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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.

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Control interventions (often called “sham,” “placebo,” or “attention controls”) are essential for studying the efficacy or mechanism of physical, psychological, and self-management interventions in clinical trials. This article presents core recommendations for designing, conducting, and reporting control interventions to establish a quality standard in non-pharmacological intervention research. A framework of additional considerations supports researchers’ decision making in this context. We also provide a reporting checklist for control interventions to enhance research transparency, usefulness, and rigour.

Music interventions accommodate the profound need for non-pharmacological pain treatment. The analgesic effect of listening to music has been widely demonstrated across studies. Yet, the specific mechanisms of action have still to be elucidated. Although the endogenous opioid and dopamine systems have been suggested to play an important role, a direct link has not been established. In addition, the involvement of placebo mechanisms is likely while largely unexplored. We examined the analgesic effect of music in healthy participants (n = 48) using a 3 × 3 within-subjects design with pharmacological manipulations and a matched, auditory control for music. Participants were exposed to thermal pain stimuli while listening to three auditory excerpts: music (active condition), nature sound (matched, auditory contextual condition), and noise (neutral control condition). The participants rated their expected and perceived pain levels in relation to each of the auditory excerpts. To investigate the involvement of the endogenous opioid and dopamine systems, the test session was performed three times on separate days featuring a double-blind randomized oral administration of naltrexone (opioid antagonist), haloperidol (dopamine antagonist), and an inactive agent (control). Our results support an analgesic effect of music. Contrary to current hypotheses, neither of the antagonists attenuated the effect of music. Yet, the participants' expectations for pain relief predicted their perceived pain levels during the auditory excerpts—even when controlling for a gradual learning effect. In conclusion, we demonstrate that the analgesic effect of music is at least partially mediated by expectations of an analgesic effect—a core mechanism in placebo effects—but not by opioid and dopamine-dependent mechanisms.Clinical Trial Registrationwww.clinicaltrials.gov, identifier: NCT03410563.