Vagus Nerve Stimulation for Pain Perception

Overseen By Alisa J Johnson

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

Trial Summary

What is the purpose of this trial?

Background: The vagus nerve runs from the brain to many organs. Stimulating it can affect the experience of pain. The nerve can be stimulated on the surface of the left ear. Researchers want to study how this stimulation affects the perception of pain. They also want to study how mood affects the experience of pain. Objective: 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 Design: Participants will be pre-screened with a 15-minute phone call. Participants will have three 2-hour visits. At the screening visit, participants will be screened with: Medical and psychiatric history Physical and psychological exams Questionnaires about physical and psychiatric health and mood Urine tests A heat probe on the forearm. The temperature will be increased until it is painful but tolerable. Participants will have 2 testing sessions within 7 days. Before the testing, they cannot do the following: Eat, use nicotine, or exercise for at least 2 hours Drink alcohol for 24 hours Take certain medicines for 3 days Testing includes: Urine drug screening Left ear stimulation: In one session, the vagus nerve will be stimulated. In the other, an area of the ear away from the vagus nerve will be stimulated. This will be done with mild electric shocks that cause a tingling, pricking, or itchy feeling. Heat applied to the forearm until it is painful but tolerable Completing several forms on a computer or on paper about how they are feeling Monitors on the chest and a finger clip to monitor heart, breathing, and blood pressure

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 data supports the effectiveness of the treatment External Ear Stimulation, Vagus Nerve Stimulation, VNS, External Ear Stimulation for pain perception?

Research shows that vagus nerve stimulation (VNS) can reduce pain in animal studies, and transcutaneous VNS (tVNS), which is a non-invasive method, is being explored for its potential to treat pain and other conditions. Some studies suggest that tVNS may activate pathways in the brain that help manage pain, although more research is needed to confirm its effectiveness. ^{1 2 3 4 5}

Is vagus nerve stimulation safe for humans?

Vagus nerve stimulation, especially the non-invasive type, is generally considered safe with mild and temporary side effects like ear pain, headache, and tingling. Serious complications are rare, and newer non-invasive methods improve safety by avoiding surgery. ^{3 6 7 8 9}

How does the treatment of external ear stimulation for pain perception differ from other treatments?

External ear stimulation, or transcutaneous vagus nerve stimulation (tVNS), is unique because it is a non-invasive method that stimulates the vagus nerve through the skin of the outer ear, unlike traditional invasive VNS which requires surgery. This makes it less expensive, more accessible, and potentially safer with fewer side effects compared to other treatments that require surgical implantation. ^{1 3 4 5 10}

Research Team

Alisa J Johnson

Principal Investigator

National Center for Complementary and Integrative Health (NCCIH)

Eligibility Criteria

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

I am between 18 and 50 years old.

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

References

1. Netherlands 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. [2014]

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

Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans. [2021]

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

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

4. Netherlands pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation and the realm of its therapeutic hopes and physiologic enigmas. [2022]

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

Vagus nerve stimulation attenuates heat- and formalin-induced pain in rats. [2019]

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

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. [2022]

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

Adverse events in children receiving intermittent left vagal nerve stimulation. [2019]

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

Video EEG monitoring prior to vagal nerve stimulator implantation. [2019]

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

Evaluation of different vagus nerve stimulation anatomical targets in the ear by vagus evoked potential responses. [2021]