A meta-analysis of brain mechanisms of placebo analgesia: consistent findings and unanswered questions

Abstract

Placebo treatments reliably reduce pain in the clinic and in the lab. Because pain is a subjective experience, it has been difficult to determine whether placebo analgesia is clinically relevant. Neuroimaging studies of placebo analgesia provide objective evidence of placebo-induced changes in brain processing and allow researchers to isolate the mechanisms underlying placebo-based pain reduction. We conducted formal meta-analyses of 25 neuroimaging studies of placebo analgesia and expectancy-based pain modulation. Results revealed that placebo effects and expectations for reduced pain elicit reliable reductions in activation during noxious stimulation in regions often associated with pain processing, including the dorsal anterior cingulate, thalamus, and insula. In addition, we observed consistent reductions during painful stimulation in the amygdala and striatum, regions implicated widely in studies of affect and valuation. This suggests that placebo effects are strongest on brain regions traditionally associated with not only pain, but also emotion and value more generally. Other brain regions showed reliable increases in activation with expectations for reduced pain. These included the prefrontal cortex (including dorsolateral, ventromedial, and orbitofrontal cortices), the midbrain surrounding the periaqueductal gray, and the rostral anterior cingulate. We discuss implications of these findings as well as how future studies can expand our understanding of the precise functional contributions of the brain systems identified here.

Fig. 1

Typical neuroimaging placebo paradigm. In a typical placebo study, participants are given an inert treatment (e.g., a topical cream) along with verbal instructions (e.g., “This is a potent analgesic”) that induce expectations for pain relief. This is compared to a control condition—the same inert substance without expected pain relief. To reinforce verbal instructions, the placebo is paired with reduced stimulus intensity during an associative learning, or conditioning, phase. Finally, participants go through neuroimaging testing during a test phase during which the same stimuli are administered under both control and placebo conditions and experimenters test whether pain reports and brain responses are modulated by beliefs about treatment

Fig. 2

Meta-analysis 1: expectancy-based pain modulation. (a) Peaks included in a meta-analysis of expectancy-based reductions during pain. (b) Brain regions that showed reliable reductions during placebo administration and expectations for reduced pain (see Table 3). (c) Peaks included in meta-analysis of modulatory increases during pain. (d) Regions that showed consistent increases during anticipation or pain stimulation with expectations for reduced pain (see Table 4)

Fig. 3

Decreases: treatment expectancies vs. stimulus expectancies. (a) Brain regions that showed reliable reductions during placebo analgesia (see Table 5). (b) Differences between placebo analgesia and stimulus expectancy-induced reductions (placebo analgesia > stimulus expectancies; see Table 8). Left anterior insula was significantly more likely to show reductions with placebo analgesia than with stimulus expectancies

Fig. 4

Modulatory increases: treatment expectancies vs. stimulus expectancies. (a) Brain regions that showed reliable increases prior to or during placebo analgesia (see Table 6). (b) Brain regions that showed reliable increases as a function of stimulus expectancy (i.e., increased activity with expectation for reduced pain; see Table 7). (c) Differences between placebo analgesia and stimulus expectancy-induced increases (placebo analgesia > stimulus expectancies; see Table 8). (d) Regions that showed larger increases with stimulus expectancy than placebo analgesia (see Table 9)