Pain, Learning, and Nocebo

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

Interventions

DRUG

D-cycloserine

Antibiotic medication that augments the function of NMDA-receptors

BEHAVIORAL

Conditioning

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.

BEHAVIORAL

Extinction

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.

OTHER

fMRI

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

DRUG

Placebo

Placebo control in oral form

Sponsors & Collaborators

• Leiden University

  collaborator OTHER

• Leiden University Medical Center

  lead OTHER

Principal Investigators

• Andrea WM Evers, PhD · Leiden University Medical Center

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

35 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2021-02-28

Primary Completion

2021-08-20

Completion

2021-08-20

Countries

• Netherlands

Study Locations