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.

Keywords: conditioning; contextual factor; expectation; nocebo effect; pain; placebo effect.

Figure 1

Pharmacological evidences. As reported by different pharmacological studies, placebo administration activates endogenous opioid, cannabinoid, and dopamine systems (A). Participants in the placebo groups experienced analgesic effects, namely pain reduction, compared to participants that received no treatments (natural history group). This analgesic effect is enhanced by proglumide, oxytocin, and vasopressine ((B), upper graph) while it is disrupted by rimonabant, naloxone, and pentagastrin ((B), middle graph). Nocebo effects exacerbate pain perception compared no treatment groups (natural history group). This effect is partially reversed by CCK antagonist proglumide ((B), bottom graph).

Figure 2

Neuroimaging studies: temporal aspects (expectation and perception phases) related to brain area activity after placebo or nocebo administration. As reported by different neuroimaging studies, expectations of pain relief, triggered by placebos, activate brain areas such as PFC, ACC, and PAG (P1); in the perception phase, deactivation has been found in different brain regions, including MCC, PCC, MTG, STG, PreCG, Thal, INS, CLA, and DS (A). On the contrary, expectations of pain worsening, triggered by nocebos, enhance activity in brain regions that include PFC, ACC, INS, SI, and CBM; in the perception phase, increased activity in PFC, ACC, MFG, INS, CLA, PU, HPC, MTG, SPL, STG, OPERCULUM, and INS has been found (B). Electroencephalographic (EEG) studies report that placebos and nocebos change EEG brain activity. In particular, the expectation of receiving no painful or painful stimuli respectively decreases (green line) or increases (red line) the amplitude of the contingent negative variation (CNV). Considering the “perception phase”, placebo treatments produce a decrease (blue line) in laser-evoked potential (LEP), an EEG wave that represents an early measure of nociceptive processes (C).

Figure 3

Connectivity analysis data. Connectivity studies have documented changes in functional connectivity in the placebo analgesic effect between PreCUN-HPC, MTG–PoCG, and rACC–PAG–RVM). In the nocebo hyperalgesic effect, functional connectivity changes have been observed among HPC/Operculum and many brain areas, namely ACC, INS, M1, and S1. In addition, functional connectivity between HPC and PAG and Amg has been suggested to play a role in the nocebo hyperalgesic effect.