Eisenach James C, Tong Chuanyao, Curry Regina S
Department of Anesthesiology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA.
Pain. 2015 Jan;156(1):81-87. doi: 10.1016/j.pain.0000000000000005.
In rodents, acute exposure to opioids results in transient antinociception followed by longer lasting hypersensitivity to tactile or thermal stimuli, a phenomenon termed opioid-induced hyperalgesia. This hypersensitivity can be blocked or reversed by intrathecally administered cyclooxygenase inhibitors, including ketorolac, suggesting a role for spinal prostaglandins. In surgical patients, the dose of intraoperative opioid, particularly the short-acting drug, remifentanil, is directly related to increased pain and opioid requirements for many hours postoperatively. In addition, experimentally induced tactile hypersensitivity in humans is exaggerated after cessation of remifentanil infusions. The degree of this experimental opioid-induced hyperalgesia is reduced by systemic treatment with cyclooxygenase inhibitors, and investigators have speculated that this reduction reflects the actions in the central nervous system, most likely in the spinal cord. To test this hypothesis, we measured cerebrospinal fluid prostaglandin E2 concentrations during and after remifentanil infusion in 30 volunteers. These volunteers received intrathecal ketorolac or saline in a random, blinded manner during intravenous remifentanil infusion after generation of hypersensitivity by topical capsaicin. Remifentanil reduced pain to noxious heat stimuli and reduced areas of capsaicin-induced hypersensitivity similarly in those receiving intrathecal ketorolac or saline. The primary outcome measure, area of capsaicin-induced hypersensitivity after stopping remifentanil, showed a similar increase in those receiving ketorolac as in those receiving saline. Cerebrospinal fluid prostaglandin E2 concentrations did not increase during postinfusion hyperalgesia compared with those during infusion, and they were not increased during infusion compared with those in historical controls. These data fail to support the hypothesis that acute opioid-induced hyperalgesia reflects spinal cyclooxygenase activation causing central sensitization.
在啮齿动物中，急性暴露于阿片类药物会导致短暂的抗伤害感受，随后对触觉或热刺激产生持续时间更长的超敏反应，这种现象称为阿片类药物诱导的痛觉过敏。鞘内注射环氧化酶抑制剂（包括酮咯酸）可阻断或逆转这种超敏反应，提示脊髓前列腺素发挥了作用。在外科手术患者中，术中阿片类药物的剂量，尤其是短效药物瑞芬太尼的剂量，与术后数小时疼痛加剧及阿片类药物需求增加直接相关。此外，在人体中，停止输注瑞芬太尼后，实验诱导的触觉超敏反应会加剧。全身使用环氧化酶抑制剂可减轻这种实验性阿片类药物诱导的痛觉过敏程度，研究人员推测这种减轻反映了其在中枢神经系统（很可能是脊髓）中的作用。为验证这一假设，我们在30名志愿者输注瑞芬太尼期间及之后测量了脑脊液中前列腺素E2的浓度。这些志愿者在通过局部应用辣椒素产生超敏反应后，于静脉输注瑞芬太尼期间，以随机、盲法的方式接受鞘内注射酮咯酸或生理盐水。在接受鞘内注射酮咯酸或生理盐水的受试者中，瑞芬太尼对有害热刺激的疼痛缓解程度以及对辣椒素诱导的超敏反应区域的减小程度相似。主要观察指标，即停止瑞芬太尼输注后辣椒素诱导的超敏反应区域，在接受酮咯酸的受试者中与接受生理盐水的受试者中显示出相似的增加。与输注期间相比，输注后痛觉过敏期间脑脊液中前列腺素E2的浓度并未升高，与历史对照相比，输注期间其浓度也未升高。这些数据未能支持急性阿片类药物诱导的痛觉过敏反映脊髓环氧化酶激活导致中枢敏化这一假设。
