- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04197154
Pain-related Fear as a Facilitator of Nocebo Hyperalgesia (LFS)
Pain-related Fear as a Facilitator of Nocebo Hyperalgesia: An Experimental Study
Study Overview
Status
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.
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).
- 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).
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
South Holland
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Leiden, South Holland, Netherlands, 2333 AK
- Leiden University
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Aged 17 - 35 years
- Good understanding of the English language
- Normal or corrected to normal vision
Exclusion Criteria:
- Ever having experienced serious medical or psychiatric conditions (e.g., heart or lung disease, panic attacks, drug addiction, clinical depression),
- Ever having experienced chronic pain complaints (pain for more than 6 months),
- Experiencing acute physical pain (e.g., headache; above 3 on a 10-point NRS scale), or having used pain medication on the day of testing,
- Pregnancy or breastfeeding,
- Having recent injuries to the wrists or arms on the day of testing,
- Previous participation in this or similar studies (e.g., using conditioning or thermal pain).
- Having consumed psychotropic medication, recreational drugs, analgesic medication, or more than 3 units of alcohol, in the 24 hours prior to the study appointment.
- After inclusion, participants who do not reach a sensation of high pain (at least 6 on the NRS) with the highest administered temperature or participants who appear unable to distinguish between moderate and high pain stimuli (reporting at least a mean difference of 1.5 NRS points between nocebo and control trials during induction) will also be excluded.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 1. Control nocebo group
Conditioning and extinction of a nocebo response using moderate pain stimuli, nocebo negative suggestions, and no threat suggestions.
|
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.
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.
Other Names:
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 Names:
|
Experimental: 2. High-pain nocebo group
Conditioning and extinction of a nocebo response using higher pain stimuli, nocebo negative suggestions, and no threat suggestions.
|
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.
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 Names:
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.
Other Names:
|
Experimental: 3. High-threat nocebo
Conditioning and extinction of a nocebo response using moderate pain stimuli, nocebo negative suggestions, and threat suggestions (i.e., fear-inducing suggestions).
|
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.
Other Names:
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 Names:
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.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Magnitude of nocebo hyperalgesia
Time Frame: On the testing day, in the first trials of the extinction phase
|
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.
|
On the testing day, in the first trials of the extinction phase
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Reduction of nocebo hyperalgesia
Time Frame: On the testing day, in the extinction phase
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The reduction of nocebo hyperalgesia is defined as the change in reported pain between the first and last nocebo trial of the extinction phase.
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On the testing day, in the extinction phase
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Fear levels
Time Frame: On the testing day, in both experimental phases
|
Fear levels (for mediation analyses) are measured via eye-blink startle modulation
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On the testing day, in both experimental phases
|
Fear self report levels
Time Frame: On the testing day, in both experimental phases
|
Fear levels (for mediation analyses) are also measured via self-reported fear during nocebo trials (relative to control trials).
|
On the testing day, in both experimental phases
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Andrea WM Evers, Leiden University Medical Center
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- CEP19-0614/347
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
- SAP
- ANALYTIC_CODE
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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