Mapping Stress and Pain Interactions (G072323N) (STRAIN)

STRAIN (STRessinpAIN): a Comprehensive Mapping of Stress System Interactions with Pain and Their Contribution to Extent and Chronification of Musculoskeletal Pain

The over-arching goal of this observational (case-control, with a cross-sectional and longitudinal arm) study is to comprehensively map stress system (dys)function (including reactivity and recovery) in people with primary musculoskeletal (MSK) pain and a pain-free control group.

• The primary objective is to characterize stress systems functioning and their relation to pain in individuals with subacute versus chronic, and localized versus widespread MSK pain, and compare to pain-free controls.
• The secondary objective is to define the contribution of stress system functioning to trajectories of MSK pain, including pain chronification or recovery from pain.

Researchers will compare primary musculoskeletal pain groups with pain-free controls. Participants will:

• Fill out online questionnaires.
• Provide a sample of hair and saliva to assess chronic and acute stress hormone levels, respectively. Saliva samples will be collected both in the lab and at home.
• Be subject to psychophysiological monitoring.
• Partake in quantitative sensory testing measuring pain thresholds, tolerances and pain modulation of pressure and heat. These tests will be repeated twice: before and after an acute-stress induction task.
• Partake in a series of stress-inducting tasks.
• Be subject to MRI-scans of the brain, including structural and functional MR acquisitions (e.g., during rest and during pain inductions).

Participants will be invited for a second session of the same assessments six months later to observe possible connection between pain trajectory and stress system (dys)function.

Study Overview

• Status: Enrolling by invitation
• Conditions: Fibromyalgia; Chronic Low Back Pain; Subacute Low Back Pain

• Study Type: Observational
• Enrollment (Estimated): 140

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • Ghent University, Department of Rehabilitation Sciences

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Study population is a community sample.

Description

Inclusion Criteria:

• Participants aged 18 to 45 years with a BMI between 18.5 and 35 kg/m², who are proficient in the Dutch language and do not meet the exclusion criteria listed below

Exclusion Criteria:

• Body weight >150 kg (maximum weight for the MRI scanner).
• Postmenopausal individuals.
• Use of hormone replacement therapy.
• Current or history of severe psychiatric, neurological (related to the brain, spinal cord, or nerves), endocrine (related to the hormonal system), or cardiovascular (related to the heart and blood vessels) conditions (e.g., cancer, cardiovascular disease, epilepsy, diabetes, etc.).
• History of spinal surgery, spinal trauma, severe spinal deformities, or neurogenic back pain.
• Having a severe communicative or cognitive disorder.
• Use of medication that is not stable for at least 1 month prior to the test session.
• Regular drug use (≥1 time per week).
• Contraindications for MRI (such as claustrophobia, implanted electronic devices like a pacemaker, metal splinters in the body, etc.).
• Currently pregnant or have been pregnant in the past year.
• Breastfeeding.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
fibromyalgia; Proof of a primary fibromyalgia diagnosis with chronic widespread pain by a specialist-doctor, with an average pain intensity of ≥2/10 on a Visual Analogue Scale, and with pain-related disability indicated by a score of ≥14/70 on the Pain Disability Index.
chronic low back pain; Chronic primary (non-specific) low back pain with primary onset ≥6 months ago, with an average pain intensity of ≥2/10 on a Visual Analogue Scale, and with pain-related disability indicated by a score of ≥14/70 on the Pain Disability Index.
subacute low back pain; Non-specific low back pain with primary onset <3 months ago, with an average pain intensity of ≥2/10 on a Visual Analogue Scale, and with pain-related disability indicated by a score of ≥14/70 on the Pain Disability Index.
pain-free/healthy control; Exclusion criteria include current pain (>0 on a Visual Analogue Scale); a pain condition in the last 6 months for which treatment was sought; history of a chronic pain syndrome.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quantitative sensory testing - pressure pain threshold	Determination of mechanical pain sensitivity with a digital pressure algometer, recorded in kg.	At baseline
Quantitative sensory testing - heat pain suprathreshold	Determination of the mean of heat pain threshold and heat pain tolerance with TSA-2, recorded in °C.	At baseline
Quantitative sensory testing - conditioned pain modulation	Determination of conditioned pain modulation with a parallel protocol, with test stimulus and conditioning stimulus equal to the heat pain suprathreshold temperature. Pain will be scored on a verbal rating scale 0-100.	At baseline
Quantitative sensory testing - temporal summation of pain	Determination of temporal summation of pain with a tonic protocol. Heat stimuli will be applied for two minutes, with the temperature equal to the heat pain suprathreshold. Pain will be scored on a verbal rating scale 0-100.	At baseline
Task-based functional MRI - experimental pain induction task	This type of functional MRI-scanning will allow to capture acute brain responses to (painful) heat stimuli and processes of pain modulation.	At baseline
Salivary cortisol concentration	Saliva samples will be taken, with a swab under the tongue for 2 minutes to analyse cortisol concentration; providing information about the hypothalamus-pituitary-adrenal-axis functioning.	At baseline
Salivary alpha-amylase concentration	Saliva samples will be taken, with a swab under the tongue for 2 minutes to analyse alpha-amylase concentrations; which gives information about the autonomic nervous system functioning.	At baseline
Salivary oxytocin concentration	Saliva samples will be taken, with a swab under the tongue for 2 minutes to analyse oxytocin concentrations; providing information about the oxytocinergic system.	At baseline
Heart rate	Heart rate, the number of times the heart beat within a certain period, will be measured continuously using ECG (electrocardiogram), providing information on the autonomic nervous system.	At baseline
Heart rate variability	Heart rate variability (HRV), the fluctuations in time between heart beats, will be measured continuously using ECG. Both time domain and frequency domain of HRV will be examined; providing information on the autonomic nervous system.	At baseline
Skin conductance	Skin conductance reflects sweat gland activity and will be measured continuously; providing information on the autonomic nervous system.	At baseline
Skin temperature	Skin temperature, the measurement of the temperature at the skin's surface will be measured continuously; providing information on the autonomic nervous system.	At baseline
Respiration rate	Respiration rate, the number of breaths taken per minute will be measured continuously; providing information on the autonomic nervous system.	At baseline
Blood pressure	Blood pressure, the force exerted by circulating blood on the walls of blood vessels, will be measured using non-continuously; providing information on the autonomic nervous system.	At baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Analogue Scale - Self-reported	Assessment of momentary pain, unpleasantness and stress on a VAS scale ranging from 0-100	At baseline and at the 6-month follow-up
Pain Disability Index - Self-reported	Assessment of pain-related interference in daily activities, recorded on a 0-70 scale	At baseline and at the 6-month follow-up
Pain Catastrophizing Scale - Self-reported	Measurement of catastrophic thinking related to pain, recorded on a scale of 0-52.	At baseline and at the 6-month follow-up
Pain Vigilance and Awareness Questionnaire - Self-reported	Assessment of attention and awareness to pain, recorded on a 0-80 scale.	At baseline and at the 6-month follow-up
General Perceived Recovery - Self-reported	11-point scale to rate perceived recovery from - 5 (vastly worse), through 0 (no change) to + 5 (greatly improved), to assess recovery or persistence of low back pain	At baseline and at the 6-month follow-up
Pain Anxiety Symptoms Scale - Self-reported	Assessment of fear and anxiety associated with pain, recorded on a 0-100 scale.	At baseline and at the 6-month follow-up
Positive and Negative Affect Schedule - Self-reported	Measurement of positive and negative affect levels. Total scores for positive and negative affect range for 10-50 separately.	At baseline and at the 6-month follow-up
Brief Resilience Scale - Self-reported	Measurement of the ability to recover from stress, recorded on a 5-point Likert scale. This questionnaire contains 6 items.	At baseline and at the 6-month follow-up
Intolerance of Uncertainty Scale - Self-reported	Assessment of intolerance to uncertainty, recorded on a scale of 1-5 for each item, with 12 items in total.	At baseline and at the 6-month follow-up
Stress Mindset Measure - Self-reported	Evaluation of beliefs about the nature of stress (enhancing vs. debilitating), recorded on a scale of 0-4 for each item, with 8 items in total.	At baseline and at the 6-month follow-up
Perceived Stress Scale - Self-reported	Measurement of perceived stress over the past month, recorded on a scale of 0-40.	At baseline and at the 6-month follow-up
Hospital Anxiety and Depression Scale - Self-reported	Assessment of anxiety and depression symptoms, recorded on a scale of 0-21 for anxiety and depression subscales separately.	At baseline and at the 6-month follow-up
Childhood Trauma Questionnaire - Self-reported	Measurement of childhood trauma experiences. A shortened version will be used with scores ranging from 0-25. Emotional abuse, physical abuse, and neglect components will be assessed.	At baseline and at the 6-month follow-up
Pittsburgh Sleep Quality Index - Self-reported	Measurement of sleep quality over the past month. A shortened version will be used with scores ranging from 0-12. Component 1-4 will be scored.	At baseline and at the 6-month follow-up
Gender and Pain Questionnaire - Self-reported	Collection of scales of measures for gender conceptualization, gender identity and gendered pain beliefs	At baseline and at the 6-month follow-up
T1 weighted anatomical MRI data	Through Magnetization Prepared-Rapid Gradient Echo, macro-structural properties of grey matter, such as surface area, cortical thickness or volume will be characterized.	At baseline and at the 6-month follow-up
Resting state functional MRI	This type of MRI-scan will allow us to evaluate functional connectivity of the brain.	At baseline and at the 6-month follow-up
Diffusion weighted MRI data	Diffusion weighted MR imaging will provide insights in microstructural properties of white matter (i.e., factional anisotropy, mean diffusivity, etc.).	At baseline and at the 6-month follow-up
Pseudo-Continuous Arterial Spin Labeling - MRI	This type of MRI will provide information on brain blood perfusion parameters.	At baseline and at the 6-month follow-up
Quantitative sensory testing - pressure pain threshold (at follow-up)	Determination of mechanical pain sensitivity with a digital pressure algometer, recorded in kg.	At the 6-month follow-up
Quantitative sensory testing - heat pain suprathreshold (at follow-up)	Determination of the mean of heat pain threshold and heat pain tolerance with TSA-2, recorded in °C.	At the 6-month follow-up
Quantitative sensory testing - conditioned pain modulation (at follow-up)	Determination of conditioned pain modulation with a parallel protocol, with test stimulus and conditioning stimulus equal to the heat pain suprathreshold temperature. Pain will be scored on a verbal rating scale 0-100.	At the 6-month follow-up
Quantitative sensory testing - temporal summation of pain (at follow-up)	Determination of temporal summation of pain with a tonic protocol. Heat stimuli will be applied for two minutes, with the temperature equal to the heat pain suprathreshold. Pain will be scored on a verbal rating scale 0-100.	At the 6-month follow-up
Task-based functional MRI - experimental pain induction task (at follow-up)	This type of functional MRI-scanning will allow to capture acute brain responses to (painful) heat stimuli and processes of pain modulation.	At the 6-month follow-up
Salivary cortisol concentration (at follow-up)	Saliva samples will be taken, with a swab under the tongue for 2 minutes to analyse cortisol concentrations; providing information about the hypothalamus-pituitary-adrenal-axis functioning.	At the 6-month follow-up
Salivary alpha-amylase concentration (at follow-up)	Saliva samples will be taken, with a swab under the tongue for 2 minutes to analyse alpha-amylase concentrations; providing information about the autonomic nervous system functioning.	At the 6-month follow-up
Salivary oxytocin concentration (at follow-up)	Saliva samples will be taken, with a swab under the tongue for 2 minutes to analyse oxytocin concentrations; providing information on the oxytocinergic system.	At the 6-month follow-up
Heart rate (at follow-up)	Heart rate, the number of times the heart beat within a certain period, will be measured with ECG continuously, and is part of the autonomic nervous system.	At the 6-month follow-up
Heart rate variability (at follow-up)	Heart rate variability, the fluctuations in time between heart beats, will be measured with ECG continuously. Both time domains and frequency domains of HRV will be examined. This parameter is part of the autonomic nervous system.	At the 6-month follow-up
Skin conductance (at follow-up)	Skin conductance reflects sweat gland activity and will be measured continuously; providing information on the autonomic nervous system.	At the 6-month follow-up
Skin temperature (at follow-up)	Skin temperature, the measurement of the temperature at the skin's surface will be measured continuously; providing information on the autonomic nervous system.	At the 6-month follow-up
Respiration rate (at follow-up)	Respiration rate, the number of breaths taken per minute will be measured continuously; providing information on the autonomic nervous system.	At the 6-month follow-up
Blood pressure (at follow-up)	Blood pressure, the force exerted by circulating blood on the walls of blood vessels, will be measured using non-continuously; providing information on the autonomic nervous system.	At the 6-month follow-up

Collaborators and Investigators

• Sponsor: University Ghent
• Collaborators: Vrije Universiteit Brussel; Tilburg University

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2025
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: January 31, 2025
• First Submitted That Met QC Criteria: March 17, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 17, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Low back pain; Oxytocin; Fibromyalgia; Chronic widespread pain; Musculoskeletal pain; Pain processing; Stress reactivity; Autonomic nervous system (ANS); Stress system; Pain chronification; Neural correlates of pain; Stress recovery; Hypothalamus-pituitary-adrenal axis (HPA axis); Chronic localized pain
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Rheumatic Diseases; Back Pain; Musculoskeletal Pain; Fibromyalgia; Myofascial Pain Syndromes; Low Back Pain
• Other Study ID Numbers: ONZ-2024-0391

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Ghent University will be the data controller. The collected data can only be shared upon request and after finalization of the predetermined statistical analyses and publication of the results. Identifiable data will not be shared. Data sharing is only permitted if all involved parties agree, and if a Data Sharing Agreement is signed.

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