The Role of Epigenetic Mechanisms in Stress Intolerance in Patients With Chronic Widespread Pain (EPISIP)

Patients with chronic widespread pain (CWP) frequently experience stress intolerance - an exacerbation of symptoms in response to stress. Although it severely affects their quality of life, stress intolerance remains a mystery. Hence, unravelling the mechanisms underlying stress intolerance is crucial to understand CWP pathophysiology and to develop novel treatments. Epigenetic mechanisms hold the potential to provide an answer as they have been found to be altered in patients with CWP at baseline, and in response to stress. However, research on epigenetic mechanisms in CWP is very scarce. Hence, this study aims to address this knowledge gap by assessing stress-induced epigenetic changes in patients with CWP and healthy controls aiming to unravel whether epigenetic mechanisms can help explain stress intolerance. The regulatory role of epigenetic mechanisms will be researched in relation to the activity of enzymes affected by the epigenetic mechanisms, neurophysiological measures, and stress-induced symptom changes in patients with CWP.

Study Overview

• Status: Completed
• Conditions: Chronic Widespread Pain
• Intervention / Treatment: Other: Montreal Imaging Stress Test; Other: Relaxation breathing

Detailed Description

The objectives of this project will be tackled by a randomized cross-over study including 44 patients with CWP and 44 healthy controls. Participants are expected to come to the hospital twice and fill in questionnaires at several defined timepoints. Two days before their first visit, participants will complete baseline questionnaires at home via REDCap, which will take approximately one hour. Next, participants will be randomised into Group 1 (undergoing the mental stress test at their first visit and then relaxation breathing) or Group 2 (undergoing relaxation breathing at their first visit and then the mental stress test). During each hospital visit, the participants will be assessed before, during and after the intervention. The Pre-test assessment consists of a blood withdrawal, five short questionnaires, examination of pain thresholds, and neurophysiological measurements. The latter will continue during the intervention, which consists of a mental stress test or relaxation breathing. The Post-test assessment consists of a blood withdrawal, one short questionnaire, examination of pain thresholds, and neurophysiological measurements. Then there are again 2 home-based assessments via REDCap 24h and 7 days after the intervention during which the participants will in 1 or 5 short questionnaires, respectively.

• Study Type: Observational
• Enrollment (Actual): 84

Contacts and Locations

Study Locations

• Belgium
  • Brussels Capital
    • Brussels, Brussels Capital, Belgium, 1050
      • Vrije Universiteit Brussel - UZ Brussel

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Potential study participants will be recruited mainly through online advertisements, but also in hospitals.

Description

Inclusion Criteria:

• female
• age between 18 and 70 years old
• body mass index (BMI) below 30
• inactive lifestyle
• for patients only: received the diagnosis of fibromyalgia

Exclusion Criteria:

• other neurological, endocrine, cardiac, or systemic syndromes
• history of cancer or heart failure
• women that are pregnant or within one year after pregnancy

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Women with chronic widespread pain; Women who received the diagnosis of fibromyalgia from a doctor.	Other: Montreal Imaging Stress Test; A mental stress test that induces stress via a series of arithmetic tasks participants need to solve in a few seconds.; Other: Relaxation breathing; 3 short sessions (4 minutes) of relaxation breathing
Healthy women; Healthy women without any chronic diseases or pain in daily life.	Other: Montreal Imaging Stress Test; A mental stress test that induces stress via a series of arithmetic tasks participants need to solve in a few seconds.; Other: Relaxation breathing; 3 short sessions (4 minutes) of relaxation breathing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DNA methylation of catecholamine-degrading enzymes	DNA methylation status of catechol-O-methyltransferase (COMT), monoamine oxidase (MAO)-A and MAO-B	At baseline (i.e. before the mental stress test or relaxation breathing), and 20 minutes after the mental stress test and relaxation breathing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genetic variations in catecholamine-degrading enzymes	COMT: rs4818; rs4680 MAO-A: rs6323; MAOA-uVNTR MAO-B: rs1799836 COMT: rs4818; rs4680 MAO-A: rs6323; MAOA-uVNTR MAO-B: rs1799836 COMT: rs4818; rs4680 MAO-A: rs6323; MAOA-uVNTR MAO-B: rs1799836 COMT: rs4818; rs4680; MAO-A: rs6323; MAOA-uVNTR; MAO-B: rs1799836	At baseline
Catecholamine levels	Levels of adrenaline, noradrenaline and dopamine in plasma	At baseline (i.e. before the mental stress test or relaxation breathing), and 20 minutes after the mental stress test and relaxation breathing
Heart rate variability	Heart rate variability measured continuously using the Polar H10	Continuously starting 10 minutes before until 10 minutes after the mental stress test and relaxation breathing
Blood pressure	Blood pressure, both systolic and diastolic, measured at specified moments using a digital device	At baseline (i.e. before the mental stress test or relaxation breathing), during (3 times with 4 minutes in between) and 10 minutes after the mental stress test and relaxation breathing
Activity of catecholamine-degrading enzymes	Activity of the enzymes will be defined in plasma or PBMCs	At baseline (i.e. before the mental stress test or relaxation breathing), and 20 minutes after the mental stress test and relaxation breathing
Symptom severity	Symptom severity which is assessed through the Chronic Fatigue Syndrome Symptom List	At baseline (i.e. before the mental stress test or relaxation breathing), and 10 minutes, 24 hours and 7 days after the mental stress test and relaxation breathing

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Temperature and pressure pain thresholds	Pain thresholds for warmth and cold measured with the TSA-II, and pressure measured with a digital algometer on the hand and leg. Pain intensity is reported through a numeric rating scale ranging from 0 (no pain) to 10 (worst pain).	At baseline (i.e. before the mental stress test or relaxation breathing), and 20 minutes after the mental stress test and relaxation breathing
Level of stress	Numeric rating scale ranging from 0 (no stress) to 10 (worst stress) indicating the level of stress	At baseline (i.e. before the mental stress test or relaxation breathing), during (3 times with 4 minutes in between) and 10 minutes, 24 hours and 7 days after the mental stress test and relaxation breathing

Collaborators and Investigators

• Sponsor: Vrije Universiteit Brussel
• Collaborators: KU Leuven; Research Foundation Flanders
• Investigators: Principal Investigator: Jo Nijs, PhD, Vrije Universiteit Brussel

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2023
• Primary Completion (Actual): April 18, 2025
• Study Completion (Actual): April 18, 2025

Study Registration Dates

• First Submitted: May 16, 2024
• First Submitted That Met QC Criteria: June 20, 2024
• First Posted (Actual): June 26, 2024

Study Record Updates

• Last Update Posted (Estimated): September 19, 2025
• Last Update Submitted That Met QC Criteria: September 15, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Autonomic Nervous System; Chronic Widespread Pain; Epigenetics; Stress Intolerance
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Chronic Pain
• Other Study ID Numbers: EC-2022-118

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No