Auricular Neurostimulation for Chronic Pain

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: The University of Texas Medical Branch, Galveston

Must be taking: Opioids

Must not be taking: Benzodiazepines, Illicit drugs

Disqualifiers: Cancer, Epileptic seizures, Neurological diseases, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 2 days

60 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

You will need to reduce your pain medication by at least 10% as part of the study. The protocol does not specify stopping other medications, but you must not be taking benzodiazepines or have a high opioid dose.

What data supports the effectiveness of the treatment for chronic pain?

Research suggests that transcutaneous auricular vagus nerve stimulation (taVNS) may have potential pain-relieving effects, as it can modulate pain perception and influence the body's pain control systems. Additionally, taVNS has shown promise in relieving symptoms in conditions like migraines, which may indicate its potential effectiveness for chronic pain. ^{1 2 3 4 5}

Is auricular neurostimulation safe for humans?

Auricular neurostimulation, also known as transcutaneous auricular vagus nerve stimulation (taVNS), is generally considered safe for humans. Most studies report only mild and temporary side effects like ear pain, headache, and tingling, with no severe adverse events linked to the treatment. ^{4 6 7 8 9}

How is transcutaneous auricular neurostimulation different from other treatments for chronic pain?

Transcutaneous auricular neurostimulation (taVNS) is unique because it is a non-invasive treatment that stimulates the vagus nerve through the skin of the ear, potentially offering pain relief without the need for surgery or medication. Unlike other treatments, it uses electrical impulses to modulate pain pathways in the brain, and it is generally considered safe with mild and transient side effects. ^{1 4 5 6 10}

What is the purpose of this trial?

The purpose of the study is to find out how a stimulation device worn on the ear works. This device is thought to stimulate nerves in the area around the ear to change the signals in the brain. The device has been shown to reduce pain and to reduce the symptoms of withdrawal. The investigator will also investigate changes in the way each participant perceive sensations of pressure and heat. The participant will be asked to reduce the amount of pain medication that they take. Then, the participant will spend several days and nights in the Clinical Research Center at UTMB (University of Texas Medical Branch) in Galveston. During that time, the participant will be monitored for withdrawal symptoms and will receive either active (e.g., "real") brain stimulation or sham (e.g., "fake") brain stimulation for two days (four hours each day). At two times over the course of the study (before and after ear stimulation treatment), the participant will complete questionnaires about their pain score and how they are feeling, sensory testing, and will undergo magnetic resonance imaging (MRI) of their brain. The investigator will collect the following information from the participant's medical record: age, gender, medication history, medical diagnoses, recent vital signs, past doctor visits or hospital stays, and results of urine drug tests. Participation in this study will last approximately four days, and the participant will stay in the Clinical Research Center.

Eligibility Criteria

This trial is for adults aged 18-65 with chronic pain, who are on opioid medication and willing to reduce their dose by at least 10%. They must not have a history of seizures, neurological diseases, or ear problems. Participants should test negative for illicit drugs and nonprescribed opioids but positive for prescribed ones. Pregnant women or those at risk of pregnancy without proper contraception are excluded.

Inclusion Criteria

I understand the study and can make decisions about my participation.

I want to lower or stop my opioid medication.

I am willing to reduce my opioid dose by at least 10%.

Exclusion Criteria

I have had a neurological disease or a traumatic brain injury.

I am currently taking prescribed benzodiazepine medication.

I take more than 50 MME of opioid pain medication daily.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 day

1 visit (in-person)

Treatment

Participants receive either active or sham transcutaneous auricular neurostimulation for two days, with four hours of stimulation each day.

2 days

Continuous stay at Clinical Research Center

Monitoring

Participants are monitored for withdrawal symptoms and complete questionnaires, sensory testing, and MRI scans.

4 days

Continuous stay at Clinical Research Center

Follow-up

Participants are monitored for safety and effectiveness after treatment, including completion of questionnaires and MRI.

1 day

1 visit (in-person)

Treatment Details

Interventions

• Transcutaneous Auricular Neurostimulation

Trial Overview The study tests transcutaneous auricular neurostimulation (TAN), a device worn on the ear believed to alleviate pain and opioid withdrawal symptoms by stimulating nerves. Participants will receive either real TAN or sham (fake) treatment while reducing opioid use over four days in a clinical setting.

Participant Groups

Group I: tAN stimulation - active Active Control 1 Intervention

Active or sham auricular stimulation will be conducted using the FDA-cleared tAN device (Sparrow®) manufactured by Spark Biomedical (Dallas, TX). The tAN devices are portable, wearable systems with two channels of stimulation (auricular vagus and auricular trigeminal). Two individual stimulation frequencies will be set: 15 Hz at cymba concha (Region1/Channel 1; vagal innervation) and 100 Hz adjacently anterior to the tragus (Region 2/Channel 2; trigeminal innervation). The pulse duration will be set at 250 µs for all participants. The stimulation intensities (mA) will be set at 1.0 and 1.4 (for Regions 1 and 2, respectively) based on values observed in previous clinical studies. If the participant states that the stimulation intensity is discomforting or unperceivable, the study personnel will gradually decrease/increase the intensity until a comfortable stimulation intensity is achieved

Group II: tAN stimulation - sham Placebo Group 1 Intervention

Active or sham auricular stimulation will be conducted using the FDA-cleared tAN device (Sparrow®) manufactured by Spark Biomedical (Dallas, TX). The tAN devices are portable, wearable systems with two channels of stimulation (auricular vagus and auricular trigeminal). Two individual stimulation frequencies will be set: 15 Hz at cymba concha (Region1/Channel 1; vagal innervation) and 100 Hz adjacently anterior to the tragus (Region 2/Channel 2; trigeminal innervation). The pulse duration will be set at 250 µs for all participants. The stimulation intensities (mA) will be set at 1.0 and 1.4 (for Regions 1 and 2, respectively) based on values observed in previous clinical studies. If the participant states that the stimulation intensity is discomforting or unperceivable, the study personnel will gradually decrease/increase the intensity until a comfortable stimulation intensity is achieved.

Transcutaneous Auricular Neurostimulation is already approved in United States, European Union for the following indications:

Approved in United States as Transcutaneous Auricular Neurostimulation for:

• Chronic pain
• Opioid withdrawal
• Irritable bowel syndrome

Approved in European Union as Transcutaneous Auricular Vagus Nerve Stimulation for:

• Chronic pain
• Temporomandibular disorders

Who Is Running the Clinical Trial?

The University of Texas Medical Branch, Galveston

Lead Sponsor

Trials

263

Recruited

55,400+

Medical University of South Carolina

Collaborator

Trials

994

Recruited

7,408,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

Findings from Research

In a study involving 24 episodic migraine patients, transcutaneous auricular vagus nerve stimulation (taVNS) at 1 Hz significantly increased connectivity in brain regions associated with pain modulation compared to a resting state and to 20 Hz stimulation.

The results indicate that the frequency of taVNS is crucial for its effectiveness, as 1 Hz stimulation produced greater connectivity changes in the descending pain modulation system than 20 Hz, highlighting the importance of optimizing stimulation parameters for migraine treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Different modulation effects of 1 Hz and 20 Hz transcutaneous auricular vagus nerve stimulation on the functional connectivity of the periaqueductal gray in patients with migraine. Cao, J., Zhang, Y., Li, H., et al.[2021]

Transcutaneous auricular vagus nerve stimulation (taVNS) showed promising results in two patients with structural focal epilepsy, leading to seizure freedom in one patient after 4 weeks and significant reduction in seizures for the other after 20 weeks.

Both patients experienced improved quality of life with no significant adverse events reported, suggesting that taVNS could be a safe and effective treatment option for individuals with focal epilepsy and preserved cognitive function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation therapy in patients with cognitively preserved structural focal epilepsy: A case series report. Shiraishi, H., Egawa, K., Murakami, K., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) effectively increases heart rate variability (HRV), indicating a shift towards parasympathetic dominance, with the most significant effects observed at the cymba conchae and fossa triangularis targets.

The study found that HRV increases in a charge-dependent manner, with optimal stimulation parameters being bursts of taVNS at a pulse duration of 100 μs and a current intensity of 2 mA, suggesting these parameters are both comfortable and effective for enhancing HRV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation and heart rate variability: Analysis of parameters and targets. Machetanz, K., Berelidze, L., Guggenberger, R., et al.[2021]

Transcutaneous auricular Vagal Nerve Stimulation (taVNS) did not show any significant effects on pain perception or nociception in healthy participants, as measured by event-related potentials and sensory testing across three experiments involving 22 and 15 subjects.

Both taVNS and standard cervical VNS (cVNS) failed to produce objective changes in behavioral and cerebral responses to pain stimuli, suggesting that the analgesic effects of taVNS may not be as effective as previously thought.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular VNS applied to experimental pain: A paired behavioral and EEG study using thermonociceptive CO2 laser. Dumoulin, M., Liberati, G., Mouraux, A., et al.[2021]

In a study involving 17 healthy adults, transcutaneous auricular vagus nerve stimulation (taVNS) at the left tragus significantly increased brain activity in areas associated with the vagal pathway, indicating its potential efficacy in neuromodulation.

Compared to control stimulation at the earlobe, tragus stimulation resulted in greater activation in key brain regions, suggesting that taVNS could be a promising therapeutic approach for influencing brain function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review. Badran, BW., Dowdle, LT., Mithoefer, OJ., et al.[2020]

Transcutaneous auricular vagus nerve stimulation (taVNS) is generally safe, with a low incidence of mild and transient adverse effects, such as ear pain, headache, and tingling, reported in only 24.86% of the studies analyzed.

In a systematic review of 177 studies involving 6322 subjects, there was no significant difference in the risk of adverse events between taVNS and control groups, indicating that taVNS is a feasible option for clinical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Kim, AY., Marduy, A., de Melo, PS., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) is a safe and effective neuromodulation therapy for a variety of conditions, including epilepsy, depression, and anxiety, indicating its broad therapeutic potential.

Despite its effectiveness, there is currently no standardization among taVNS devices, and further research is needed to clarify the relationship between stimulation parameters and therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulators: a review of past, present, and future devices. Wang, L., Wang, Y., Wang, Y., et al.[2022]

Transcutaneous auricular vagus nerve stimulation (TaVNS) effectively normalized gastric dysrhythmias in healthy individuals during a water-load test, indicating its potential as a treatment for gastric symptoms.

The study found that TaVNS at 40 Hz improved heart rate variability and reduced bloating, suggesting it positively influences both parasympathetic and sympathetic nervous system pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Auricular Vagus Nerve Stimulation Normalizes Induced Gastric Myoelectrical Dysrhythmias in Controls Assessed by Body-Surface Gastric Mapping. Du, P., Maharjan, A., Calder, S., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) is a safe and well-tolerated method for treating conditions like drug-resistant epilepsy, but a recent randomized double-blind trial found no significant difference in outcomes between high- and low-stimulation groups.

The most common side effect of taVNS is a tingling sensation or pain at the stimulation site, and while it shows promise, further research is needed to fully understand its efficacy and to potentially gain approval for insurance coverage in Japan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Application of Transcutaneous Auricular Vagus Nerve Stimulation]. Yamamoto, T.[2022]

Vagus nerve stimulation (VNS), particularly through non-invasive methods like transcutaneous VNS (tVNS), shows promise for treating various clinical disorders, including heart failure and migraines, by stimulating the auricular branch of the vagus nerve without the need for surgical implantation.

Current research highlights the need for more detailed studies on the neuroanatomy of the auricular branch of the vagus nerve (ABVN) to better understand its therapeutic effects and optimize stimulation parameters, as existing literature lacks consensus on the most effective stimulation sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anatomical basis for transcutaneous auricular vagus nerve stimulation. Butt, MF., Albusoda, A., Farmer, AD., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Different modulation effects of 1 Hz and 20 Hz transcutaneous auricular vagus nerve stimulation on the functional connectivity of the periaqueductal gray in patients with migraine. [2021]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation therapy in patients with cognitively preserved structural focal epilepsy: A case series report. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation and heart rate variability: Analysis of parameters and targets. [2021]

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

Transcutaneous auricular VNS applied to experimental pain: A paired behavioral and EEG study using thermonociceptive CO2 laser. [2021]

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

Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: A concurrent taVNS/fMRI study and review. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. [2023]

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

Transcutaneous auricular vagus nerve stimulators: a review of past, present, and future devices. [2022]

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

Transcutaneous Auricular Vagus Nerve Stimulation Normalizes Induced Gastric Myoelectrical Dysrhythmias in Controls Assessed by Body-Surface Gastric Mapping. [2023]

9. Japan pubmed.ncbi.nlm.nih.gov

[Clinical Application of Transcutaneous Auricular Vagus Nerve Stimulation]. [2022]

10. England pubmed.ncbi.nlm.nih.gov

The anatomical basis for transcutaneous auricular vagus nerve stimulation. [2022]