This randomized controlled noninferiority trial will compare effects of ta-VNS and t-SNS in patients with chronic migraine. Participants will be randomly assigned in a 1:1 ratio to either ta-VNS or t-SNS. Outcome assessors will, however, be blinded to group allocation.

After approval by the ethics committee (DMIHER[DU]/IEC/2025/562), eligible participants according to the inclusion criteria will be recruited at the physiotherapy outpatient department (OPD), Centre of Neurosciences and Medicine, Acharya Vinoba Bhave Rural Hospital, Datta Meghe Institute of Higher Education and Research (DMIHER; Deemed to be University [DU]), Sawangi (Meghe), Wardha. All participants will be required to provide written informed consent before participating in the study. Participants selected according to the inclusion criteria will be randomly assigned in a 1:1 ratio to 2 groups. Before the initiation of treatment, the preintervention outcome measures will be recorded, followed by assessments at baseline and at 4, 8, and 12 weeks.

The inclusion and exclusion criteria are provided in Textbox 1.

The study will be conducted among male and female participants diagnosed with chronic migraine by a neurologist and selected based on specific inclusion and exclusion criteria. Participants will be enrolled through simple random sampling using computer-generated numbers. Study procedures will be explained in detail before obtaining informed consent. Using simple random sampling, participants will be randomly assigned to 2 groups: experimental group (t-SNS) and control group (ta-VNS). The experimental group (t-SNS) will receive supraorbital nerve stimulation and conventional physiotherapy, while the control group will receive ta-VNS and conventional physiotherapy. The allocation ratio is 1:1. The effectiveness of the assessment will be assessed by comparing preintervention and postintervention outcomes between groups. Follow-up assessments will be conducted immediately after the 4-week treatment period, at 8 weeks, and at 12 weeks. Nerve stimulation will be administered in 20-minute daily sessions for 4 weeks. Conventional physiotherapy will be administered 3 times per week for 4 weeks in both groups.

t-SNS is also known as external trigeminal nerve stimulation. The maximum skin impedance of the constant-current generator is 2.2 kΩ. In clinical practice, electrical impulses are transmitted via a supraorbital electrode, which stimulates branches of the ophthalmic nerve (V1) located beneath the skin of the forehead. The parameters used for the electrical impulses will include a mean electric current of 0, an impulse width of 250 µs, a frequency of 60 Hz, and a maximum intensity of 16 mA, with a progressive slope from 1 to 16 mA. The electrode will be placed on the forehead. A transcutaneous electrical nerve stimulator device will be used for the stimulation.

The patient will receive 20-minute daily sessions for 4 weeks. As the current intensity progressively increases, the patient will be able to stabilize the intensity when the tingling or prickling sensation in the forehead becomes uncomfortable [13].

The vagal nerve stimulation (VNS) device will generate a proprietary electrical signal that provides a low voltage at its peak, 24 V, and a maximum output current of 60 mA [14]. The NEMOS ta-VNS stimulator device will be placed on the skin of the concha of the ear to provide sensory stimulation to the auricular branches of the vagus nerve. This handheld device will contain a stimulator with an ear electrode that will be placed on the skin of the concha. The device will automatically measure impedance; if the electrode is not in contact with the skin, an alarm will be triggered. During stimulation, a train of electrical pulses (pulse width 250 μs; frequency 1 Hz; duty cycle of 30 seconds on and 30 seconds off, to prevent habituation) will be applied to the skin of the concha. Stimulus intensity will be individually adjusted during visit 2 to elicit a tingling sensation without pain and may be further adjusted by participants as needed [15]. The patient will receive 20-minute daily sessions for 4 weeks.

Conventional physiotherapy will be provided to both the experimental and control groups. It will include the following [16]:

This standardized protocol will be common to both groups.

Participants will receive a daily 20-minute stimulation session for 4 weeks, followed by 45 minutes of conventional physiotherapy after t-SNS or ta-VNS. The preintervention outcome measures will be recorded prior to the initiation of the intervention. Upon completion of the 4-week intervention, the postintervention outcome measures will be collected. To evaluate the long-term effects of the intervention, additional follow-up assessments will be conducted at the eighth week and 12th week after the intervention period.

The sample size was calculated based on values from a reference article (Eslami et al [25]), considering the mean difference in change in headache intensity between baseline and after intervention. The mean change in headache intensity was 5.79 (SD 1.58) at baseline and 4.22 (SD 2.07) in the high-intensity aerobic exercise group (Textbox 2).

Considering a 10% dropout, the revised sample size will be 36+4=40 participants per group. Thus, the total sample size will be 40×2=80 participants.

The estimated period for recruitment, intervention, and data collection will be approximately 3 months. Eligible participants attending the Physiotherapy OPD, Centre of Neurosciences and Medicine, Acharya Vinoba Bhave Rural Hospital, DMIHER (DU), Sawangi (Meghe), Wardha, will be recruited. The time required for participant recruitment and baseline assessment will be approximately 30 to 45 minutes.

Participants will be allocated to either the experimental or control group by simple randomization. The process will follow a 1:1 allocation ratio. Allocation will be performed by the study coordinator, who will not be directly involved in data collection. The randomization list will be kept strictly confidential. Allocation will be performed by the study coordinator in a sequentially numbered fashion using identical, opaque, sealed envelopes.

The recruiting clinicians will be blinded to study group allocation and will not have access to the allocation sequence. Trained clinicians will enroll eligible participants. The study coordinator will independently assign participants to either the intervention or control group. Outcome assessors will be blinded. The analysis team will receive aggregated data for the control and experimental groups.

After informed consent is obtained from participants and they are enrolled in the study, any adverse events will be collected and recorded throughout the study period. Any serious adverse event that occurs will be reported to the principal investigator and documented.

Data will be entered onto a paper-based clinical research form, which will be designed by the research team, by trained clinicians. Data for each participant will be entered, once data collection has been completed, into an electronic database containing checks to ensure completeness of data. Throughout the study, data monitoring will take place on a periodic basis. The database, once verified, will be appropriately saved. The database, once verified to be accurate, will be locked and submitted to an independent statistical team for analysis.

Stata (version 16.0; StataCorp) was used to perform statistical analyses. The primary analysis will follow the intention-to-treat (ITT) principle, including all randomized participants in their allocated intervention groups regardless of protocol deviations or treatment adherence. A per-protocol (PP) analysis will also be performed as a sensitivity analysis, including only participants who complete the study according to the protocol. The primary and secondary outcomes will be analyzed using a mixed-design repeated-measures ANOVA (mixed ANOVA), with group (intervention A and intervention B) as the between-subject factor and time (baseline, after intervention, and follow-up, where applicable) as the within-subject factor. The group×time interaction will be considered the primary indicator of treatment effectiveness. When significant interaction effects are observed, Bonferroni-adjusted post hoc comparisons will be conducted to identify differences between groups and time points. If baseline imbalances are identified or adjustment is required, analysis of covariance (ANCOVA) will be performed using baseline values as covariates to compare postintervention outcomes. For data that do not satisfy parametric assumptions, the Wilcoxon signed-rank test will be used for within-group comparisons, and the Mann-Whitney U test will be used for between-group comparisons. Effect sizes will be reported as partial η² for ANOVA or ANCOVA and Cohen d for between-group comparisons.

Missing data will be assessed to determine the pattern and mechanism of missingness using Little’s missing completely at random (MCAR) test. If the proportion of missing data is less than 5%, a complete-case analysis will be performed. If missing data exceed 5%, multiple imputation (MI) using chained equations will be applied under the assumption that the data are missing at random (MAR), and the primary ITT analysis will be conducted using the imputed dataset. Baseline values of the primary and secondary outcome measures will be included as covariates where appropriate to improve statistical precision and account for any residual baseline imbalance between groups. To control the risk of type I error arising from multiple comparisons, 1 predefined primary outcome will be tested at a significance level of α=.05, while Bonferroni correction will be applied for multiple secondary outcomes and post hoc analyses. All adverse events occurring during the intervention period will be recorded and classified according to severity and their relationship to the intervention. The incidence of adverse events will be summarized using frequencies and percentages and compared between groups using the chi-square test or Fisher exact test, as appropriate. Sensitivity analyses will be performed by comparing the results of the ITT and PP analyses, as well as the findings obtained from complete-case and MI datasets. All statistical tests will use a significance threshold of α=.05 and will be 2-sided. At P<.05, differences will be deemed statistically significant.

The study was registered with the Clinical Trials Registry–India (CTRI) on January 1, 2026, and was approved by the DMIHER (DU) Institutional Ethics Committee (DMIHER[DU]/IEC/2025/562) on October 3, 2025. Prior to their involvement in the study, each participant will provide written informed consent. There is no danger or damage associated with withdrawing from the research at any time, and participation is completely optional. The principal investigator will permit participants to withdraw from the study at any time without imposing any penalties. All information gathered for the study will be kept completely private and used only for research; participant names will not be revealed through disclosure or publication.

Over time, the pharmaceutical treatment of migraine has changed, shifting from a mostly symptomatic approach to a more focused one. For both acute and preventive care, triptans, nonsteroidal anti-inflammatory drugs (NSAIDs), and oral preventive drugs continue to be important choices [26]. Compared to opioids, ergotamine and triptan-containing medications were shown to be more advantageous in a comprehensive review of 29 studies. However, there is a 2-fold increase in migraine development associated with opiates and barbiturates. Conversely, those with a high baseline frequency of migraines are more likely to develop chronic headaches when using triptans. Anti-inflammatory medications, such as NSAIDs, were protective in those who had a lower frequency of headache (<10 days), but similar to triptans, they were associated with an increased risk of migraine progression in those who had a high frequency of headache at baseline (>10 days) [27]. Even with the appropriate use of current acute treatments, there are still unmet therapeutic needs, as not all patients may benefit from these available treatments [27]. Drug therapy, both preventive and abortive, is the foundation of most therapeutic approaches. Conventional pharmaceutical treatments, however, have severe side effects and are only partially successful. Drug resistance and possibly the development of refractory medication-overuse headaches can result from overuse of symptomatic headache medications. Therefore, nonpharmacological therapeutic strategies with better efficacy and tolerance are urgently needed [28]. ta-VNS and t-SNS represent noninvasive neuromodulation techniques that act directly on central pain-processing pathways implicated in migraine pathophysiology. Both modalities influence key brain regions involved in nociceptive modulation, including the trigeminovascular system, locus coeruleus, nucleus tractus solitarius, and cortical pain networks. Previous evidence suggests that ta-VNS enhances parasympathetic activity and activates descending inhibitory pathways, thereby reducing cortical hyperexcitability and central sensitization. Similarly, t-SNS modulates trigeminal nerve afferents, leading to decreased cortical excitability and reduced propagation of migraine-related nociceptive signals [29].

Several studies have demonstrated that both ta-VNS and t-SNS can significantly reduce migraine attack frequency, intensity, and duration when compared with conventional physiotherapy or sham interventions alone. These neuromodulatory effects appear to be more consistent and sustained because of direct central nervous system engagement rather than solely peripheral musculoskeletal mechanisms. Although conventional physiotherapy contributes to symptom relief through postural correction, muscle relaxation, and improved cervical biomechanics, it may not adequately address central sensitization, which plays a critical role in chronic migraine.

The incorporation of ta-VNS and t-SNS alongside conventional physiotherapy may therefore provide a multimodal approach, targeting both central and peripheral mechanisms of migraine. However, limited comparative evidence exists regarding the relative efficacy of ta-VNS vs t-SNS when combined with conventional physiotherapy. This study aims to address this gap by evaluating and comparing their effects on pain intensity, migraine frequency, and functional outcomes. The findings may contribute to evidence-based clinical decision-making and help optimize nonpharmacological management strategies for migraine.

This study protocol proposes to evaluate and compare the effectiveness of ta-VNS and t-SNS combined with conventional physiotherapy in the management of migraine. By targeting central pain modulation pathways along with peripheral musculoskeletal components, the proposed interventions aim to address key mechanisms involved in migraine pathophysiology. The findings of this study are expected to provide valuable evidence regarding the comparative efficacy of these noninvasive neuromodulation techniques and may help to identify an effective, safe, and clinically feasible adjunct to conventional physiotherapy for migraine management. The results may also contribute to the development of standardized, evidence-based physiotherapy protocols for migraine care.