Exploiting learning mechanisms to maximize analgesic treatment outcome

行为条件反射被认为是安慰剂和非安慰剂反应的关键机制，而且，它是任何治疗方法的一部分，包括药物治疗。在这里，我们提出了两个项目，旨在阐明疼痛治疗中行为条件性安慰剂反应的机制和调节器，以提高药理学疼痛治疗的有效性和耐受性，作为药物干预的范例。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)条件性止痛反应与条件性不良反应是如何联系的？(Ii)将亚治疗剂量的吗啡与条件性刺激(CS)配对，能否增强条件性镇痛反应？(Iii)心理或生理特征变量能预测吗啡条件镇痛的个体差异吗？与其他类型的安慰剂止痛相比，条件性药物镇痛有哪些不同的神经机制？这些问题对于在临床背景下开发药理反应的条件作用，以最大化条件治疗效果，最大限度地减少条件反应的潜在不良影响，并预测治疗策略在个别患者中的益处，具有特别重要的意义。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，条件反射刺激的外观越相似，就越有可能产生“遗留效应”。更具体地说，我们将系统地在两个后续治疗之间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。为了能够在不考虑药理学特性的情况下评估治疗史的效果，将使用安慰剂止痛的实验模型，以允许对我们的发现进行推广。我们预计，申请形式的改变和/或研究医生的改变将使治疗失败后的负面影响降至最低。这些项目中使用的实验方法所期望的洞察力可以很容易地转移到临床背景中，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.