Neurotransmitter Systems Involved in Placebo and Nocebo Effects in Healthy Participants and Patients With Chronic Pain

A Systematic Review

Ina Skyt; Sigrid J. Lunde; Cathrine Baastrup; Peter Svensson; Troels S. Jensen; Lene Vase

Disclosures

Pain. 2020;161(1):11-23. 

In This Article

Abstract and Introduction

Abstract

The investigation of neurotransmitter systems in placebo and nocebo effects has improved our understanding of these phenomena. Yet, most studies involve healthy participants. Because the pain modulatory system may differ in healthy participants and patients with chronic pain, it is important to investigate the evidence for neurotransmitter involvement in placebo and nocebo effects in each of these populations. PubMed, Embase, and Scopus databases, and the Cochrane Library were searched for articles investigating the endogenous opioid, endocannabinoid, dopaminergic, oxytocinergic, vasopressinergic, and cholecystokininergic (CCKergic) systems in placebo and nocebo effects in pain. Twenty-eight placebo and 2 nocebo studies were included. Vote counting was used to balance the number of positive vs negative findings. In healthy participants, the endogenous opioid, endocannabinoid, and vasopressinergic systems were involved in placebo effects, whereas findings on the dopaminergic and oxytocinergic systems were mixed. In patients with chronic pain, only 4 studies investigated neurotransmitters showing no involvement of the endogenous opioid system and mixed findings regarding the dopaminergic system. As to nocebo effects, 2 studies suggest that the CCKergic system is involved in nocebo effects in healthy participants. Overall, research has come a long way in specifying the neurotransmitter systems involved in placebo effects in healthy participants. Yet, evidence for the involvement of neurotransmitter systems in placebo effects in patients with chronic pain and in nocebo effects in healthy participants and patients is scarce. Based on the existing evidence, this systematic review suggests that knowledge obtained in healthy participants may not necessarily be transferred to chronic pain.

Introduction

Neurotransmitters, defined as substances that transmit nerve impulses across a synapse, have been investigated as potential mediators of placebo and nocebo effects in pain to improve our understanding of these phenomena and the underlying mechanisms. Most of these studies have been conducted in healthy participants exposed to experimental pain1,6,10,14,25 or experiencing acute postoperative pain.[29,40,41] Yet, a current objective in this research field is to understand how to optimize placebo effects and minimize nocebo effects in clinical practice,[18,38] and it is therefore essential to directly investigate the neurotransmitter systems involved in placebo and nocebo effects in patients with chronic pain. The endogenous opioid system has repeatedly been found to be involved in placebo effects in healthy participants,[14,25,40,41,69] and 2 systematic reviews (one also a meta-analysis) support this finding.[58,65] Studies have also found involvement of the endocannabinoid,[12,47] dopaminergic,[60] oxytocinergic,[37] and vasopressinergic[20] systems in placebo effects in healthy participants. Furthermore, studies have shown that the cholecystokininergic (CCKergic) system is involved in nocebo effects in healthy participants.[10,13]

Although valuable knowledge can be derived from studies in healthy participants, it is important to be aware that short-duration experimental or acute pain in healthy participants differs from chronic pain in patients. Healthy participants typically have an intact nociceptive system to modulate pain, whereas chronic pain involves complex pathophysiology and different mechanisms may be causing the pain.[5,43,64] For example, some types of chronic pain, including neuropathic pain, are related to central sensitization,[43] whereas other types of chronic pain are due to a disturbed endogenous pain modulatory system.[43,64] Moreover, the psychological components of pain processing, including negative emotions and cognitions, are often more pronounced in patients with chronic pain, given that their pain is persistent or recurrent.[54] Therefore, the mechanisms underlying placebo effects in healthy participants may not necessarily be transferred to patients with chronic pain.[56]

Reviews discussing the neurotransmitter systems in placebo and nocebo effects exist but past reviews have either been qualitative[7,8,19] or limited to pharmacological studies of the endogenous opioid system.[58,65] Whereas pharmacological studies have investigated the involvement of neurotransmitter systems in both placebo[1,40,41] and nocebo[10] effects, studies on neurotransmitters involved in placebo effects also include brain imaging[16,49,69] and genetic studies.[31] In pharmacological studies, the involvement of a neurotransmitter system is evidenced by changes in the magnitude of the placebo or nocebo effect through antagonism or agonism of the neurotransmitter system.[10,41,54,63] Functional brain imaging (functional magnetic resonance imaging, positron emission tomography) can reveal changes in activity in relevant brain areas (eg, opioid-rich regions) or in neurotransmission activity.[25] Genetic analyses explore the association between placebo effects and genetic variations (eg, within the μ-opioid receptor gene) and may thereby point to neurotransmitter systems in placebo effects.[31,32] Accordingly, to obtain a comprehensive understanding of the neurotransmitter involvement in placebo and nocebo effects, it is of great importance to systematically summarize the findings across different methodologies.

This is the first study to systematically review the existing evidence for the involvement of neurotransmitter systems in both healthy participants experiencing experimental or acute postoperative pain and patients with chronic pain. Specifically, this review investigates the endogenous opioid, endocannabinoid, dopaminergic, oxytocinergic, vasopressinergic, and CCKergic systems in placebo and nocebo effects. To the best of our knowledge, this encompasses the traditional neurotransmitter systems that have been found to be involved in placebo and nocebo effects in pain as well as the growing field of oxytocin and vasopressin in placebo effects, which may also act as neurotransmitters. Contrary to previous systematic reviews,[58,65] no limitations were applied as to the methods used to study these neurotransmitter systems.

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