Effect of a high-dose target-controlled naloxone infusion on pain and hyperalgesia in patients following groin hernia repair: study protocol for a randomized controlled trial.
Effect of a high-dose target-controlled naloxone infusion on pain and hyperalgesia in patients following groin hernia repair: study protocol for a randomized controlled trial.
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DOI：
10.1186/s13063-015-1021-6
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发表时间：
2015-11-10
期刊：
影响因子：
2.5
通讯作者：
Dahl JB
中科院分区：
文献类型：
--
作者：
Pereira MP;Werner MU;Dahl JB
中枢致敏是由内源性阿片系统调节的，在疼痛的发生和维持中起着重要作用。最近在炎性疼痛消退后进行的动物研究显示，给予阿片拮抗剂可引起触觉超敏反应的恢复，这表明潜在的致敏反应是由内源性阿片介导的。在最近一项健康志愿者的交叉研究中，在一级烧伤消退后，12名志愿者中有4名在纳洛酮输注后出现大面积继发性痛感过敏，而没有志愿者在安慰剂输注后出现明显的继发性痛感过敏。为了持续地证明人类的潜在致敏性，可能需要一种诱导深层组织炎症的疼痛模型，就像在动物研究中使用的那样。本研究的目的是研究大剂量靶向控制的纳洛酮输注是否可以恢复开放式腹股沟疝修复后的疼痛和痛觉过敏，从而一致地证明阿片类药物介导的人类潜在致敏。接受单侧、原发性、开放式腹股沟疝修补术的患者将被纳入这项随机、安慰剂对照、双盲、交叉研究。实验时间在手术后6-8周，在这个时间点上，病人几乎没有疼痛。在给予纳洛酮或安慰剂之前，将评估主要结果（疼痛的汇总测量：休息时，从仰卧位到站立位的转变，并由压力测量引起）和次要结果（继发性痛觉过敏/异常性痛，压力痛阈，在手术部位和对侧腹股沟镜像部位评估，以及阿片类戒断症状）。这些评估将在目标控制输注安慰剂或纳洛酮的每个步骤中重复，估计中位（95% CI）血浆浓度为344 ng/ml (130;567), 1059 ng/ml（400;1752）和3196 ng/ml（1205;5276）。我们的目标是证明阿片类药物介导的潜在致敏在术后设置，使用疼痛作为临床相关变量。保护性内源性阿片系统的损伤可能在急性到慢性疼痛的转变中起重要作用。根据最近在动物研究中的发现，为了充分阻断内源性阿片系统，使用高剂量靶向控制的纳洛酮输注。EUDRACT: 2015-000793-36（注册日期：2015年2月16日）临床试验网站：NCT01992146（注册日期：2014年12月12日）
Central sensitization is modulated by the endogenous opioid system and plays a major role in the development and maintenance of pain. Recent animal studies performed following resolution of inflammatory pain showed reinstatement of tactile hypersensitivity induced by administration of a mu-opioid-antagonist, suggesting latent sensitization is mediated by endogenous opioids. In a recent crossover study in healthy volunteers, following resolution of a first-degree burn, 4 out of 12 volunteers developed large secondary areas of hyperalgesia areas after a naloxone infusion, while no volunteer developed significant secondary hyperalgesia after the placebo infusion. In order to consistently demonstrate latent sensitization in humans, a pain model inducing deep tissue inflammation, as used in animal studies, might be necessary. The aim of the present study is to examine whether a high-dose target-controlled naloxone infusion can reinstate pain and hyperalgesia following recovery from open groin hernia repair and thus consistently demonstrate opioid-mediated latent sensitization in humans. Patients submitted to unilateral, primary, open groin hernia repair will be included in this randomized, placebo-controlled, double-blind, crossover study. The experimental days take place 6–8 weeks after surgery, time-points at which patients are expected to be almost pain- free. Prior to administration of naloxone or placebo, the primary outcome (a summated measure of pain: at rest, during transition from supine to standing position, and evoked by pressure algometry) and the secondary outcomes (secondary hyperalgesia/allodynia, pressure pain thresholds, assessed at the surgical site and at the mirror-site in the contralateral groin, and, opioid withdrawal symptoms) will be assessed. These assessments will be repeated at each step of the target-controlled infusion of placebo or naloxone at estimated median (95 % CI) plasma concentrations of 344 ng/ml (130;567), 1059 ng/ml (400;1752) and 3196 ng/ml (1205;5276). We aim to demonstrate opioid-mediated latent sensitization in a post-surgical setting, using pain as a clinical relevant variable. Impairment of the protective endogenous opioid system may play an important role in the transition from acute to chronic pain. In order to sufficiently block the endogenous opioid system, a high-dose target-controlled naloxone-infusion is used, in accordance with recent findings in animal studies. EUDRACT: 2015-000793-36 (Registration date: 16 February 2015) Clinicaltrials.gov: NCT01992146 (Registration date: 12 December 2014)