Efficacy and Safety of Transcutaneous Auricular Vagus Nerve Stimulation on Radiotherapy-Related Neuropathic Pain

NCT ID: NCT05543239

Last Updated: 2022-10-12

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 116 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-09-16
• Study Completion Date: 2024-03-01

Brief Summary

This multi-center, randomized, double-blind, sham-controlled trial aims to investigate the effect and safety of TaVNS in treating radiotherapy-related neuropathic pain.

Detailed Description

Radiotherapy-related neuropathic pain(RRNP) is one of the most distressing complications after radiotherapy for head and neck cancers. The prevalence of neuropathic pain in cancer pain patients is as high as 31-45%.Our previous RCT of pregabalin for RRNP showed that nearly 41.6% of patients still did not achieve 30% pain relief even with standard doses of pregabalin. At the same time, drug side effects such as dizziness and obesity are common, and a dose titration process for at least one week is required.Therefore, new treatments that effectively relieve pain and improve quality of life must be explored.

Transcutaneous Auricular Vagus Nerve Stimulation (TaVNS) works by stimulating the auricular branches of the vagus nerve through electrical impulses. Previous studies have shown it can relieve various pains including migraine, cluster headache, musculoskeletal pain with few adverse events. This study plans to evaluate the efficacy of TaVNS versus sham stimulation for relieving RRNP, and assessed its safety.

Conditions

Neuropathic Pain; Radiotherapy Side Effect

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

TaVNS

Patients will receive TaVNS stimulation for 30 minutes, twice a day (between 9:00 to 10:00 and 15:00 to 16:00), for 7 consecutive days. Stimulation pulses (30 Hz frequency, 300 μs pulse width) were generated by a commercial transcutaneous auricular vagus nerve stimulation unit (tVNS 501，Jiangsu, China), and the amplitude was increased to the maximum amount tolerated by the subject without pain, then stimulate for 30 min. All subjects were told that they may or may not feel any sensation from the stimulation, and the unit is packed in an opaque bag throughout the treatment.

Group Type: ACTIVE_COMPARATOR

Transcutaneous Auricular Vagus Nerve Stimulation(TaVNS)

Intervention Type: DEVICE

Transcutaneous Auricular Vagus Nerve Stimulation (TaVNS) works by stimulating the auricular branches of the vagus nerve (mainly distributed in the concha cavity and conchae) through electrical impulses.Electrodes were placed on the concha of the left ear after cleaning the skin of the concha with a small disposable alcohol pad. Stimulation pulses (frequency 30 Hz, pulse width 300 us) were generated by TaVNS device, the amplitude was increased within 30 seconds to the subject produced a tingling sensation, and then descend within 15 seconds to the maximum tolerable amount without pain. Inform the subject that "target stimulus has been reached", then stimulate for 30 minutes.

Sham TaVNS

Patients will receive sham TaVNS stimulation for 30 minutes, twice a day (between 9:00 to 10:00 and 15:00 to 16:00), for 7 consecutive days. Stimulation unit was active for the first 30s, stimulation pulses (30 Hz frequency, 300 μs pulse width) were generated by a commercial transcutaneous auricular vagus nerve stimulation unit (tVNS 501，Jiangsu, China).Then dropped to zero stimulation during 15s and shut down. All subjects were told that they may or may not feel any sensation from the stimulation, and the unit is packed in an opaque bag throughout the treatment.

Group Type: SHAM_COMPARATOR

Sham Transcutaneous Auricular Vagus Nerve Stimulation(SS)

Intervention Type: DEVICE

Place electrodes on the concha of the left ear after cleaning the skin of the concha with a small disposable alcohol pad. The same stimulation pulses (30 Hz frequency, 300 us pulse width) were generated by the same device, the amplitude was increased within 30 seconds to the subject produced a tingling sensation, and then ramps down to zero stimulus over 15 seconds. The subjects were told that "the target stimulus has been reached". Patients receive sham stimulation for 30minutes.

Interventions

Transcutaneous Auricular Vagus Nerve Stimulation(TaVNS)

Transcutaneous Auricular Vagus Nerve Stimulation (TaVNS) works by stimulating the auricular branches of the vagus nerve (mainly distributed in the concha cavity and conchae) through electrical impulses.Electrodes were placed on the concha of the left ear after cleaning the skin of the concha with a small disposable alcohol pad. Stimulation pulses (frequency 30 Hz, pulse width 300 us) were generated by TaVNS device, the amplitude was increased within 30 seconds to the subject produced a tingling sensation, and then descend within 15 seconds to the maximum tolerable amount without pain. Inform the subject that "target stimulus has been reached", then stimulate for 30 minutes.

Intervention Type: DEVICE

Sham Transcutaneous Auricular Vagus Nerve Stimulation(SS)

Place electrodes on the concha of the left ear after cleaning the skin of the concha with a small disposable alcohol pad. The same stimulation pulses (30 Hz frequency, 300 us pulse width) were generated by the same device, the amplitude was increased within 30 seconds to the subject produced a tingling sensation, and then ramps down to zero stimulus over 15 seconds. The subjects were told that "the target stimulus has been reached". Patients receive sham stimulation for 30minutes.

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

1. Male or female patients aged ≥18 years with an estimated survival of at least 5 months;

2. Prior radiotherapy for histologically confirmed cancer ≥ 6 months prior to study entry;

3. Pain for at least 4 weeks with an average intensity of ≥ 4 on an 11-point numeric rating scale (NRS) in the run-in period, and pain locations in accordance with radiated innervated areas, e.g. head, face, neck and arms;

4. Neuropathic pain defined according to clinical history, symptoms, physical signs, and a score ≥ 12 in the Chinese version of Leeds Assessment of Neuropathic Symptoms and Signs questionnaire (LANSS) by two trained and experienced neurology specialists.

Exclusion Criteria

1. Current diagnosis of tumor recurrence or metastasis and evidence of tumor-associated pain;

2. Patients with non-radiotherapy induced neuropathic pain, e.g. postherpetic neuralgia, diabetes mellitus, HIV infection, spinal cord injury and other neurological disease;

3. Use of carbamazepine, gabapentin, pregabalin, TaVNS or transcranial magnetic stimulation within the last 30 days prior to study entry;

4. Other ongoing treatment for neuropathic pain, including antidepressants with norepinephrine and serotonin reuptake inhibition, calcium channel α2-δ ligands and other anticonvulsant medications, and topical lidocaine;

5. Concomitant medication that may cause an adverse interaction with pregabalin, including sedative (e.g., benzodiazepines);

6. Significant renal impairment: plasma creatinine>1.5mg/ml, creatinine clearance < 60 mL/min;

7. History of anaphylactic response to pregabalin;

8. Ulceration of the auricle skin; Diagnosis of mental illness, peptic ulcer,AV III degree block, heart rate< 50/min, heart rate corrected QT interval > 450ms;

9. Patients with cardiac pacemakers or implanted ECG monitoring equipment;

10. Evidence of severe systemic diseases;

11. Subjects with any other condition which, in the investigator's judgment might interfere the outcome of the study;

12. Refuse to provide written informed consent;

13. Cognitive function and language skills are insufficient to complete study questionnaires;

14. Pregnant or lactating women.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Yamei Tang, M.D.;PHD.

Role: PRINCIPAL_INVESTIGATOR

Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University

Locations

Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University

Guangzhou, Guangdong, China

Site Status: RECRUITING

Department of Nasopharyngeal Carcinoma, Sun Yat-Sen University Cancer Center

Guangzhou, , China

Site Status: NOT_YET_RECRUITING

Department of Nasopharyngeal Carcinoma, The Affiliated Cancer Hospital and Institute of Guangzhou Medical University

Guangzhou, , China

Site Status: NOT_YET_RECRUITING

Department of Neurology, The Affiliated Brain Hospital of Guangzhou Medical University

Guangzhou, , China

Site Status: NOT_YET_RECRUITING

Countries

China

Central Contacts

Yamei Tang, M.D.;PHD.

Role: CONTACT

tangym@mail.sysu.edu.cn

+86-020-34070569

Facility Contacts

Yamei Tang, M.D., PhD.

Role: primary

Qiuyan Chen

Role: primary

Dongping Chen

Role: primary

Dong Zheng

Role: primary

References

Zuo X, Xu Y, Li S, Jiang J, Wang J, Zhu Y, Pan D, Li H, Chen Y, Chen Y, Rong X, Zheng D, Lu K, Mai H, Chen M, Chen P, Li J, Simone CB, Chua MLK, Li Y, Shen Q, Xiao S, Tang Y. Efficacy and safety of transcutaneous auricular vagus nerve stimulation plus pregabalin for radiotherapy-related neuropathic pain in patients with head and neck cancer (RELAX): a phase 2 randomised trial. EClinicalMedicine. 2025 Jul 12;86:103345. doi: 10.1016/j.eclinm.2025.103345. eCollection 2025 Aug.

Reference Type: DERIVED

PMID: 40697962 (View on PubMed)

Zuo X, Li Y, Rong X, Yang X, Zhu Y, Pan D, Li H, Shen QY, Tang Y. Efficacy of transcutaneous auricular vagus nerve stimulation on radiotherapy-related neuropathic pain in patients with head and neck cancers (RELAX): protocol for a multicentre, randomised, double-blind, sham-controlled trial. BMJ Open. 2023 Sep 20;13(9):e072724. doi: 10.1136/bmjopen-2023-072724.

Reference Type: DERIVED

PMID: 37730386 (View on PubMed)

Other Identifiers

20220901

Identifier Type: -

Identifier Source: org_study_id