Placebo analgesia and its opioidergic regulation suggest that empathy for pain is grounded in self pain

Abstract

Empathy for pain activates brain areas partially overlapping with those underpinning the first-hand experience of pain. It remains unclear, however, whether such shared activations imply that pain empathy engages similar neural functions as first-hand pain experiences. To overcome the limitations of previous neuroimaging research, we pursued a conceptually novel approach: we used the phenomenon of placebo analgesia to experimentally reduce the first-hand experience of pain, and assessed whether this results in a concomitant reduction of empathy for pain. We first carried out a functional MRI experiment (n = 102) that yielded results in the expected direction: participants experiencing placebo analgesia also reported decreased empathy for pain, and this was associated with reduced engagement of anterior insular and midcingulate cortex: that is, areas previously associated with shared activations in pain and empathy for pain. In a second step, we used a psychopharmacological manipulation (n = 50) to determine whether these effects can be blocked via an opioid antagonist. The administration of the opioid antagonist naltrexone blocked placebo analgesia and also resulted in a corresponding "normalization" of empathy for pain. Taken together, these findings suggest that pain empathy may be associated with neural responses and neurotransmitter activity engaged during first-hand pain, and thus might indeed be grounded in our own pain experiences.

Keywords: empathy; fMRI; pain; placebo; psychopharmacology.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Self-report results in the control (n = 53) and placebo group (n = 49), for ratings of self-directed pain (“how painful was this stimulus for you?”), other-directed pain (“how painful was this stimulus for the other person?”), and self-experienced negative affect (unpleasantness) when witnessing other-directed pain (“how unpleasant did it feel when the other person was stimulated?”). Asterisks (*P < 0.05, **P < 0.01) mark significant planned comparisons (independent samples t tests) of the main hypothesis that placebo analgesia reduced both empathy for pain and its first-hand experience.

Fig. 2.

Group differences in brain activation in the empathy network. (A) Bar-plot of mean contrast estimates within ROIs (arbitrary units), plotted separately for self- and other-directed conditions and the two groups, in three ROIs (aMCC, left and right AI). Asterisks (*P < 0.05) mark significant planned comparisons (independent samples t tests) of the main hypothesis that placebo analgesia reduced activation during both self-directed and other-directed stimulation. (B) Activation maps displaying the spatial distribution of brain activity within the ROIs (taken from a two-sample t test contrasting the two groups, for the contrast pain > no pain, separately for self- and other-directed conditions). The yellow circles mark the ROI sphere used to extract the mean activation. Note that these maps are shown for illustration purposes only (and for this reason are thresholded at P = 0.05 uncorrected) and that they are not independent of the ROI results (59).

Fig. 3.

Self-reported affect ratings of the psychopharmacological experiment in the placebo-placebo (n = 25) and the placebo-naltrexone group (n = 25), for the different types of ratings (self-directed pain, other-directed pain, and unpleasantness in response to other-directed pain). Asterisks (*P < 0.05) mark significant planned comparisons (independent samples t tests) of the main hypothesis that naltrexone reduced the effects of placebo analgesia for both empathy for pain and its first-hand experience.

Fig. 4.

Structure and timeline of two exemplary trials. (A) Self-directed pain trial, (B) Other-directed no pain trial. An anticipation cue indicated the target (left = self, right = other) and intensity (red = painful, green = nonpainful) of the upcoming electrical stimulus. After a variable interval of 3.5 ± 1.5 s, electrical stimulation (duration = 500 ms) was delivered concurrently with visual presentation (duration = 1,000 ms) of either a scrambled face (self-directed trials) or the other person’s face (other-directed trials) accompanied by a red (in case of painful stimulation) or green (nonpainful stimulation) flash. Afterward, affect ratings (6 s per rating) were collected, but only in about one-third of all trials.