Nocebo hyperalgesia can be induced by classical conditioning without involvement of expectancy

Abstract

Influential theoretical accounts take the position that classical conditioning can induce placebo effects through conscious expectancies. In the current study two different conditioning procedures (hidden and open) were used to separate expectancy from conditioning in order to reveal the role of expectancy in the formation of nocebo hyperalgesia. Eighty-seven healthy females were randomly assigned to three groups (hidden conditioning, open conditioning, and control). Participants were selected according to the Fear of Pain Questionnaire scores and assigned to two subgroups: high and low level of fear of pain (trait). They received electrocutaneous pain stimuli preceded by either an orange or blue color. During the conditioning phase, one color was paired with pain stimuli of moderate intensity (control stimuli) and the other color was paired with pain stimuli of high intensity (nocebo stimuli) in both hidden and open conditioning groups. Only participants in the open conditioning group were informed about this association, however just before the testing phase the expectancy of hyperalgesia induced in this way was withdrawn. In the control group, both colors were followed by control pain stimuli. During the testing phase all participants received a series of stimuli of the same intensity, regardless of the preceding color. Participants rated pain intensity, expectancy of pain intensity and fear (state). We found that nocebo hyperalgesia was induced by hidden rather than open conditioning. The hidden conditioning procedure did not produce conscious expectancies related to pain. Nocebo hyperalgesia was induced in participants with low and high fear of pain and there was no difference in the magnitude of the nocebo effect between both groups. Nocebo hyperalgesia was not predicted by the fear of upcoming painful stimuli.

Fig 1. Study design.

Participants were randomly assigned to the one of three groups: open conditioning, hidden condition or control group. They received series of electrical stimuli during three successive phases of the experimental session, i.e. calibration, conditioning and testing. Before the conditioning phase, participants in the open conditioning group were informed that one of the colors, e.g. orange (counterbalanced across participants), was related to the higher intensity of electrical stimuli (verbal suggestion, VS+), and before the testing phase they were informed that colors were no longer related to the intensity of the electrical stimuli (VS-). Participants in the hidden conditioning group and control group did not receive any verbal suggestions. Participants in either the hidden conditioning or control group were not informed about any associations between pain and color stimuli, however, the hidden conditioning group received different stimulus levels depending on the color displayed on the screen. *Only participants with low or high fear of pain level were included in the study.

Fig 2. Study design for the hidden conditioning group (example where orange color stimuli serve as nocebos).

Part ‘A’ refers to the course of the procedure: there were four blocks of conditioning trials, two of which consisted only of color stimuli without any additional instructions (block 1 and 3). After conditioning, one testing block was applied. Each conditioning block consisted of the application of 18 pain stimuli, whereas the testing block was comprised of 24 pain stimuli. Orange stimuli (orange vertical bars) served as nocebos (painful intensity, i.e. 2.2T mA), while blue stimuli served as control stimuli (moderate intensity, i.e. 1.5T mA). During the testing phase, the applied stimuli were of the same moderate intensity (i.e. 1.5T mA), regardless of the color stimuli. Part ‘B’ refers to the single trial design. Color stimuli were presented for 10 seconds. Note that color stimuli were presented in three different conditions: 1. with the NRS for fear rating; 2. with the NRS for expectancy rating; and 3. without any additional instruction before, but with the NRS for pain intensity rating just after the application of the pain stimulus. Each type of the NRS was presented for 6 seconds, which is the NRS for pain, fear and expectancy. Note that after the presentation of the color stimuli was completed, a pain stimulus of 200 μs duration (depicted by red lightning) was applied.

Fig 3

Mean pain intensity ratings during the conditioning and testing phases of the study (separated by vertical dotted lines) in A–the hidden conditioning group (nocebo- vs. control-associated ratings), B–the open conditioning group (nocebo- vs. control-associated ratings), and C–the control group (orange- vs. blue-associated control stimuli). In the conditioning phase, which was divided into 4 blocks, participants rated pain intensity only in one-third of all trials during the second and the fourth block of stimuli. In the testing phase of the study, which consisted of 24 control stimuli, pain intensity was rated 12 times. Error bars represent the SE.

Fig 4. Between-group comparisons of mean pain intensity.

Nocebo hyperalgesia was induced only in the hidden conditioning group. The difference between mean pain intensities was significant for both the hidden vs. open conditioning group and hidden conditioning vs. control group. * p < 0.05, ** p < 0.01. Error bars represent the SE.