TMS for Neuropathic Pain

Overseen By Dennis Lambert

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of California, San Francisco

Must be taking: Chronic pain medications

Disqualifiers: Dementia, Seizure disorder, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 24

Duration: 2 weeks

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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.

Do I have to stop taking my current medications for the trial?

No, you don't have to stop taking your current medications. You need to be stable on your chronic pain medications for 4 weeks before the study and continue them throughout the study. Some medications will be reviewed by a TMS specialist to ensure they are safe to use with TMS.

What safety data exists for TMS in treating neuropathic pain?

The safety data for TMS in treating neuropathic pain indicates that it is generally well-tolerated. In a randomized, multicenter, double-blind, crossover, sham-controlled trial, no serious adverse events were observed with daily high-frequency rTMS of the primary motor cortex. This suggests that TMS is a safe treatment option for neuropathic pain, although the analgesic effects are modest and transient. ^{1 2 3 4 5}

Is the treatment High Frequency rTMS promising for neuropathic pain?

Yes, High Frequency rTMS is a promising treatment for neuropathic pain. It can relieve pain by stimulating the brain non-invasively, and studies show it can provide long-lasting pain relief. It is already approved for treating depression and has shown effectiveness in small studies for neuropathic pain. ^{2 3 6 7 8}

What data supports the idea that TMS for Neuropathic Pain is an effective treatment?

The available research shows that repetitive transcranial magnetic stimulation (rTMS) can effectively relieve neuropathic pain. Studies indicate that high-frequency rTMS applied to specific brain areas can reduce pain. For example, a meta-analysis found that rTMS is more effective for pain that originates in the central nervous system compared to pain from peripheral nerves. Additionally, research suggests that rTMS may work by releasing natural pain-relieving chemicals in the brain. Overall, these findings support the idea that TMS is a promising treatment for neuropathic pain. ^{2 5 6 9 10}

Who Is on the Research Team?

Julian C Motzkin, MD/PhD

Principal Investigator

University of California, San Francisco

Prasad Shirvalkar, MD/PHD

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for adults aged 18-80 with chronic neuropathic pain lasting over 6 months due to nerve damage or disease. Participants must have a certain level of continuous pain, be able to tolerate the procedures, and give informed consent. They should be stable on their current pain medications and not pregnant, nursing, or have specific psychiatric conditions or contraindications for TMS.

Inclusion Criteria

I have been on the same pain medication for 4 weeks and can continue it during the study.

I have been on the same pain medication for 4 weeks and can continue during the study.

I have been diagnosed with chronic nerve pain.

Exclusion Criteria

I am not pregnant or nursing.

I am unable to commit to the full duration of the study.

I have not had major psychiatric disorders, thoughts of suicide, brain surgery, or electroconvulsive therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive daily rTMS sessions for 10 consecutive weekdays

2 weeks

10 visits (in-person)

Optional Extension

Participants may receive additional stimulation at the same or new target region

2 weeks

10 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

3 visits (in-person) at 1 week, 1 month, and 6 months

What Are the Treatments Tested in This Trial?

Interventions

• High Frequency rTMS
• Low Frequency rTMS

Trial Overview The study tests high frequency rTMS versus low frequency rTMS as treatments for chronic neuropathic pain. It aims to determine if stimulating the brain's motor cortex can reduce pain by modulating brain activity without the side effects common in other treatments.

How Is the Trial Designed?

Group I: High Frequency rTMS Experimental Treatment 1 Intervention

High frequency 10 Hz stimulation of motor cortex (M1)

Group II: Low Frequency rTMS Active Control 1 Intervention

Low frequency 1 Hz stimulation of motor cortex (M1)

High Frequency rTMS is already approved in United States for the following indications:

Approved in United States as rTMS for:

• Major Depressive Disorder
• Obsessive-Compulsive Disorder
• Migraine

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Published Research Related to This Trial

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) is effective in reducing neuropathic pain, with significant pain relief observed after just one and five treatment sessions, based on a meta-analysis of 25 studies involving 589 patients.

The analgesic effects of HF-rTMS can last for at least one month after five sessions, indicating its potential for long-term pain management in neuropathic pain patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High Frequency Repetitive Transcranial Magnetic Stimulation Therapy For Chronic Neuropathic Pain: A Meta-analysis. Jin, Y., Xing, G., Li, G., et al.[2018]

A study involving 66 patients with neuropathic pain showed that high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) targeting the specific pain region using navigation techniques provided significant pain relief, particularly for upper and lower limb pain.

The pain relief from navigated rTMS lasted for one week, indicating that navigation may enhance the efficacy of rTMS compared to traditional non-navigated methods, although it was less effective for facial or diffuse pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analgesic effects of navigated motor cortex rTMS in patients with chronic neuropathic pain. Ayache, SS., Ahdab, R., Chalah, MA., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) significantly reduces neuropathic pain, with a notable overall analgesic effect compared to sham treatment, as shown in a meta-analysis of 149 patients from 5 randomized controlled trials.

The greatest pain relief was observed in patients with trigeminal nerve pain (28.8% reduction), followed by post-stroke pain (16.7%) and spinal cord pain (14.7%), indicating that rTMS is more effective for centrally originated pain compared to peripheral sources.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

rTMS for suppressing neuropathic pain: a meta-analysis. Leung, A., Donohue, M., Xu, R., et al.[2022]

Repetitive transcranial magnetic stimulation (rTMS) applied to the M1/S1 cortex significantly lowers μ-opioid receptor availability, indicating the release of endogenous opioids in various brain regions associated with pain processing, which may contribute to its pain-relieving effects.

Despite the activation of the endogenous opioid system, rTMS did not change thermal pain thresholds or sensory discrimination of painful stimuli, suggesting that while rTMS enhances opioid-mediated inhibition, it does not alter the perception of pain intensity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurotransmitters behind pain relief with transcranial magnetic stimulation - positron emission tomography evidence for release of endogenous opioids. Lamusuo, S., Hirvonen, J., Lindholm, P., et al.[2018]

In a study involving 17 patients with spinal cord injury and chronic neuropathic pain, repetitive transcranial magnetic stimulation (rTMS) did not show a significant advantage over sham treatment in reducing pain levels, indicating that its analgesic effect may not be superior to placebo.

Despite the lack of significant difference compared to sham treatment, rTMS did provide encouraging pain relief at 10 days and 6 weeks post-treatment, suggesting potential for further research with larger sample sizes to explore its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of repetitive transcranial magnetic stimulation on refractory neuropathic pain in spinal cord injury. Yılmaz, B., Kesikburun, S., Yaşar, E., et al.[2021]

In a study involving 70 patients with neuropathic pain, 10 daily sessions of repetitive transcranial magnetic stimulation (rTMS) showed significant short-term pain relief compared to sham treatment, as measured by visual analogue scale (VAS) and the short form of the McGill pain questionnaire (SF-MPQ).

The treatment was found to be safe, with no serious adverse events reported, indicating that daily high-frequency rTMS is a tolerable option for providing modest pain relief in neuropathic pain patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Daily repetitive transcranial magnetic stimulation of primary motor cortex for neuropathic pain: a randomized, multicenter, double-blind, crossover, sham-controlled trial. Hosomi, K., Shimokawa, T., Ikoma, K., et al.[2022]

Transcranial magnetic stimulation (TMS) is a promising non-invasive treatment for neuropathic pain (NP), which is often difficult to manage with traditional medications due to ineffectiveness and side effects.

Recent advancements in TMS technology, including neuronavigation systems that use MRI for precise targeting, may enhance its efficacy and support the need for larger clinical trials to gain regulatory approval for treating neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-invasive Transcranial Magnetic Stimulation (TMS) of the Motor Cortex for Neuropathic Pain-At the Tipping Point? Treister, R., Lang, M., Klein, MM., et al.[2021]

In a study of 34 patients with malignant neuropathic pain, 10 sessions of real repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex resulted in significant short-term pain relief compared to sham treatment, as measured by various pain and depression scales.

The pain relief effects from rTMS were observed to last for up to 15 days after treatment, indicating its potential as a therapeutic option for managing malignant neuropathic pain, although the benefits did not persist beyond one month.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation in neuropathic pain secondary to malignancy: a randomized clinical trial. Khedr, EM., Kotb, HI., Mostafa, MG., et al.[2022]

Motor cortex stimulation can effectively control neuropathic pain in many patients, and repetitive transcranial magnetic stimulation (rTMS) can provide analgesic effects as well.

In a reported case, a woman with drug-resistant peripheral pain experienced 16 months of pain relief from monthly rTMS sessions before receiving a surgical cortical stimulator, highlighting rTMS as a valuable interim treatment before surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuropathic pain controlled for more than a year by monthly sessions of repetitive transcranial magnetic stimulation of the motor cortex. Lefaucheur, JP., Drouot, X., Ménard-Lefaucheur, I., et al.[2011]

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex has been shown to provide short-term therapeutic effects for patients suffering from therapy-refractory neuropathic pain.

The results suggest that rTMS can predict the benefits of more invasive treatments like epidural motor cortex stimulation (MCS), indicating a potential pathway for effective pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Transcranial magnetic stimulation and motor cortex stimulation in neuropathic pain]. Mylius, V., Ayache, SS., Teepker, M., et al.[2021]

Citations

1. United States pubmed.ncbi.nlm.nih.gov

High Frequency Repetitive Transcranial Magnetic Stimulation Therapy For Chronic Neuropathic Pain: A Meta-analysis. [2018]

2. England pubmed.ncbi.nlm.nih.gov

Analgesic effects of navigated motor cortex rTMS in patients with chronic neuropathic pain. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

rTMS for suppressing neuropathic pain: a meta-analysis. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Neurotransmitters behind pain relief with transcranial magnetic stimulation - positron emission tomography evidence for release of endogenous opioids. [2018]

5. England pubmed.ncbi.nlm.nih.gov

The effect of repetitive transcranial magnetic stimulation on refractory neuropathic pain in spinal cord injury. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Daily repetitive transcranial magnetic stimulation of primary motor cortex for neuropathic pain: a randomized, multicenter, double-blind, crossover, sham-controlled trial. [2022]

7. Israel pubmed.ncbi.nlm.nih.gov

Non-invasive Transcranial Magnetic Stimulation (TMS) of the Motor Cortex for Neuropathic Pain-At the Tipping Point? [2021]

8. England pubmed.ncbi.nlm.nih.gov

Repetitive transcranial magnetic stimulation in neuropathic pain secondary to malignancy: a randomized clinical trial. [2022]

9. France pubmed.ncbi.nlm.nih.gov

Neuropathic pain controlled for more than a year by monthly sessions of repetitive transcranial magnetic stimulation of the motor cortex. [2011]

10. Germany pubmed.ncbi.nlm.nih.gov

[Transcranial magnetic stimulation and motor cortex stimulation in neuropathic pain]. [2021]