Effects of auricular vagus nerve stimulation on increased pain sensitivity

ISRCTN	ISRCTN14751087
DOI	https://doi.org/10.1186/ISRCTN14751087
OSF preregistration ID	https://osf.io/twqux
Sponsor	KU Leuven
Funders	Narodowe Centrum Nauki, Fonds Wetenschappelijk Onderzoek, Onderzoeksraad, KU Leuven

Submission date: 04/03/2026
Registration date: 05/03/2026
Last edited: 05/03/2026

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Signs and Symptoms

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Plain English summary of protocol not provided at time of registration

Contact information

Dr Mikołaj Szulczewski
Principal investigator, Scientific, Public

Institute of Psychology of the Polish Academy of Sciences
Warsaw
00-378
Poland

ORCID ID	0000-0003-1251-3498
Phone	+48 22 583 13 80
Email	mszulczewski@psych.pan.pl

Study information

Primary study design	Interventional
Allocation	Randomized controlled trial
Masking	Blinded (masking used)
Control	Placebo
Assignment	Crossover
Purpose	Basic science
Scientific title	Randomized crossover study of transcutaneous auricular vagus nerve stimulation compared with sham stimulation on high-frequency stimulation–induced secondary mechanical hypersensitivity in healthy women
Study objectives	The study aims to examine whether transcutaneous auricular vagus nerve stimulation (taVNS), compared with sham stimulation, reduces experimentally induced secondary mechanical hypersensitivity following high-frequency stimulation (HFS) in healthy women. A secondary objective is to examine whether taVNS affects affective state (pleasant and unpleasant arousal).
Ethics approval(s)	Approved 08/06/2022, Ethics Committee Research UZ Leuven (Herestraat 49, Leuven, B-3000, Belgium; +32 16 34 86 00; ec@uzleuven.be), ref: S66478
Health condition(s) or problem(s) studied	Experimental secondary mechanical hypersensitivity induced by high-frequency stimulation in healthy women.
Intervention	The study uses a randomized within-subject crossover laboratory design with two conditions: transcutaneous auricular vagus nerve stimulation (taVNS) and sham stimulation. Participants attend two laboratory visits conducted on separate days. In one session, participants receive taVNS and in the other session, sham stimulation. The order of the two conditions is counterbalanced across participants. Randomisation of condition order was performed using block randomisation. Before the experiment, a list was generated in LibreOffice Calc in which each row contained the order of conditions and a random number generated by LibreOffice Calc’s random number generator. The random numbers were then ordered from low to high and this new sequence of ordered conditions was followed, with the first signed-up participant assigned to the first row, the second to the second row, and so on. At the beginning of each session, three electrocardiogram (ECG) electrodes are attached to monitor cardiac activity throughout the experiment. After a 5-minute baseline recording period, participants report their affective state and rate the intensity and unpleasantness of mechanical pinprick stimulation applied to the volar forearm of both arms. High-frequency electrical stimulation (HFS; 2.5 mA) is then applied to one forearm to induce secondary mechanical hypersensitivity. Affective state ratings are collected again following HFS. Electrical stimulation of the left ear is delivered using a DS5 constant-current stimulator (Digitimer Ltd., UK) controlled by MATLAB. In the taVNS condition, a modified NEMOS® electrode is used, with its contacts combined into one pole, while an EEG electrode serves as the second pole. The electrodes are positioned at the cymba conchae and cavum concha to stimulate auricular regions innervated by the vagus nerve. In the sham condition, two EEG electrodes are attached to the earlobe. Stimulation intensity is individually calibrated using a 0–100 sensation scale to reach an intense but non-painful level. Stimulation begins after the HFS procedure and continues until 20 minutes after HFS, during which the post-stimulation assessments are conducted. Affective state ratings are collected again during the post-stimulation assessment period. Mechanical pinprick stimulation is then repeated and participants rate the intensity and unpleasantness of the stimuli. The area of secondary hyperalgesia is assessed by applying pinprick stimulation at 1 cm intervals along the forearm while participants report any change in perceived intensity. After a 20-minute break, a final pinprick stimulation procedure identical to the previous assessment is performed and rated by the participant. At the end of the session, participants report any experienced side effects.
Intervention type	Device
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	DS5 constant-current stimulator, NEMOS® electrode
Primary outcome measure(s)	Secondary mechanical hypersensitivity measured using numerical ratings of pain intensity and unpleasantness evoked by mechanical pinprick stimulation (64 mN) using a 0–100 numerical rating scale at baseline, after high-frequency stimulation and stimulation (taVNS or sham), and 20 minutes after stimulation
Key secondary outcome measure(s)	Affective state measured using pleasant and unpleasant arousal assessed via bipolar scales from the Swedish Core Affect Scale (Västfjäll et al., 2002) at baseline, directly after high-frequency stimulation, and 20 minutes after high-frequency stimulation Heart rate variability measured using root mean square of successive differences between normal heartbeats (RMSSD) derived from electrocardiography (ECG) at baseline, during stimulation (taVNS or sham), and after stimulation
Completion date	14/11/2022

Eligibility

Participant type(s)
Age group	Adult
Lower age limit	18 Years
Upper age limit	35 Years
Sex	Female
Target sample size at registration	32
Total final enrolment	37
Key inclusion criteria	1. Healthy women aged 18–35 years 2. Able to understand spoken and written English 3. Able and willing to comply with study procedures and provide informed consent
Key exclusion criteria	1. Bradycardia, cardiac arrhythmia, or any cardiac disease 2. History of or current neurological disorder 3. Current psychiatric disorder 4. Other serious medical condition 5. Use of chronic and ongoing medication (women using contraceptive pills are allowed) 6. Pregnancy 7. Use of recreational drugs within the past week 8. Recovery from serious trauma or an operation 9. Previous participation in studies using the same stimulation device
Date of first enrolment	07/07/2022
Date of final enrolment	14/11/2022

Locations

Countries of recruitment

Belgium

Study participating centres

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Statistical Analysis Plan			05/03/2026	No	No

Additional files

49137_SAP.pdf: Statistical Analysis Plan

Editorial Notes

04/03/2026: Study’s existence confirmed by the Ethics Committee Research (EC Research) of University Hospitals Leuven (UZ Leuven), Belgium.