Pain-related Fear as a Facilitator of Nocebo Hyperalgesia
Condition: Hyperalgesia; Chronic Pain Syndrome; Chronic Pain, Psychogenic; Fear of Pain
MeSH terms: Hyperalgesia; Chronic Pain
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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).
    

Intervention name(s): Threat manipulation (control, no threat); Threat manipulation; Conditioning of moderate pain; Conditioning of high pain; Extinction
Intervention type(s): Behavioral; Behavioral; Behavioral; Behavioral; Behavioral
Intervention description(s): Before the start of conditioning, a mock skin-sensitivity test informs participants that their skin reacts to heat normally and it is safe for them to participate. A skin-sensitivity reading shows participants a scale that is in the green (no danger) zone.; Before the start of conditioning, a mock skin-sensitivity test informs participants that their skin is very sensitive and their nerve fibers are very responsive and they may have adverse reactions to the heat-pain application. A skin-sensitivity reading shows participants a scale that is in the red (higher danger) zone.; During nocebo trials of the acquisition phase, conditioned stimuli (i.e., on-screen visual cues "ON" signaling the activation of sham electrical stimulation) are paired to unconditioned moderate-pain stimuli, to induce a negative association between the activation of electrical stimuli and an increase in pain. During control trials of the acquisition phase, the deactivation of the sham electrical stimulation (i.e., on-screen message "OFF") is paired to 'baseline' pain of lower intensity.; During nocebo trials of the acquisition phase, conditioned stimuli (i.e., on-screen visual cues "ON" signaling the activation of sham electrical stimulation) are paired to unconditioned high-pain stimuli, to induce a negative association between the activation of electrical stimuli and an increase in pain. During control trials of the acquisition phase, the deactivation of the sham electrical stimulation (i.e., on-screen message "OFF") is paired to pain of lower intensity.; During extinction, the previously conditioned nocebo effects on pain are attenuated by pairing the nocebo and control visual cues (i.e., on-screen messages "ON" and "OFF") to pain stimuli of only lower intensity.
Other intervention name(s): Nocebo Induction; Nocebo Induction; Nocebo Attenuation
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Nocebo; Pain; Fear; Conditioning; Negative suggestions; Extinction