Valeria Volpino, Alessandro Piedimonte, Francesco Campaci, Eleonora Camerone Maria, Francesca Persiani, Elisa Carlino
"Rita Levi Montalcini" Department of Neurosciences, University of Turin, Turin, Italy.
Carlo Molo Foundation, Turin, Italy.
Eur J Pain. 2025 Sep;29(8):e70093. doi: 10.1002/ejp.70093.
Placebo and nocebo effects have been thoroughly studied during the last decades using pain models. Two characteristics have been investigated, namely the direction of the effects (i.e., placebo, amelioration of symptoms/nocebo, worsening of symptoms) and their magnitude (i.e., the robustness of the effects). Here, we propose an investigation of the placebo effects considering a third characteristic: time. We employed functional near-infrared spectroscopy (fNIRS), an emerging neuroimaging technique suitable for long-term monitoring and ecological experimental paradigms, to investigate cerebral cortices' activity through oxy-haemoglobin (OHb).
42 healthy volunteers were randomised into three groups (No Expectations-NE, Placebo 5'-P5 and Placebo 20'-P20), placebo groups received different information on the timing of a cream's effectiveness (i.e., "the cream will work in 5/20 min"), while the NE group was said they were receiving an inert cream.
Behavioural results showed that pain perception fluctuations mimicked verbal suggestions on cream effectiveness onset. Exploratory analyses of fNIRS signals seem to follow the same pattern: OHb levels varied by group and time course. In the NE group, no significant differences emerged. In the P5 group, frontal areas were engaged when placebo analgesia occurred soon after treatment, while later, both P5 and P20 showed sustained placebo-related activations alongside areas linked to time perception and memory.
This study proposes that the cortical network related to the placebo effect may be active and modulated by temporal information of cream effectiveness, as well as their behavioural respective.
Implementing fNIRS technology, this study confirms previous behavioral findings and begins to show that cerebral networks respond and encode the temporal characteristics of placebo analgesia. Understanding whether the placebo effect can be switched on and off at specific time points through verbal suggestion could be harnessed when clinically beneficial, aligning its timing with that of pharmacological action, especially for drugs with delayed onset, to ensure continuous pain relief, reduce drug intake, and enhance patient comfort.
在过去几十年中，使用疼痛模型对安慰剂和反安慰剂效应进行了深入研究。研究了两个特征，即效应的方向（即安慰剂，症状改善/反安慰剂，症状恶化）及其强度（即效应的稳健性）。在此，我们建议考虑第三个特征来研究安慰剂效应：时间。我们采用功能近红外光谱（fNIRS），一种适用于长期监测和生态实验范式的新兴神经成像技术，通过氧合血红蛋白（OHb）来研究大脑皮层的活动。
42名健康志愿者被随机分为三组（无期望组-NE、5分钟安慰剂组-P5和20分钟安慰剂组-P20），安慰剂组收到关于乳膏起效时间的不同信息（即“乳膏将在5/20分钟内起效”），而NE组被告知他们正在使用一种惰性乳膏。
行为结果表明，疼痛感知波动模仿了关于乳膏起效的言语暗示。fNIRS信号的探索性分析似乎遵循相同的模式：OHb水平因组和时间进程而异。在NE组中，未出现显著差异。在P5组中，治疗后不久出现安慰剂镇痛时额叶区域被激活，而后来，P5组和P20组都显示出与安慰剂相关的持续激活，同时还有与时间感知和记忆相关的区域。
本研究表明，与安慰剂效应相关的皮层网络可能是活跃的，并受到乳膏起效时间信息及其行为反应的调节。
本研究采用fNIRS技术，证实了先前的行为学发现，并开始表明大脑网络对安慰剂镇痛的时间特征做出反应并进行编码。了解是否可以通过言语暗示在特定时间点开启和关闭安慰剂效应，在临床上有益时可加以利用，使其时间与药理作用的时间一致，特别是对于起效延迟的药物，以确保持续缓解疼痛、减少药物摄入并提高患者舒适度。
