The METRIC Study Protocol

Study Overview
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Brief Summary
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The goal of this clinical trial is to test the effects of spinal manipulative therapy in individuals with chronic primary low back pain and determine the neurophysiological mechanisms underlying pain relief. The main questions it aims to answer are: • Is pain relief produced by spinal manipulative therapy in patients with chronic primary low back pain caused by a reduction of C-fiber-related nociceptive processing? • Are these effects greater when spinal manipulative therapy is applied to the whole spine where it is clinically indicated compared with lumbar spine only? • Are these effects greater after 36 treatments over 3 months compared with 12 treatments over 1 month. Participants will receive spinal manipulative therapy (all clinically indicated spine segments or back only) or a control intervention. A group of healthy volunteers will be recruited to assess secondary outcome measures over the same time period, as reference data for comparisons. Researchers will compare the two groups receiving spinal manipulative therapy to the group receiving the control intervention to see if clinical pain relief and the reduction of temporal summation of second pain (produced experimentally) is significantly greater with spinal manipulative therapy.

Official Title
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The METRIC Study Protocol: an Explanatory Randomized Controlled Trial Investigating the Neurophysiological Mechanisms Underlying the Therapeutic Effects of Spinal Manipulative Therapy for Chronic Primary Low Back Pain

Conditions
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Chronic Low-back Pain

Intervention / Treatment
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* Procedure: lumbar spinal manipulative therapy
* Procedure: sham spinal manipulative therapy
* Procedure: full spine spinal manipulative therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Duration of current low back pain (LBP) episode ≥ 6 months; Average LBP intensity during the last 7 days ≥ 3/10; (For healthy volunteers only) To be of the same sex and age (± 1 year) as a participant with low back pain. Exclusion Criteria: Diagnosis of back conditions other than chronic primary LBP e.g., failed back surgery syndrome, spondylosis, spondylolisthesis, spinal stenosis, herniated disc, infection, etc.; Presence of pain in another body location that is more severe than the pain in the lower back; Presence of a neurological deficit i.e., sensation loss, muscle weakness, decreased deep tendon reflexes; Presence of contraindications to spinal manipulative therapy e.g., recent fracture, history of spinal surgery, cauda equina syndrome, inflammatory arthritis, taking anticoagulant medication, active cancer, moderate to severe osteoporosis, abdominal aortic aneurysm; Underwent surgery in the last 3 months; Pregnancy, ≤ 3 months post-partum or planning to get pregnant in the next 12 months; History of spinal manipulative therapy in the past 12 months; Scoliosis ≥ 20°; BMI ≥ 40; Insufficient language skills in French to complete the questionnaires; Open or pending litigation for LBP or seeking/receiving disability compensation; Diagnosis of an illness affecting the sensorimotor functions e.g., diabetes, multiple sclerosis, amyotrophic lateral sclerosis; Diagnosis of mental health disorders (with the exception of anxiety and depression); Current drug or alcohol dependence; Skin of type I on the Fitzpatrick scale; (For healthy volunteers only) Regular use of pain medication or usage in the 48 h prior to data collection; (For healthy volunteers only) History of chronic pain; (For healthy volunteers only) Acute pain on the days of data collection.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lumbar spinal manipulative therapy<br>Participants will receive spinal manipulative therapy (SMT) exclusively at dysfunctional lumbar segments. Participants will receive 36 SMT sessions over 12 weeks, 3 times per week, each session lasting ≈15 min. Spinal manipulation will be performed using the diversified technique. For each treatment, the SMT provider will perform two spinal manipulations, one on each side of the most painful lumbar vertebra. During spinal manipulations, participants will lay on their side and they will be instructed to inhale and exhale fully before each thrust. | Procedure: lumbar spinal manipulative therapy<br>* Spinal manipulative therapy involves the application of spinal manipulation over several sessions. Spinal manipulation is defined as a high-velocity, low-amplitude thrust performed by a clinician to move a segment of the spine in a specific direction. This type of intervention often generates cavitation sounds (audible pops).<br>* Other names: grade 5 spinal mobilization;|
| Experimental: full spine spinal manipulative therapy<br>Participants will receive spinal manipulative therapy (SMT) at dysfunctional spinal segments in the lumbar AND other spine regions. Participants will receive 36 spinal manipulative therapy (SMT) sessions over 12 weeks, 3 times per week, each session lasting ≈15 min. Spinal manipulation will be performed using the diversified technique. For each treatment, the SMT provider will perform a minimum of two spinal manipulations, one on each side of the most painful lumbar vertebra. Spinal manipulation will also be delivered at other dysfunctional spinal segments, based on clinical examination. During spinal manipulations, participants will lay prone, supine or on their side and they will be instructed to inhale and exhale fully before each thrust. | Procedure: full spine spinal manipulative therapy<br>* Spinal manipulative therapy involves the application of spinal manipulation over several sessions. Spinal manipulation is defined as a high-velocity, low-amplitude thrust performed by a clinician to move a segment of the spine in a specific direction. This type of intervention often generates cavitation sounds (audible pops).<br>* Other names: grade 5 spinal mobilization;|
| Sham Comparator: sham spinal manipulative therapy<br>Participants will receive 36 sham SMT sessions (3x/week for 12 weeks, each session ≈15 min). This will target dysfunctional segments in the lumbar and other spine regions. Three maneuvers will be used: Ventral decubitus: 1 to 5 light and brief manual contacts (≈ 20 N and 5 s) will be applied and quickly released over the spinous process of dysfunctional vertebrae identified during clinical examination. Dorsal decubitus: sections of the treatment table will be slightly raised or lowered (≈ 5 cm) and their lower limbs' position changed once or twice e.g., knees bent, hips internally or externally rotated. Each position maintained during ≈ 30 s. Lateral decubitus: 1 to 5 impulses at the lowest setting of the Activator V instrument (Activator Methods Int. Ltd., Phoenix, Arizona, USA) will be applied on their gluteus and quadratus lumborum muscles. The position of the instrument will change after each impulse. | Procedure: sham spinal manipulative therapy<br>* Sham spinal manipulative therapy (sham SMT), was designed to be structurally equivalent to SMT, i.e., to attend to the same body regions with the same amount of contact as well as to have the same number, frequency and length of sessions. SMT and sham SMT will be provided by the same treatment provider and will appear to be similarly tailored to the participants' condition. Sham SMT does not share the component of interest of SMT, i.e., the activation of deep high-threshold mechanoreceptors via high-velocity, low-amplitude thrusts applied to the spine. Yet, it shares all the other components not of interest in this study that may contribute to the placebo response, such as therapeutic alliance, contextual factors, physical touch, and expectations. Furthermore, deception will be used to balance expectations and enhance blinding.<br>* Other names: placebo;|
| No Intervention: no intervention<br>This fourth arm will comprise healthy volunteers (age/sex-matched to the participants in the test intervention - lumbar group) who will not receive any intervention. The main purpose of this fourth group is to provide reference values to interpret some results obtained in participants with chronic primary low back pain. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| low back pain intensity | In accordance with recommendations for chronic pain trials, participants will be instructed to rate the intensity of their LBP using a numerical rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable). As in the brief pain inventory (BPI), they will be instructed to rate their pain: 1) right now; 2) on average over the last 7 days; 3) at its worst over the last 7 days; 4) at its best over the last 7 days. | baseline, 1- , 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 26-, 39-, 52- and 64-weeks post-randomization. | 
| temporal summation of second pain | Participants will receive a total of 160 painful laser stimuli, 80 single-pulse stimuli and 80 pulse trains (3 pulses delivered at 0.67 Hz). After each stimulus, participants will be prompted to rate second pain with the display of a numerical pain rating scale. The pain ratings of single pulses will be subtracted from the pain ratings of pulse trains to estimate the intensity of the temporal summation of second pain. | baseline, 4- and 12-weeks post-randomization. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| low back pain frequency and duration | A modified version of the pain frequency-severity-duration scale will be used. Participants will be instructed to answer these 3 questions: Is the pain recurrent (it comes in episodes) or continuous (it is always present)? How many days in the past week have you had low back pain? (0, 1, 2, 3, 4, 5, 6, 7 days; a higher score means a worse outcome) On average, how many hours per day does the pain last? (0; 1-4; 5-8; 9-12; 13-16; 17-20; 21-24 hours; a higher score means a worse outcome) | baseline, 1- , 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 26-, 39-, 52- and 64-weeks post-randomization. | 
| Pressure pain thresholds (PPTs) | PPT will be measured using a handheld digital algometer (Wagner Pain TestTM FPX, Greenwich, Connecticut, USA) and a standardized protocol. The algometer will be applied perpendicularly to the skin of the first test location and the pressure increased at approximately 50 kPa/s until pain is reported by the participant. This procedure will be repeated three times at the same test location. The PPT will be the average of the values obtained during these 3 trials. The same procedures will be repeated at the two other test locations. PPT will be tested on three different body locations: 1) Over the spinous process of the most painful vertebra between L1 and S1; 2) On the right lower limb in the dermatome corresponding to the level of the most painful vertebra; 3) in the center of the right thenar eminence. | baseline, 4- and 12-weeks post-randomization. | 
| C-fiber-related brain responses | Electroencephalography (EEG) will be recorded using a 64-channel BrainVision system with active Ag-AgCl electrodes mounted on an actiCAP, according to the International 10-20 system (Brain Products, Gilching, Germany). Electrodes will be nose-referenced, and the ground will be set at FPz. Signals will be sampled at 500 Hz. Eye movements and blinks will be recorded using electrooculography (EOG). Electrode impedance will be kept below 20 kΩ. Closed eyes resting state EEG will be recorded for 5 min prior to laser stimuli for exploratory EEG analyses. EEG activity will be recorded continuously. The outcome of interest from laser-evoked-brain activity is the response evoked by C-fiber activation. Laser-evoked potentials (LEP) and event-related spectral perturbations (ERSP) will be analyzed using validated methods. | baseline, 4- and 12-weeks post-randomization. | 
| Oswestry Disability Index (ODI) | Self-reported low back pain related disability will be evaluated using the French-Canadian version of the ODI (0-100%; a higher score means a worse outcome). | baseline, 4-, 12-, 26-, 39-, 52- and 64-weeks post-randomization. | 
| Back performance scale (BPS) | The BPS will be used as a performance based outcome of physical function. It includes five daily activities such as putting socks on or picking something on the floor (see PMID: 12444880 for more details). Each activity is rated from 0 to 3, and the five scores are added up (min = 0, max = 15; a higher score means a worse outcome). | baseline, 4- and 12-weeks post-randomization. | 
| Five times sit-to-stand test | The five times sit-to-stand test will be used as performance based outcome of physical function. Participant sitting on a supported chair will be instructed to stand and sit again as fast as possible, five times in a row. Time will be measured in seconds. The test will be performed twice and the average time for the two trials will be recorded (a higher score means a worse outcome). | baseline, 4- and 12-weeks post-randomization. | 
| Depression | Depression levels will be measured using the French-Canadian version of the Beck Depression Inventory (BDI; min = 0, max = 63; a higher score means a worse outcome). | baseline, 4- and 12-weeks post-randomization. | 
| Anxiety | Anxiety levels will be measured using the French-Canadian version of the State-Trait Anxiety Inventory, version Y (STAI-Y; min = 20, max = 80; a higher score means a worse outcome). | baseline, 4- and 12-weeks post-randomization. | 
| Pain catastrophizing | The main elements contributing to the pain experience according to the fear avoidance model of pain will be measured. Pain catastrophizing will be measured with the French-Canadian version of the pain catastrophizing scale (PCS; min = 0, max = 52; a higher score means a worse outcome). | baseline, 4- and 12-weeks post-randomization. | 
| Kinesiophobia | The main elements contributing to the pain experience according to the fear avoidance model of pain will be measured. Pain-related fear will be measured with a French adaptation of the Tampa scale for kinesiophobia (TSK; min = 17, max = 68; a higher score means a worse outcome). | baseline, 4- and 12-weeks post-randomization. | 
| Pain vigilance | The main elements contributing to the pain experience according to the fear avoidance model of pain will be measured. Hypervigilance will be measured with a French adaptation of the pain vigilance and awareness questionnaire (PVAQ; min = 0, max = 80; a higher score means a worse outcome). | baseline, 4- and 12-weeks post-randomization. | 
| Patient's global impression of change | Participants will be instructed to give their global impression of change on a scale from -100 to 100 (-100 = very much worse, 0 = no change, 100 = very much improved). | After the last treatment session (12-weeks post-randomization) | 
| Expectations of pain relief | Participants will be instructed to rate their expectations of pain relief after the treatment on a scale from 0 to 100, 0 being no relief and 100 being complete relief. | baseline and 4-weeks post-randomization. | 
| Contextual factors (healing encounters and attitudes lists (HEAL)) | Contextual factors will be measured using a French adaptation of the healing encounters and attitudes lists (HEAL). | baseline, 4- and 12-weeks post-randomization. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic primary low back pain, spinal manipulative therapy, nociplastic pain, central sensitization, C-fibers, brain, electroencephalography