Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA.
Pain. 2012 May;153(5):974-981. doi: 10.1016/j.pain.2012.01.014. Epub 2012 Feb 22.
Acute and chronic exposure to opioids has been associated with hyperalgesia in both animals and humans. A genetic analysis of opioid-induced hyperalgesia in mice linked the β(2)-adrenergic receptor to mechanical sensitization after opioid exposure. In humans, expansion of the area of mechanical hyperalgesia surrounding an experimentally induced lesion after the cessation of remifentanil infusion is a commonly used model of opioid hyperalgesia (remifentanil-induced postinfusion hyperalgesia, RPH). The purpose of our translational study was to test the hypothesis that the β-adrenergic receptor antagonist propranolol modulates the expression of RPH in humans. This double-blinded, randomized, placebo-controlled, crossover study was performed in 10 healthy human volunteers. During test sessions, intracutaneous electrical stimulation was used to generate areas of secondary mechanical hyperalgesia. The area of this sensitization was measured before, during, and after remifentanil infusion. Heat pain sensitivity was also followed. During one test session, subjects received propranolol infusion. We observed an average increase in the areas of secondary mechanical hyperalgesia to 141% of the baseline in subjects infused with remifentanil and placebo (P=0.00040). However, when remifentanil infusion was combined with propranolol, the area of secondary hyperalgesia after terminating remifentanil was not significantly different than the area before beginning the opioid infusion (P=0.13). Thermal hyperalgesia was not observed after remifentanil infusion. Propranolol infusion at the selected dose had minor hemodynamic effects. Concomitant infusion of propranolol with remifentanil prevented the expression of RPH. β-adrenergic receptor blockade may be a useful pharmacological strategy for preventing hyperalgesia in patients exposed to opioids.
急性和慢性接触阿片类药物会导致动物和人类出现痛觉过敏。对小鼠的阿片类药物诱导痛觉过敏的基因分析将β（2）-肾上腺素能受体与阿片类药物暴露后的机械致敏联系起来。在人类中，停止瑞芬太尼输注后，实验性诱导损伤周围机械性痛觉过敏区域的扩大是一种常用的阿片类药物痛觉过敏模型（瑞芬太尼输注后痛觉过敏，RPH）。我们的转化研究的目的是检验这样一个假设，即β-肾上腺素能受体拮抗剂普萘洛尔调节人类 RPH 的表达。这项双盲、随机、安慰剂对照、交叉研究在 10 名健康人类志愿者中进行。在测试过程中，使用皮内电刺激产生继发性机械性痛觉过敏区域。在瑞芬太尼输注前、输注中和输注后测量这种敏化的区域。还监测了热痛觉敏感性。在一次测试过程中，受试者接受了普萘洛尔输注。我们观察到，接受瑞芬太尼和安慰剂输注的受试者的继发性机械性痛觉过敏区域平均增加到基线的 141%（P=0.00040）。然而，当瑞芬太尼输注与普萘洛尔联合使用时，停止瑞芬太尼输注后的继发性痛觉过敏区域与开始输注阿片类药物前的区域没有显著差异（P=0.13）。输注瑞芬太尼后未观察到热痛觉过敏。选择剂量的普萘洛尔输注对血液动力学有轻微影响。瑞芬太尼与普萘洛尔同时输注可防止 RPH 的表达。β-肾上腺素能受体阻断可能是预防接触阿片类药物患者痛觉过敏的一种有用的药理学策略。
