How the number of learning trials affects placebo and nocebo responses

Abstract

Conditioning procedures are used in many placebo studies because evidence suggests that conditioning-related placebo responses are usually more robust than those induced by verbal suggestions alone. However, it has not been shown whether there is a causal relation between the number of conditioning trials and the resistance to extinction of placebo and nocebo responses. Here we test the effects of either one or four sessions of conditioning on the modulation of both non-painful and painful stimuli delivered to the dorsum of the foot. Placebo and nocebo manipulations were obtained by pairing green or red light to a series of stimuli that were made lower or higher with respect to a yellow light associated with a series of control stimuli. Subjects were told that the lights would indicate a treatment that would reduce or increase non-painful and painful stimuli to the foot. They were randomly assigned to either Group 1 or 2. Group 1 underwent one session of conditioning and Group 2 received four sessions of conditioning. We found that one session of conditioning (Group 1) induced nocebo responses, but not placebo responses in no pain condition. After one session of conditioning, we observed both nocebo and placebo responses to painful stimulation. However, these effects extinguished over time. Conversely, four sessions of conditioning (Group 2) induced robust placebo and nocebo responses to both non-painful and painful stimuli that persisted over the entire experiment. These findings suggest that the strength of learning may be clinically important for producing long-lasting placebo effects.

Figure 1. Experimental design

Subjects were pseudorandomly assigned to either Group 1 (A) or Group 2 (B). Note that subjects of Group 1 underwent one session of conditioning, whereas subjects of Group 2 received four sessions of conditioning. In both the groups, there were two sessions of testing. As shown in legend (bottom right) each session consisted of a nocebo, control and placebo condition. Each condition was repeated twice for each session. A colored cue informed subjects about the condition under investigation throughout the experiment: they were told that the green cue would signal the procedure (a sub-threshold electric shock at the ankle) that in turn, induced a reduction of either non-painful or painful perception, the red cue would signal the procedure for increasing either non-painful or painful perception, whereas the yellow cue would indicate the control intensity of stimulation in which the sub-threshold electric shock at the ankle was turned off and no modulation of non-painful and painful perception was expected. The intensity of stimulation was respectively lower in green trials and increased in the red trials during the conditioning sessions, so that subjects experienced respectively real decrease and increase of their non-painful and painful perception. The characteristics of each trial of learning are detailed (C). At the beginning of each trial, the subjects received a visual warning about what condition was tested, either non-painful or painful. Then a visual cue, lasting 60s was presented on the monitor in front of the subject and a total of five stimuli were delivered at the same intensity but with a different inter-stimulus duration. A chain-light appeared from 4 to 9s before each electrical shock. Before the end of the trial, there was 1s for resting and 5s for rating. The inter-trial interval (ITI) was 35s. Behavioral ratings were assessed in each trial by means of two Visual Analogue Scales (VASs) differently anchored for non-painful and painful stimuli.

Figure 2. Results following a short-lasting module of learning (Group 1)

The histograms show the conditioning and testing phase for the non-painful (A) and painful stimuli (C) following a short-lasting training. Note that in the testing phase only nocebo responses were found for the non-painful stimuli and both placebo and nocebo responses for the painful intensity. The graphics on the right present the time-course of VAS reports respectively for non-painful (C) and painful (D) trials. We can observe that a short-training of learning induced nocebo responses which were inconstant over the entire experimental session and placebo responses which extinguished very early. The asterisks show the level of significance related to the comparison between red- vs. yellow- stimuli and green- vs. yellow stimuli (*** p<0.001; **p<0.01; * p<0.05).

Figure 3. Results following a long-lasting module of learning (Group 2)

The histograms present the conditioning and testing phase for the non-painful (A) and painful condition (C) following a long-term module of learning. Note that robust nocebo and placebo responses were constantly found in the testing phase for both the conditions. The graphics on the right show the time-course of non-painful (B) and painful (D) VAS values. Enhancing the number of learning trials induced responses which lasted over the entire experiments. The asterisks show the level of significance related to the comparison between red- vs. yellow- stimuli and green- vs. yellow stimuli (*** p<0.001; **p<0.01; * p<0.05).

Figure 4. Placebo and nocebo correlations

After a short-training in Group 1, placebo and nocebo responses were correlated for the painful condition (p<0.0001). A significant correlation was found between placebo and nocebo responses for the non-painful (p<0.01), but not for the painful condition (p=0.308) in Group 2.

Figure 5. Average of the responses in each group and condition

It can be noted that in pain condition, the mean nocebo responses were not different between Group 1 and 2. Conversely, the mean placebo responses in pain condition, were sensitive to the length of learning trials. In no pain condition, the magnitude of modulation varied between Group 1 and 2 for nocebo responses, but not for placebo responses.