Conditioned placebo analgesia persists when subjects know they are receiving a placebo

Abstract

Belief in the effectiveness of a placebo treatment is widely thought to be critical for placebo analgesia. Many types of placebo responses--even those that depend on conditioning--appear to be mediated by expectations that are strengthened as treatment cues are reinforced with positive outcomes. However, placebo effects may occur even when participants are aware they are receiving a placebo. To address the question of whether conditioned placebo analgesia can persist in the absence of expectations, we studied the effects of long (4 days) versus short (1 day) conditioning to a placebo treatment. After an initial placebo test, a "reveal" manipulation convincingly demonstrated to participants that they had never received an active drug. Placebo analgesia persisted after the reveal in the long conditioning group only. These findings suggest that reinforcing treatment cues with positive outcomes can create placebo effects that are independent of reported expectations for pain relief.

Perspective: This article demonstrates a form of placebo analgesia that relies on prior conditioning rather than current expected pain relief. This highlights the importance of prior experience on pain relief and offers insight into the variability of placebo effects across individuals.

Keywords: Placebo; conditioning; expectancy; pain; reversal.

Conflict of interest statement

Disclosures

The authors declare no conflicts of interest.

Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Study Design. A) Participants in the LONG group had four sessions during the conditioning phase and participants in the SHORT group had a single session. B) During the testing phase, the placebo reveal occurred after the first placebo run for half of all subjects and after the second placebo run for the remaining subjects.

Figure 2

Expectancy. Expected Analgesia [Placebo - Control] significantly decreased following the reveal in both long and short conditioning groups, with no significant differences between groups. The solid dark grey and light grey lines represent the Long and Short group, respectively. Data are presented as means ± sem.

Figure 3

Placebo Analgesia × Conditioning Group. A) Average time course of Pre-Reveal placebo analgesia [Placebo – Control] during painful stimulation. Negative values indicate reduced pain with the placebo (analgesia), whereas positive values indicate increased pain with the placebo (hyperalgesia). The solid dark grey and light grey lines represent the average of subjects within the Long and Short conditioning groups, respectively. The dashed line shows the onset and offset of the painful stimulus, as well as the duration of peak temperature. B) Average time course of Post-Reveal placebo analgesia during painful stimulation. The lines are defined as in panel A. C) Mean Pre-Reveal placebo analgesia. Analgesia scores are generated by averaging over the placebo effect [Placebo-Control] time course for each subject. Long subjects had significant placebo analgesia Pre-Reveal, but Short subjects did not. Placebo analgesia was not different between groups. D) Mean Post-Reveal placebo analgesia. Long subjects continued to demonstrate placebo analgesia Post-Reveal, and had significantly greater placebo analgesia than the Short group. There was no significant Post-Reveal placebo effect in the Short group. Error bars represent sem.

Figure 4

Placebo Analgesia × Expected Analgesia. In both conditioning groups, placebo analgesia [Placebo – Control] was not correlated with expected analgesia [Placebo-Control] either A) Pre-Reveal or B) Post-Reveal. In both panels, the dark grey line represents the relationship between expected and reported analgesia in the Long group, with the dark grey circles representing individual subjects. Similarly, the light grey line represents the relationship between expected and reported analgesia in the Short group, with light grey circles representing individual subjects.

Figure 5

Placebo Analgesia by Conditioning Order, Conditioning Group, and Reveal State. A) Average time course of Pre-Reveal placebo analgesia [Placebo – Control] during painful stimulation for subjects who received the Control First order. Negative values indicate reduced pain with the placebo (analgesia), whereas positive values indicate increased pain with the placebo (hyperalgesia). The solid dark grey and light grey lines represent the average of subjects within the Long and Short conditioning groups, respectively. The dashed line shows the onset and offset of the painful stimulus, as well as the duration of peak temperature. On average, subjects who received the Control First order had significant placebo analgesia, and this effect was not significantly different between conditioning groups (Long – Short). B) Average time course of Post-Reveal placebo analgesia during painful stimulation for subjects who received the Control First order. The lines are defined as in panel A. Post-Reveal, Long subjects, but not Short subjects, who received the Control First order continued to demonstrate placebo analgesia. C) Average time course of Pre-Reveal placebo analgesia during painful stimulation for subjects who received the Placebo First order The lines are defined as in panel A. Pre-Reveal, there was no significant placebo effect for subjects who received the Placebo First conditioning order. D) Average time course of Post-Reveal placebo analgesia during painful stimulation for subjects who received the Placebo First order. The lines are defined as in panel A. Post-Reveal, Placebo First subjects did not show significant analgesia or hyperalgesia on average.