Vagus Nerve Stimulation for Pain Perception

Overseen By Hayley A Owens

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: National Center for Complementary and Integrative Health (NCCIH)

Must not be taking: Opioids, Antidepressants, Anticonvulsants, others

Disqualifiers: Chronic pain, Major medical, Psychiatric, 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: 3

76 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how stimulating the vagus nerve, located in the left ear, affects pain perception and the role of mood. Participants will experience mild electrical tingling on their ear and heat on their forearm to measure pain perception. It is designed for healthy adults who speak English fluently and do not have chronic pain or major medical conditions. As an unphased trial, this study offers a unique opportunity to contribute to the scientific understanding of pain and mood interactions.

Will I have to stop taking my current medications?

Yes, you may need to stop taking certain medications. If you are taking medications that affect pain or autonomic function, like opioids, antidepressants, anticonvulsants, or blood pressure medications, you must stop them for at least one month or three medication half-lives (whichever is longer) before participating.

What prior data suggests that this vagus nerve stimulation is safe for pain perception studies?

Research has shown that stimulating the vagus nerve through the skin of the ear, known as transcutaneous auricular vagus nerve stimulation (taVNS), is generally safe and well-tolerated. Studies have found that this method usually doesn't cause serious side effects, with most individuals experiencing only mild sensations like tingling or itching at the stimulation site.

In one study, researchers tested taVNS for pain relief in individuals with knee osteoarthritis and found it to be safe. Another study found that taVNS can help increase pain tolerance. Overall, the evidence suggests that using taVNS at the tested levels is safe. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using vagus nerve stimulation through external ear stimulation for pain perception because it offers a non-invasive alternative to traditional pain management methods like medications or surgical interventions. This technique targets the vagus nerve by applying mild electrical stimulation to specific parts of the ear, which is thought to modulate pain perception in the brain. Unlike standard pain treatments that often work by blocking pain signals or reducing inflammation, this method may provide pain relief by altering how pain is processed, potentially leading to fewer side effects and a broader application for different types of pain.

What evidence suggests that vagus nerve stimulation is effective for pain perception?

This trial will compare two methods of vagus nerve stimulation for pain perception. Research has shown that stimulating the vagus nerve can increase pain tolerance, helping people feel less pain. Studies have found that transcutaneous auricular vagus nerve stimulation (taVNS) can safely reduce pain in various conditions. For instance, it helped individuals with knee osteoarthritis experience less pain. Although more research is needed, early findings suggest this treatment could be a promising way to manage pain. ^{4 5 6 7 8}

Who Is on the Research Team?

Alisa J Johnson

Principal Investigator

National Center for Complementary and Integrative Health (NCCIH)

Are You a Good Fit for This Trial?

This trial is for healthy English-speaking adults aged 18-50 who can consent to participate. Excluded are pregnant or breastfeeding individuals, those with major medical conditions, psychiatric disorders, substance abuse issues, certain medication use, ear acupuncture history, dermatological issues on the ears, excessive alcohol consumption, chronic pain history or cardiac function concerns.

Inclusion Criteria

Subjects must be able to provide written informed consent

Subjects must be fluent in English

Exclusion Criteria

I can follow the study's schedule and procedures.

I have a long-term pain condition.

I have a heart condition or a problem with my blood vessels.

Timeline for a Trial Participant

Pre-screening

Participants are pre-screened with a 15-minute phone call to assess initial eligibility.

15 minutes

Screening

Participants are screened for eligibility to participate in the trial

1 visit

1 visit (in-person)

Testing Session 1

Participants undergo testing with vagus nerve stimulation and thermal stimulation on the forearm.

2 hours

1 visit (in-person)

Testing Session 2

Participants undergo a second testing session with a different location of ear stimulation.

2 hours

1 visit (in-person)

Follow-up

Participants are monitored for any changes in mood and pain perception after the testing sessions.

End of study

What Are the Treatments Tested in This Trial?

Interventions

• External Ear Stimulation

Trial Overview The study investigates how stimulating the vagus nerve at the ear affects pain perception and mood. Participants undergo a screening visit followed by two sessions of either direct vagus nerve stimulation or stimulation away from it while experiencing controlled heat pain on their forearm.

How Is the Trial Designed?

Group I: Cymba Conchae Experimental Treatment 2 Interventions

Mild electrical stimulation is applied to the cymba conchae of the left ear, and thermal stimulation is applied to the arms.

Group II: Ear Lobe Active Control 2 Interventions

Mild electrical stimulation is applied to the earlobe of the left ear, and thermal stimulation is applied to the arms.

External Ear Stimulation is already approved in United States for the following indications:

Approved in United States as VNS Therapy System for:

• Treatment-resistant depression
• Epilepsy
• Headaches

Who Is Running the Clinical Trial?

National Center for Complementary and Integrative Health (NCCIH)

Lead Sponsor

Trials

886

Recruited

677,000+

Published Research Related to This Trial

In a study involving 22 healthy male volunteers, transcutaneous vagal nerve stimulation (TVNS) did not show a significant difference in pain threshold (PT) compared to placebo in the overall group analysis.

However, individual responses varied: 15 participants experienced an increase in PT during TVNS, indicating potential pain relief, while 6 participants reported a decrease in PT, suggesting that TVNS can have both pain-relieving and pain-enhancing effects depending on individual sensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagal nerve stimulation may elicit anti- and pro-nociceptive effects under experimentally-induced pain - a crossover placebo-controlled investigation. Laqua, R., Leutzow, B., Wendt, M., et al.[2014]

Transcutaneous vagus nerve stimulation (tVNS) is a promising non-invasive alternative to traditional vagus nerve stimulation (VNS) for treating conditions like epilepsy and depression, which can be invasive and have side effects.

There is ongoing research into the best stimulation parameters and sites for tVNS, particularly focusing on stimulation at the outer ear, to optimize its therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation and the realm of its therapeutic hopes and physiologic enigmas. Hilz, MJ., Bolz, A.[2022]

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]

Vagal nerve stimulation (VNS) is considered a safe alternative therapy for epilepsy, although it can have rare but significant complications.

The study highlights cases of four patients who were implanted with VNS without prior video-EEG monitoring, suggesting a need for better guidelines on the necessity of this monitoring before VNS implantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Video EEG monitoring prior to vagal nerve stimulator implantation. Attarian, H., Dowling, J., Carter, J., et al.[2019]

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive and less expensive alternative to invasive vagus nerve stimulation (VNS), which is used to treat conditions like epilepsy and depression, but requires further research to optimize stimulation sites and parameters.

tVNS has the potential to activate various brain areas and may be effective for a wide range of conditions, including medication-refractory epilepsy, depression, migraines, and more, suggesting it could become a standard treatment for enhancing autonomic function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation - A brief introduction and overview. Hilz, MJ.[2022]

In a study involving 26 subjects, simultaneous stimulation of the cymba and concha (CC) areas of the ear using extra-large electrodes was found to be the most effective for eliciting vagus somatosensory evoked potentials (VSEP), indicating strong neuromodulation effects.

The research demonstrated that the earlobe is not an effective target for taVNS, and using larger electrodes not only increased the amplitude of the response but also made the stimulation more comfortable for participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of different vagus nerve stimulation anatomical targets in the ear by vagus evoked potential responses. de Gurtubay, IG., Bermejo, P., Lopez, M., et al.[2021]

In a study of 24 children undergoing intermittent vagal nerve stimulation over a total of 61 patient years, 15 adverse events were reported, with 13 likely related to the device, indicating a need for careful monitoring during treatment.

Despite the occurrence of adverse events, vagal nerve stimulation was generally well tolerated, and unlike standard drug therapies, these events did not typically require stopping the treatment, although they sometimes led to unexpected surgeries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in children receiving intermittent left vagal nerve stimulation. Murphy, JV., Hornig, GW., Schallert, GS., et al.[2019]

Vagus nerve stimulation (VNS) is effective for treating refractory epilepsy and depression, but traditional methods involve surgical implantation, which carries risks such as infection and bradycardia.

New non-invasive VNS systems eliminate the need for surgery, improving safety and tolerability, and allowing patients to administer stimulation on demand, potentially expanding its use in various medical conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Ben-Menachem, E., Revesz, D., Simon, BJ., et al.[2022]

A stringent vagus nerve stimulation (VNS) protocol (20 s on/18 s off) significantly increased heat pain tolerance in awake rats by an average of 188% after 2 hours, suggesting strong analgesic effects.

A less stringent VNS protocol (30 s on/5 min off) initially decreased heat tolerance but showed significant pain relief after several days of stimulation, indicating potential long-term benefits for pain management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation attenuates heat- and formalin-induced pain in rats. Bohotin, C., Scholsem, M., Bohotin, V., et al.[2019]

Auricular stimulation can trigger acute pupillary responses (PRs), indicating that it may activate noradrenergic pathways in the brain, which are important for therapeutic effects.

The study involved 19 participants and found that higher pulse amplitudes and frequencies led to stronger and quicker pupillary responses, particularly when stimulating the canal area of the ear.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans. Urbin, MA., Lafe, CW., Simpson, TW., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11543973/

Clinical Efficacy of Auricular Vagus Nerve Stimulation in the ... The aim of this systematic review and meta-analysis is to evaluate the clinical efficacy and safety of aVNS in treating chronic and acute pain conditions.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02821741

Effects of External Ear Stimulation on Pain Perception and ... To study the effects of mood and vagus nerve stimulation on the experience of pain. Eligibility: Healthy people ages 18 and older who are fluent in English.

3. thelancet.com thelancet.com/journals/eclinm/article/PIIS2589-5370(25)00277-9/fulltext?rss=yes

Efficacy and safety of transcutaneous auricular vagus ... Previous studies have shown that transcutaneous auricular vagus nerve stimulation (taVNS) can increase the pain threshold in healthy individuals, relieve the ...

4. sciencedirect.com sciencedirect.com/science/article/pii/S2665913124001122

Safety and preliminary efficacy of transcutaneous auricular ... Our preliminary data demonstrated that tVNS may be a safe pain-relieving treatment for people with knee OA.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11543756/

Vagus nerve stimulation (VNS): recent advances and future ... Historically, VNS was found to be an effective treatment for epilepsy, and later, developed as a treatment for major depression [1]. Over the ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9772204/

Safety of transcutaneous auricular vagus nerve stimulation ... This is the first systematic review and meta-analysis of transcutaneous auricular stimulation safety. Overall, taVNS is a safe and feasible option for clinical ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1935861X18302936

Safety and tolerability of Transcutaneous Vagus Nerve ... The available evidence to date suggests that tVNS is well tolerated in humans at the doses tested and is safe.

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11647485/

Safety and preliminary efficacy of transcutaneous auricular ... Our preliminary data demonstrated that tVNS may be a safe pain-relieving treatment for people with knee OA.