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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method for treating chronic neuropathic pain using neuromodulation, which targets the insula area of the brain to manage pain. Participants will undergo both active and sham (inactive) stimulation in a randomized, blinded process to determine the method's effectiveness in reducing pain. It is designed for individuals who have suffered from severe, chronic neuropathic pain for more than six months and have not found relief from at least three different pain medications, including opioids. This includes pain from conditions such as post-stroke pain, spinal cord injury, or nerve damage. As an unphased trial, this study provides a unique opportunity to explore innovative pain management solutions.

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 prior data suggests that neuromodulation is safe for treating chronic neuropathic pain?

Research has shown that deep brain stimulation (DBS) can safely treat long-lasting pain. Studies have found that DBS is generally well-tolerated and can improve patients' quality of life. For instance, a small study confirmed that DBS is safe when targeting the anterior cingulate, a brain region involved in pain processing. This finding suggests that using DBS on the insula, another area linked to chronic pain, might also be safe.

Although DBS is usually safe, some patients may experience side effects, such as temporary changes in mood or movement, but serious issues are rare. Discussing potential risks with a healthcare provider before joining a trial is always important. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this treatment for chronic neuropathic pain because it uses a technique called deep brain stimulation (DBS) targeting the insula, a part of the brain involved in pain perception. Unlike standard treatments like medications, which often focus on symptom relief and can have significant side effects, DBS directly modulates neural activity. This approach offers the potential for more precise and effective pain management with fewer systemic side effects. Additionally, DBS provides a reversible and adjustable treatment option, which means it can be tailored to each patient's needs over time.

What evidence suggests that neuromodulation might be an effective treatment for chronic neuropathic pain?

Studies have shown that deep brain stimulation (DBS) can help treat long-lasting nerve pain. One study found that patients experienced pain relief for many years. Another study reported that 43% of patients had a significant decrease in pain after DBS. In this trial, participants will receive either active DBS of the insula or sham stimulation at random. These findings suggest that using DBS on areas like the insula may help reduce chronic nerve pain. Overall, the research supports DBS as a promising treatment option for managing this type of pain. ^{6 7 8 9 10}

Who Is on the Research Team?

Jeff Elias, MD

Principal Investigator

University of Virginia

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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 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]

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It is present in 7 % of the general population and may not fully respond to first- and second-line treatments in up to 40 % of cases.