Pain-related Fear as a Facilitator of Nocebo Hyperalgesia

NCT04197154 | Completed DMC

• 1 other identifier: CEP19-0614/347
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hyperalgesia; Chronic Pain Syndrome; Chronic Pain, Psychogenic; Fear of Pain

Keywords

Nocebo; Pain; Fear; Conditioning; Negative suggestions; Extinction

Outcome Measures

Primary Outcomes (1)

• Magnitude of nocebo hyperalgesia

  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

Secondary Outcomes (1)

• Reduction of nocebo hyperalgesia

  On the testing day, in the extinction phase

Other Outcomes (2)

• Fear levels

  On the testing day, in both experimental phases

• Fear self report levels

  On the testing day, in both experimental phases

Study Arms (3)

1. Control nocebo group

EXPERIMENTAL

Conditioning and extinction of a nocebo response using moderate pain stimuli, nocebo negative suggestions, and no threat suggestions.

Behavioral: Threat manipulation (control, no threat); Behavioral: Conditioning of moderate pain; Behavioral: Extinction

2. High-pain nocebo group

EXPERIMENTAL

Conditioning and extinction of a nocebo response using higher pain stimuli, nocebo negative suggestions, and no threat suggestions.

Behavioral: Threat manipulation (control, no threat); Behavioral: Conditioning of high pain; Behavioral: Extinction

3. High-threat nocebo

EXPERIMENTAL

Conditioning and extinction of a nocebo response using moderate pain stimuli, nocebo negative suggestions, and threat suggestions (i.e., fear-inducing suggestions).

Behavioral: Threat manipulation; Behavioral: Conditioning of moderate pain; Behavioral: Extinction

Interventions

Threat manipulation (control, no threat) BEHAVIORAL

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.

1. Control nocebo group; 2. High-pain nocebo group

Threat manipulation BEHAVIORAL

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.

3. High-threat nocebo

Conditioning of moderate pain BEHAVIORAL

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.

Also known as: Nocebo Induction

1. Control nocebo group; 3. High-threat nocebo

Conditioning of high pain BEHAVIORAL

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.

Also known as: Nocebo Induction

2. High-pain nocebo group

Extinction BEHAVIORAL

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.

Also known as: Nocebo Attenuation

1. Control nocebo group; 2. High-pain nocebo group; 3. High-threat nocebo

Eligibility Criteria

• Age: 17 Years - 35 Years
• Gender Eligibility Details: Participants whose lived gender is male, will be included as male and participants whose lived gender is female, will be included as female.
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Aged 17 - 35 years
• Good understanding of the English language
• Normal or corrected to normal vision

You may not qualify if:

• 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.

Sponsors & Collaborators

• Leiden University Medical Center: lead
• Universiteit Leiden: collaborator
• KU Leuven: collaborator
• Maastricht University: collaborator

Study Sites (1)

Leiden University

Leiden, South Holland, 2333 AK, Netherlands

Location

MeSH Terms

Conditions

Hyperalgesia; Chronic Pain; Pain

Interventions

Extinction, Biological

Condition Hierarchy (Ancestors)

Somatosensory Disorders; Sensation Disorders; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Biological Phenomena

Study Officials

• Andrea WM Evers

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: A double-blind randomization list (stratified for gender) was created by an independent researcher. Complete blinding of the researchers during the experiment is not possible due to the nature of the conditioning paradigms. However, in this study blinding is optimized: the researchers are informed of the (conditioning) group to which participants are allocated after their final inclusion to the study and after the start of the experiment.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 9, 2019
• First Posted: December 12, 2019
• Study Start: October 14, 2019
• Primary Completion: February 14, 2020
• Study Completion: February 14, 2020
• Last Updated: February 19, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ANALYTIC CODE
• Time Frame: Data will become available immediately after publication of the study and will be retained for 15 years.
• 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).

Locations

NL (1)