Hyperalgesia Clinical Trial
Official title:
Pain-related Fear as a Facilitator of Nocebo Hyperalgesia: An Experimental Study
Nocebo hyperalgesia is characterized by adverse pain outcomes, induced by patients' expectations. In the lab, nocebo effects are commonly studied via classical conditioning, a method that employs pairings of neutral cues/treatments with different pain intensities to install differential pain-related expectations. In such conditioning experiments, participants are typically taught that a (sham) treatment exaggerates their pain, by surreptitiously administering high intensity (e.g. pain) stimuli in combination with this treatment. Verbal suggestions are also often used to inform participants of the supposed adverse effects of such treatments. In nocebo studies, higher pain levels and suggestions that are of more threatening nature may induce fear, thereby adding a crucial element to the experimental manipulation. Since nocebo effects are hypothesized to arise in clinical settings due to a combination of several psychological and cognitive mechanisms, it is important to study the role that factors such as higher pain levels, conditioned pain-related fear, or more threatening verbal suggestions may play in the formation of nocebo hyperalgesia. To date, no studies have focused on the fear-inducing effect that different pain intensities or verbal threat suggestions may have and how this fear, in turn, may strengthen the acquisition of nocebo effects. This study aims to investigate whether higher pain intensity or higher pain-related fear induced via threatening suggestions facilitate the acquisition and hinder subsequent extinction of nocebo hyperalgesia. This study will be conducted at Leiden University.
The investigators expect that higher pain intensity and/or higher pain-related fear induced
via threatening suggestions will lead to stronger acquisition of nocebo hyperalgesia and/or
more durable nocebo hyperalgesia after extinction.
Main outcome variables:
- The magnitude of induced nocebo hyperalgesia is defined as the difference in pain
ratings for the first nocebo trial compared to the first control trial of the extinction
phase.
- The reduction of nocebo hyperalgesia is defined as the change in reported pain between
the first and last nocebo trial of the extinction phase.
- Fear levels (for mediation analyses) are measured via eye-blink startle modulation and
self-reported fear during nocebo trials (relative to control trials).
For EMG analyses this study follows typical pre-processing of EMG recordings, similar to
previous studies. The EMG signal will be digitized at 1,000 Hz from 200 ms before the startle
probe until 1,500 ms after probe onset. The startle probe is a 100 dBA burst of white noise
with instantaneous rise time presented binaurally for 100 ms through earphones. Each 2-4
consecutive startle probe responses of the same cue (nocebo vs control) will be averaged for
further analyses. Participants who exhibited a startle response in less than 20% of trials in
the first half of induction will be labeled as non-responders. Trials during which, for
example, baseline is higher than startle response peak due to an occasional blink before the
probe presentation, will be labelled as non-response or reject trials.
1. Main planned analyses:
To examine whether higher pain stimulation (high-pain nocebo group) leads to stronger
nocebo hyperalgesia, as compared to lower pain stimulation (control nocebo group), a 2x2
mixed model analysis of variance (ANOVA) will be performed with group (high-pain nocebo
group, control nocebo group) as the between-subjects factor and trial type as
within-subjects factor with two levels (first nocebo extinction trial, first control
extinction trial).
2. Secondary analyses:
2a. To examine whether an impact of higher pain stimulation on the magnitude of nocebo
hyperalgesia was mediated by pain-related fear levels, a mediation analysis will be conducted
for the high pain nocebo and control nocebo groups, to assess if fear mediates the
relationship between pain levels and the magnitude of nocebo hyperalgesia (calculated
difference scores between the first nocebo extinction trial and the first control extinction
trial).
2b. To examine whether higher pain-related fear induced via a threat suggestion (high-threat
nocebo) led to stronger nocebo hyperalgesia, as compared to no threat suggestion (control
nocebo group), a 2x2 mixed model ANOVA will be performed with group (high-threat nocebo,
control nocebo group) as the between-subjects factor and trial type as within-subjects factor
with two levels (first nocebo extinction trial, first control extinction trial).
2c. To examine whether higher pain stimulation (high-pain nocebo group) led to more durable
nocebo effect, as compared to lower pain stimulation (control nocebo group), a 2x2 mixed
model ANOVA will be performed with group (high-pain nocebo group, control nocebo group) as
the between-subjects factor and trial as within-subjects factor with two levels (first nocebo
extinction trial, last nocebo extinction trial).
2d. To examine whether an impact of higher pain stimulation on the durability of nocebo
hyperalgesia was mediated by pain-related fear levels, a mediation analysis will be conducted
to assess if fear mediates the relationship between pain levels and the magnitude of nocebo
hyperalgesia after extinction (calculated difference scores between the first nocebo
extinction trial and the last nocebo extinction trial).
2e. To examine whether higher pain-related fear induced via a threat suggestion led to more
durable nocebo hyperalgesia, as compared to no threat suggestion, a 2x2 mixed model ANOVA
will be performed with group (high-threat nocebo, control nocebo group) as the
between-subjects factor and trial as within-subjects factor with two levels (first nocebo
extinction trial, last nocebo extinction trial).
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