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Transcranial Magnetic Stimulation for Chronic Neuropathic Pain

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05593237
Recruitment Status : Recruiting
First Posted : October 25, 2022
Last Update Posted : May 26, 2023
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
Chronic neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system. It is highly prevalent, debilitating, and challenging to treat. Current available treatments have low efficacy, high side effect burden, and are prone to misuse and dependence. Emerging evidence suggests that the transition from acute to chronic neuropathic pain is associated with reorganization of central brain circuits involved in pain processing. Repetitive transcranial magnetic stimulation (rTMS) is a promising alternative treatment that uses focused magnetic pulses to non-invasively modulate brain activity, a strategy that can potentially circumvent the adverse effects of available treatments for pain. RTMS is FDA-approved for the treatment of major depressive disorder, obsessive-compulsive disorder, and migraine, and has been shown to reduce pain scores when applied to the contralateral motor cortex (M1). However, available studies of rTMS for chronic neuropathic pain typically show variable and often short-lived benefits, and many aspects of optimal treatment remain unknown, including ideal rTMS stimulation parameters, duration of treatment, and relationship to the underlying pain etiology. Here the investigators propose to evaluate the efficacy of high frequency rTMS to M1, the region with most evidence of benefit in chronic neuropathic pain, and to use functional magnetic resonance imaging (fMRI) to identify alternative rTMS targets for participants that do not respond to stimulation at M1. The central aim is to evaluate the pain relieving efficacy of multi-session high-frequency M1 TMS for pain. In secondary exploratory analyses, the investigator propose to investigate patient characteristic that are predictive of responsive to M1 rTMS and identify viable alternative stimulation targets in non-responders to M1 rTMS.

Condition or disease Intervention/treatment Phase
Chronic Neuropathic Pain Post-Stroke Pain Trigeminal Neuralgia Nerve Injury Spinal Cord Injuries Pain, Postoperative Complex Regional Pain Syndromes Post-herpetic Neuralgia Nerve Root Avulsion Device: High Frequency rTMS Device: Low Frequency rTMS Not Applicable

Detailed Description:

The investigators will recruit 20 patients diagnosed with chronic neuropathic pain for a randomized, single-blind, 2-arm crossover pilot TMS treatment trial. Participants will be recruited outpatients from departments of neurosurgery, neurology, and pain medicine at UCSF; patients referred from other hospitals or clinics as candidates of this trial. Baseline screening, clinical interviews, behavioral testing, and recording of pain scores will be performed in either the UCSF Nancy Friend Pritzker Psychiatry Building, UCSF Pain Management Center, or UCSF Mount Zion Hospital prior to the first treatment session. Eligible patients will be randomized to one of two stimulation frequencies: high frequency (10Hz) excitatory vs low frequency (1Hz) inhibitory repetitive transcranial magnetic stimulation (rTMS). We will use clinical and research TMS devices that have been cleared by the FDA for treating obsessive compulsive disorder and refractory major depressive disorder (located in the Pritzker Building) through a collaboration with Dr. Andrew Krystal (Director of UCSF Interventional Psychiatry Program and Co-Director of the TMS & Neuromodulation Clinic) and Dr. Moses Lee (Director of OCD clinic) at UCSF.

Randomized patients will return for once daily rTMS sessions for 10 consecutive weekdays. On the first randomization visit, participants will record their current pain level using a visual analog scale (VAS), complete a variety of self-report scales (e.g., NIH PROMIS questionnaires, pain map, McGill Pain Questionnaire (MPQ), Pain Catastrophizing Scale (PCS), Pain Anxiety Symptom Scale (PASS), Beck Depression Inventory-II (BDI-II), WHO Disability Assessment Schedule (WHODAS), Patient Global Impression of Change (PGIC), and Pittsburgh Sleep Quality Index (PSQI)), and undergo a brain MRI session consisting of T1-weighted, T2-weighted, and diffusion tensor anatomical scans as well as functional MRI (fMRI) scans at rest and while rating spontaneous pain. Using single-pulse TMS, the investigators will estimate individual resting motor thresholds (RMT) of the affected extremity. Each treatment visit will consist of either: a series of thirty 10-Hz stimulations to the target brain regions at 90% RMT (each lasting 10 s with 50 s between stimulations, for a total of 3,000 pulses per visit) or thirty 1-Hz stimulations to the target brain regions at 90% RMT (total of 300 pulses per visit). Each treatment session will last ~30 min. Electromyography (EMG), heart rate and galvanic skin conductance will be recorded continuously throughout each session.

After completing the first 10 sessions, participants will have the option to receive additional stimulation with at either the same region or at a new target region, determined by each subject's baseline MRI scan, at the same frequency with the same schedule as the first session of treatment. Non-responders (<35% improvement of VAS scores) and those with relapse post-treatment to within 35% pre-treatment baseline pain severity will cross over to the new target arm. Participants will be followed for 6-months to evaluate the duration of benefit with follow up assessments at 1 week, 1 month, and 6 months.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Blinded, randomized, crossover pilot TMS treatment trial
Masking: Single (Participant)
Masking Description: Participants will not be informed of their assigned stimulation frequency. Analysis of outcomes will be conducted by an investigator blinded to the treatment that participants received.
Primary Purpose: Treatment
Official Title: A Pilot Trial of Longitudinal Repetitive Transcranial Magnetic Stimulation (rTMS) for Chronic Neuropathic Pain
Actual Study Start Date : April 25, 2022
Estimated Primary Completion Date : December 30, 2024
Estimated Study Completion Date : January 30, 2025


Arm Intervention/treatment
Experimental: High Frequency rTMS
High frequency 10 Hz stimulation of motor cortex (M1)
Device: High Frequency rTMS
Stimulation provided at 10 Hz over target brain regions in thirty trains consisting of 10 seconds of stimulation alternating with 50 seconds of rest (3,000 pulses/session)

Active Comparator: Low Frequency rTMS
Low frequency 1 Hz stimulation of motor cortex (M1)
Device: Low Frequency rTMS
Stimulation provided at 1 Hz over target brain regions in thirty trains consisting of 10 seconds of stimulation alternating with 50 seconds of rest (300 pulses/session)




Primary Outcome Measures :
  1. Change in Pain Intensity Over 2 weeks [ Time Frame: Baseline and 2 weeks ]
    Change in visual analog scores (VAS) of pain intensity on 0-100 mm scale. 0 indicates no pain, 100 indicates most pain imaginable.


Secondary Outcome Measures :
  1. Change in Pain Intensity Over 6 months [ Time Frame: Baseline and 6 months ]
    Change in visual analog scores (VAS) of pain intensity on 0-100 mm scale. 0 indicates no pain, 100 indicates most pain imaginable.

  2. Change in Pain Unpleasantness Over 2 weeks [ Time Frame: Baseline and 2 weeks ]
    Change in visual analog scores (VAS) of pain unpleasantness on 0-100 mm scale. 0 indicates not bothersome at all, 100 indicates most bothersome pain imaginable.

  3. Change in Pain Unpleasantness Over 6 months [ Time Frame: Baseline and 6 months ]
    Change in visual analog scores (VAS) of pain unpleasantness on 0-100 mm scale. 0 indicates not bothersome at all, 100 indicates most bothersome pain imaginable.

  4. Percent Responders [ Time Frame: Baseline and 2 weeks ]
    Proportion of patients in each group with >50% reduction in pain intensity VAS

  5. Percent Responders [ Time Frame: Baseline and 6 months ]
    Proportion of patients in each group with >50% reduction in pain intensity VAS

  6. Change in medication use [ Time Frame: Baseline and 2 weeks ]
    Change in daily as-needed medication use from baseline, in number of doses per day.

  7. Change in medication use [ Time Frame: Baseline and 6 months ]
    Change in daily as-needed medication use from baseline, in number of doses per day.

  8. Change in McGill Pain Questionnaire (MPQ) Pain scores [ Time Frame: Baseline and 6 months ]
    The McGill Pain Questionnaire is a validated measure of multiple domains of pain processing, including sensory and affective pain processing as well as nociceptive and neuropathic pain. Scores range from 0-45 with 0 indicating low pain and 45 indicating high pain.

  9. Change in Beck Depression Inventory (BDI-II) Scores [ Time Frame: Baseline and 6 months ]
    Validated measure of clinical depression symptoms to quantify and track mood over time. Scores index depression severity and range from 0-63: 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe.


Other Outcome Measures:
  1. Change in NIH PROMIS Toolbox Scores [ Time Frame: Baseline and 6 months ]

    The NIH PROMIS toolbox contains a host of survey questions tailored to measurement of specific disease states such as pain, global health and function.

    The patient impression evaluates patient self-evaluation and physician evaluation of the patient's general health ranging form 0 to 7 with 7 being the worst general health.


  2. Change in WHO Disability Assessment Schedule (WHODAS) Scores [ Time Frame: Baseline and 6 months ]
    Assessment of functional disability from the WHO to track level of function throughout the trial. The total score for WHODAS ranges from 0-100. A high score indicates major living limitations.

  3. Pain Catastrophizing Scale (PCS) [ Time Frame: Baseline and 6 months ]
    Validated scale measuring emotional responses to pain to track pain-related symptoms during the trial. It is a 13-item scale, with a total range of 0 to 52. Higher scores are associated with higher amounts of pain catastrophizing.

  4. Change in Pain Anxiety Symptom Scale (PASS) Scores [ Time Frame: Baseline and 6 months ]
    Validated scale measuring pain-related anxiety. It is a 20 item scale with a total range of 0-100. Higher scores indicate higher pain-related anxiety symptoms.

  5. Patient Global Impression of Change (PGIC) [ Time Frame: 6 months ]
    Standardized assessment to assess subject's overall impression of improvement. Scores range from 1 to 7, with 1 representing "no change" and 7 representing "a great deal better"

  6. Change Pittsburgh Sleep Quality Index (PSQI) Scores [ Time Frame: Baseline and 6 months ]
    Validated insomnia and sleep symptom scale. PSQI ranges from 0-21. Higher scores indicate worse sleep quality.

  7. Brain Network Assessment [ Time Frame: Baseline and 2 weeks ]
    T1-weighted high-resolution anatomical image will be acquired to facilitate neuronavigation for TMS treatment. A variety of other sequences including T2 FLAIR and diffusion tensor imaging (DTI) anatomical scans, as well as functional MRI scans (at rest and during ratings of spontaneous pain) will be acquired for research aims. Network features after TMS will be compared with baseline network features.

  8. Change in Heart Rate Variability [ Time Frame: Baseline and 2 weeks ]
    Single estimate of heart rate variability to assess change in autonomic physiology after TMS relative to baseline.

  9. Change in Skin Conductance Level [ Time Frame: Baseline and 2 weeks ]
    Single estimate of galvanic skin conductance to assess change in autonomic physiology after TMS relative to baseline.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Meets Criteria for Chronic Neuropathic Pain (NP):

    1. "Pain caused by a lesion or disease of the somatosensory nervous system
    2. Intractable pain longer than 6 months after pain onset
    3. Baseline VAS score 30-94-mm
    4. Currently prescribed pain medication for NP, history of prior medication trials without adequate pain control, or refused treatments for individual reasons
    5. Continuous pain in face and/or extremities
  • Age 18-80
  • Any gender and all ethnoracial categories
  • Stable on chronic pain medications for 4 weeks prior to the study and agreeable to continue throughout the study. These medications include: Tricyclic antidepressants (e.g., nortriptyline, amitriptyline), SNRIs (e.g., duloxetine, venlafaxine), gabapentinoids (e.g., gabapentin, pregabalin), antiepileptics (e.g., valproic acid, carbamazepine, lamotrigine), and daily anti-inflammatories (e.g., meloxicam), among others (as determined by study physician at the time of screening). Note: Medications that are known to increase cortical excitability (e.g., buproprion, maprotiline, tricyclic antidepressants, classical antipsychotics) or to have an inhibitory effect on brain excitability (e.g., antiepileptics, benzodiazepines, and atypical antipsychotics), or any other medications with relative hazard for use in TMS will be allowed upon review of medications and/or motor threshold determination by TMS specialist.
  • Participants may continue to take as-needed pain medications and record daily usage throughout the experiment
  • Capacity to provide informed consent
  • Ability to tolerate study procedures
  • Successfully complete the screening forms without contraindications

Exclusion Criteria:

  • Neurologic: Dementia, Severe neurocognitive disorder (MoCA < 22), Severe aphasia, Seizure disorder, certain structural brain lesions (e.g., intracranial mass lesions, hydrocephalus, sequelae of meningitis), or complete paralysis at target site
  • Psychiatric: DSM Axis I disorder, Suicidal thoughts, prior psychosurgery, prior ECT
  • Procedural: prior rTMS within 1 year of consent, enrollment in other clinical trial in the past 6 months
  • TMS contraindications: implanted device; presence of metal in the head, including eyes and ears (excluding dental implants); certain tics; medications or systemic illness that predispose seizure risk
  • Participants with an unstable physical, systemic, or metabolic disorder (e.g., unstable hypertension, cardiac disease)
  • Females who are pregnant or nursing
  • Inability to complete the research study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05593237


Contacts
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Contact: Dennis Lambert, BS 415-758-1182 dennis.lambert@ucsf.edu
Contact: Julian C Motzkin, MD/PhD 415-758-1182 julian.motzkin@ucsf.edu

Locations
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United States, California
UCSF Medical Center Recruiting
San Francisco, California, United States, 94158
Sponsors and Collaborators
University of California, San Francisco
Investigators
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Principal Investigator: Julian C Motzkin, MD/PhD University of California, San Francisco
Principal Investigator: Prasad Shirvalkar, MD/PHD University of California, San Francisco
Publications:
Rossi S, Antal A, Bestmann S, Bikson M, Brewer C, Brockmoller J, Carpenter LL, Cincotta M, Chen R, Daskalakis JD, Di Lazzaro V, Fox MD, George MS, Gilbert D, Kimiskidis VK, Koch G, Ilmoniemi RJ, Lefaucheur JP, Leocani L, Lisanby SH, Miniussi C, Padberg F, Pascual-Leone A, Paulus W, Peterchev AV, Quartarone A, Rotenberg A, Rothwell J, Rossini PM, Santarnecchi E, Shafi MM, Siebner HR, Ugawa Y, Wassermann EM, Zangen A, Ziemann U, Hallett M; basis of this article began with a Consensus Statement from the IFCN Workshop on "Present, Future of TMS: Safety, Ethical Guidelines", Siena, October 17-20, 2018, updating through April 2020. Safety and recommendations for TMS use in healthy subjects and patient populations, with updates on training, ethical and regulatory issues: Expert Guidelines. Clin Neurophysiol. 2021 Jan;132(1):269-306. doi: 10.1016/j.clinph.2020.10.003. Epub 2020 Oct 24.

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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT05593237    
Other Study ID Numbers: 21-33344
First Posted: October 25, 2022    Key Record Dates
Last Update Posted: May 26, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Product Manufactured in and Exported from the U.S.: No
Keywords provided by University of California, San Francisco:
Pain
Neuropathic Pain
TMS
Neuromodulation
Additional relevant MeSH terms:
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Trigeminal Neuralgia
Spinal Cord Injuries
Neuralgia
Complex Regional Pain Syndromes
Reflex Sympathetic Dystrophy
Neuralgia, Postherpetic
Radiculopathy
Pain, Postoperative
Wounds and Injuries
Spinal Cord Diseases
Central Nervous System Diseases
Nervous System Diseases
Trauma, Nervous System
Peripheral Nervous System Diseases
Neuromuscular Diseases
Pain
Neurologic Manifestations
Postoperative Complications
Pathologic Processes
Autonomic Nervous System Diseases
Trigeminal Nerve Diseases
Facial Neuralgia
Facial Nerve Diseases
Mouth Diseases
Stomatognathic Diseases
Cranial Nerve Diseases