Amanzio Martina, Pollo Antonella, Maggi Giuliano, Benedetti Fabrizio
Department of Neuroscience, University of Torino Medical School, Corso Raffaello 30, 10125 Torino, Italy Division of Thoracic Surgery, University of Torino, 10126 Torino, Italy Rita Levi-Montalcini Center for Brain Repair, University of Torino, 10125 Torino, Italy.
Pain. 2001 Feb 15;90(3):205-215. doi: 10.1016/S0304-3959(00)00486-3.
Individual differences in pharmacokinetics and pharmacodynamics, the type of pain and the method of drug administration can account for the response variability to analgesics. By integrating a clinical and an experimental approach, we report here that another important source of variability is represented by individual differences in non-specific (placebo) activation of endogenous opioid systems. In the first part of this study, we analyzed the effectiveness of buprenorphine, tramadol, ketorolac and metamizol in the clinical setting, where the placebo effect was completely eliminated by means of hidden infusions. We found that the hidden injections were significantly less effective and less variable compared with open injections (in full view of the subject), suggesting that part of the response variability was due to non-specific factors (placebo). Since we could not administer the opioid antagonist, naloxone, to these patients, in the second part of this study, we induced experimental ischemic arm pain in healthy volunteers and found that, as occurred in clinical pain, the analgesic response to a hidden injection of the non-opioid ketorolac was less effective and less variable than an open injection. Most importantly, we obtained the same effects by adding naloxone to an open injection of ketorolac, thus blocking the opioid-mediated placebo component of analgesia. These findings indicate that both the psychological (hidden injection) and pharmacological (naloxone) blockade of the placebo response reduce the effectiveness of, and the response variability to, analgesic drugs. Therefore, an important source of response variability to analgesics appears to be due to differences in non-specific activation of endogenous opioid systems.
药代动力学和药效学的个体差异、疼痛类型以及药物给药方法都可能导致镇痛药反应的变异性。通过整合临床和实验方法，我们在此报告，变异性的另一个重要来源是内源性阿片系统非特异性（安慰剂）激活的个体差异。在本研究的第一部分，我们分析了丁丙诺啡、曲马多、酮咯酸和安乃近在临床环境中的有效性，在该环境中，通过隐蔽输注完全消除了安慰剂效应。我们发现，与开放注射（在受试者完全可见的情况下）相比，隐蔽注射的效果明显较差且变异性较小，这表明部分反应变异性是由非特异性因素（安慰剂）导致的。由于我们无法给这些患者使用阿片类拮抗剂纳洛酮，在本研究的第二部分，我们在健康志愿者中诱发实验性缺血性手臂疼痛，并发现，与临床疼痛情况一样，隐蔽注射非阿片类药物酮咯酸的镇痛反应比开放注射效果更差且变异性更小。最重要的是，我们通过在开放注射酮咯酸时添加纳洛酮获得了相同的效果，从而阻断了阿片类介导的镇痛安慰剂成分。这些发现表明，安慰剂反应的心理（隐蔽注射）和药理学（纳洛酮）阻断都会降低镇痛药的有效性和反应变异性。因此，镇痛药反应变异性的一个重要来源似乎是内源性阿片系统非特异性激活的差异。
