The Biology of Placebo and Nocebo Effects on Experimental and Chronic Pain: State of the Art

Abstract

(1) Background: In recent years, placebo and nocebo effects have been extensively documented in different medical conditions, including pain. The scientific literature has provided strong evidence of how the psychosocial context accompanying the treatment administration can influence the therapeutic outcome positively (placebo effects) or negatively (nocebo effects). (2) Methods: This state-of-the-art paper aims to provide an updated overview of placebo and nocebo effects on pain. (3) Results: The most common study designs, the psychological mechanisms, and neurobiological/genetic determinants of these phenomena are discussed, focusing on the differences between positive and negative context effects on pain in experimental settings on healthy volunteers and in clinical settings on chronic pain patients. Finally, the last section describes the implications for clinical and research practice to maximize the medical and scientific routine and correctly interpret the results of research studies on placebo and nocebo effects. (4) Conclusions: While studies on healthy participants seem consistent and provide a clear picture of how the brain reacts to the context, there are no unique results of the occurrence and magnitude of placebo and nocebo effects in chronic pain patients, mainly due to the heterogeneity of pain. This opens up the need for future studies on the topic.

The neural dynamics of positive and negative expectations of pain

“…Alternatively, some studies have reported the absence of shared brain activations during the perception of pain (Bingel et al, 2011; Freeman et al, 2015; Fu et al, 2021; Shi et al, 2021; Shih et al, 2019). Similar findings have been reported during pain anticipation, as some areas have been reported to be specifically activated for either placebo or nocebo (Fu et al, 2021; Rossettini et al, 2023) or show opposing valence-dependent responses (Amanzio et al, 2013; Kong et al, 2008; Palermo et al, 2015). However, there is conflicting evidence of shared anticipatory activation for both placebo and nocebo in some areas of the DPMS like the DLPFC and ACC (Amanzio et al, 2013; Amanzio & Palermo, 2019; Colloca & Benedetti, 2007; Frisaldi et al, 2015; Manaï et al, 2019; Palermo et al, 2015; Rossettini et al, 2023; Schmid et al, 2015).…”

“…Similar findings have been reported during pain anticipation, as some areas have been reported to be specifically activated for either placebo or nocebo (Fu et al, 2021; Rossettini et al, 2023) or show opposing valence-dependent responses (Amanzio et al, 2013; Kong et al, 2008; Palermo et al, 2015). However, there is conflicting evidence of shared anticipatory activation for both placebo and nocebo in some areas of the DPMS like the DLPFC and ACC (Amanzio et al, 2013; Amanzio & Palermo, 2019; Colloca & Benedetti, 2007; Frisaldi et al, 2015; Manaï et al, 2019; Palermo et al, 2015; Rossettini et al, 2023; Schmid et al, 2015). This illustrates an ongoing debate about whether there is a common neural basis of positive and negative expectations instead of entirely separated representations (Freeman et al, 2015; Fu et al, 2021).…”

“…The effect of the bilateral ACC at the transition from the anticipation to the pain phase could be interpreted as a preparatory mechanism for the modulation of incoming sensory information in downstream areas, consistent with its supposed role in the DPMS (Geuter et al, 2013; Geuter et al, 2017; Kong et al, 2008). Using this framework, reports of ACC activations for both positive and negative expectations during pain anticipation could be understood as a pre-activation of the ACC for pain modulation in either direction (Rossettini et al, 2023). As anticipatory activity in the ACC was related to increased gamma band power, high frequency oscillations may not only signal higher actual or perceived pain intensity during pain processing (Nickel et al, 2022; Ploner et al, 2017; Strube et al, 2021; Tu et al, 2016), but might also be important for the transfer of expectations from anticipation into pain processing.…”

The Efficacy of Neuromodulation Interventions for Chemotherapy-Induced Peripheral Neuropathy: A Systematic Review and Meta-Analysis

“…Secondly, the neuromodulation intervention treatment process involves a high level of doctor-patient interaction, which can produce certain neurobiological effects. 70,71 Thirdly, patient expectations are another primary source of the placebo effect for analgesia. [72][73][74][75] A secondary analysis 76 of one study concluded that it may be due to higher expectations of baseline outcomes among subjects in the sham acupuncture group.…”

A Manifesto in Defense of Pain Complexity: A Critical Review of Essential Insights in Pain Neuroscience

“…Moreover, studies have demonstrated the capacity to evoke nocifensive behaviors by exploring specific engrams, which represent the intricate configuration of neural connections associated with a particular memory [149]. These learning processes also modulate nocebo and placebo effects arising in pain treatment through expectations, where prior conditioning and/or suggestion can influence both the exacerbation and alleviation of the patient's pain experience [150][151][152].…”