Hyperalgesia and Persistent Pain after Breast Cancer Surgery: A Prospective Randomized Controlled Trial with Perioperative COX-2 Inhibition

Background
Persistent 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.
Methods
138 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.
Results
48 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.
Conclusions
Perioperative 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.

背景
乳腺癌治疗后持续性疼痛是一项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感受性输入可诱导中枢敏感化，这或许在持续性疼痛的发病机制中发挥重要作用。本研究采用定量感觉测试（quantitative sensory testing），验证了如下假说：在标准治疗基础上加用COX-2抑制疗法（COX-2 inhibition），可减轻乳腺癌术后痛觉超敏。次要假说为：出现持续性疼痛的患者，其术后痛觉超敏程度更为显著。
方法
本研究纳入138名拟接受全身麻醉联合椎旁神经阻滞下乳房肿块切除术/乳房切除术的女性患者，将其随机分为COX-2抑制疗法组与安慰剂组：COX-2抑制疗法组于手术当日给予帕瑞昔布40mg/次，每日2次，术后每日给予塞来昔布200mg/次，每日2次，持续至术后第5日；安慰剂组则给予对应方案的安慰剂。分别于术前、术后1、5、15日以及1、3、6、12个月时，我们测定了患者C6、T4、L1皮节区域的电刺激痛阈与压力痛阈，并采用100mm视觉模拟评分法（Visual Analogue Scale, VAS）评估疼痛程度。我们计算了痛阈总和，并以用药方案作为因素，采用混合效应模型分析各时间点痛阈总和相较于术前的变化情况。为评估持续性疼痛患者的痛觉超敏情况，我们对术后12个月时VAS评分＞30的患者开展了额外分析。
结果
经改良意向性治疗分析后，最终纳入COX-2抑制疗法组48例、安慰剂组46例患者进行结果分析。与首要假说相悖，COX-2抑制疗法组的痛阈总和变化情况与安慰剂组无显著差异。但COX-2抑制疗法可改善术后第5日的活动时疼痛症状（p＜0.01）。与次要假说一致，术后第5日至1年内，出现持续性疼痛的11例患者的压力痛阈总和变化呈下降趋势，与无痛患者相比差异具有统计学意义（p＜0.01）。
结论
围手术期COX-2抑制疗法在预防乳腺癌术后中枢敏感化与持续性疼痛方面的价值有限。中枢敏感化或许在术后持续性疼痛的发病机制中发挥作用。