Department of Psychology and Behavioural Sciences, Aarhus University, Bartholins Allé 11, Building 1350, DK-8000 Aarhus C, Denmark.
Scand J Pain. 2020 Jul 28;20(3):451-467. doi: 10.1515/sjpain-2019-0183.
Background and aims The randomized controlled trial (RCT) is currently facing several challenges, one of these being that the placebo response appears to be increasing in RCTs, thereby making it difficult to demonstrate an effect of potentially new treatments over placebo. This problem has primarily been approached by predicting the magnitude of the placebo response via stable factors, such as demographic variables, and/or by developing complex designs aimed at reducing the placebo response in the hope that it will improve the test of the active treatment. Yet, the success of this approach has so far been limited. Methods A new approach toward improving the RCT is put forward based on placebo and nocebo mechanism studies, i.e. studies that investigate the mechanisms underlying placebo analgesia and nocebo hyperalgesia. In a series of meta-analyses the magnitude of placebo and nocebo effects were determined. Experimental studies across nociplastic and neuropathic pain conditions and across pharmacological and acupuncture treatments investigated psychological and neurobiological mechanisms underlying these effects. The obtained results were used to make approximations of expectations to see if that could predict the placebo response in RCTs and function as a new way of tapping into the placebo component of treatment effects. Results The magnitude of placebo and nocebo effects is large and highly variable. Placebo effects exist across chronic pain conditions with varying degrees of known etiology as well as across pharmacological and non-pharmacological treatments. Patients' perception of the treatment, the verbal suggestions given for pain relief, and the patients' expectations toward pain relief contribute to the magnitude of the placebo effect and to pain relief following placebo interventions. Also, unintentional unblinding and patients' perception of a treatment markedly influence the treatment outcome. By making approximations of expectations toward treatment effects it was possible to predict the magnitude of the placebo response in RCTs. Conclusions and implications The new approach of tapping into or directly asking patients about their perception and expectations toward a treatment, along with the account of the natural history of pain, has the potential to improve the information that can be obtained from RCTs. Thus, by interfacing insights from placebo and nocebo mechanism studies, it may be possible to enhance the information that can be obtained from RCTs and to account for a large part of the variability in the placebo component of the overall treatment effect. This approach has the potential to improve the scientific evaluation of treatments, as well as to illustrate how the effect of treatments can be optimized in clinical practice, which is the crux of evidence-based medicine.
背景与目的 随机对照试验（RCT）目前面临着一些挑战，其中之一是安慰剂反应似乎在 RCT 中增加，从而使得很难证明潜在新治疗方法相对于安慰剂的效果。这一问题主要通过预测安慰剂反应的幅度来解决，这些因素包括人口统计学变量等稳定因素，或者通过开发旨在减少安慰剂反应的复杂设计，以期提高对活性治疗的检验。然而，迄今为止，这种方法的效果有限。
方法 本文提出了一种基于安慰剂和反安慰剂机制研究的改进 RCT 的新方法，即研究安慰剂镇痛和反安慰剂痛觉过敏背后的机制。通过一系列荟萃分析确定了安慰剂和反安慰剂效应的幅度。在各种神经病理性疼痛和伤害感受性疼痛条件下，以及在各种药物和针刺治疗中进行的实验研究，探讨了这些效应背后的心理和神经生物学机制。所获得的结果用于预测期望，以观察是否可以预测 RCT 中的安慰剂反应，并作为一种新的方法来挖掘治疗效果中的安慰剂成分。
结果 安慰剂和反安慰剂效应的幅度很大且高度可变。安慰剂效应存在于具有不同程度已知病因的慢性疼痛条件中，也存在于药物和非药物治疗中。患者对治疗的感知、为缓解疼痛而给出的口头建议以及患者对疼痛缓解的期望，都会影响安慰剂效应的幅度以及安慰剂干预后的疼痛缓解程度。此外，意外的未设盲和患者对治疗的感知会显著影响治疗结果。通过预测期望对治疗效果的影响，可以预测 RCT 中的安慰剂反应幅度。
结论和意义 利用安慰剂和反安慰剂机制研究的见解，直接询问患者对治疗的感知和期望，同时考虑疼痛的自然史，有可能改善从 RCT 中获得的信息。因此，通过结合安慰剂和反安慰剂机制研究的见解，有可能提高从 RCT 中获得的信息，并解释整体治疗效果中安慰剂成分的大部分变异性。这种方法有可能改善对治疗的科学评估，并说明如何在临床实践中优化治疗效果，这是循证医学的核心。
