Clinical trial NCT06973837: Studying the Neurobiological Mechanisms of Non-specific Chronic Low Back Pain and Chronic Insomnia: a Four-group Cross-sectional Study
Official title: Unravelling the Neurobiological Mechanisms Underlying the Bidirectional Relationship Between Chronic Sleep Disturbances and Pain Sensitivity in People With Non-specific Chronic Low Back Pain and Chronic Insomnia
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Chronic Low Back Pain (CLBP)
Chronic Insomnia
Neuroinflammation
Keywords: Pain
Chronic pain
Chronic low back pain
Sleep
Insomnia
Chronic insomnia
Magnetic resonance imaging
Functional magnetic resonance imaging
Magnetic resonance spectroscopy
Diffusion weighted imaging
Quantitative sensory testing
Temporal summation
Conditioned pain modulation
Experience sampling method
Ecological momentary assessment
Microbiota
Gut-Brain axis
Short-chain fatty acids
Lead sponsor: Vrije Universiteit Brussel
Sponsor class: OTHER
Collaborators: name: Research Foundation - Flanders (FWO: Fonds Wetenschappelijk Onderzoek)
name: Universitaire Ziekenhuizen KU Leuven
First posted: 2025-05-15
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: Participants across all study groups will be recruited from the area around Leuven, Belgium, via local flyers. Participants with non-specific chronic low back pain and/or chronic insomnia will also be recruited from the pain and/or sleep clinic of UZ Leuven, Belgium, as well as via primary care units and patient support groups targeting people in the Leuven area. Participants will be recruited and stratified according to sex and age to enable matching to the primary group of interest (chronic low back pain and comorbid insomnia), and a majority of females (\~two thirds) will be recruited to better represent the sex-distribution within the population representative of this group.

Brief summary: This study is a part of a larger project aiming to evaluate the neurobiological mechanisms underlying the bidirectional sleep-pain relationship in people with non-specific chronic low back pain. Specifically, this study aims to evaluate the neurobiological mechanisms underlying the relationship between chronic sleep disturbances and pain sensitivity in people with non-specific chronic low back pain and chronic insomnia.

Detailed description: Sleep disturbances, and especially insomnia, reflect one of the most common comorbidities in people with chronic pain, including people with chronic low back pain. Previous research has furthermore demonstrated that a lack of sleep is associated with an increased pain sensitivity. The goal of this study is to evaluate the role of brain neuroinflammation in the relationship between chronic sleep disturbances and both clinical and experimental pain sensitivity in people non-specific chronic low back pain and/or chronic insomnia.

Specifically, a cross-sectional study will be conducted across four age- and sex-matched study groups: healthy controls with good sleep habits (Group 1); people with non-specific chronic low back pain and good sleep habits (Group 2); pain-free individuals with chronic insomnia (Group 3); and people with non-specific chronic low back pain and comorbid chronic insomnia (Group 4). The study will be performed over nine consecutive days. On the first study day, all participants will be provided an online-based baseline questionnaire battery to be completed at home. During the following seven days, all participants will then complete a sleep diary once per day, provide momentary ratings of pain, sleepiness, fatigue, and affect eight times per day, and wear an Actigraph at all times (except during heavy water contact). During this seven-day period, the participants will also be instructed to collect a stool sample at a time of their own convenience, but preferably within the first three days, to be used for gut microbiota composition analyses. Continuous dietary intake will therefore also be recorded during the first three days of the seven-day period, while participants who are not able to collect their stool sample during any of these three days will continue to record their dietary intake until a stool sample has been collected. On the last study day (day nine), experimental pain sensitivity and pain-evoked brain activity will be assessed via quantitative sensory testing and a pain-task-based functional magnetic resonance imaging (fMRI), respectively, whereas markers of brain neuroinflammation will be measured via magnetic resonance spectroscopy and (multicompartment) diffusion-weighted magnetic resonance imaging. During the last study day, a venous blood sample will also be collected to measure systemic levels of short chain fatty acids. All participants will therefore also be provided standardized low-fiber meals, alongside standardized boluses of pure fiber, to consume in the evening before, and in the morning of their last study day.

Eligibility criteria: General inclusion criteria (all groups):

* 18-60 years old.
* Ability to speak and understand the Dutch Language.
* Body mass index \<30.
* No smoking or nicotine use.
* Low caffeine use (≤3 cups of coffee/day, ≤1 energy drink/day).
* Low alcohol use (≤9 alcoholic units/week).
* No use of neuro- and/or psychopharmacological treatments and/or immunosuppressive agents (including NSAIDs) with a suspected influence on neuroinflammation unless terminated within a sufficient time frame before the start of the study, or unless falling under the Pharmacological exceptions criteria (see below).
* Willing to (try to) adhere to the acute pre-test restrictions, including refraining from analgesics (unless stable use), caffeine, alcohol, and/or strenuous physical activity (\>3 METs) in the 24 hours preceding the main test day.

General exclusion criteria (all groups):

* Shift worker.
* Use of blood thinners.
* (History of) Substance dependence/abuse.
* Chronic pain conditions (≥3 months) other than chronic low back pain.
* Intrinsic sleep disorders (e.g., apnea, periodic limb movement disorder; assessed during a one-night, laboratory-based polysomnography screening).
* Restless leg syndrome
* Central or peripheral neurological disorder/condition (e.g., epilepsy, multiple sclerosis, peripheral neuropathy).
* History of spinal surgery.
* Major medical (e.g., cardiac disease, cancer) and/or psychiatric disorder/disease (e.g., major depressive disorder, bipolar disorder).
* Claustrophobia.
* Contraindications for magnetic resonance imaging (e.g., metal/cochlear implants, pacemaker).
* Pregnancy or being \<12 months post-natal.

Pharmacological exceptions criteria:

- Participants with chronic low back pain and/or (comorbid) insomnia will be allowed to be on a stable low dose of weak pain and/or sleep agents (e.g., Tramadol, Zolpidem) if medically prescribed specifically for their low back pain and/or insomnia, and if approved by the national medicine register of Belgium (FAMHP, Federal Agency for Medicine and Health Products). These participants will also be allowed stable and/or occasional use of low-to-moderate doses of over-the-counter medications for pain and/or sleep that are suspected to have no or minimal impact on neuroinflammation (e.g., paracetamol, melatonin). Habitual use of medications according to the above-stated criteria should be maintained across the entire study period, with the only exception being analgesics taken on an occasional basis. Specifically, because of the extensive battery of pain tests that will be utilized in the study, all analgesics that are only taken occasionally should be refrained from during the 24 hours preceding the main test day (pre-test instructions).

Specific inclusion criteria for "pain-free" groups:

* Currently pain free, defined as having no pain that affects daily living/functioning and/or which has led to a consultation with a healthcare practitioner.
* No episode of low back pain that interfered with daily functioning/living and/or which led to a consultation with a healthcare practitioner within 12 months from the time of inclusion.
* No history of chronic low back pain.

Specific inclusion criteria for "chronic low back pain" groups:

* Low back pain reported on most days (≥50%), every week, for at least 3 months.
* At least moderate low-back-pain-related disability according to the Oswestry disability index.

Specific inclusion criteria for "good sleeper" groups:

* Stable sleep phase within 10 PM and 10 AM (assessed using the Pittsburgh Sleep Quality Index).
* Average habitual total sleep time between 7 and 9 hours (assessed using the Pittsburgh Sleep Quality Index).
* A Pittsburgh Sleep Quality Index ≤5.
* An Insomnia Severity Index ≤7.
* An Epworth Sleepiness Scale ≤10.
* Sleep efficiency ≥85% during a one-night, laboratory-based polysomnography screening.
* No episode of sleep disturbances that interfered with daily functioning/living and/or which led to a consultation with a healthcare practitioner within the preceding 12 months from the time of inclusion.
* No history of chronic insomnia.

Specific inclusion criteria for "chronic insomnia" groups:

* Chronic insomnia according to the ICSD-3-TR criteria (assessed using an ICSD-3-TR-adapted version of the Pittsburgh Sleep Quality Index).
* An Insomnia Severity Index ≥15.

Primary outcomes:
measure: Brain metabolite concentrations
timeFrame: Main test day (Day 9)
Secondary outcomes:
measure: Brain-tissue microstructure diffusivity
timeFrame: Main test day (Day 9)
measure: Functional brain responses to evoked low back pain
timeFrame: Main test day (Day 9)
measure: Manual pressure pain detection thresholds (mPDT)
timeFrame: Main test day (Day 9)
measure: Computerized pressure pain detection thresholds (cPDT)
timeFrame: Main test day (Day 9)
measure: Computerized pressure pain tolerance thresholds (cPTT)
timeFrame: Main test day (Day 9)
measure: Temporal summation of (pressure) pain
timeFrame: Main test day (Day 9)
measure: Conditioned (pressure) pain modulation
timeFrame: Main test day (Day 9)
measure: Daily self-reported pain distribution assessed via experience sampling methodology (m-Path smartphone application)
timeFrame: Seven days before the main test day (Day 2-8)
measure: Daily self-reported low back pain (fluctuations) assessed via experience sampling methodology (m-Path smartphone application)
timeFrame: Seven days before the main test day (Day 2-8)
measure: Daily self-reported affect (fluctuations) assessed via experience sampling methodology (m-Path smartphone application)
timeFrame: Seven days before the main test day (Day 2-8)
measure: Daily self-reported fatigue (fluctuations) assessed via experience sampling methodology (m-Path smartphone application)
timeFrame: Seven days before the main test day (Day 2-8)
measure: Daily self-reported sleepiness (fluctuations) assessed via the Karolinska Sleepiness Scale (KSS) implemented into the experience sampling methodology smartphone application (m-Path)
timeFrame: Seven days before the main test day (Day 2-8)
measure: Daily sleep-wake cycles assessed by Actigraphy
timeFrame: Seven days before and on the main test day (Day 2-9)
measure: Daily self-reported perceived sleep duration assessed via sleep diaries
timeFrame: Seven days before and on the main test day (Day 2-9)
measure: Daily self-reported nighttime pain assessed via sleep diaries
timeFrame: Seven days before and on the main test day (Day 2-9)
measure: Daily self-reported subjective sleep quality assessed via sleep diaries
timeFrame: Seven days before and on the main test day (Day 2-9)
measure: Daily self-reported subjective wake quality assessed via sleep diaries
timeFrame: Seven days before the main test day (Day 2-8)
measure: Serum short chain fatty acid levels
timeFrame: Main test day (Day 9)
measure: Microbiota composition
timeFrame: One of the seven days preceding the main test day (Day 2-8)
measure: Habitual self-reported macronutrient intake (including fibre) assessed via continuous dietary records (MyFitnessPal smartphone application)
timeFrame: At least the first three, up to all of the seven days preceding the main test day (Day 2-8, dependent on the day at which a stool sample is collected)
Other outcomes:
measure: Pain distribution assessed via a digital body chart
timeFrame: Main test day (Day 9)
measure: Self-reported (REDCap) mood state assessed via a short (32-item) version of the Profile of Mood States (POMS-32)
timeFrame: Main test day (Day 9)
measure: Self-reported (REDCap) sleepiness assessed via the Karolinska Sleepiness Scale (KSS)
timeFrame: Main test day (Day 9)
measure: Self-reported (REDCap) morningness/eveningness phenotype assessed via the Morning-Eveningness Questionnaire (MEQ)
timeFrame: Baseline (Day 1) and main test day (Day 9)
measure: Self-reported (REDCap) pain severity assessed via the Brief Pain Inventory (BPI)
timeFrame: Baseline (Day 1) and main test day (Day 9)
measure: Self-reported (REDCap) fatigue assessed via the Brugmann Fatigue Scale (BFS)
timeFrame: Baseline (Day 1) and main test day (Day 9)
measure: Self-reported (REDCap) pain hypervigilance assessed via the Pain Vigilance and Awareness Questionnaire (PVAQ)
timeFrame: Baseline (Day 1)
measure: Self-reported (REDCap) pain catastrophizing assessed via the Pain Catastrophizing Scale (PCS)
timeFrame: Baseline (Day 1)
measure: Self-reported (REDCap) pain-related disability assessed via Oswestry Low Back Pain Disability Questionnaire (ODI)
timeFrame: Baseline (Day 1)
measure: Self-reported (REDCap) insomnia severity assessed via the Insomnia Severity Index (ISI)
timeFrame: Baseline (Day 1)
measure: Self-reported (REDCap) sleepiness assessed via the Epworth Sleepiness Scale (ESS)
timeFrame: Baseline (Day 1)
measure: Self-reported (REDCap) sleepiness-related disability assessed via the short (10-item) version of the Functional Outcomes of Sleep Questionnaire (FOSQ-10)
timeFrame: Baseline (Day 1)
measure: Self-reported (REDCap) affect trait assessed via Positive and Negative Affect Schedule (PANAS)
timeFrame: Baseline (Day 1)
measure: Self-reported (REDCap) features of depression assessed via the Patient Health Questionnaire-9 (PHQ-9)
timeFrame: Baseline (Day 1)
measure: Self-reported (REDCap) features of anxiety assessed via the General Anxiety Disorder-7 (GAD-7)
timeFrame: Baseline (Day 1)
measure: Self-reported (REDCap) stress assessed via the Perceived Stress Scale (PSS)
timeFrame: Baseline (Day 1)
Locations:
city: Leuven
country: Belgium
facility: UZ/KU Leuven
Study officials:
References: