Insula Neuromodulation for Chronic Neuropathic Pain

Overseen By Zak Sturgill

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Virginia

Must not be taking: Antiplatelets, Anticoagulants

Disqualifiers: Idiopathic pain, Substance abuse, Psychiatric illness, Cardiac issues, others

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

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will comprehensively investigate the insula as a brain target for neuromodulation to treat chronic neuropathic pain.

Do I need to stop my current medications for the trial?

You need to stay on stable doses of your current pain medications for 30 days before and during the study. However, you must stop taking certain medications that increase bleeding risk, like aspirin or anticoagulants, for a specified period before treatment.

What data supports the effectiveness of the treatment Insula Neuromodulation for Chronic Neuropathic Pain?

Research shows that spinal cord stimulation, a type of neuromodulation, has been effective for chronic neuropathic pain, especially when other treatments fail. Additionally, the posterior-superior insula has been identified as a safe and potentially effective target for neuromodulation in peripheral neuropathic pain. ^{1 2 3 4 5}

Is insula neuromodulation safe for treating chronic neuropathic pain?

The posterior-superior insula (PSI) has been shown to be a safe target for neuromodulation in peripheral neuropathic pain in humans and animal models. ^{1 2 3 6 7}

How is insula neuromodulation different from other treatments for chronic neuropathic pain?

Insula neuromodulation is unique because it targets the posterior insula, a specific brain region involved in pain processing, using electrical stimulation to potentially reduce pain without the side effects associated with drugs. This approach is still being studied, but it offers a novel, non-drug option for those who do not respond to traditional treatments. ^{1 3 5 8 9}

Research Team

Jeff Elias, MD

Principal Investigator

University of Virginia

Eligibility Criteria

This trial is for adults aged 18-75 with chronic neuropathic pain lasting over 6 months, severe enough to disrupt daily life and work. Participants must have tried at least three different pain medications, including opioids, without relief and not responded to other treatments like injections or surgery. They should be able to attend all visits, have stable medication doses for 30 days prior, and their insula region must be visible on MRI.

Inclusion Criteria

My pain stops me from working or doing daily activities at home.

My pain has not improved with injections, stimulations, or surgery.

I have been experiencing pain for 6 months or more.

Exclusion Criteria

Criterion: You are currently taking certain medications that increase the risk of bleeding, or have specific medical conditions such as brain tumors, seizure history, or recent stroke, which would prevent you from participating in the study.

I do not have chronic pain conditions like fibromyalgia or irritable bowel syndrome.

A team of pain doctors and specialists have decided that you are not a good candidate for the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Inpatient Stage

Subjects undergo insular brain mapping with acute stimulation and neurophysiological brain monitoring. Electrodes are implanted for stimulation and recording.

Duration not specified

Inpatient stay

Outpatient Stage

Subjects receive chronic deep brain stimulation of the insula in a randomized, sham-stimulation-controlled, double-blinded, cross-over design.

6 months

Regular outpatient visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, including adverse event reporting and neurological assessments.

6 months post DBS implantation

Treatment Details

Interventions

• Neuromodulation

Trial Overview The study tests neuromodulation targeting the insula in the brain as a potential treatment for chronic neuropathic pain. It involves participants who've had specific injuries causing this type of pain such as post-stroke or spinal cord injury.

Participant Groups

Group I: DBS of the insula Active Control 1 Intervention

Subjects who respond favorably to test/trial stimulation of the insula will be implanted with DBS devices. In an outpatient clinical trial, each subject will receive 3 months of active stimulation and 3 months of sham stimulation. The assignment for stimulation will be randomized and blinded to the subject and to the outcome assessors.

Group II: Control Placebo Group 1 Intervention

Subjects who respond favorably to test/trial stimulation of the insula will be implanted with DBS devices. In an outpatient clinical trial, each subject will receive 3 months of active stimulation and 3 months of sham stimulation. The assignment for stimulation will be randomized and blinded to the subject and to the outcome assessors.

Neuromodulation is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Neuromodulation Therapy for:

• Chronic Neuropathic Pain
• Epilepsy
• Parkinson's Disease
• Urinary Incontinence

Approved in United States as Neuromodulation Therapy for:

• Chronic Neuropathic Pain
• Failed Back Surgery Syndrome
• Complex Regional Pain Syndrome
• Epilepsy
• Parkinson's Disease

Approved in Canada as Neuromodulation Therapy for:

• Chronic Neuropathic Pain
• Epilepsy
• Parkinson's Disease

Approved in Japan as Neuromodulation Therapy for:

• Chronic Neuropathic Pain
• Parkinson's Disease

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Boston Scientific Corporation

Industry Sponsor

Trials

758

Recruited

867,000+

Michael F. Mahoney

Boston Scientific Corporation

Chief Executive Officer since 2016

MBA from Wake Forest University, BBA in Finance from the University of Iowa

Kenneth Stein

Boston Scientific Corporation

Chief Medical Officer since 2020

MD from Harvard Medical School, MMSc in Clinical Investigation from Harvard-MIT Division of Health Sciences and Technology

Findings from Research

A systematic review of neuromodulation techniques for neuropathic pain (NP) found that motor cortex stimulation (MCS) and deep brain stimulation (DBS) can lead to pain improvement rates of 35% to 80% and 50% to 60%, respectively, indicating their potential efficacy in treating NP.

Spinal cord stimulation (SCS) also showed promising results with success rates ranging from 38% to 89%, but the review did not find sufficient evidence to recommend posterior insula stimulation (PIS) as a routine treatment for NP.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromodulation for Medically Refractory Neuropathic Pain: Spinal Cord Stimulation, Deep Brain Stimulation, Motor Cortex Stimulation, and Posterior Insula Stimulation. Galafassi, GZ., Simm Pires de Aguiar, PH., Simm, RF., et al.[2021]

Spinal cord stimulation is a key treatment for chronic neuropathic pain, serving as a neuromodulation therapy that can help manage pain symptoms effectively.

The article outlines the criteria for determining which patients are suitable for spinal cord stimulation therapy, ensuring that the right individuals receive this intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromodulation. Love-Jones, S.[2021]

In a study involving 31 participants with peripheral neuropathic pain, the response to repetitive transcranial magnetic stimulation (rTMS) targeting the posterior-superior insula (PSI) was found to be influenced more by the specific type of pain symptoms rather than the precise targeting of the PSI.

Notably, none of the participants with evoked pain symptoms responded positively to the rTMS treatment, suggesting that the effectiveness of PSI stimulation may vary based on the neuropathic pain symptom profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-invasive insular stimulation for peripheral neuropathic pain: Influence of target or symptom? da Cunha, PHM., Dongyang, L., Fernandes, AM., et al.[2022]

Spinal cord stimulation has proven effective for chronic neuropathic pain, particularly in patients with peripheral nerve or posterior root lesions, where other treatments often fail.

In a retrospective study of 84 patients over 16 years, 56 continued to use their stimulators, with 72% reporting satisfactory pain relief, highlighting the importance of trial stimulation for long-term success.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Spinal cord stimulation in chronic neuropathic pain]. Meyerson, B., Linderoth, B., Lind, G.[2016]

A multicenter study involving 76 patients demonstrated that a single probe percutaneous electrical nerve stimulation (PENS) significantly reduced chronic peripheral neuropathic pain immediately after treatment and maintained pain relief over a 6-month follow-up period.

The PENS therapy was found to be safe, with only two minor adverse events reported, confirming its feasibility and effectiveness as a minimally invasive treatment option for various types of neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Novel Mini-invasive Approach to the Treatment of Neuropathic Pain: The PENS Study. Rossi, M., DeCarolis, G., Liberatoscioli, G., et al.[2018]

Neuromodulation techniques, such as spinal cord stimulation and peripheral nerve field stimulation, show promising efficacy in treating painful conditions like coronary artery disease, peripheral vascular disease, and headaches, despite not being FDA approved for these uses.

The review analyzed a total of 24 studies, including 10 controlled studies for coronary artery disease, 6 for peripheral vascular disease, and 3 for headaches, providing compelling evidence that neuromodulation could benefit patients suffering from these serious conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Some Non-FDA Approved Uses for Neuromodulation: A Review of the Evidence. Lee, S., Abd-Elsayed, A.[2018]

Spinal cord stimulation (SCS) therapies show low-to-moderate quality evidence of being more effective than reoperation or conventional medical management for failed back surgery syndrome, although evidence comparing different SCS modalities is conflicting.

Peripheral nerve stimulation has rapidly developed and is less invasive, with low-to-moderate quality evidence supporting its effectiveness for neuropathic pain in extremities, but mixed results for back pain and migraine prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuromodulation for chronic pain. Knotkova, H., Hamani, C., Sivanesan, E., et al.[2021]

Stimulation of the posterior insular cortex (PIC) in rats with chronic neuropathic pain significantly reduced both mechanical and cold allodynia, indicating its potential as a nonpharmacologic therapy for pain relief.

The effectiveness of PIC stimulation is linked to the NMDA glutamatergic system, as blocking NMDA receptors in the PIC diminished the pain-relieving effects, suggesting that this neurochemical pathway plays a crucial role in the antinociceptive response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cortical Neurostimulation and N-Methyl-D-Aspartate Glutamatergic Receptor Activation in the Dysgranular Layer of the Posterior Insular Cortex Modulate Chronic Neuropathic Pain. Martins Pereira, RC., Medeiros, P., Coimbra, NC., et al.[2023]

In a preclinical study on neuropathic pain in rats, insular cortex stimulation (ICS) effectively reduced pain, with the best results observed at a frequency of 50 Hz and intensity of 120 μA, lasting up to 4 days after treatment ended.

ICS appears to work by decreasing the levels of phosphorylated extracellular signal-regulated kinase (pERK) in neurons, suggesting a specific mechanism of action that could be targeted for therapeutic use in managing neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insular cortex stimulation alleviates neuropathic pain via ERK phosphorylation in neurons. Kim, K., Nan, G., Kim, L., et al.[2023]

References

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

Neuromodulation for Medically Refractory Neuropathic Pain: Spinal Cord Stimulation, Deep Brain Stimulation, Motor Cortex Stimulation, and Posterior Insula Stimulation. [2021]

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

Neuromodulation. [2021]

3. France pubmed.ncbi.nlm.nih.gov

Non-invasive insular stimulation for peripheral neuropathic pain: Influence of target or symptom? [2022]

4. Sweden pubmed.ncbi.nlm.nih.gov

[Spinal cord stimulation in chronic neuropathic pain]. [2016]

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

A Novel Mini-invasive Approach to the Treatment of Neuropathic Pain: The PENS Study. [2018]

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

Some Non-FDA Approved Uses for Neuromodulation: A Review of the Evidence. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Neuromodulation for chronic pain. [2021]

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

Cortical Neurostimulation and N-Methyl-D-Aspartate Glutamatergic Receptor Activation in the Dysgranular Layer of the Posterior Insular Cortex Modulate Chronic Neuropathic Pain. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Insular cortex stimulation alleviates neuropathic pain via ERK phosphorylation in neurons. [2023]