Electrophysiological Correlates of Nocebo Effects on Pain

NCT ID: NCT04199858

Last Updated: 2020-01-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 36 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-21
• Study Completion Date: 2020-01-07

Brief Summary

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.

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.

Conditions

Chronic Pain Syndrome; Chronic Pain, Psychogenic; Chronic Pain; Hyperalgesia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Baseline pain stimulations

Intervention Type: BEHAVIORAL

During baseline pain stimulations, a comparison block will include 6 high- and 2 moderate-pain stimulations.

Conditioning

Intervention Type: BEHAVIORAL

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).

Evocation

Intervention Type: BEHAVIORAL

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.

Electroencephalography (EEG)

Intervention Type: OTHER

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.

Interventions

Baseline pain stimulations

During baseline pain stimulations, a comparison block will include 6 high- and 2 moderate-pain stimulations.

Intervention Type: 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).

Intervention Type: 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.

Intervention Type: BEHAVIORAL

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.

Intervention Type: OTHER

Other Intervention Names

Nocebo Induction phase; Nocebo testing phase

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Universiteit Leiden

OTHER

Sponsor Role: collaborator

VU University of Amsterdam

OTHER

Sponsor Role: collaborator

Leiden University Medical Center

OTHER

Sponsor Role: lead

Responsible Party

AWMEvers

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andrea WM Evers, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Leiden University Medical Center

Locations

Leiden University

Leiden, South Holland, Netherlands

Countries

Netherlands

Other Identifiers

CEP19-1031/532

Identifier Type: -

Identifier Source: org_study_id