Prevention of opioid-induced hyperalgesia in surgical patients: does it really matter?
Prevention of opioid-induced hyperalgesia in surgical patients: does it really matter?
复制标题
预防手术患者阿片类药物引起的痛觉过敏：这真的很重要吗？
DOI：
10.1093/bja/aes278
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发表时间：
2012
影响因子：
9.8
通讯作者：
D. Fletcher
中科院分区：
文献类型：
--
作者：
V. Martinez;D. Fletcher
302手术。使用手持式冯弗雷细丝在手臂上进行疼痛测量。两组机械刺激的基线疼痛阈值相似，无 N2O 组的平均值为 69 [95% 置信区间 (CI)：50.2, 95.1] g，有 N2O 组的平均值为 71 (95% CI: 45.7, 112.1) g。两组之间的术后疼痛评分和累积吗啡消耗量相似。分析显示两组的阈值均有所下降。然而，事后比较显示，术后12-18小时，无N2O组的机械阈值下降幅度大于N2O组。 OIH 已在动物模型 2 和人类志愿者中得到明确证实。 3 在这些实验条件下可能导致 OIH 的阿片类药物包括瑞芬太尼和芬太尼。 OIH 的神经生物学很复杂，可能涉及多个系统，急性和慢性环境在突触前和突触后水平上可能存在差异，影响 N-甲基-D-天冬氨酸受体活性、G 蛋白和细胞内系统。 4瑞芬太尼累积剂量和快速停药可能是瑞芬太尼引起痛觉过敏的因素。 5 6 在小鼠切口痛模型中，瑞芬太尼诱导伤害感受效应，该效应呈剂量依赖性，但不随给药时间的延长而改变。 5 阿片类药物累积剂量的重要性似乎已通过手术患者瑞芬太尼引起的痛觉过敏的临床研究得到证实。在阴性研究中，使用的累积剂量范围为 20-30 mg kgJ1、6-10，而阳性研究中使用的累积剂量范围为 80-120 mg kgJ1。 11-15 一项体外研究表明，阿片类激动剂的突然停药会引起疼痛通路第一个突触的长期增强。 16 这为选择性地对抗阿片类药物的伤害感受作用而不影响阿片类药物的镇痛作用提供了一个以前未被认识的目标。逐渐减少戒断对于减少瑞芬太尼引起的痛觉过敏表达的重要性尚未在人类中进行研究。手术患者中的 OIH 是如何定义的？国际疼痛研究协会将痛觉过敏定义为“因通常引起疼痛的刺激而增加疼痛”。因此，阿片类药物麻醉后疼痛感的增加可能是与 OIH 相关的关键因素。此外，手术后阿片类药物使用增加的耐受性是 OIH 的另一个潜在的、共存的方面。最近在一篇社论中讨论了阿片类药物耐受的机制，该社论还研究了 b-arrestin 2 在阿片类药物耐受的啮齿动物模型中的作用。 17 18 这两种现象可能通过共同的神经基质相互关联。 19 在手术患者中，OIH、耐受性或两者主要在瑞芬太尼麻醉后被发现。 11–15 20 然而，在这些研究中，只有两项研究测试了疼痛敏感性以明确识别 OIH。 12 20 尽管 OIH 是一个有趣的概念，但其预防对于手术患者重要吗？已经测试了不同的预防 OIH 的方法，包括围术期氯胺酮、12 镁、15 异丙酚、14 和一氧化二氮。 1 在这些旨在预防 OIH 的临床研究中，术后即刻的临床获益要么不存在，1 仅限于中度阿片类药物的节约效果，12 14 要么疼痛评分略有降低。 14 15 这些研究均未发现吗啡节约效应对阿片类药物相关副作用有任何影响。最后，这些研究不足以充分估计与预防技术相关的副作用。因此，临床...
302 surgery. Pain measurements were performed on the arm using hand-held von Frey filaments. Baseline pain thresholds to mechanical stimuli were similar in both groups, with the mean values of 69 [95% confidence interval (CI): 50.2, 95.1] g in the group without N2O and 71 (95% CI: 45.7, 112.1) g in the group with N2O. Postoperative pain scores and cumulative morphine consumption were similar between the groups. The analysis revealed a decrease in the threshold value in both groups. However, post hoc comparisons showed that at 12–18 h after surgery, the decrease in mechanical threshold was greater in the group without N2O than the group with N2O. OIH has been clearly identified in animal models 2 and in human volunteers. 3 Opioids which are potentially responsible for OIH in these experimental conditions include remifentanil and fentanyl. The neurobiology of OIH is complex and likely to involve more than one system, with probable differences between acute and chronic settings at both pre-and post-synaptic levels, affecting N-methyl-D-aspartate receptor activity, G-proteins, and intracellular systems. 4 The cumulative dose of remifentanil and the rapid withdrawal may be factors in remifentanil-induced hyperalgesia. 5 6 In a model of incisional pain in mice, remifentanil induced pro-nociceptive effects, which were dosedependent but unaltered by the duration of administration. 5 The importance of the cumulative dose of opioid appears to be confirmed by clinical studies of remifentanil-induced hyperalgesia in surgical patients. In negative studies, the cumulative dose range used was 20–30 mg kgJ1, 6–10 in contrast to a range of 80–120 mg kgJ1 used in positive studies. 11–15 An in vitro study showed that abrupt withdrawal of opioid agonists induced long-term potentiation at the first synapse in pain pathways. 16 This provides a previously unrecognized target for selectively combating pronociceptive effects of opioids without compromising opioid analgesia. The importance of tapered withdrawal to reduce the expression of remifentanil-induced hyperalgesia has not been investigated in humans. How is OIH defined in the surgical patient? The International Association of the Study of Pain defines hyperalgesia as ‘Increased pain from a stimulus that normally provokes pain’. Therefore, the increased perception of pain after opioid-based anaesthesia could be the key factor associated with OIH. In addition, tolerance with the increased use of opioid after surgery is another potential, coexisting aspect of OIH. The mechanisms of opioid tolerance were recently addressed in an editorial accompanying a study of the role of b-arrestin 2 in a rodent model of opioid tolerance. 17 18 These two phenomena may be interrelated by common neural substrates. 19 In surgical patients, OIH, tolerance, or both have been identified mainly after remifentanil-based anaesthesia. 11–15 20 However, of these studies, only two have tested pain sensitivity to clearly identify OIH. 12 20 Although OIH is an interesting concept, does its prevention matter for surgical patients? Different methods to prevent OIH have been tested, including perioperative ketamine, 12 magnesium, 15 propofol, 14 and nitrous oxide. 1 In these clinical studies aimed at preventing OIH, the clinical benefit in the immediate postoperative period is either absent, 1 limited to a moderate opioid-sparing effect, 12 14 or a slight reduction in pain scores. 14 15 None of these studies found that the morphine-sparing effect had any impact on the opioid-related side-effects. Finally, these studies were not powered to adequately estimate the side-effects related to the prevention technique. Therefore, the clinical …