Exploiting learning mechanisms to maximize analgesic treatment outcome

行为条件反射被认为是安慰剂和反安慰剂反应的关键机制，而且，它是包括药物治疗在内的任何治疗方法的一部分。在这里，我们提出了两个项目，旨在阐明行为条件安慰剂反应在疼痛治疗中的机制和调节剂，以提高药物疼痛治疗的疗效和耐受性，作为药物干预的一个例子。在项目1中，我们将研究吗啡暴露后的行为条件性安慰剂镇痛，以回答以下问题：(i)条件性镇痛反应如何与条件性不良反应相关？（ii）将亚治疗剂量的吗啡与条件刺激（CS）配对，是否可以增强条件性镇痛反应？（iii）条件吗啡镇痛的个体间差异是否可以通过心理或生理特征变量来预测？（iv）与其他类型的安慰剂镇痛相比，条件性药物镇痛的独特神经机制是什么？这些问题与在临床环境中利用药理学反应的条件作用来最大化条件治疗效果，最小化条件反应的潜在不良影响以及预测个体患者治疗策略的益处特别相关。在项目2中，我们将调查先前治疗经验对后续治疗方法的影响是否取决于两种治疗方法的相似性。根据条件反射文献，条件刺激在外观上越相似，“携带效应”就越有可能出现。更具体地说，我们将在两个后续治疗之间系统地改变治疗背景的两个重要变量，即应用形式（例如，从局部应用到全身应用）和研究医生。为了评估治疗历史的影响而不考虑药理学特性，我们将使用安慰剂镇痛的实验模型来推广我们的研究结果。我们期望改变申请表格和/或改变研究医生将减少治疗失败后的负面遗留效应。这些项目中使用的实验方法所期望的见解可以很容易地转移到临床环境中，以优化治疗方法。

Behavioral conditioning is considered a key mechanism of placebo and nocebo responses and, moreover, it is part of any therapeutic approach, including pharmacotherapy. Here we propose two projects that aim at elucidating mechanisms and modulators of behaviorally conditioned placebo responses in pain therapy to improve the efficacy and tolerability of pharmacological pain treatment as an example for pharmacological interventions. In project 1, we will investigate behaviorally conditioned placebo analgesia following morphine exposure to answer the following questions: (i) How is the conditioned analgesic response related to conditioned adverse effects? (ii) Can the conditioned analgesic response be enhanced by pairing sub-therapeutic doses of morphine with the conditioned stimulus (CS)? (iii) Can interindividual differences in conditioned morphine analgesia be predicted by psychological or physiological trait variables? And (iv) what are the distinct neural mechanisms of conditioned pharmacological analgesia compared to other types of placebo analgesia? These questions are particularly relevant for the exploitation of the conditioning of pharmacological responses in the clinical context to maximize conditioned therapeutic effects, minimize potential adverse effects of the conditioned response and predict the benefit of a treatment strategy in individual patients. In project 2, we will investigate whether the effect of prior treatment experience on a subsequent treatment approach depends on the similarity of both treatments. According to the conditioning literature, ‘carry-over effects’ are more likely the more similar the conditioned stimuli are in appearance. More specifically, we will systematically vary two important variables of the treatment context between two subsequent treatments, namely the application form (e.g., from topical to systemic application) and the study physician. To allow for the assessment of treatment history effects irrespective of pharmacological peculiarities, experimental models of placebo analgesia will be used that allow for the generalization of our findings. We expect that a change in application form and/or a change in study physician will minimize negative carry-over effects after treatment failure. The insights that are expected from the experimental approaches used in these projects could easily be transferred into a clinical context to optimize therapeutic approaches.