Neurotransmitter systems involved in placebo and nocebo effects in healthy participants and patients with chronic pain: a systematic review

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.

Placebos in chronic pain: evidence, theory, ethics, and use in clinical practice

“…However, acute pain in healthy participants is not an appropriate surrogate for chronic pain, given that patients with chronic pain are characterized by significant changes in their underlying neuroanatomical structural volumes as well as functional brain connectivity 505152. Furthermore, placebo treatments in chronic pain engage neurotransmitters that are distinct from those engaged by acute pain experienced in the laboratory 53. Nevertheless, acute pain experiments provide important proof of concept findings elucidating placebo effects.…”

“…This maladaptive positive feedback loop relies on internal top-down predictions that are now relatively divorced from sensory feedback (fig 5). Because of these pathophysiological differences, not surprisingly, evidence suggests that the “chronic pain brain,” compared with the brains of healthy volunteers in acute pain experiments, also responds to placebos through a different set of neurotransmitters and neuroanatomical substrates 5053125…”

“…laboratory. 53 Nevertheless, acute pain experiments provide important proof of concept findings elucidating placebo effects.…”

Modulation of a Stable Neurobehavioral Trait Using Repetitive Transcranial Magnetic Stimulation: A Preregistered Randomized Controlled Trial

“…While the effects of different sham stimulations on neural networks need to be further investigated, a placebo effect might be involved if those sham stimulations are experienced differently on the scalp. Studies examining whether chronic pain populations, including FMS, are more responsive to placebo than non-pain healthy controls show mixed findings [59][60][61] ; however, a systematic review investigating placebo-intervention against notreatment comparator groups in FMS found that the magnitude of placebo effects increases with the effect size of the active treatment 62 . While it is possible that a higher intensity sham stimulation would give rise to a stronger placebo response, we observed no significant differences in participants' guesses as to whether they received sham or active treatment between either sham group nor the active group.…”

Impact of a 12-week open-label placebo treatment on headache days in episodic and chronic migraine: a study protocol for a parallel-group, multicentre, randomised controlled trial

“…Furthermore, a blood sample will be taken at screening visit in order to identify COMT polymorphisms by PCR analysis. In addition, (1) treatment expectation will be assessed by the Treatment Expectation Questionnaire (TEX-Q 42 ), which distinguished between symptomspecific effects and effects related to quality of life and functional capability; (2) fear of pain by the Fear of Pain Questionnaire 43 ; (3) pain catastrophising by the Pain Catastrophizing Scale, 44 as these personality traits have been shown to be positively related to subjective pain intensity and fear of pain has further been shown to be the most robust predictor of pain chronification [45][46][47] ; (4) personality traits using the Behavioral Inhibition and Approach System [48][49][50] and the Short Version of the Big Five Inventory 51 due to the close link between personality traits associated to dopamine release, reward processing and expectation effects of treatment outcome 52 ; (5) anxiety and depression by the State-Trait Anxiety Depression Inventory 53 and stress by the Perceived Stress Scale 54 as depression, anxiety and psychological distress have been reported to be susceptible to modulation through OLP treatment 7 55 ; and (6) somatisation by the Somatosensory Amplification Scale 56 as a predictive role of somatosensory amplification in the development of side effects or negative expectation effects has been observed. 41 54 57 Further, a questionnaire (Generic Rating for Treatment Pre-experiences, Treatment Expectations, and Treatment…”