Placebo Effects on the Neurologic Pain Signature

Abstract

for the Placebo Imaging Consortium IMPORTANCE Placebo effects reduce pain and contribute to clinical analgesia, but after decades of research, it remains unclear whether placebo treatments mainly affect nociceptive processes or other processes associated with pain evaluation.OBJECTIVE We conducted a systematic, participant-level meta-analysis to test the effect of placebo treatments on pain-associated functional neuroimaging responses in the neurologic pain signature (NPS), a multivariate brain pattern tracking nociceptive pain.DATA SOURCES Medline (PubMed) was searched from inception to May 2015; the search was augmented with results from previous meta-analyses and expert recommendations.STUDY SELECTION Eligible studies were original investigations that were published in English in peer-reviewed journals and that involved functional neuroimaging of the human brain with evoked pain delivered under stimulus intensity-matched placebo and control conditions. The authors of all eligible studies were contacted and asked to provide single-participant data.DATA EXTRACTION AND SYNTHESIS Data were collected between December 2015 and November 2017 following the Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data guidelines. Results were summarized across participants and studies in a random-effects model. MAIN OUTCOMES AND MEASURESThe main, a priori outcome was NPS response; pain reports were assessed as a secondary outcome. RESULTSWe obtained data from 20 of 28 identified eligible studies, resulting in a total sample size of 603 healthy individuals. The NPS responses to painful stimulation compared with baseline conditions were positive in 575 participants (95.4%), with a very large effect size (g = 2.30 [95% CI, 1.92 to 2.69]), confirming its sensitivity to nociceptive pain in this sample. Placebo treatments showed significant behavioral outcomes on pain ratings in 17 of 20 studies (85%) and in the combined sample (g = −0.66 [95% CI, −0.80 to −0.53]). However, placebo effects on the NPS response were significant in only 3 of 20 studies (15%) and were very small in the combined sample (g = −0.08 [95% CI, −0.15 to −0.01]). Similarly, analyses restricted to studies with low risk of bias (g = −0.07 [95% CI, −0.15 to 0.00]) indicated very small effects, and analyses of just placebo responders (g = −0.22 [95% CI, −0.34 to −0.11]) indicated small effects, as well.CONCLUSIONS AND RELEVANCE Placebo treatments have moderate analgesic effects on pain reports. The very small effects on NPS, a validated measure that tracks levels of nociceptive pain, indicate that placebo treatments affect pain via brain mechanisms largely independent of effects on bottom-up nociceptive processing.

Placebo-induced pain reduction is associated with inverse network coupling at rest

“…1D). Thus, placebo successfully decreased subjective pain intensity with an effect size similar to previous placebo analgesia neuroimaging studies (Zunhammer et al, 2018).…”

“…This is in line with findings from Petrovic and colleagues (2002) who demonstrated similar engagement of rACC and brainstem in both placebo and opioid analgesia. Increased activation of brainstem, thalamus, striatal regions, dorsal and rostral ACC, and the insula (IC 22) might thus reflect placebo-induced, opioidergic activation related to the top-down modulation of pain (Baumgärtner et al, 2006;Eippert et al, 2009;Zunhammer et al, 2018). Most importantly, we found these connectivity changes during resting-state, in absence of actual pain anticipation or perception.…”

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

“…Evidence also strongly suggests that placebo treatments are unlikely to directly modulate bottom-up sensory signals, but rather are influencing high level top-down processes 121. Therefore, predictive coding/bayesian brain contends that in acute pain, placebos can influence pain perception through the induction of top-down expectations of pain, transiently biasing the bayesian computation toward this prediction.…”

Complex Role of Hypnotizability in the Cognitive Control of Pain

“…Both explicit suggestions and placebo responses are due to top-down mechanisms (Zunhammer et al, 2018 ), but it has been shown that, in correspondence of similar subjective response to expectation-induced placebo, highs and lows exhibit opposite patterns of activity and functional connectivity (Huber et al, 2013 ). In fact, the former exhibit reduced functional connectivity between the right dorsolateral prefrontal cortex (rDLPC) and the anterior midcingulate/medial prefrontal cortex, the left inferior frontal gyrus and the right cerebellum.…”