Chronic PainNCT04561401
IPRP Repeated Transcranial Magnetic Stimulation (rTMS)
A study testing Repeated Transcranial Magnetic Stimulation (rTMS) and Intensive Pain Rehabilitation Program (IPRP) in people with Chronic Pain, run by University of Calgary at 1 site in Canada.
Trial summary
Severe chronic pain is defined as pain persisting for three months or more that significantly impacts daily functioning. It is highly prevalent, occurring in 100,000 to 160,000 youth. Read more about this study
- Who is it for?
- Ages 10 to 18 years
- Conditions the study is for
- Chronic Pain
- What is being tested?
- Repeated Transcranial Magnetic Stimulation (rTMS) and Intensive Pain Rehabilitation Program (IPRP)
- Type of treatment
- Medical device
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 25 participants
- Where
- 1 siteCanada
- Study dates
- 19 Oct 2020to 30 Apr 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 10 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Between the ages of 10-18 years
- Patient has had the appropriate medical work-up
- Participation in accessible, evidenced based pain therapies has not demonstrated return to functional goals
- Pain is significantly impacting the patient's life and they are not meeting their functional goals in areas of life, which may include: physical function, sleep, self-care, school attendance/academic performance, social function, recreational engagement, and mood
- Patient and family agree and understand that an active, self-management approach to functional restoration is the mainstay of treatment in the IPRP
Who cannot join
- Significant developmental delay or brain injury
- Functional neurological disorder/conversion disorder
- Youth who require opioid weaning
- Extensive medical needs and/or untreated psychiatric illness that would impede a rehabilitative approach to care.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Can Brain Stimulation Enhance Outcomes Associated With Intensive Rehabilitation for Youth With Chronic Pain?
Severe chronic pain is defined as pain persisting for three months or more that significantly impacts daily functioning. It is highly prevalent, occurring in 100,000 to 160,000 youth. If left unmanaged it can lead to persistent pain and mental health problems in adulthood, posing enormous costs to society ($7.2 billion CAD/year). In 2014, health professionals at the Alberta Children's Hospital (ACH) established a pediatric Intensive Pain Rehabilitation Program (IPRP) to target youth with severe chronic pain and consequent functional disability who do not respond to outpatient pain therapies. The IPRP at the ACH is a three-week intensive day-treatment intervention provided by an interdisciplinary team, which helps youth resume engagement in normal daily functioning. Following IPRP, youth reported less anxiety, less depressive symptoms, and greater function, although their self-reported pain remained unchanged. In August 2016, the investigators began to explore brain areas related to severe chronic pain in youth. The investigators scanned a subset of youth at the start (baseline) and end (discharge) of IPRP (23 youth with 2 brain scans). From baseline to discharge, the investigators saw decreases in activity in the dorsolateral prefrontal cortex (DLPFC). Decrease in DLPFC activity was related to better mental health outcomes. The DLPFC is a well-known target for non-invasive brain stimulation. Repeated brain stimulation has been used to treat adults, but not youth with chronic pain. For the first time, the investigators will use image-guided brain stimulation (37 minutes/day, 5 days/week) to enhance the brain changes observed with IPRP. The investigators will examine whether three weeks of brain stimulation helps to reduce pain symptoms in youth. The investigators will also compare pain, brain, and mental health outcomes to our historical program data. By adding brain stimulation to our pain intervention, the investigators have the chance to target an area of the brain investigators know to be altered by chronic pain to improve outcomes.
Read the detailed description
Severe chronic pain in youth is debilitating, common, and has limited treatment options, rendering it as a major public health problem. Severe chronic pain is defined as pain persisting for three months or more that significantly impacts daily functioning (e.g. sleep, mental health, school, work, activity). It is highly prevalent, occurring in 100,000 to 160,000 youth in Canada - comparable to the rates of autism spectrum disorder. If left unmanaged, it can lead to persistent pain and mental health problems in adulthood, posing enormous costs to society ($7.2 billion CAD/year). Most treatments to address chronic pain take a "one-size-fits-all-approach," which does not account for comorbid mental health conditions, contributing to small treatment effects.
In 2014, the Vi Riddell Children's Pain and Rehabilitation Program at the Alberta Children's Hospital (ACH) established the first pediatric Intensive Pain Rehabilitation Program (IPRP) in Canada to target youth with severe chronic pain and consequent functional disability who do not respond to standard outpatient pain therapies. The IPRP at the ACH involves three- to sex-weeks of day-treatment rehabilitation, provided by an interdisciplinary team (e.g. Psychology, Physiotherapy, Family Therapy). This rehabilitative program teaches self-management strategies with the goal of helping youth and their families resume normal daily functioning. Similar to other intensive rehabilitation programs, at discharge from IPRP, youth reported less anxiety, less depressive symptoms and better functioning, although, their self-reported pain intensity remained unchanged. It is generally thought that by returning to normal daily activities, youth will learn to function with their pain, and their pain will dissipate over time. However, there is limited evidence to support this. Long-term follow-up of youth in IPRP revealed a reduction of pain interference in daily activities. However, at one-year post-IPRP, youth's self-reported ratings of depression and quality of life did not differ from their ratings prior to completing IPRP. In order to improve long-term recovery and reduce the burden of suffering on the individual, their family and society, evidence-based and targeted interventions are needed to reduce pain and pain-related disability in youth with severe chronic pain.
For a chronic pain treatment to be evidence-based, it needs to draw on the known neurobiological and psychological processes underlying the development and maintenance of severe chronic pain. In August 2016, investigators began scanning a subset of youth in our IPRP at baseline and again at discharge from the program. Preliminary analysis of this neuroimaging data (23 youth with 2 scans each) suggested decreased functional responses to emotional stimuli in the dorsolateral prefrontal cortex (DLPFC) from baseline to discharge of affected youth, commensurate with decreases in internalizing mental health symptoms.
The DLPFC is a large and functionally heterogeneous brain region. It is generally associated with driving appropriate behavioral responses, and top-down modulation. Therefore, with regards to pain it has been shown to be involved in both pain detection and in pain suppression. Given its involvement in pain modulation, it is feasible that the DLPFC could serve as a therapeutic target.
By targeting the DLPFC using repetitive transcranial stimulation (rTMS), the investigators may be able to enhance outcomes associated with IPRP. Work from our institution demonstrated that rTMS of the DLPFC is a safe and effective method for treating youth with treatment resistant major depressive disorder. In addition to treatment resistant major depressive disorder, rTMS of the DLPFC has also been found to be effective in managing chronic pain in adults. rTMS uses a magnetic field to non-invasively stimulate small targeted regions of the brain. The magnetic coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. Magnetic resonance imaging (MRI) can be used to help identify and target specific brain regions, such as the DLPFC, providing an individualized approach to treat the patient's symptoms. To date, rTMS has not been utilized to manage pain and comorbid mental health conditions in youth. Using an open-label clinical trial study design, the investigators will examine whether the addition of rTMS to IPRP reduces pain intensity and enhances brain and behavioral changes associated with standard IPRP care to improve outcomes of youth with severe chronic pain.
Aim 1: Determine whether rTMS in addition to IPRP reduces self-reported pain intensity from baseline to discharge in youth with severe chronic pain. Hypothesis 1: The addition of rTMS to IPRP will result in decreases in self-reported pain intensity from baseline to discharge in youth with severe chronic pain.
Aim 2: Examine whether youth that undergo rTMS in addition to IPRP versus IPRP alone have greater improvements in outcomes from baseline to discharge. Hypothesis 2: The addition of rTMS to IPRP will result in greater decreases in DLPFC responsivity to emotional stimuli and greater decreases in self-reported pain intensity, functional disability, anxiety, depressive and post traumatic stress disorder (PTSD) symptoms between baseline and discharge as compared to youth that underwent the standard IPRP.
Aim 3: Examine whether changes following IPRP persist beyond discharge in youth that underwent rTMS in addition to IPRP versus IPRP alone. Hypothesis 3: Parent and self-reported.
Methods: Between November 2020-2023, 25 youth aged 10-18 years with severe chronic pain will be invited to partake in IPRP. In addition to the standard three-week IPRP, youth will receive an rTMS intervention utilizing a robot-controlled, Magstim SuperRapid2, air-cooled 90mm figure-of-8-coil (Magstim, Wales UK). Following standardized protocols for youth with treatment resistant major depressive disorder, rTMS will be applied to the individual's DLPFC as defined by functional imaging for 37.5 minutes per weekday, at the same time of day, for a period of three weeks (15 days total). Participants will be monitored for adverse events and tolerability using a Pediatric TMS Safety and Tolerability Measure (20) on days 1, 6, and 11. Youth will undergo a 3T MRI at baseline and discharge from IPRP. Both structural and functional images will be acquired. At baseline and discharge, youth will also complete a battery of reliable and validated questionnaires assessing pain, functional disability, anxiety, depressive and PTSD symptoms.
rTMS: Motor evoked potentials will be recorded to determine the resting motor threshold. Initially, to locate the DLPFC target site, the five centimetre rule will be applied in which the scalp position five centimetres anterior to the hotspot along a line to the nation will be marked. Using a neuronavigation system (Brainsight2, Rogue Research, Montreal), the TMS coil will be monitored in real time and co-registered with the individual's functional MRI. Neuronavigation will be used to confirm accurate DLPFC targeting. The TMS coil will subsequently be placed tangential to the scalp, and angled at 45 degrees to the midline and fixed over the DLPFC using a mechanical arm.
rTMS will be applied at 10 Hz. Each train will consist of 40 threshold (100% resting motor threshold) pulses over 4 seconds with an inter-train interval of 26 seconds. Treatment sessions will last 37.5 minutes (75 trains/3,000 pulses), and occur at the same time of day on every weekday for a period of three weeks (15 days total). During TMS, only passive activities will be allowed (i.e., watching movies or TV, listening to music). Three weeks of treatment was selected based on existing rTMS evidence in youth with treatment resistant major depressive disorder.
Neuroimaging: Cortical volumes will be acquired from a T1-weighted anatomical scan. FreeSurfer will be used for processing, editing, and segmenting structural brain images. The automated recon-all pipeline will be used to perform brain extraction, image registration, motion and intensity correction, and segmentation/parcellation. Each image will be manually checked, and cortical volumes will be extracted.
Functional magnetic resonance imagine (fMRI) will be used to detect blood oxygen level-dependent (BOLD) signal changes during the presentation of validated pictures of facial affect that were used in the previous IPRP neuroimaging study. This paradigm consists of 36, standardized photos from female and male individuals depicting neutral, happy and fearful facial expressions. These photos will be randomized into 4 blocks presented 4 times, and each face will be presented for 200-ms with a 300-ms interstimulus. The investigators will apply standard preprocessing (slice-time correction, B0-unwarping, motion correction, bandpass temporal filtering, template registration and smoothing) in SPM. Motion will be censored using the ART toolbox. Second-level analyses will be used to compare differences in contrasts over time and between groups. All statistical tests will be corrected for multiple comparisons (cluster-corrected false discovery rate q<0.05, with cluster-forming height threshold of p<0.001).
Finally, a resting-state fMRI scan will be acquired and undergo standard preprocessing in SPM. Motion will be censored using the ART toolbox. Cortical masks derived from FreeSurfer will be used as seed regions for fMRI functional connectivity analysis. Time courses for the DLPFC will be extracted and used as a regressor to identify correlations with all other brain regions. Second-level analyses will be used to test differences in functional connectivity over time and between groups. All statistical tests will be corrected for multiple comparisons.
- Conditions
- Chronic Pain
- Being tested
- Repeated Transcranial Magnetic Stimulation (rTMS), Intensive Pain Rehabilitation Program (IPRP)
- Medical subject headings
- Chronic Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Repeated Transcranial Magnetic Stimulation (rTMS)Device
rTMS will be applied at 10 Hz. Each train will consist of 40 supra threshold (120% resting motor threshold) pulses over 4 seconds with an inter-train interval of 26 seconds. Treatment sessions will last 37.5 minutes (75 trains/3,000 pulses), and occur at the same time of day on every weekday for a period of three weeks (15 days total). During TMS, only passive activities will be allowed (i.e., watching movies or TV, listening to music). Three weeks of treatment was selected based on existing rTMS evidence in youth with treatment resistant major depressive disorder.
Intensive Pain Rehabilitation Program (IPRP)Other
The paediatric Intensive Pain Rehabilitation Program (IPRP) in Canada was established to target youth with severe chronic pain and consequent functional disability who do not respond to standard outpatient pain therapies. The IPRP at the Alberta Children's Hospital (ACH) involves three- to six-weeks of day-treatment rehabilitation, provided by an interdisciplinary team (e.g. Psychology, Physiotherapy, Family Therapy). This rehabilitative program teaches self-management strategies with the goal of helping youth and their families resume normal daily functioning.
| Study group | Role | What they receive |
|---|---|---|
| rTMS + IPRP | Experimental | 25 youth aged 10-18 years with severe chronic pain will be invited to partake in the Intensive Pain Rehabilitation Program, where they will receive Repeated Transcranial Magnetic Stimulation as one of their treatment interventions. Receives: Device: Repeated Transcranial Magnetic Stimulation (rTMS); Other: Intensive Pain Rehabilitation Program (IPRP) |
| IPRP | Active comparator | Youth within this arm will not be receiving the rTMS intervention. Rather, they will only be enrolled within the IPRP. Receives: Other: Intensive Pain Rehabilitation Program (IPRP) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pain Presence
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Measured: This outcome will be measured at baseline.
Pain Frequency
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Measured: This outcome will be measured at baseline.
Pain Duration
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Measured: This outcome will be measured at baseline.
Pain Intensity
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Measured: This outcome will be measured at baseline.
Pain Interference
Youth will complete the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Profile-25. The Pain Interference subscale uses 4 items to assess whether pain has interfered with youth's everyday activities in the past 7 days using a 5-point Likert scale (anchors: 0 = "never" and 4 = "almost always"). The PROMIS measures demonstrated good construct validity (intercept and slope equal or greater to 0.98) and internal consistency (pain interference, 4 items alpha = 0.85).
Measured: This outcome will be measured at baseline.
Brain imaging
Structural and functional imaging will be acquired using resting-state functional magnetic resonance imaging (fMRI) scan. Motion will be censored using the Artifact Detection Tools (ART). Cortical masks derived from FreeSurfer will be used as seed regions for fMRI functional connectivity analysis. Time courses for the dorsolateral prefrontal cortex (DLPFC) will be extracted and used as a regressor to identify correlations with all other brain regions. Second-level analyses will be used to test differences in functional connectivity over time and between groups. All statistical tests will be corrected for multiple comparisons.
Measured: This outcome will be measured at baseline (upon admittance into the program).
Functional disability
The Functional Disability Inventory (FDI) will be administered to assess functional disability. Youth will rate their level of difficulty in completing daily activities in a variety of settings (e.g. home, school) on a 5-point Likert scale ranging from 0 "no trouble" to 4 "impossible." Higher scores are indicative of greater pain-related disability. The FDI has high internal consistency at baseline (alpha = .90) and post-treatment (alpha = .87).
Measured: This outcome will be measured at baseline.
Anxiety and Depressive Symptoms
Anxiety and depressive symptoms will be assessed using the PROMIS Pediatric Profile-25 Anxiety and Depression subscales. Participants will report if they experienced any of the symptoms in the past 7 days using a 5-point Likert scale (anchors: 0 = "never" and 4 = "almost always"). The subscales have demonstrated good construct validity (intercept and slope equal to or greater than 0.93) and excellent internal consistency (depressive symptoms, 4 items, alpha = 0.91; anxiety symptoms, 4 items, alpha = 0.90).
Measured: This outcome will be measured at baseline.
Posttraumatic Stress Disorder (PTSD) Symptoms
Youth PTSD symptomology will be assessed using the Child PTSD Symptom Scale (CPSS-V). The CPSS-V is a 20-item measure that maps on to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition PTSD criteria, and assessed PTSD symptoms experienced by youth in the past month. Youth will be asked to identify something scary or upsetting that bothers them to think about. With that event in mind, they will be asked to respond to 20 items assessing PTSD symptoms on a 5-point Likert scale, ranging from "not at all" to "6 or more times a week/almost always." Total symptom severity scores are obtained by summing the 20 items (range: 0-80). A score of 31 or above indicates clinically elevated PTSD symptoms. The CPSS-V has excellent internal consistency, good test-retest reliability, and good convergent validity.
Measured: This outcome will be measured at baseline.
Pediatric Transcranial Magnetic Stimulation (TMS) Safety and Tolerability
Possible adverse events (headache, presyncope, nausea, etc.) will be screened and quantified as either mild, moderate, or severe. Any other potential side effects will be recorded and quantified.
Measured: This outcome will be measured at Day 1.
Pain Presence
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Measured: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Pain Frequency
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Measured: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Pain Duration
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Measured: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Pain Intensity
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Measured: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Pain Interference
Youth will complete the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Profile-25. The Pain Interference subscale uses 4 items to assess whether pain has interfered with youth's everyday activities in the past 7 days using a 5-point Likert scale (anchors: 0 = "never" and 4 = "almost always"). The PROMIS measures demonstrated good construct validity (intercept and slope equal or greater to 0.98) and internal consistency (pain interference, 4 items alpha = 0.85).
Measured: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Brain imaging
Structural and functional imaging will be acquired using resting-state functional magnetic resonance imaging (fMRI) scan. Motion will be censored using the Artifact Detection Tools (ART). Cortical masks derived from FreeSurfer will be used as seed regions for fMRI functional connectivity analysis. Time courses for the dorsolateral prefrontal cortex (DLPFC) will be extracted and used as a regressor to identify correlations with all other brain regions. Second-level analyses will be used to test differences in functional connectivity over time and between groups. All statistical tests will be corrected for multiple comparisons.
Measured: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Functional disability
The Functional Disability Inventory (FDI) will be administered to assess functional disability. Youth will rate their level of difficulty in completing daily activities in a variety of settings (e.g. home, school) on a 5-point Likert scale ranging from 0 "no trouble" to 4 "impossible." Higher scores are indicative of greater pain-related disability. The FDI has high internal consistency at baseline (alpha = .90) and post-treatment (alpha = .87).
Measured: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Anxiety and Depressive Symptoms
Anxiety and depressive symptoms will be assessed using the PROMIS Pediatric Profile-25 Anxiety and Depression subscales. Participants will report if they experienced any of the symptoms in the past 7 days using a 5-point Likert scale (anchors: 0 = "never" and 4 = "almost always"). The subscales have demonstrated good construct validity (intercept and slope equal to or greater than 0.93) and excellent internal consistency (depressive symptoms, 4 items, alpha = 0.91; anxiety symptoms, 4 items, alpha = 0.90).
Measured: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Posttraumatic Stress Disorder (PTSD) Symptoms
Youth PTSD symptomology will be assessed using the Child PTSD Symptom Scale (CPSS-V). The CPSS-V is a 20-item measure that maps on to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition PTSD criteria, and assessed PTSD symptoms experienced by youth in the past month. Youth will be asked to identify something scary or upsetting that bothers them to think about. With that event in mind, they will be asked to respond to 20 items assessing PTSD symptoms on a 5-point Likert scale, ranging from "not at all" to "6 or more times a week/almost always." Total symptom severity scores are obtained by summing the 20 items (range: 0-80). A score of 31 or above indicates clinically elevated PTSD symptoms. The CPSS-V has excellent internal consistency, good test-retest reliability, and good convergent validity.
Measured: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Pediatric Transcranial Magnetic Stimulation (TMS) Safety and Tolerability
Possible adverse events (headache, presyncope, nausea, etc.) will be screened and quantified as either mild, moderate, or severe. Any other potential side effects will be recorded and quantified.
Measured: This outcome will be measured at Day 6.
Pediatric Transcranial Magnetic Stimulation (TMS) Safety and Tolerability
Possible adverse events (headache, presyncope, nausea, etc.) will be screened and quantified as either mild, moderate, or severe. Any other potential side effects will be recorded and quantified.
Measured: This outcome will be measured at Day 11.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Sep 2020
- Study start19 Oct 2020
- Primary completion30 Apr 2028 (estimated)
- Study completion30 Apr 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (20)Papers the sponsor has linked to this study.
- Other trials for Chronic PainStudies of the same condition, open and under way.
- More trials run by University of CalgaryThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 25 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Calgary
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Jillian Vinall Miller, University of Calgary
- Investigators
- Jillian V Miller, PhD, Principal investigator, University of Calgary
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04561401
- Sponsor's protocol ID
- REB20-1464
- Status last verified
- Apr 2026
- First submitted
- 11 Sep 2020
- Last updated
- 1 May 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
- Individual data sharing
- No
Publications
Kashikar-Zuck S, Flowers SR, Claar RL, Guite JW, Logan DE, Lynch-Jordan AM, Palermo TM, Wilson AC. Clinical utility and validity of the Functional Disability Inventory among a multicenter sample of youth with chronic pain. Pain. 2011 Jul;152(7):1600-1607. doi: 10.1016/j.pain.2011.02.050. Epub 2011 Mar 31.
PubMed 21458162Noel M, Vinall J, Tomfohr-Madsen L, Holley AL, Wilson AC, Palermo TM. Sleep Mediates the Association Between PTSD Symptoms and Chronic Pain in Youth. J Pain. 2018 Jan;19(1):67-75. doi: 10.1016/j.jpain.2017.09.002. Epub 2017 Sep 27.
PubMed 28962895Vinall J, Pavlova M, Asmundson GJ, Rasic N, Noel M. Mental Health Comorbidities in Pediatric Chronic Pain: A Narrative Review of Epidemiology, Models, Neurobiological Mechanisms and Treatment. Children (Basel). 2016 Dec 2;3(4):40. doi: 10.3390/children3040040.
PubMed 27918444Perquin CW, Hazebroek-Kampschreur AAJM, Hunfeld JAM, Bohnen AM, van Suijlekom-Smit LWA, Passchier J, van der Wouden JC. Pain in children and adolescents: a common experience. Pain. 2000 Jul;87(1):51-58. doi: 10.1016/S0304-3959(00)00269-4.
PubMed 10863045Fearon P, Hotopf M. Relation between headache in childhood and physical and psychiatric symptoms in adulthood: national birth cohort study. BMJ. 2001 May 12;322(7295):1145. doi: 10.1136/bmj.322.7295.1145.
PubMed 11348907Shelby GD, Shirkey KC, Sherman AL, Beck JE, Haman K, Shears AR, Horst SN, Smith CA, Garber J, Walker LS. Functional abdominal pain in childhood and long-term vulnerability to anxiety disorders. Pediatrics. 2013 Sep;132(3):475-82. doi: 10.1542/peds.2012-2191. Epub 2013 Aug 12.
PubMed 23940244Hogan ME, Taddio A, Katz J, Shah V, Krahn M. Incremental health care costs for chronic pain in Ontario, Canada: a population-based matched cohort study of adolescents and adults using administrative data. Pain. 2016 Aug;157(8):1626-33. doi: 10.1097/j.pain.0000000000000561.
PubMed 26989805Eccleston C, Palermo TM, Williams AC, Lewandowski Holley A, Morley S, Fisher E, Law E. Psychological therapies for the management of chronic and recurrent pain in children and adolescents. Cochrane Database Syst Rev. 2014 May 5;2014(5):CD003968. doi: 10.1002/14651858.CD003968.pub4.
PubMed 24796681Hechler T, Kanstrup M, Holley AL, Simons LE, Wicksell R, Hirschfeld G, Zernikow B. Systematic Review on Intensive Interdisciplinary Pain Treatment of Children With Chronic Pain. Pediatrics. 2015 Jul;136(1):115-27. doi: 10.1542/peds.2014-3319. Epub 2015 Jun 22.
PubMed 26101358Hurtubise K, Blais S, Noel M, Brousselle A, Dallaire F, Rasic N, Camden C. Is It Worth It? A Comparison of an Intensive Interdisciplinary Pain Treatment and a Multimodal Treatment for Youths With Pain-related Disability. Clin J Pain. 2020 Nov;36(11):833-844. doi: 10.1097/AJP.0000000000000869.
PubMed 32769416Simons LE, Pielech M, Erpelding N, Linnman C, Moulton E, Sava S, Lebel A, Serrano P, Sethna N, Berde C, Becerra L, Borsook D. The responsive amygdala: treatment-induced alterations in functional connectivity in pediatric complex regional pain syndrome. Pain. 2014 Sep;155(9):1727-1742. doi: 10.1016/j.pain.2014.05.023. Epub 2014 May 23.
PubMed 24861582Glasser MF, Coalson TS, Robinson EC, Hacker CD, Harwell J, Yacoub E, Ugurbil K, Andersson J, Beckmann CF, Jenkinson M, Smith SM, Van Essen DC. A multi-modal parcellation of human cerebral cortex. Nature. 2016 Aug 11;536(7615):171-178. doi: 10.1038/nature18933. Epub 2016 Jul 20.
PubMed 27437579O'Reilly RC. The What and How of prefrontal cortical organization. Trends Neurosci. 2010 Aug;33(8):355-61. doi: 10.1016/j.tins.2010.05.002. Epub 2010 Jun 22.
PubMed 20573407Sallet J, Mars RB, Noonan MP, Neubert FX, Jbabdi S, O'Reilly JX, Filippini N, Thomas AG, Rushworth MF. The organization of dorsal frontal cortex in humans and macaques. J Neurosci. 2013 Jul 24;33(30):12255-74. doi: 10.1523/JNEUROSCI.5108-12.2013.
PubMed 23884933Bornhovd K, Quante M, Glauche V, Bromm B, Weiller C, Buchel C. Painful stimuli evoke different stimulus-response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single-trial fMRI study. Brain. 2002 Jun;125(Pt 6):1326-36. doi: 10.1093/brain/awf137.
PubMed 12023321
Study at a glance
From the registry record, last updated by the sponsor on 1 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Can Brain Stimulation Enhance Outcomes Associated With Intensive Rehabilitation for Youth With Chronic Pain?
- ClinicalTrials.gov ID
- NCT04561401
- Acronym / sponsor ID
- REB20-1464
- Conditions
- Chronic Pain
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 25 participants (estimated)
- Lead sponsor
- University of CalgaryUniversity, hospital or other
- Study start
- 19 Oct 2020 (actual)
- Primary completion
- 30 Apr 2028 (estimated)
- Study completion
- 30 Apr 2028 (estimated)
- First posted
- 23 Sep 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Severe chronic pain is defined as pain persisting for three months or more that significantly impacts daily functioning. It is highly prevalent, occurring in 100,000 to 160,000 youth. If left unmanaged it can lead to persistent pain and mental health problems in adulthood, posing enormous costs to society ($7.2 billion CAD/year). In 2014, health professionals at the Alberta Children's Hospital (ACH) established a pediatric Intensive Pain Rehabilitation Program (IPRP) to target youth with severe chronic pain and consequent functional disability who do not respond to outpatient pain therapies. The IPRP at the ACH is a three-week intensive day-treatment intervention provided by an interdisciplinary team, which helps youth resume engagement in normal daily functioning. Following IPRP, youth reported less anxiety, less depressive symptoms, and greater function, although their self-reported pain remained unchanged. In August 2016, the investigators began to explore brain areas related to severe chronic pain in youth. The investigators scanned a subset of youth at the start (baseline) and end (discharge) of IPRP (23 youth with 2 brain scans). From baseline to discharge, the investigators saw decreases in activity in the dorsolateral prefrontal cortex (DLPFC). Decrease in DLPFC activity was related to better mental health outcomes. The DLPFC is a well-known target for non-invasive brain stimulation. Repeated brain stimulation has been used to treat adults, but not youth with chronic pain. For the first time, the investigators will use image-guided brain stimulation (37 minutes/day, 5 days/week) to enhance the brain changes observed with IPRP. The investigators will examine whether three weeks of brain stimulation helps to reduce pain symptoms in youth. The investigators will also compare pain, brain, and mental health outcomes to our historical program data. By adding brain stimulation to our pain intervention, the investigators have the chance to target an area of the brain investigators know to be altered by chronic pain to improve outcomes.
Detailed description
Severe chronic pain in youth is debilitating, common, and has limited treatment options, rendering it as a major public health problem. Severe chronic pain is defined as pain persisting for three months or more that significantly impacts daily functioning (e.g. sleep, mental health, school, work, activity). It is highly prevalent, occurring in 100,000 to 160,000 youth in Canada - comparable to the rates of autism spectrum disorder. If left unmanaged, it can lead to persistent pain and mental health problems in adulthood, posing enormous costs to society ($7.2 billion CAD/year). Most treatments to address chronic pain take a "one-size-fits-all-approach," which does not account for comorbid mental health conditions, contributing to small treatment effects.
In 2014, the Vi Riddell Children's Pain and Rehabilitation Program at the Alberta Children's Hospital (ACH) established the first pediatric Intensive Pain Rehabilitation Program (IPRP) in Canada to target youth with severe chronic pain and consequent functional disability who do not respond to standard outpatient pain therapies. The IPRP at the ACH involves three- to sex-weeks of day-treatment rehabilitation, provided by an interdisciplinary team (e.g. Psychology, Physiotherapy, Family Therapy). This rehabilitative program teaches self-management strategies with the goal of helping youth and their families resume normal daily functioning. Similar to other intensive rehabilitation programs, at discharge from IPRP, youth reported less anxiety, less depressive symptoms and better functioning, although, their self-reported pain intensity remained unchanged. It is generally thought that by returning to normal daily activities, youth will learn to function with their pain, and their pain will dissipate over time. However, there is limited evidence to support this. Long-term follow-up of youth in IPRP revealed a reduction of pain interference in daily activities. However, at one-year post-IPRP, youth's self-reported ratings of depression and quality of life did not differ from their ratings prior to completing IPRP. In order to improve long-term recovery and reduce the burden of suffering on the individual, their family and society, evidence-based and targeted interventions are needed to reduce pain and pain-related disability in youth with severe chronic pain.
For a chronic pain treatment to be evidence-based, it needs to draw on the known neurobiological and psychological processes underlying the development and maintenance of severe chronic pain. In August 2016, investigators began scanning a subset of youth in our IPRP at baseline and again at discharge from the program. Preliminary analysis of this neuroimaging data (23 youth with 2 scans each) suggested decreased functional responses to emotional stimuli in the dorsolateral prefrontal cortex (DLPFC) from baseline to discharge of affected youth, commensurate with decreases in internalizing mental health symptoms.
The DLPFC is a large and functionally heterogeneous brain region. It is generally associated with driving appropriate behavioral responses, and top-down modulation. Therefore, with regards to pain it has been shown to be involved in both pain detection and in pain suppression. Given its involvement in pain modulation, it is feasible that the DLPFC could serve as a therapeutic target.
By targeting the DLPFC using repetitive transcranial stimulation (rTMS), the investigators may be able to enhance outcomes associated with IPRP. Work from our institution demonstrated that rTMS of the DLPFC is a safe and effective method for treating youth with treatment resistant major depressive disorder. In addition to treatment resistant major depressive disorder, rTMS of the DLPFC has also been found to be effective in managing chronic pain in adults. rTMS uses a magnetic field to non-invasively stimulate small targeted regions of the brain. The magnetic coil produces small electric currents in the region of the brain just under the coil via electromagnetic induction. Magnetic resonance imaging (MRI) can be used to help identify and target specific brain regions, such as the DLPFC, providing an individualized approach to treat the patient's symptoms. To date, rTMS has not been utilized to manage pain and comorbid mental health conditions in youth. Using an open-label clinical trial study design, the investigators will examine whether the addition of rTMS to IPRP reduces pain intensity and enhances brain and behavioral changes associated with standard IPRP care to improve outcomes of youth with severe chronic pain.
Aim 1: Determine whether rTMS in addition to IPRP reduces self-reported pain intensity from baseline to discharge in youth with severe chronic pain. Hypothesis 1: The addition of rTMS to IPRP will result in decreases in self-reported pain intensity from baseline to discharge in youth with severe chronic pain.
Aim 2: Examine whether youth that undergo rTMS in addition to IPRP versus IPRP alone have greater improvements in outcomes from baseline to discharge. Hypothesis 2: The addition of rTMS to IPRP will result in greater decreases in DLPFC responsivity to emotional stimuli and greater decreases in self-reported pain intensity, functional disability, anxiety, depressive and post traumatic stress disorder (PTSD) symptoms between baseline and discharge as compared to youth that underwent the standard IPRP.
Aim 3: Examine whether changes following IPRP persist beyond discharge in youth that underwent rTMS in addition to IPRP versus IPRP alone. Hypothesis 3: Parent and self-reported.
Methods: Between November 2020-2023, 25 youth aged 10-18 years with severe chronic pain will be invited to partake in IPRP. In addition to the standard three-week IPRP, youth will receive an rTMS intervention utilizing a robot-controlled, Magstim SuperRapid2, air-cooled 90mm figure-of-8-coil (Magstim, Wales UK). Following standardized protocols for youth with treatment resistant major depressive disorder, rTMS will be applied to the individual's DLPFC as defined by functional imaging for 37.5 minutes per weekday, at the same time of day, for a period of three weeks (15 days total). Participants will be monitored for adverse events and tolerability using a Pediatric TMS Safety and Tolerability Measure (20) on days 1, 6, and 11. Youth will undergo a 3T MRI at baseline and discharge from IPRP. Both structural and functional images will be acquired. At baseline and discharge, youth will also complete a battery of reliable and validated questionnaires assessing pain, functional disability, anxiety, depressive and PTSD symptoms.
rTMS: Motor evoked potentials will be recorded to determine the resting motor threshold. Initially, to locate the DLPFC target site, the five centimetre rule will be applied in which the scalp position five centimetres anterior to the hotspot along a line to the nation will be marked. Using a neuronavigation system (Brainsight2, Rogue Research, Montreal), the TMS coil will be monitored in real time and co-registered with the individual's functional MRI. Neuronavigation will be used to confirm accurate DLPFC targeting. The TMS coil will subsequently be placed tangential to the scalp, and angled at 45 degrees to the midline and fixed over the DLPFC using a mechanical arm.
rTMS will be applied at 10 Hz. Each train will consist of 40 threshold (100% resting motor threshold) pulses over 4 seconds with an inter-train interval of 26 seconds. Treatment sessions will last 37.5 minutes (75 trains/3,000 pulses), and occur at the same time of day on every weekday for a period of three weeks (15 days total). During TMS, only passive activities will be allowed (i.e., watching movies or TV, listening to music). Three weeks of treatment was selected based on existing rTMS evidence in youth with treatment resistant major depressive disorder.
Neuroimaging: Cortical volumes will be acquired from a T1-weighted anatomical scan. FreeSurfer will be used for processing, editing, and segmenting structural brain images. The automated recon-all pipeline will be used to perform brain extraction, image registration, motion and intensity correction, and segmentation/parcellation. Each image will be manually checked, and cortical volumes will be extracted.
Functional magnetic resonance imagine (fMRI) will be used to detect blood oxygen level-dependent (BOLD) signal changes during the presentation of validated pictures of facial affect that were used in the previous IPRP neuroimaging study. This paradigm consists of 36, standardized photos from female and male individuals depicting neutral, happy and fearful facial expressions. These photos will be randomized into 4 blocks presented 4 times, and each face will be presented for 200-ms with a 300-ms interstimulus. The investigators will apply standard preprocessing (slice-time correction, B0-unwarping, motion correction, bandpass temporal filtering, template registration and smoothing) in SPM. Motion will be censored using the ART toolbox. Second-level analyses will be used to compare differences in contrasts over time and between groups. All statistical tests will be corrected for multiple comparisons (cluster-corrected false discovery rate q<0.05, with cluster-forming height threshold of p<0.001).
Finally, a resting-state fMRI scan will be acquired and undergo standard preprocessing in SPM. Motion will be censored using the ART toolbox. Cortical masks derived from FreeSurfer will be used as seed regions for fMRI functional connectivity analysis. Time courses for the DLPFC will be extracted and used as a regressor to identify correlations with all other brain regions. Second-level analyses will be used to test differences in functional connectivity over time and between groups. All statistical tests will be corrected for multiple comparisons.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| rTMS + IPRP | Experimental | Device: Repeated Transcranial Magnetic Stimulation (rTMS), Other: Intensive Pain Rehabilitation Program (IPRP)25 youth aged 10-18 years with severe chronic pain will be invited to partake in the Intensive Pain Rehabilitation Program, where they will receive Repeated Transcranial Magnetic Stimulation as one of their treatment interventions. |
| IPRP | Active comparator | Other: Intensive Pain Rehabilitation Program (IPRP)Youth within this arm will not be receiving the rTMS intervention. Rather, they will only be enrolled within the IPRP. |
Who may qualify
- Ages
- 10 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (5 listed)
- Between the ages of 10-18 years
- Patient has had the appropriate medical work-up
- Participation in accessible, evidenced based pain therapies has not demonstrated return to functional goals
- Pain is significantly impacting the patient's life and they are not meeting their functional goals in areas of life, which may include: physical function, sleep, self-care, school attendance/academic performance, social function, recreational engagement, and mood
- Patient and family agree and understand that an active, self-management approach to functional restoration is the mainstay of treatment in the IPRP
Key exclusion criteria (4 listed)
- Significant developmental delay or brain injury
- Functional neurological disorder/conversion disorder
- Youth who require opioid weaning
- Extensive medical needs and/or untreated psychiatric illness that would impede a rehabilitative approach to care.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Repeated Transcranial Magnetic Stimulation (rTMS)rTMS will be applied at 10 Hz. Each train will consist of 40 supra threshold (120% resting motor threshold) pulses over 4 seconds with an inter-train interval of 26 seconds. Treatment sessions will last 37.5 minutes (75 trains/3,000 pulses), and occur at the same time of day on every weekday for a period of three weeks (15 days total). During TMS, only passive activities will be allowed (i.e., watching movies or TV, listening to music). Three weeks of treatment was selected based on existing rTMS evidence in youth with treatment resistant major depressive disorder. | Device | rTMS + IPRP |
| Intensive Pain Rehabilitation Program (IPRP)The paediatric Intensive Pain Rehabilitation Program (IPRP) in Canada was established to target youth with severe chronic pain and consequent functional disability who do not respond to standard outpatient pain therapies. The IPRP at the Alberta Children's Hospital (ACH) involves three- to six-weeks of day-treatment rehabilitation, provided by an interdisciplinary team (e.g. Psychology, Physiotherapy, Family Therapy). This rehabilitative program teaches self-management strategies with the goal of helping youth and their families resume normal daily functioning. | Other | IPRP, rTMS + IPRP |
Primary outcome
Pain Presence
Time frame: This outcome will be measured at baseline.
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Pain Frequency
Time frame: This outcome will be measured at baseline.
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Pain Duration
Time frame: This outcome will be measured at baseline.
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Pain Intensity
Time frame: This outcome will be measured at baseline.
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Pain Interference
Time frame: This outcome will be measured at baseline.
Youth will complete the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Profile-25. The Pain Interference subscale uses 4 items to assess whether pain has interfered with youth's everyday activities in the past 7 days using a 5-point Likert scale (anchors: 0 = "never" and 4 = "almost always"). The PROMIS measures demonstrated good construct validity (intercept and slope equal or greater to 0.98) and internal consistency (pain interference, 4 items alpha = 0.85).
Brain imaging
Time frame: This outcome will be measured at baseline (upon admittance into the program).
Structural and functional imaging will be acquired using resting-state functional magnetic resonance imaging (fMRI) scan. Motion will be censored using the Artifact Detection Tools (ART). Cortical masks derived from FreeSurfer will be used as seed regions for fMRI functional connectivity analysis. Time courses for the dorsolateral prefrontal cortex (DLPFC) will be extracted and used as a regressor to identify correlations with all other brain regions. Second-level analyses will be used to test differences in functional connectivity over time and between groups. All statistical tests will be corrected for multiple comparisons.
Functional disability
Time frame: This outcome will be measured at baseline.
The Functional Disability Inventory (FDI) will be administered to assess functional disability. Youth will rate their level of difficulty in completing daily activities in a variety of settings (e.g. home, school) on a 5-point Likert scale ranging from 0 "no trouble" to 4 "impossible." Higher scores are indicative of greater pain-related disability. The FDI has high internal consistency at baseline (alpha = .90) and post-treatment (alpha = .87).
Anxiety and Depressive Symptoms
Time frame: This outcome will be measured at baseline.
Anxiety and depressive symptoms will be assessed using the PROMIS Pediatric Profile-25 Anxiety and Depression subscales. Participants will report if they experienced any of the symptoms in the past 7 days using a 5-point Likert scale (anchors: 0 = "never" and 4 = "almost always"). The subscales have demonstrated good construct validity (intercept and slope equal to or greater than 0.93) and excellent internal consistency (depressive symptoms, 4 items, alpha = 0.91; anxiety symptoms, 4 items, alpha = 0.90).
Posttraumatic Stress Disorder (PTSD) Symptoms
Time frame: This outcome will be measured at baseline.
Youth PTSD symptomology will be assessed using the Child PTSD Symptom Scale (CPSS-V). The CPSS-V is a 20-item measure that maps on to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition PTSD criteria, and assessed PTSD symptoms experienced by youth in the past month. Youth will be asked to identify something scary or upsetting that bothers them to think about. With that event in mind, they will be asked to respond to 20 items assessing PTSD symptoms on a 5-point Likert scale, ranging from "not at all" to "6 or more times a week/almost always." Total symptom severity scores are obtained by summing the 20 items (range: 0-80). A score of 31 or above indicates clinically elevated PTSD symptoms. The CPSS-V has excellent internal consistency, good test-retest reliability, and good convergent validity.
Pediatric Transcranial Magnetic Stimulation (TMS) Safety and Tolerability
Time frame: This outcome will be measured at Day 1.
Possible adverse events (headache, presyncope, nausea, etc.) will be screened and quantified as either mild, moderate, or severe. Any other potential side effects will be recorded and quantified.
Pain Presence
Time frame: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Pain Frequency
Time frame: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Pain Duration
Time frame: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Pain Intensity
Time frame: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
The commonly used Pain Questionnaire will be administered to measure the presence and characteristics of pain. Youth will rate the average frequency ("not at all" to "daily"), duration ("less than 1 hour" to "all day"), and intensity ("no pain" to "worst pain possible") of their pain.
Pain Interference
Time frame: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Youth will complete the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Profile-25. The Pain Interference subscale uses 4 items to assess whether pain has interfered with youth's everyday activities in the past 7 days using a 5-point Likert scale (anchors: 0 = "never" and 4 = "almost always"). The PROMIS measures demonstrated good construct validity (intercept and slope equal or greater to 0.98) and internal consistency (pain interference, 4 items alpha = 0.85).
Brain imaging
Time frame: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Structural and functional imaging will be acquired using resting-state functional magnetic resonance imaging (fMRI) scan. Motion will be censored using the Artifact Detection Tools (ART). Cortical masks derived from FreeSurfer will be used as seed regions for fMRI functional connectivity analysis. Time courses for the dorsolateral prefrontal cortex (DLPFC) will be extracted and used as a regressor to identify correlations with all other brain regions. Second-level analyses will be used to test differences in functional connectivity over time and between groups. All statistical tests will be corrected for multiple comparisons.
Functional disability
Time frame: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
The Functional Disability Inventory (FDI) will be administered to assess functional disability. Youth will rate their level of difficulty in completing daily activities in a variety of settings (e.g. home, school) on a 5-point Likert scale ranging from 0 "no trouble" to 4 "impossible." Higher scores are indicative of greater pain-related disability. The FDI has high internal consistency at baseline (alpha = .90) and post-treatment (alpha = .87).
Anxiety and Depressive Symptoms
Time frame: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Anxiety and depressive symptoms will be assessed using the PROMIS Pediatric Profile-25 Anxiety and Depression subscales. Participants will report if they experienced any of the symptoms in the past 7 days using a 5-point Likert scale (anchors: 0 = "never" and 4 = "almost always"). The subscales have demonstrated good construct validity (intercept and slope equal to or greater than 0.93) and excellent internal consistency (depressive symptoms, 4 items, alpha = 0.91; anxiety symptoms, 4 items, alpha = 0.90).
Posttraumatic Stress Disorder (PTSD) Symptoms
Time frame: This outcome will be measured at discharge from the program, which is approximately 3 weeks from the time of admittance.
Youth PTSD symptomology will be assessed using the Child PTSD Symptom Scale (CPSS-V). The CPSS-V is a 20-item measure that maps on to the Diagnostic and Statistical Manual of Mental Disorders 5th Edition PTSD criteria, and assessed PTSD symptoms experienced by youth in the past month. Youth will be asked to identify something scary or upsetting that bothers them to think about. With that event in mind, they will be asked to respond to 20 items assessing PTSD symptoms on a 5-point Likert scale, ranging from "not at all" to "6 or more times a week/almost always." Total symptom severity scores are obtained by summing the 20 items (range: 0-80). A score of 31 or above indicates clinically elevated PTSD symptoms. The CPSS-V has excellent internal consistency, good test-retest reliability, and good convergent validity.
Pediatric Transcranial Magnetic Stimulation (TMS) Safety and Tolerability
Time frame: This outcome will be measured at Day 6.
Possible adverse events (headache, presyncope, nausea, etc.) will be screened and quantified as either mild, moderate, or severe. Any other potential side effects will be recorded and quantified.
Pediatric Transcranial Magnetic Stimulation (TMS) Safety and Tolerability
Time frame: This outcome will be measured at Day 11.
Possible adverse events (headache, presyncope, nausea, etc.) will be screened and quantified as either mild, moderate, or severe. Any other potential side effects will be recorded and quantified.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 May 2026.
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- Background: PubMed 27918444Vinall J, Pavlova M, Asmundson GJ, Rasic N, Noel M. Mental Health Comorbidities in Pediatric Chronic Pain: A Narrative Review of Epidemiology, Models, Neurobiological Mechanisms and Treatment. Children (Basel). 2016 Dec 2;3(4):40. doi: 10.3390/children3040040.
- Background: PubMed 10863045Perquin CW, Hazebroek-Kampschreur AAJM, Hunfeld JAM, Bohnen AM, van Suijlekom-Smit LWA, Passchier J, van der Wouden JC. Pain in children and adolescents: a common experience. Pain. 2000 Jul;87(1):51-58. doi: 10.1016/S0304-3959(00)00269-4.
- Background: PubMed 11348907Fearon P, Hotopf M. Relation between headache in childhood and physical and psychiatric symptoms in adulthood: national birth cohort study. BMJ. 2001 May 12;322(7295):1145. doi: 10.1136/bmj.322.7295.1145.
- Background: PubMed 23940244Shelby GD, Shirkey KC, Sherman AL, Beck JE, Haman K, Shears AR, Horst SN, Smith CA, Garber J, Walker LS. Functional abdominal pain in childhood and long-term vulnerability to anxiety disorders. Pediatrics. 2013 Sep;132(3):475-82. doi: 10.1542/peds.2012-2191. Epub 2013 Aug 12.
- Background: PubMed 26989805Hogan ME, Taddio A, Katz J, Shah V, Krahn M. Incremental health care costs for chronic pain in Ontario, Canada: a population-based matched cohort study of adolescents and adults using administrative data. Pain. 2016 Aug;157(8):1626-33. doi: 10.1097/j.pain.0000000000000561.
- Background: PubMed 24796681Eccleston C, Palermo TM, Williams AC, Lewandowski Holley A, Morley S, Fisher E, Law E. Psychological therapies for the management of chronic and recurrent pain in children and adolescents. Cochrane Database Syst Rev. 2014 May 5;2014(5):CD003968. doi: 10.1002/14651858.CD003968.pub4.
- Background: PubMed 26101358Hechler T, Kanstrup M, Holley AL, Simons LE, Wicksell R, Hirschfeld G, Zernikow B. Systematic Review on Intensive Interdisciplinary Pain Treatment of Children With Chronic Pain. Pediatrics. 2015 Jul;136(1):115-27. doi: 10.1542/peds.2014-3319. Epub 2015 Jun 22.
- Background: PubMed 32769416Hurtubise K, Blais S, Noel M, Brousselle A, Dallaire F, Rasic N, Camden C. Is It Worth It? A Comparison of an Intensive Interdisciplinary Pain Treatment and a Multimodal Treatment for Youths With Pain-related Disability. Clin J Pain. 2020 Nov;36(11):833-844. doi: 10.1097/AJP.0000000000000869.
- Background: PubMed 24861582Simons LE, Pielech M, Erpelding N, Linnman C, Moulton E, Sava S, Lebel A, Serrano P, Sethna N, Berde C, Becerra L, Borsook D. The responsive amygdala: treatment-induced alterations in functional connectivity in pediatric complex regional pain syndrome. Pain. 2014 Sep;155(9):1727-1742. doi: 10.1016/j.pain.2014.05.023. Epub 2014 May 23.
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- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jillian V Miller, PhD principal investigator
University of Calgary
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Repeated Transcranial Magnetic Stimulation (rTMS) and Intensive Pain Rehabilitation Program (IPRP) in people with Chronic Pain, run by University of Calgary at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 1 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pain Presence (time frame: This outcome will be measured at baseline.). The study lists 21 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04561401, which also lists 20 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 May 2026; AzTrials last refreshed its copy on 3 Nov 2026.