Transcranial Magnetic Stimulation for Chronic Neuropathic Pain

NCT05593237 | Active Not Recruiting FDA Device

• 1 other identifier: 21-33344
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Keywords

Pain; Neuropathic Pain; TMS; Neuromodulation

Outcome Measures

Primary Outcomes (1)

• Change in Pain Intensity Over 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.

  Baseline and 2 weeks

Secondary Outcomes (9)

• Change in Pain Intensity Over 6 months

  Baseline and 6 months

• Change in Pain Unpleasantness Over 2 weeks

  Baseline and 2 weeks

• Change in Pain Unpleasantness Over 6 months

  Baseline and 6 months

• Percent Responders

  Baseline and 2 weeks

• Percent Responders

  Baseline and 6 months

Other Outcomes (9)

• Change in NIH PROMIS Toolbox Scores

  Baseline and 6 months

• Change in WHO Disability Assessment Schedule (WHODAS) Scores

  Baseline and 6 months

• Pain Catastrophizing Scale (PCS)

  Baseline and 6 months

Study Arms (2)

High Frequency rTMS

EXPERIMENTAL

High frequency 10 Hz stimulation of motor cortex (M1)

Device: High Frequency rTMS

Low Frequency rTMS

ACTIVE COMPARATOR

Low frequency 1 Hz stimulation of motor cortex (M1)

Device: Low Frequency rTMS

Interventions

High Frequency rTMS DEVICE

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)

High Frequency rTMS

Low Frequency rTMS DEVICE

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)

Low Frequency rTMS

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Meets Criteria for Chronic Neuropathic Pain (NP):
• "Pain caused by a lesion or disease of the somatosensory nervous system
• Intractable pain longer than 6 months after pain onset
• Baseline VAS score 30-94-mm
• Currently prescribed pain medication for NP, history of prior medication trials without adequate pain control, or refused treatments for individual reasons
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of California, San Francisco: lead
• Facial Pain Research Foundation: collaborator

Study Sites (1)

UCSF Medical Center

San Francisco, California, 94158, United States

Location

Related Publications (10)

• Apkarian AV, Baliki MN, Geha PY. Towards a theory of chronic pain. Prog Neurobiol. 2009 Feb;87(2):81-97. doi: 10.1016/j.pneurobio.2008.09.018. Epub 2008 Oct 5.

  PMID: 18952143 BACKGROUND

• Arendt-Nielsen L, Morlion B, Perrot S, Dahan A, Dickenson A, Kress HG, Wells C, Bouhassira D, Drewes AM. Assessment and manifestation of central sensitisation across different chronic pain conditions. Eur J Pain. 2018 Feb;22(2):216-241. doi: 10.1002/ejp.1140. Epub 2017 Nov 5.

  PMID: 29105941 BACKGROUND

• Chou YH, Ton That V, Chen AY, Sundman M, Huang YZ. TMS-induced seizure cases stratified by population, stimulation protocol, and stimulation site: A systematic literature search. Clin Neurophysiol. 2020 May;131(5):1019-1020. doi: 10.1016/j.clinph.2020.02.008. Epub 2020 Mar 3. No abstract available.

  PMID: 32193163 BACKGROUND

• Hosomi K, Sugiyama K, Nakamura Y, Shimokawa T, Oshino S, Goto Y, Mano T, Shimizu T, Yanagisawa T, Saitoh Y; TEN-P11-01 investigators. A randomized controlled trial of 5 daily sessions and continuous trial of 4 weekly sessions of repetitive transcranial magnetic stimulation for neuropathic pain. Pain. 2020 Feb;161(2):351-360. doi: 10.1097/j.pain.0000000000001712.

  PMID: 31593002 BACKGROUND

• Lefaucheur JP, Andre-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH, Cantello RM, Cincotta M, de Carvalho M, De Ridder D, Devanne H, Di Lazzaro V, Filipovic SR, Hummel FC, Jaaskelainen SK, Kimiskidis VK, Koch G, Langguth B, Nyffeler T, Oliviero A, Padberg F, Poulet E, Rossi S, Rossini PM, Rothwell JC, Schonfeldt-Lecuona C, Siebner HR, Slotema CW, Stagg CJ, Valls-Sole J, Ziemann U, Paulus W, Garcia-Larrea L. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin Neurophysiol. 2014 Nov;125(11):2150-2206. doi: 10.1016/j.clinph.2014.05.021. Epub 2014 Jun 5.

  PMID: 25034472 BACKGROUND

• Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, Filipovic SR, Grefkes C, Hasan A, Hummel FC, Jaaskelainen SK, Langguth B, Leocani L, Londero A, Nardone R, Nguyen JP, Nyffeler T, Oliveira-Maia AJ, Oliviero A, Padberg F, Palm U, Paulus W, Poulet E, Quartarone A, Rachid F, Rektorova I, Rossi S, Sahlsten H, Schecklmann M, Szekely D, Ziemann U. Corrigendum to "Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018)" [Clin. Neurophysiol. 131 (2020) 474-528]. Clin Neurophysiol. 2020 May;131(5):1168-1169. doi: 10.1016/j.clinph.2020.02.003. Epub 2020 Feb 19. No abstract available.

  PMID: 32122766 BACKGROUND

• Lerner AJ, Wassermann EM, Tamir DI. Seizures from transcranial magnetic stimulation 2012-2016: Results of a survey of active laboratories and clinics. Clin Neurophysiol. 2019 Aug;130(8):1409-1416. doi: 10.1016/j.clinph.2019.03.016. Epub 2019 Apr 6.

  PMID: 31104898 BACKGROUND

• Leung A, Shirvalkar P, Chen R, Kuluva J, Vaninetti M, Bermudes R, Poree L, Wassermann EM, Kopell B, Levy R; and the Expert Consensus Panel. Transcranial Magnetic Stimulation for Pain, Headache, and Comorbid Depression: INS-NANS Expert Consensus Panel Review and Recommendation. Neuromodulation. 2020 Apr;23(3):267-290. doi: 10.1111/ner.13094. Epub 2020 Mar 25.

  PMID: 32212288 BACKGROUND

• O'Connell NE, Marston L, Spencer S, DeSouza LH, Wand BM. Non-invasive brain stimulation techniques for chronic pain. Cochrane Database Syst Rev. 2018 Apr 13;4(4):CD008208. doi: 10.1002/14651858.CD008208.pub5.

  PMID: 29652088 BACKGROUND

• 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.

  PMID: 33243615 BACKGROUND

MeSH Terms

Conditions

Trigeminal Neuralgia; Spinal Cord Injuries; Pain, Postoperative; Complex Regional Pain Syndromes; Neuralgia, Postherpetic; Radiculopathy; Pain; Neuralgia

Condition Hierarchy (Ancestors)

Trigeminal Nerve Diseases; Facial Neuralgia; Facial Nerve Diseases; Mouth Diseases; Stomatognathic Diseases; Cranial Nerve Diseases; Nervous System Diseases; Spinal Cord Diseases; Central Nervous System Diseases; Trauma, Nervous System; Wounds and Injuries; Postoperative Complications; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neurologic Manifestations; Signs and Symptoms; Autonomic Nervous System Diseases; Peripheral Nervous System Diseases; Neuromuscular Diseases

Study Officials

• Julian C Motzkin, MD/PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Prasad Shirvalkar, MD/PHD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Blinded, randomized pilot TMS treatment trial

Study Record Dates

• First Submitted: October 20, 2022
• First Posted: October 25, 2022
• Study Start: April 25, 2022
• Primary Completion (Estimated): September 20, 2026
• Study Completion (Estimated): December 30, 2026
• Last Updated: March 13, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)