Ultrasound Stimulation for Neuropathic Pain

Overseen By Jan Kubanek, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: University of Utah

Disqualifiers: Poorly managed condition, Pregnant, Implanted device, 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: Unknown

Duration: 1 week

Trial Summary

What is the purpose of this trial?

This study will apply low-intensity transcranial focused ultrasound to dorsal root ganglia in patients with chronic neuropathic pain. The target will be validated using magnetic resonance imaging. The stimulation will first be delivered using a range of stimulation parameters during psychophysical and physiological monitoring. A well-tolerated stimulation protocol will be selected for subsequent testing in a blinded randomized sham-controlled cross-over trial. The level of pain will be evaluated using the Numerical Rating Scale (NSR-11) and the Patient-Reported Outcomes Measurement Information System (PROMIS) numerical rating scales of pain.

Will I have to stop taking my current medications?

No, you will not have to stop taking your current medications. The study requires that you avoid changes to your current treatments for the duration of the study.

What data supports the effectiveness of this treatment for neuropathic pain?

Research shows that low-intensity focused ultrasound (liFUS) can reduce pain by affecting nerve activity and inflammation, and a study found that low-energy focused ultrasound reduced pain levels in patients with chronic neuropathic pain without side effects. This suggests that ultrasound treatments may be effective for managing neuropathic pain. ^{1 2 3 4 5}

Is ultrasound stimulation safe for humans?

Research shows that low-intensity focused ultrasound (LIFU) is generally safe for humans, with no serious adverse effects reported. Some participants experienced mild symptoms like neck pain and sleepiness, similar to other non-invasive brain stimulation methods. ^{2 6 7 8 9}

How is the ultrasound treatment for neuropathic pain different from other treatments?

This ultrasound treatment is unique because it uses low-intensity focused ultrasound (LIFU) to non-invasively target specific brain areas or nerves, potentially reducing pain without the need for surgery or medication. It offers a novel approach by modulating nerve activity and has shown promise in reducing pain levels with minimal side effects. ^{1 2 4 10 11}

Research Team

Jan Kubanek, PhD

Principal Investigator

University of Utah

Daniel Odell, MD

Principal Investigator

University of Utah

Eligibility Criteria

This trial is for individuals with a primary diagnosis of chronic neuropathic pain that's been ongoing for at least two months. Participants should be willing to stick to their current treatments without changes and, if female and able to have children, must not be pregnant or agree to use effective contraception.

Inclusion Criteria

For females of reproductive potential: negative pregnancy test or use of highly effective contraception for at least 1 month prior to baseline; agreement to use such a method throughout the study

I have had chronic pain for at least 2 months.

I have been primarily diagnosed with chronic pain.

Exclusion Criteria

Implanted device in the back

Pregnant or breast feeding

Clinically inappropriate for participation in the study as determined by the study team

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Low-intensity transcranial focused ultrasound is applied to the dorsal root ganglia with psychophysical and physiological monitoring

1 week

Daily visits during the intervention

Follow-up

Participants are monitored for pain intensity using NRS-11 and PROMIS scales

1 week

Daily assessments

Treatment Details

Interventions

• Low-frequency ultrasonic transducer

Trial Overview The study tests low-intensity focused ultrasound on dorsal root ganglia in patients with chronic pain, using MRI validation. It involves initial testing of various stimulation parameters followed by a blinded comparison between real and sham (fake) stimulations to see which reduces pain better.

Participant Groups

Group I: Active stimulation Active Control 1 Intervention

Low-intensity focused ultrasound stimulation of dorsal root ganglion involved in pain conduction

Group II: Sham stimulation Placebo Group 1 Intervention

Zero-intensity focused ultrasound stimulation of dorsal root ganglion involved in pain conduction

Low-frequency ultrasonic transducer is already approved in United States for the following indications:

Approved in United States as Low-intensity transcranial focused ultrasound for:

• Chronic neuropathic pain
• Radiculopathy (sciatica)
• Spinal cord injury
• Phantom limb pain

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Findings from Research

This study demonstrated that MR-guided high intensity focused ultrasound (MR-HIFU) can effectively and accurately ablate targeted peripheral nerves in pigs, with temperatures reaching up to 85.7°C, indicating its potential for treating neuropathic pain noninvasively.

The use of 3D MR neurography allowed for precise identification and targeting of nerves, suggesting that this imaging technique could enhance the safety and efficacy of nerve ablation procedures by ensuring accurate treatment delivery and post-treatment verification.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-Invasive Targeted Peripheral Nerve Ablation Using 3D MR Neurography and MRI-Guided High-Intensity Focused Ultrasound (MR-HIFU): Pilot Study in a Swine Model. Huisman, M., Staruch, RM., Ladouceur-Wodzak, M., et al.[2018]

In a study involving 30 male Sprague Dawley rats with common peroneal nerve injury, low intensity focused ultrasound (liFUS) applied to the L5 dorsal root ganglion significantly altered neuronal activity, increasing pyramidal neuron spike frequency in the primary somatosensory cortex (SI) and reducing interneuron firing in the anterior cingulate cortex (ACC).

These changes in neuronal activity occurred 80 to 120 minutes after liFUS treatment and may correlate with improved sensory thresholds, suggesting a potential mechanism for how liFUS can help alleviate neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of low intensity focused ultrasound on neuronal activity in pain processing regions in a rodent model of common peroneal nerve injury. Bao, J., Byraju, K., Patel, VJ., et al.[2022]

Focused ultrasound (FUS) is a promising noninvasive technique for managing chronic pain, with approved uses for thalamotomy in neuropathic pain and treatment of pain from bone metastases.

Different intensities of FUS can produce varying effects: low-intensity ultrasound (LILFUS) can facilitate or suppress neural activity, while high-intensity focused ultrasound (HIFU) can ablate tissue, showing potential for treating conditions like knee osteoarthritis and refractory chronic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focused Ultrasound (FUS) for Chronic Pain Management: Approved and Potential Applications. di Biase, L., Falato, E., Caminiti, ML., et al.[2021]

In a study involving 11 patients with chronic neuropathic pain, low-energy focused ultrasound (FUS) significantly reduced pain levels, with median current pain decreasing from 10.0 to 7.0 after 4 weeks, indicating its efficacy as a treatment.

The procedure was found to be safe, with no reported side effects such as burns or seizures, and no significant changes observed in follow-up brain imaging, suggesting that low-energy tcNgFUS is a noninvasive option for pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low-Energy Transcranial Navigation-Guided Focused Ultrasound for Neuropathic Pain: An Exploratory Study. Shin, DH., Son, S., Kim, EY.[2023]

Low intensity focused ultrasound (liFUS) significantly reduces allodynia in rats with common peroneal nerve injury (CPNI) by increasing mechanical nociceptive thresholds, indicating its potential as a pain management therapy.

liFUS treatment leads to a significant decrease in inflammatory cytokines (such as TNFa, IL6, CNTF, and IL1b) in the dorsal root ganglion and dorsal horn tissues, suggesting that its mechanism of action involves modulating inflammatory pathways associated with neuropathic pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of external low intensity focused ultrasound on inflammatory markers in neuropathic pain. Hellman, A., Clum, A., Maietta, T., et al.[2021]

Transcranial focused ultrasound (FUS) can effectively stimulate the motor area of the brain in rats using lower acoustic intensities (4.9-5.6 W/cm²) with specific pulsing parameters, indicating its potential for safe brain stimulation.

The study found that pulsed sonication is more effective than continuous sonication for eliciting motor responses, suggesting that this method could be optimized for therapeutic applications while adhering to safety limits for biological tissue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focused ultrasound-mediated non-invasive brain stimulation: examination of sonication parameters. Kim, H., Chiu, A., Lee, SD., et al.[2022]

A study involving 120 participants evaluated the safety of low intensity transcranial focused ultrasound (LIFU) for neuromodulation, finding no serious adverse effects and only mild to moderate symptoms reported by 7 participants, which were generally transient.

The symptom profile from LIFU was similar to other non-invasive brain stimulation methods, suggesting that LIFU is a safe option for neuromodulation with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. Legon, W., Adams, S., Bansal, P., et al.[2021]

Low intensity focused ultrasound (liFUS) can modulate pain responses without causing significant heating, as demonstrated in swine models, with magnetic resonance thermometry imaging (MRTI) effectively measuring temperature changes of less than 2.0 °C at the L5 dorsal root ganglion (DRG).

The study identified that referenceless MRTI is capable of accurately detecting small thermal changes, which is crucial for establishing safe parameters for future liFUS therapy in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MR thermometry imaging for low intensity focused ultrasound modulation of spinal nervous tissue. Olinger, C., Vest, J., Tarasek, M., et al.[2023]

Transcranial focused ultrasound (tFUS) can precisely target specific brain areas with low acoustic intensity, effectively modulating brain excitability and potentially promoting neural plasticity for neurorehabilitation.

The review highlights the excellent safety profile of tFUS, but emphasizes the need for new safety guidelines and recommendations for its use in healthy volunteers and clinical settings, based on a comprehensive analysis of acoustic parameters and their effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Review and Perspectives of Transcranial Focused Ultrasound Brain Stimulation. Lee, W., Weisholtz, DS., Strangman, GE., et al.[2023]

High intensity-focused ultrasound (HIFU) can temporarily and reversibly block nerve conduction in diabetic neuropathic rats without causing nerve damage, suggesting its potential for pain relief.

The study involved creating diabetic neuropathic models in rats and successfully demonstrated the ability of HIFU to suppress action potentials in these nerves, paving the way for future clinical applications in ultrasound-based pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An Ultrasonic Tool for Nerve Conduction Block in Diabetic Rat Models. Lee, YF., Lin, CC., Cheng, JS., et al.[2019]

High-density gel polymer matrices are effective couplants for low-intensity focused ultrasound (LIFU) neuromodulation, showing low acoustic attenuation (3.3%) and minimal beam distortion, making them suitable for clinical use.

The study highlights the importance of using standardized methods for preparing these gels to ensure consistent performance, as factors like thickness and de-gassing can significantly affect acoustic transmission and pressure attenuation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of a Novel Acoustic Coupling Medium for Human Low-Intensity Focused Ultrasound Neuromodulation Applications. Strohman, A., In, A., Stebbins, K., et al.[2023]

References

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

Non-Invasive Targeted Peripheral Nerve Ablation Using 3D MR Neurography and MRI-Guided High-Intensity Focused Ultrasound (MR-HIFU): Pilot Study in a Swine Model. [2018]

2. Ireland pubmed.ncbi.nlm.nih.gov

The effects of low intensity focused ultrasound on neuronal activity in pain processing regions in a rodent model of common peroneal nerve injury. [2022]

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

Focused Ultrasound (FUS) for Chronic Pain Management: Approved and Potential Applications. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Low-Energy Transcranial Navigation-Guided Focused Ultrasound for Neuropathic Pain: An Exploratory Study. [2023]

5. Ireland pubmed.ncbi.nlm.nih.gov

Effects of external low intensity focused ultrasound on inflammatory markers in neuropathic pain. [2021]

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

Focused ultrasound-mediated non-invasive brain stimulation: examination of sonication parameters. [2022]

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

A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans. [2021]

8. Netherlands pubmed.ncbi.nlm.nih.gov

MR thermometry imaging for low intensity focused ultrasound modulation of spinal nervous tissue. [2023]

9. Korea (South) pubmed.ncbi.nlm.nih.gov

Safety Review and Perspectives of Transcranial Focused Ultrasound Brain Stimulation. [2023]

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

An Ultrasonic Tool for Nerve Conduction Block in Diabetic Rat Models. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Evaluation of a Novel Acoustic Coupling Medium for Human Low-Intensity Focused Ultrasound Neuromodulation Applications. [2023]