Pain, Learning, and Nocebo

NCT04762836 | Completed DMC

• 1 other identifier: NL66693.058.18
• Study Type: interventional
• Target: 53
• Locations: 1 country
• Sites: 1

Brief Summary

Nocebo effects, negative responses to inert or active treatments which are putatively induced by negative outcome expectations, have been shown to play a significant role in pain perception. The underlying neurobiological mechanisms of these effects remain largely unexplored. The primary objective of this study is to test the role of N-methyl-D-aspartate (NMDA) receptor-dependent learning in an experimental model of conditioned nocebo effects on self-reported pain. Secondary objectives are to examine the role of the NMDA manipulation and related neural correlates during the acquisition and extinction of nocebo effects using statistical learning models. This study will utilize a placebo controlled, double-blind design with respect to the pharmacological administration of 80 mg D-Cycloserine (DCS), an NMDA agonist, or placebo. Validated conditioning and verbal suggestion (VS) paradigms will induce nocebo effects on pain in a random sample of 50 healthy adults. The primary endpoint of the study is the magnitude of the induced nocebo effect on pain measured as the difference between self-reported pain, between the first conditioned and control extinction trials. Secondary endpoints include the classification analysis of the Blood Oxygen Level Dependent (BOLD) responses of participants into pharmacological groups with multivariate pattern analysis. This study will be conducted at Leiden University and the Leiden University Medical Center (LUMC), The Netherlands.

Conditions

Chronic Pain; Pain Syndrome

Keywords

Nocebo; Pain; BOLD; fMRI; Conditioning

Outcome Measures

Primary Outcomes (1)

• Magnitude of induced nocebo hyperalgesia

  is defined as the difference in pain numerical rating scale ratings (self-report, scale from 0 - no pain to 10 - worst pain imaginable) for the first nocebo trial compared to the first control trial of the extinction phase. A significant difference here is assessed within the mixed model ANOVA, comparing within-subjects differences for the control and nocebo trials between DCS and placebo groups

  Through study completion, an average of 2 weeks

Secondary Outcomes (7)

• The difference in blood-oxygen level dependent (BOLD) response at a series of a priori ROIs between pharmacological groups during the acquisition of nocebo effects.

  Through study completion, an average of 2 weeks

• The classification accuracy (into pharmacological groups), indicating that patterns of activation in the network of a priori ROIs form a model that can detect differences in neural activations during the acquisition of nocebo effects.

  Through study completion, an average of 2 weeks

• The difference in BOLD response at a series of a priori ROIs between pharmacological groups during the extinction of nocebo effects.

  Through study completion, an average of 2 weeks

• The classification accuracy (into pharmacological groups), indicating that patterns of BOLD activation in the network of a priori ROIs form a model that can detect differences in neural activations during the first trials of the extinction phase.

  Through study completion, an average of 2 weeks

• The difference in BOLD response at a series of a priori ROIs between pain at baseline and nocebo-augmented pain.

  Through study completion, an average of 2 weeks

Study Arms (2)

Augmented learning

EXPERIMENTAL

Conditioning and extinction of a nocebo response to the activation of a sham electrode, controlled within subjects. All participants in this arm receive a double-blind oral dose of DCS two hours prior to conditioning and fMRI

Drug: D-cycloserine; Behavioral: Conditioning; Behavioral: Extinction; Other: fMRI

Baseline learning

PLACEBO COMPARATOR

Conditioning and extinction of a nocebo response to the activation of a sham electrode, controlled within subjects. All participants in this arm receive a double-blind oral dose of placebo two hours prior to conditioning and fMRI

Behavioral: Conditioning; Behavioral: Extinction; Other: fMRI; Drug: Placebo

Interventions

D-cycloserine DRUG

Antibiotic medication that augments the function of NMDA-receptors

Also known as: DCS

Augmented learning

Conditioning BEHAVIORAL

During nocebo acquisition trials, the conditioned stimulus (i.e., activation of a sham electrode that can increase pain sensitivity, is paired to unconditioned high-pain stimuli (nocebo trials). During control trials of the acquisition phase, moderate-pain stimuli are paired to no sham electrode activation.

Augmented learning; Baseline learning

Extinction BEHAVIORAL

During nocebo extinction, moderate pain stimulations are administered both after the administration of the conditioned stimulus (i.e., activation of the sham electrode) and the control stimulus (no activation of the sham electrode), in order to evoke nocebo responses to the sham hyperalgesic procedure.

Augmented learning; Baseline learning

fMRI OTHER

In both arms of the study, BOLD response data will be collected with fMRI during the acquisition and extinction of nocebo effects on pain.

Augmented learning; Baseline learning

Placebo DRUG

Placebo control in oral form

Baseline learning

Eligibility Criteria

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

You may qualify if:

• Aged 18 - 35 years
• Good understanding of the English language
• Normal or corrected to normal vision

You may not qualify if:

• History of serious or chronic medical or psychiatric conditions (e.g., convulsions (epilepsy), cardiovascular problems, depression; careful and detailed screening will be carried out for both medical and psychiatric conditions)
• History of chronic pain or itch conditions
• Experiencing pain or itch of 1 or more on a 0-10 pain / itch NRS on the day of testing
• Currently using antihistamines, analgesic medication, or itch-reducing medication (in the 24 hours prior to testing)
• Use of psychotropic drugs (including recreational drugs such as cannabis and psychotropic prescription-medication; in the past month)
• Currently being (or intending to become) pregnant, or currently breastfeeding, or planning to father a child in the next 3 months
• Colour-blindness
• Body Mass Index under 16 or over 30
• Having too high of a threshold for pain (where high pain cannot be induced with temperatures lower than 49.5 °C).

Sponsors & Collaborators

• Leiden University Medical Center: lead
• Leiden University: collaborator

Study Sites (1)

Leiden University

Leiden, South Holland, 2333 AK, Netherlands

Location

MeSH Terms

Conditions

Chronic Pain; Somatoform Disorders; Pain

Interventions

Cycloserine; Extinction, Biological

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Mental Disorders

Intervention Hierarchy (Ancestors)

Isoxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Oxazolidinones; Oxazoles; Serine; Amino Acids, Neutral; Amino Acids; Amino Acids, Peptides, and Proteins; Biological Phenomena

Study Officials

• Andrea WM Evers, PhD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 13, 2020
• First Posted: February 21, 2021
• Study Start: February 28, 2021
• Primary Completion: August 20, 2021
• Study Completion: August 20, 2021
• Last Updated: January 11, 2022

Record last verified: 2022-01

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: Anonymized 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)