Electrophysiological Correlates of Nocebo Effects on Pain

January 7, 2020 updated by: AWMEvers, Leiden University Medical Center
Pain is a nociceptive somatosensory process that can arise as a debilitating and chronic symptom in various diseases or following an injury. How pain is experienced can vary widely within and across individuals, and can be shaped by cognitive processes such as learning. Nocebo effects, negative changes in symptom severity attributed to learned outcome-expectations, demonstrate how learning processes can be detrimental for the experience of pain. Research to date has produced inconclusive findings regarding the electrophysiological correlates on nocebo effects. The few studies that have applied electroencephalography (EEG) in this field have pointed towards a potential involvement of alpha-band activity, but the direction of this involvement remains unclear. For example, an EEG study of conditioned nocebo hyperalgesia found a pre to post increase in resting state alpha band power that was correlated with pain catastrophizing scores and not with the magnitude of the nocebo effect. Later, other studies also found pre to post changes in alpha band power, however, these changes were correlated with the magnitude of nocebo effects and not pain catastrophizing. Given the discrepancy in findings, in this study the investigators plan to primarily investigate whether EEG components predict the magnitude of nocebo responses to thermal-pain stimuli. The investigators will also explore electrophysiological correlates during pain anticipation and whether nocebo responses would be significantly related to spectral and temporal EEG biomarkers. This study will utilize a validated model of instructional and associative learning methods (i.e., negative suggestions and classical conditioning, respectively) to experimentally induce nocebo effects on heat-evoked pain. Developing objective, brain-derived markers for nocebo responses, or the detection of individuals most susceptible to nocebo hyperalgesia, will aid in the comprehensive management of pain. This study is conducted at Leiden University.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

  1. Primary hypothesis:

    Pre-induction to post-induction decreases in resting-state alpha band power will positively correlate with the magnitude of induced nocebo hyperalgesia.

  2. 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.

  3. 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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
36

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
    • South Holland
      • Leiden, South Holland, Netherlands, 2333 AK
        • Leiden University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 35 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

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

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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.
Behavioral: Baseline pain stimulations
During baseline pain stimulations, a comparison block will include 6 high- and 2 moderate-pain stimulations.
Behavioral: Conditioning
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:
  • Nocebo Induction phase
Behavioral: Evocation
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:
  • Nocebo testing phase
Other: Electroencephalography (EEG)
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.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Magnitude of induced nocebo hyperalgesia
Time Frame: Through study completion, an average of 3 months

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

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Magnitude of nocebo responses during evocation
Time Frame: Through study completion, an average of 3 months
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.
Through study completion, an average of 3 months
Nocebo-augmented pain
Time Frame: Through study completion, an average of 3 months
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

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Electroencephalography components (EEG power in alpha 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
Electroencephalography components (EEG power in beta 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
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
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Leiden University Medical Center

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
VU University of Amsterdam
Universiteit Leiden

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 21, 2019

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
January 7, 2020

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 7, 2020

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 9, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 13, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 16, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
January 9, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 7, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
January 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • CEP19-1031/532

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

All data are collected pseudonymised thus no personal data are stored or shared. Consent forms are the only sources containing personal data and will not be shared, but are monitored by the department's Data Monitor.

IPD Sharing Time Frame

Data will become available immediately after publication of the study and will be retained for 15 years.

IPD Sharing Access Criteria

Data can be shared with scientists in relevant fields for the purpose of future studies such as replication or meta-analysis (or with designated persons for monitoring purposes).

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

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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