- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04199858
Electrophysiological Correlates of Nocebo Effects on Pain
Study Overview
Status
Detailed Description
Main outcome variable for nocebo responses:
- 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 evocation phase.
Note: A significant difference will be assessed using a Repeated Measures ANOVA as a manipulation check. Then, calculated difference scores represent the magnitude of induced nocebo hyperalgesia and will be used for the primary and first and second secondary hypotheses.
Definitions of other outcome variables:
- The magnitude of nocebo responses (and nocebo-augmented pain) during the evocation phase is defined in the specific nocebo evocation trials that show heightened pain relative to the preceding control trials, for each subject. For EEG analyses, all trials that show the experience of heightened pain in nocebo trials relative to the preceding control trials, during the evocation phase will be used.
Note: Calculated difference scores between the specific nocebo evocation trials that show heightened pain relative to control trials will be used in further analyses of EEG data. While the entirety of the evocation data will be reported and analyzed, the main EEG analyses will include a selection of evocation trials where nocebo responses were reported. It is necessary to use EEG data for trials that show a nocebo response in order to explore electrophysiological correlates of nocebo effects.
0. Manipulation checks: Induction of nocebo hyperalgesia First, the investigators will examine whether significant nocebo hyperalgesia was induced. A Repeated-Measures Analysis of Variance (RM ANOVA) will be performed for nocebo responses (on the pain Numeric Rating Scale), with trial type as the within-subjects factor with two levels (first nocebo evocation trial, first control evocation trial). First evocation trial pairs were chosen based on the clearest effects being observed during piloting and in previous nocebo studies.
Primary hypothesis:
Pre-induction to post-induction decreases in resting-state alpha band power will positively correlate with the magnitude of induced nocebo hyperalgesia.
Secondary hypotheses:
2.1. The magnitude of induced nocebo hyperalgesia in all nocebo-response evocation trials, will be related to temporal (e.g., Detrended Fluctuation Analysis) and spectral (e.g., Absolute Power, Relative Power and Central Frequency) biomarker values of alpha, beta, and gamma oscillations.
2.2. The experience of nocebo-augmented pain in nocebo trials and pain during control trials of the evocation phase will be characterized by divergent alpha, beta, and gamma oscillation power and peak frequencies.
2.3. The experience of nocebo-augmented pain in nocebo evocation trials and baseline high-pain stimulations, will be characterized by divergent alpha oscillation power and peak frequencies.
2.4. The experience of control and nocebo trials during the induction phase, will be characterized by divergent alpha, beta, and gamma oscillation power and peak frequencies.
2.5. Nocebo induction trials will be characterized by increased gamma band coherence relative to control induction trials during anticipation.
- Questionnaires To assess the influence of psychological and personality traits, questionnaires will also be included. These will include the Pain Catastrophizing Scale (PSC), the Fear of Pain Questionnaire-III (FPQ-III), the Experience of Cognitive Intrusion of Pain (ECIP) scale, and the Amsterdam Resting State Questionnaire (ARSQ 2.0).
3.1. Correlation analyses will be performed between scores on the questionnaires and the magnitude of the nocebo effect.
3.2. Correlation analyses will be performed between scores on the questionnaires and measures of EEG, as well as pre-to post resting-state differences, in alpha, beta, and gamma frequency bands.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
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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 18 - 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),
- Having experienced persisting painful health problems in the last 6 months,
- Experiencing acute physical pain (e.g., headache, 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 will also be excluded.
- After inclusion, participants who do not reliably report a difference (a mean of at least 1,5 on the NRS) between the administered temperatures for control and nocebo trials in the induction phase will also be excluded. Nocebo conditioning relies upon the pairing of high-pain stimuli to the nocebo stimulus and lower pain to the control stimulus, therefore it is deemed that participants who do not experience this difference do not receive the necessary conditioning manipulation.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Nocebo induction
Conditioning and evocation of a nocebo response to a sham (inert) medication contained in a blue or a brown jar, controlled within subjects.
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During baseline pain stimulations, a comparison block will include 6 high- and 2 moderate-pain stimulations.
During nocebo induction trials, the conditioned stimulus (i.e., a sham medical gel that can increase pain sensitivity, named "TDA" and contained in either a brown or a blue jar) is paired to unconditioned high-pain stimuli (nocebo trials).
Lower 'baseline' pain is paired with no gel application (control trials).
Other Names:
During nocebo evocation, lower pain stimulations are administered both after the administration of the conditioned stimulus (i.e., a sham medical gel "TDA") and the control stimulus (no medical gel), in order to evoke nocebo responses to the sham hyperalgesic medication.
Other Names:
In the single group of participants, EEG recordings will be conducted during baseline, during a first resting-state of 5-minutes, during induction/evocation of nocebo responses, and during a second resting-state of 5-minutes.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Magnitude of induced nocebo hyperalgesia
Time Frame: Through study completion, an average of 3 months
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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 nocebo block evocation phase. A significant difference here is assessed within the mixed model ANOVA. Then, calculated difference scores represent the magnitude of induced effects and will be used in further analyses of EEG data. |
Through study completion, an average of 3 months
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Magnitude of nocebo responses during evocation
Time Frame: Through study completion, an average of 3 months
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The magnitude of nocebo responses during the evocation phase is defined in the specific nocebo evocation trials that show heightened pain relative to control trials, for each subject.
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Through study completion, an average of 3 months
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Nocebo-augmented pain
Time Frame: Through study completion, an average of 3 months
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Nocebo-augmented pain is defined as the experience of heightened pain in nocebo trials relative to control trials, during the evocation phase.
|
Through study completion, an average of 3 months
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Electroencephalography components (EEG power in alpha band)
Time Frame: Through study completion, an average of 3 months
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Please refer to section Study Description / Detailed description.
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Through study completion, an average of 3 months
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Electroencephalography components (EEG power in beta band)
Time Frame: Through study completion, an average of 3 months
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Please refer to section Study Description / Detailed description.
|
Through study completion, an average of 3 months
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Electroencephalography components (EEG power in gamma band)
Time Frame: Through study completion, an average of 3 months
|
Please refer to section Study Description / Detailed description.
|
Through study completion, an average of 3 months
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Electroencephalography components (EEG coherence in gamma band)
Time Frame: Through study completion, an average of 3 months
|
Please refer to section Study Description / Detailed description.
|
Through study completion, an average of 3 months
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Collaborators and Investigators
Sponsor
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
- CEP19-1031/532
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
- Statistical Analysis Plan (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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