Focus on Pain

Getting the pain you expect: mechanisms of placebo, nocebo and reappraisal effects in humans

Journal name:
Nature Medicine
Year published:
Published online


The perception of pain is subject to powerful influences. Understanding how these are mediated at a neuroanatomical and neurobiological level provides us with valuable information that has a direct impact on our ability to harness positive and minimize negative effects therapeutically, as well as optimize clinical trial designs when developing new analgesics. This is particularly relevant for placebo and nocebo effects. New research findings have directly contributed to an increased understanding of how placebo and nocebo effects are produced and what biological and psychological factors influence variances in the magnitude of the effect. The findings have relevance for chronic pain states and other disorders, where abnormal functioning of crucial brain regions might affect analgesic outcome even in the normal therapeutic setting.

At a glance


  1. Factors influencing pain perception and the neural basis for endogenous pain modulation, placebo and nocebo effects.
    Figure 1: Factors influencing pain perception and the neural basis for endogenous pain modulation, placebo and nocebo effects.

    (a,b) Schematic illustration of key brain regions involved in generating a pain experience (green, blue and purple) with core brain regions that comprise the cognitive and descending pain modulatory networks (blue) (a) and a description of the various factors that influence the pain experience listed in the text boxes (b). (a) The regions highlighted in blue indicate the core descending endogenous pain and cognitive modulatory networks that many of these factors, including placebo and nocebo effects, use to elicit their influence on nociceptive processing and resultant pain perception. The hippocampal region (purple) is important for amplifying pain experiences during nocebo or increased anxiety. (c) Schematic illustration indicating where endogenous opioid and dopamine neurotransmission occurs in the human brain during placebo analgesia. Note the overlap with many of the brain regions involved in cognitive modulation of pain, and for some brain regions (NAc) there is a bidirectional response of both opioid and dopamine release that produces either placebo (increased release) or nocebo (decreased release) effects. vmPFC, ventromedial prefrontal cortex; Amy, amygdala; Hypo, hypothalamus; Hipp, hippocampus; S2, secondary somatosensory cortex; S1, primary somatosensory cortex; dlPFC, dorsolateral prefrontal cortex; rACC, rostral anterior cingulate cortex; mACC, midanterior cingulate cortex; CCK, cholecystokinin.

  2. The patient environment.
    Figure 2: The patient environment.

    (ac) Schematic of a treatment environment where both drug and therapeutic context interact to produce resultant pain report (a), where without drug only the therapeutic context influences pain report (b) and where, due to conditions that affect the key brain regions listed in Figure 1, there is only the drug and its pharmacodynamics able to influence the pain report (c).


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  1. Nuffield Department of Anaesthetics and Oxford Centre for Functional Magnetic Resonance Imaging of the Brain, Department of Clinical Neurology, University of Oxford, Oxford, UK.

    • Irene Tracey

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