本研究采用改良意向性治疗分析，最终纳入环氧合酶-2抑制组48例、安慰剂组46例患者。与本研究的主要假说相悖，环氧合酶-2抑制组的痛阈总和变化与安慰剂组无显著差异。环氧合酶-2抑制可改善术后第5天的活动痛（p＜0.01）。与次要假说一致，术后第5天至1年期间，出现持续性疼痛的11例患者的压力痛阈总和变化较无痛患者呈下降趋势，且差异具有统计学意义（p＜0.01）。

结论：围手术期环氧合酶-2抑制在预防乳腺癌术后中枢敏化与持续性疼痛方面价值有限。中枢敏化或参与术后持续性疼痛的发生发展。