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Chronic pain is a serious public health problem with estimates as high as nearly half of the adult population experiencing some form of pain that lasts for more than 6 months. Chronic use of opiates is a rapidly escalating crisis in the United States, with over 4.3 million Americans dependent on opiate analgesics, an escalating rate of opiate overdose deaths, and a resurgence of intravenous heroin use leading to total societal cost exceeding $55 billion. While opiates are effective at treating acute pain, tolerance to the analgesic effects develops quickly, leading to high abuse liability and dependence potential. Consequently, the development of a new, non-pharmacologic intervention to treat pain, such as repetitive transcranial magnetic stimulation (rTMS), which would provide analgesic benefit while also directly remodeling the neural circuitry responsible for cognitive control over opiate craving, would fill an increasingly urgent public health need.
Chronic pain is a serious public health problem with estimates as high as nearly half of the adult population experiencing some form of pain that lasts for more than 6 months. Chronic use of opiates is a rapidly escalating crisis in the United States, with over 4.3 million Americans dependent on opiate analgesics, an escalating rate of opiate overdose deaths, and a resurgence of intravenous heroin use leading to total societal cost exceeding $55 billion. While opiates are effective at treating acute pain, tolerance to the analgesic effects develops quickly, leading to high abuse liability and dependence potential. Consequently, the development of a new, non-pharmacologic intervention to treat pain, such as repetitive transcranial magnetic stimulation (rTMS), which would provide analgesic benefit while also directly remodeling the neural circuitry responsible for cognitive control over opiate craving, would fill an increasingly urgent public health need.
Acute pain is associated with elevated magnetic resonance imaging (MRI) blood-oxygen-level-dependent (BOLD) signal in targets of ascending nociceptive fibers including the insula, dorsal anterior cingulate (dACC), thalamus and somatosensory cortex - the 'Pain Network'. Perceived pain, and corresponding BOLD signal in the Pain Network, is attenuated by 10 Hz rTMS (a form of brain stimulation that results in long term potentiation (LTP) to the left dorsolateral prefrontal cortex (dlPFC, a node of the Executive Control Network). Dr. Borckardt was the first person to demonstrate that when LTP-like dlPFC rTMS was delivered in the postoperative recovery room, patients used less morphine in the hospital and require less morphine long-term. These analgesic effects are now widely known, with over 33 clinical trials utilizing rTMS as a tool to decrease acute and chronic pain in various clinical populations.
These data all suggest that LTP-like DLPFC rTMS is a very strong candidate alleviating chronic pain (LTP-like dlPFC rTMS (Strategy 1, Aim 1)). An alternative approach, however, *which may also target opiate craving*, is to attenuate the Pain Network (through long term depression (LTD) of the ventromedial PFC) (LTD-like mPFC rTMS, Strategy 2, Aim 1). In a cohort of 49 individuals with chronic pain, Dr. Hanlon (Primary Investigator) recently demonstrated that LTD-like mPFC rTMS reduced baseline BOLD signal in multiple regions of interest (ROIs) *involved in craving which also overlap with the Pain Network* (e.g. dACC and Insula). To parametrically evaluate these 2 promising treatment strategies, the investigator has developed a 1-visit cross-sectional design wherein a cohort of healthy control individuals will receive Quantitative Sensory Testing before and after rTMS with the H1 and H7-coil for dlPFC stimulation (Strategy 1) and mPFC depression (Strategy 2), respectively. The investigator aims to:
Aim 1. Quantify the effects of LTP-like and LTD-like RTMS on Quantitative Sensory Testing Hypothesis: The pressure pain tolerance of individuals in these two groups will increase after one session of rTMS administered by the H1- and H7-coil design.
Aim 2. Evaluate the effects of rTMS on subjective experience of discomfort. Hypothesis: Subjective experience of discomfort will decrease in individuals after one session of LTP-like or LTD-like rTMS administered to the dlPFC and mPFC, respectively.
The relative efficacy of Strategy 1 vs 2 will directly translate to development of a large clinical trial of rTMS as an innovative, new treatment option for pain in opiate dependent individuals.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| First H1 coil, then H7 coil | Experimental | There will be 1 screening and 2 TMS visits. The procedures will be identical for each TMS visit, except for the type of TMS delivered (H1 or H7 coil). Each participant will be assigned to both coils, with TMS type. Participants assigned to this arm will receive the H1 coil at TMS visit 1, H7 coil at TMS visit 2 |
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| First H7 coil, then H1 coil | Experimental | There will be 1 screening and 2 TMS visits. The procedures will be identical for each TMS visit, except for the type of TMS delivered (H1 or H7 coil). Each participant will be assigned to both coils, with TMS type. Participants assigned to this arm will receive the H7 coil at TMS visit 1, H1 coil at TMS visit 2. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Real rTMS to the mPFC using H7 Coil | Device | This will be delivered with the Brainsway H7 coil system; 1200 pulses with the H7 coil helmet. Blinded using active/sham operator cards. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Painfulness Thresholds Using the Quantitative Pain Testing (QST) Task, Which Utilizes Pressure From the Medoc Algomed Device (Measured in kiloPascals). | Based on pilot data, the investigators expect an interaction between treatment (DLPFC or MPFC TMS) and time (Before vs. After rTMS) on reported painfulness using a quantitative sensory testing technique which determines the sensation and pain thresholds of pressure. Painfulness ratings will be assessed and reported before and after rTMS. | rTMS treatment visit, an average of 2 and a half hours |
| Measure | Description | Time Frame |
|---|---|---|
| Changes in Pain Tolerance Thresholds Using the Quantitative Pain Testing (QST) Task, Which Utilizes Pressure From the Medoc Algomed Device (Measured in kiloPascals). | The investigators do not expect an interaction between treatment (DLPFC or MPFC TMS) and time (Before vs. After rTMS) on pain tolerance thresholds using a quantitative sensory testing technique which determines the sensation and pain thresholds of pressure. Pain tolerance ratings will be assessed and reported before and after rTMS. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Colleen Hanlon, PhD | Wake Forest University Health Sciences | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Atrium Health Wake Forest Baptist | Winston-Salem | North Carolina | 27157 | United States |
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There were 8 screen failures. Only 31 randomized.
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| ID | Title | Description |
|---|---|---|
| FG000 | First H1 Coil, Then H7 Coil | There will be 1 screening and 2 TMS visits. The procedures will be identical for each TMS visit, except for the type of TMS delivered (H1 or H7 coil). Each participant will be assigned to both coils, with TMS type. Participants assigned to this arm will receive the H1 coil at TMS visit 1, H7 coil at TMS visit 2 Real rTMS to the mPFC using H7 Coil: This will be delivered with the Brainsway H7 coil system; 1200 pulses with the H7 coil helmet. Blinded using active/sham operator cards. Real rTMS to the dlPFC using H1 Coil: This will be delivered with the Brainsway H1 coil system; 3000 pulses with the H1 coil helmet. Blinded using active/sham operator cards. |
| FG001 | First H7 Coil, Then H1 Coil | There will be 1 screening and 2 TMS visits. The procedures will be identical for each TMS visit, except for the type of TMS delivered (H1 or H7 coil). Each participant will be assigned to both coils, with TMS type. Participants assigned to this arm will receive the H7 coil at TMS visit 1, H1 coil at TMS visit 2. Real rTMS to the mPFC using H7 Coil: This will be delivered with the Brainsway H7 coil system; 1200 pulses with the H7 coil helmet. Blinded using active/sham operator cards. Real rTMS to the dlPFC using H1 Coil: This will be delivered with the Brainsway H1 coil system; 3000 pulses with the H1 coil helmet. Blinded using active/sham operator cards. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
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| First Intervention Period |
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Includes subjects who randomized only.
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| ID | Title | Description |
|---|---|---|
| BG000 | First H1 Coil, Then H7 Coil | There will be 1 screening and 2 TMS visits. The procedures will be identical for each TMS visit, except for the type of TMS delivered (H1 or H7 coil). Each participant will be assigned to both coils, with TMS type. Participants assigned to this arm will receive the H1 coil at TMS visit 1, H7 coil at TMS visit 2 Real rTMS to the mPFC using H7 Coil: This will be delivered with the Brainsway H7 coil system; 1200 pulses with the H7 coil helmet. Blinded using active/sham operator cards. Real rTMS to the dlPFC using H1 Coil: This will be delivered with the Brainsway H1 coil system; 3000 pulses with the H1 coil helmet. Blinded using active/sham operator cards. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Changes in Painfulness Thresholds Using the Quantitative Pain Testing (QST) Task, Which Utilizes Pressure From the Medoc Algomed Device (Measured in kiloPascals). | Based on pilot data, the investigators expect an interaction between treatment (DLPFC or MPFC TMS) and time (Before vs. After rTMS) on reported painfulness using a quantitative sensory testing technique which determines the sensation and pain thresholds of pressure. Painfulness ratings will be assessed and reported before and after rTMS. | Posted | Mean | Standard Deviation | kPascals | rTMS treatment visit, an average of 2 and a half hours |
|
Baseline through end of second visit - time frame varied. Two weeks maximum
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Real rTMS to the mPFC Using H7 Coil | One session of low frequency repetitive transcranial magnetic stimulation (rTMS) will be delivered to the left medial prefrontal cortex (mPFC) using the H7-coil (20 min total, 1200 pulses delivered at 1 Hz continuously, 1 train, 120% resting motor threshold (rMT)). Real rTMS to the mPFC using H7 Coil: This will be delivered with the Brainsway H7 coil system; 1200 pulses with the H7 coil helmet. Blinded using active/sham operator cards. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Colleen Hanlon, PhD | Wake Forest University Health Sciences | 844-386-7001 | DeepTMS@brainsway.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Feb 14, 2022 | Aug 15, 2023 | Prot_SAP_001.pdf |
| ICF | No | No | Yes | Informed Consent Form | Dec 20, 2021 | Mar 17, 2023 | ICF_000.pdf |
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| ID | Term |
|---|---|
| D059350 | Chronic Pain |
| ID | Term |
|---|---|
| D010146 | Pain |
| D009461 | Neurologic Manifestations |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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The proposed study will employ a 1-visit cross sectional, double-blind, placebo-controlled design to parametrically evaluate two promising treatment strategies of rTMS using the H1 and H7-coil for dlPFC stimulation (Strategy 1) or mPFC stimulation (Strategy 2), respectively. Participants will be randomized to receive TMS to the dlPFC or mPFC (50% at each site). This will be done in a cohort of healthy control individuals recruited from the local Wake Forest University (WFU) community. Quantitative Sensory Testing (QST) and subjective pain ratings will be measured before and after the rTMS session.
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| Real rTMS to the dlPFC using H1 Coil | Device | This will be delivered with the Brainsway H1 coil system; 3000 pulses with the H1 coil helmet. Blinded using active/sham operator cards. |
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| rTMS treatment visit, an average of 2 and a half hours |
| NOT COMPLETED |
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| BG001 | First H7 Coil, Then H1 Coil | There will be 1 screening and 2 TMS visits. The procedures will be identical for each TMS visit, except for the type of TMS delivered (H1 or H7 coil). Each participant will be assigned to both coils, with TMS type. Participants assigned to this arm will receive the H7 coil at TMS visit 1, H1 coil at TMS visit 2. Real rTMS to the mPFC using H7 Coil: This will be delivered with the Brainsway H7 coil system; 1200 pulses with the H7 coil helmet. Blinded using active/sham operator cards. Real rTMS to the dlPFC using H1 Coil: This will be delivered with the Brainsway H1 coil system; 3000 pulses with the H1 coil helmet. Blinded using active/sham operator cards. |
| BG002 | Total | Total of all reporting groups |
| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| OG001 | Real rTMS to the dlPFC Using H1 Coil | One session of high frequency repetitive transcranial magnetic stimulation (rTMS) will be delivered to the left dorsolateral prefrontal cortex (dlPFC) using the H1-coil (20 min total, 3000 pulses delivered at 10 Hz, 60 trains, 50 pulses/train, 5 sec on/15 sec off, 120% resting motor threshold (rMT)). Real rTMS to the dlPFC using H1 Coil: This will be delivered with the Brainsway H1 coil system; 3000 pulses with the H1 coil helmet. Blinded using active/sham operator cards. |
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| Secondary | Changes in Pain Tolerance Thresholds Using the Quantitative Pain Testing (QST) Task, Which Utilizes Pressure From the Medoc Algomed Device (Measured in kiloPascals). | The investigators do not expect an interaction between treatment (DLPFC or MPFC TMS) and time (Before vs. After rTMS) on pain tolerance thresholds using a quantitative sensory testing technique which determines the sensation and pain thresholds of pressure. Pain tolerance ratings will be assessed and reported before and after rTMS. | Posted | Mean | Standard Deviation | kPascals | rTMS treatment visit, an average of 2 and a half hours |
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| 0 |
| 29 |
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| 29 |
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| 29 |
| EG001 | Real rTMS to the dlPFC Using H1 Coil | One session of high frequency repetitive transcranial magnetic stimulation (rTMS) will be delivered to the left dorsolateral prefrontal cortex (dlPFC) using the H1-coil (20 min total, 3000 pulses delivered at 10 Hz, 60 trains, 50 pulses/train, 5 sec on/15 sec off, 120% resting motor threshold (rMT)). Real rTMS to the dlPFC using H1 Coil: This will be delivered with the Brainsway H1 coil system; 3000 pulses with the H1 coil helmet. Blinded using active/sham operator cards. | 0 | 29 | 0 | 29 | 0 | 29 |
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