Auricular neuromodulation by low level laser therapy versus placebo laser therapy in prophylactic treatment of episodic migraine: a randomized controlled study protocol

Abstract

Background

Migraine is a ubiquitous condition affecting more than 1 billion people worldwide. Prophylactic first-line treatments are hindered by unsatisfactory tolerability, and the accessibility of second-line treatment is hampered by cost or regulatory provisions.

Auricular acupuncture and auriculotherapy appear to be effective as prophylactic treatments for migraines but are based only on secondary outcome measures or case series. Auricular neuromodulation is a recent technique that uses the stimulation zones of the auricle described by these two methods but with a different rationale. No study has compared the efficacy of auricular neuromodulation in the prophylactic treatment of episodic migraines with that of low-laser-level therapy (LLLT) with that of a placebo.

Methods

This double-blind randomized placebo-controlled two-arm study will include 106 adult patients suffering from episodic migraines, i.e., with the number of days of migraines ranging from 4–15 days per month. After randomization, patients benefit from three sessions of LLLT or sham LLLT on selected zones of the ear, one month apart. Efficiency will be assessed by measuring the number of days of migraine week 9–12 compared with the number of days of migraine 4 weeks before the first session.

Discussion

This study will assess whether three sessions of LLLT on selected zones on the ear, one month apart, increase the number of migraine-free days for patients suffering episodic migraine. This study is the first to demonstrate the efficacy of a noninvasive procedure in a placebo-controlled two-arm study.

Trial registration

This trial was registered in the US National Library of Medicine with the identifier NCT06623188. First registered: September 30, 2024. Last updated: October 2nd, 2024.

Introduction

Background and rationale

Migraine is a ubiquitous neurological condition affecting more than 1 billion people worldwide [1]. The main feature of migraine is recurrent headache attacks lasting 4 to 72 h with moderate to severe pain intensity [2]. The diagnosis is supported by clinical features such as unilateral pulsatile pain, nausea or vomiting, photophobia and phonophobia [3]. Pharmacologic therapy comprises two parts: acute treatments that aim to relieve pain from migraine attacks and preventive treatments that aim to reduce migraine frequency, duration and severity. Most traditional preventive treatments have not been developed for the indication of migraine: they are antihypertensive agents such as candesartan or propranolol, antiepileptic agents such as topiramate, or antidepressant agents such as amitriptyline. The use of these traditional treatments is hampered by their unsatisfactory tolerability and safety profiles, and they reduce the mean number of migraine days by month from 0.4 to 1.5 days [4]. Recently, new treatments have been proposed for chronic migraine, such as onabotulinum toxin A (Botox®) and chronic or episodic migraine, such as calcitonin gene-related peptide (CGRP) monoclonal antibodies or CGRP receptor antagonists [2]. The prescription of these new treatments is restricted in France by regulatory provisions.

In addition to pharmacologic therapies, nonpharmacological approaches, such as acupuncture or noninvasive devices, have some benefits [5, 6]. Noninvasive vagal nerve stimulation has been shown to reduce pain in acute migraine patients up to 60 min after an attack, but this stimulation is cervical [7]. Because the sensory innervation of the concha is conveyed by the auricular branch of the vagus nerve, its stimulation was conceived as a noninvasive alternative method to stimulate the vagus nerve. Auricular neuromodulation is a recent concept that goes beyond transauricular vagal stimulation [8]. It includes other mechanisms, such as trigeminal stimulation or superficial cervical plexus stimulation via auricular pavilion. It focuses on auricular mapping described by traditional approaches such as auriculotherapy or auricular acupuncture as areas of interest for stimulation while acknowledging the lack of scientific validation for all the described points. Auriculotherapy, a traditional method thought to elicit transauricular vagal nerve stimulation, has been shown to reduce the intake of triptans, the number of days with nonmigraine headaches and the MIDAS score in a controlled multicenter open study [9]. However, no double-blind randomized study investigating the effectiveness of auricular stimulation for migraine prevention has been conducted, and no study has used a noninvasive and harmless means of stimulation.

Low-level laser therapy (LLLT) is a therapeutic modality that involves the application of low-intensity laser light to biological tissues [10]. This noninvasive modality has been explored for a wide range of applications, including pain management, wound healing, and dermatological conditions, with proposed mechanisms of action involving photobiomodulation of cellular processes. LLLT is effective for acupuncture-based pain treatment [11]. However, its use for ear acupuncture is less well researched, and no studies have investigated the effectiveness of LLLT for treating migraine through ear stimulation.

Objectives

The objectives of this study were to demonstrate that 3 sessions of auricular modulation by LLLT, one month apart, reduce the number of migraine days, duration of migraine attacks, use of medication for functional disability and increase quality of life.

Trial design

This multicenter, randomized, double-blind, placebo-controlled superiority trial will assess the efficacy of auricular neuromodulation for the preventive treatment of migraine. The allocation ratio will be 1:1 with two parallel groups, one with sham stimulation and the other with true stimulation.

Methods

Participants, interventions and outcomes

Study settings

This multicenter double-blind study will be performed in one secondary hospital, two tertiary hospitals and a private office.

Eligibility criteria

Inclusion criteria

1. Adult men and women aged 18–65 years.

2. With at least a 1-year history of migraine with or without aura, as defined by the International Classification of Headache Disorders, 3rd edition [3], and an initial presentation of migraine before 50 years.

3. The participants will have to have at least 4 but not more than 15 moderate to severe migraine attacks per month, with one month being defined as 4 weeks.

4. Participants will have to be able to distinguish migraine attacks from tension-like headaches.

5. Participants will have to be able to fill out a migraine tracking diary daily.

6. The participants will have to provide their written consent after providing thorough information about the study.

Noninclusion criteria

1. Patients with cutaneous infection, inflammation, defects, or cancer of the pinna.

2. Patients with piercings or ear gauges.

3. Patients under treatment with anti-CGRP monoclonal antibodies or CGRP receptor antagonists: last injection administered within 90 days prior to inclusion.

4. Patients treated by auricular acupuncture, auriculotherapy or auricular neuromodulation techniques: last treatment performed within 180 days prior to inclusion, regardless of the method of stimulation, whether invasive (e.g., acupuncture needles) or noninvasive (e.g., LASER)

5. Patients with a history of cluster headache, cranial surgery, or malignant brain tumors.

6. Untreated severe obstructive sleep apnea.

7. Patients treated with beta blockers (propranolol, atenolol, etc.), sartans (candesartan, etc.) or antidepressants, with the exception of amitriptyline if the dosage was less than 75 mg per day and clomipramine if the dosage was less than 20 mg per day.

Informed consent

Informed consent from potential trial participants will be obtained from the investigators of the study.

Interventions

Choice of comparators

The active comparator is an LLLT delivering 1.25 J on each stimulated point with a brand-made frequency protocol to avoid any warming of the skin. The placebo comparator is a device with the same appearance and emitting the same noise as the active LLLT but with no laser beam emission. Neither the patient nor the practitioner can distinguish the active comparator from the placebo.

Intervention description

Three sessions of auricular neuromodulation are scheduled and follow the same procedure. Ten auricular points are assessed on each pinna via two different methods to find the most reactive points. Table 1 and Fig. 1 list the 10 points and their locations, respectively.

Table 1.

Locations of auricular points

Points #	Auricular points (WFCMS)	Auricular points (WFAS)	Anatomical location
1	Locus coeruleus	LO 6	On the lobe of the ear
2	Trigeminal point	LO 6 – LO 9	On the lower and posterior part of the lateral side of the lobe of the ear
3	Thalamus	AT 4	On the inner side of the antitragus
4	Marvellous point	AH 8	On the root of the anthelix
5	Sympathetic masterpoint	SF 5	At the bottom of the scapha
6	Reticular masterpoint	AT 1 – AT 2	On the apex of the antitragus
7	Spinal nerve point	R3	On the medial side of lobe of the ear
8	Sensory masterpoint	LO 5	At the middle of the lobe of the ear
9	Superficial cervical plexus	HX 12	At the end of the tail of the helix
10	Brainstem	LO 3	On the medial side of the antitragus

WFCMS World Federation of Chinese Moxibustion Societies, WFAS World Federation of Acupuncture-Moxibustion Societies

Fig. 1.

Localization of ear points likely to be stimulated

To assess the points, two methods are used. The first method is to measure the impedance of the point via a detector (PREMIO 20®, Sedatelec, Irigny, France). The impedance is measured via a differential detection principle. The detector uses two electrodes, a central electrode and a peripheral electrode, separated by 1 mm. The patient acts as a ground reference and holds a ground electrode handle. The detector measures the differential impedance by comparing the impedance between the central electrode and ground to that between the peripheral electrode and ground. When the probe is placed on a point, the device returns a light signal, allowing the decrease in impedance to be quantified on a scale ranging from 1–10. The second method involves physically stimulating the point with a 250 g calibrated probe and assessing the resulting pain on a 0–10 visual analog scale. Figure 2 illustrates the two methods.

Fig. 2.

The two methods used to assess the points. A Mechanical probe calibrated to 250 g of pressure; B Impedance meter using differential detection. Copyright Sedatelec, Irigny, France, with permission

Four out of ten points are stimulated. These four points are selected on the basis of their impedance, retaining only those with the lowest impedance. If more than four points have the lowest impedance, only the first four points will be retained in the specified order. If fewer than four points have the lowest impedance, the four first points will be stimulated.

Criteria for discontinuing or modifying allocated interventions

The protocol does not allow for changing the allocation for a subject owing to the absence of expected side effects. However, the subject may leave the study at any time and without explanation if they wish.

Strategies to improve adherence to interventions

Because the intervention is performed by the investigator and not the subject, there is no policy aimed at improving patient adherence. However, a subject’s absence from an appointment will systematically prompt a follow-up phone call.

Relevant concomitant care and interventions that are permitted or prohibited during the trial

Throughout the trial, any therapy involving the earlobe, such as acupuncture, acupressure, or auriculotherapy, is not permitted. Similarly, any permanent alteration of the earlobe, such as piercing, is prohibited. However, there are no restrictions on the treatment of acute migraine attacks.

Outcomes

The primary outcome is the number of migraine days in the last 4 weeks of treatment, i.e., weeks 9–12, compared with the initial assessment period (4-week pretreatment observation).

The secondary outcomes are as follows:

1. Number of days without migraines or headache

2. Migraine attack duration

3. Rate of responders, i.e., patients with a 50% reduction in the number of migraine days after treatment compared with the initial assessment period (4-week pretreatment observation).

4. Quality of life of patients measured by the SF-36 questionnaire [12]

5. Functional disability due to headache or migraine as measured by the MIDAS and HIT-6 questionnaires [13, 14]

6. Use of rescue medication

7. Number of days with no medication

Participant timeline

Figure 3 and Table 2 present the time schedules of enrollment, interventions and visits for the participants.

Fig. 3.

Study visit schedule

Table 2.

Flowchart of the study

	STUDY PERIOD
	Enrollment				Allocation	Post allocation				Close out
Timepoint	-t4	-t3	-t2	-t1	0	t1	t2	t3	t4	t5
Enrolment
Preeligibility screen	X
Eligibility screen		X
Washout period, if applicable			X
Informed consent				X
Run-in period				X	X
Allocation					X
Interventions
Sham LLLT					X	X	X
Verum LLLT					X	X	X
Assessements
Primary outcome					X			X
Secondary outcomes					X	X	X	X	X	X
SF-36					X	X	X	X		X
MIDAS					X	X	X	X		X
HIT 6					X	X	X	X		X

Sample size

Sample size calculation was performed using the PROC POWER procedure under SAS 9.4 (SAS Institute, Cary, NC, USA). The primary hypothesis of this study was that the average number of migraine days would be lower in the group of patients receiving auricular neuromodulation (verum) compared to the sham (placebo) group.

To detect a mean difference of at least three days between the verum and sham groups, assuming a standard deviation of 5 days, with a two-sided alpha level of 0.05 and a statistical power of 80%, a minimum of 90 participants (i.e., 45 per group) is required.

Anticipating a 10% dropout rate, at least 50 patients per group need to be enrolled to preserve adequate statistical power. Additionally, a prerandomization exclusion rate of approximately 5% is expected. Consequently, 53 participants per group, for a total of 106 patients, will be included to meet the study requirements.

Recruitment

Recruitment will be conducted through general practitioners and neurologists, whether hospital-based or private, within a defined area surrounding one of the investigation centers corresponding to a community healthcare sector (in French, ‘Communauté Professionnelle Territoriale de Santé’, meaning ‘territorial professional health communities’, each of which is a local network of healthcare professionals aimed at coordinating care within a defined territory).

Assignment of interventions

Allocation

The allocation sequence is generated by REDCap software v14.5.18 [15] without stratification. The use of this software makes allocation concealment unnecessary. The latter will be performed in RedCap software by the clinical research associate of the principal investigator’s center during the inclusion of the subject by one of the investigators.

Blinding

After assignment to the intervention, all participants will be blinded, i.e., trial participants, investigators, care providers, outcome assessors and data analysts.

Unblinding is not planned during the trial, as the intervention has no side effects.

Data collection, management and analysis

Data collection methods and management

Data will be recorded by the investigators via a paper case report form and then transcribed into the REDCap database by research assistants. All patients are anonymized via an identification number when their data are entered into REDCap. Therefore, no clear names are recorded. Access to the database is restricted to the principal investigator, the data scientist and the research assistants.

Statistical methods

Statistical analyses will be performed via SAS v9.4 (SAS Institute, Cary, NC). Overall, data will be described according to their type, using means (standard deviations) and medians (interquartile ranges), or counts and percentages [95% confidence intervals (CIs)]. No method of imputing missing data is planned. All analyses will be performed on an intention-to-treat basis.

Subgroup analyses may be conducted. Quantitative data will be compared between groups via Student’s t test, provided that the distributions follow a normal distribution; the normality assumption of the distributions will be evaluated via the Shapiro‒Wilk test. In cases of nonnormality, data will be compared via nonparametric tests on the basis of their type (Wilcoxon, Kruskal‒Wallis). Qualitative data will be compared between groups via the chi-square test or Fisher’s exact test when appropriate.

For the primary outcome, the means and standard deviations of the average number of migraine days before treatment and after 12 weeks of treatment (averages over weeks 9 to 12) will be reported for each group. An analysis of covariance (ANCOVA) will be performed on the results of the average number of migraine days at the end of the treatment period to compare the intervention groups. The analysis accounts for an adjustment based on pretreatment values. The results will be interpreted at a significance level of alpha = 0.05.

For the secondary outcomes:

• Number of days without migraine or headache: the means and standard deviations of the average number of migraine days before treatment and at the end of treatment (three months after the end of treatment) will be reported for each group. An ANCOVA will be performed on the results of the average number of migraine days at t₅ (Fig. 2) to compare the intervention groups. The analysis will be adjusted for pretreatment values.

• Migraine attack duration: the means and standard deviations of the duration of migraine attacks will be reported for each group at each follow-up time (pretreatment, t₃, and t₅). Two-factor repeated measures analysis of variance (ANOVA) will be performed to assess differences in attack duration between the intervention groups.

• Rate of responders: the rate will be expressed as a percentage for each group and will be determined independently at t₃ and t₅. A patient will be considered a responder if a reduction of at least 50% is observed in the number of migraine days between pretreatment and t₃ and then t₅. The rates will be compared between the intervention groups via the chi-square test or Fisher’s exact test, depending on the statistical conditions.

• Quality of life: the means and standard deviations of the SF-36 quality of life score will be reported for each group at each follow-up time (pretreatment, t₃ and t₅). Two-factor repeated-measures ANOVA will be performed to assess differences in quality of life between the intervention groups.

• Functional disability: Using the same approach as the previous secondary outcome, the means and standard deviations of the MIDAS and HIT-6 questionnaires assessing functional disability will be reported for each group at each follow-up time (pretreatment, t₃ and t₅). Two-factor repeated-measures ANOVA will be performed to assess differences between the intervention groups.

• Use of rescue medication: The use of antimigraine medication will be reported by frequency and the rate of patients who used medication at each follow-up time (pretreatment, t₃ and t₅). The rates will be compared between the intervention groups via the chi-square test or Fisher’s exact test, depending on the statistical conditions. Additionally, a mixed-effects repeated measures model will be performed to assess differences between the intervention groups in terms of frequency of use, types of medication, dosage, and duration.

• Number of days with no medication: the means and standard deviations of the number of days without medication will be reported for each group at each follow-up time (pretreatment, t₃ and t₅). Two-factor repeated-measures ANOVA will be performed to assess differences in the number of days of treatment between the intervention groups.

Monitoring

This study will include a steering data committee that includes the Clinical Research Director of the main center, the Project Manager, and the Data Manager.

A data monitoring committee is not needed because there are no competing interests and all investigators are independent from the sponsor.

Ethics and dissemination

The participants and their health care providers will be informed of the trial results by the principal investigator. The principal investigator will oversee communicating the results via oral communications and publications through peer-reviewed academic journals.

Research ethics approval

The study was approved by the French ethics committee (“Comité de Protection des Personnes EST I”) under reference 2024-A01258-39 on 27/08/2024.

Protocol amendments

The protocol amendments will be reported to the regulatory authorities, practitioners, and participants and will result in modifications to the information sheets if necessary.

Consent or ascent

Not applicable.

Confidentiality

All study staff and investigators have completed human subject research training, including training on policies regarding participant privacy. All are also trained in research procedures. The data files are locked. Each subject is assigned a unique numerical ID. Consent forms are stored in locked cabinets within locked offices.

Declaration of interest

The authors declare that they have no competing interests in relation to this study.

Access to data

The datasets used and analyzed during the current study will be available from the principal investigator upon reasonable request.

Ancillary and posttrial care

No side effects were anticipated from this study. Therefore, no compensation is anticipated, should participants experience harm during this study.

Dissemination policy

All findings will be documented in ClinicalTrials.org. The study results will be disseminated through peer-reviewed publications and presentations at both domestic and international conferences. A public outreach campaign will be conducted via traditional and social media.

Discussion

A few studies have investigated the efficacy of ear stimulation for the treatment of episodic migraine. Ceccherelli et al. compared somatic acupuncture with ear acupuncture in an open study including 35 patients [16]. Ear stimulation was performed with acupuncture needles. After electrical and mechanical detection, 6 points were stimulated on each ear. Of these 6 points, 3 points were identical from one patient to another (aggressiveness point, lung, or thalamus), and 3 points differed between patients, depending on the decrease in impedance observed using an ohmmeter (Agiscop®, Sedatelec, Irigny, France). Weekly sessions were performed for 8 weeks. Auricular acupuncture was efficient for up to 6 months after the end of the procedure, with the migraine index decreasing by 50%. However, the absence of a control group, blinding, and validated outcome criteria makes interpretation challenging.

Habibabadi et al. compared ear acupuncture versus sham in a single-blinded study including 80 patients [17]. Ear stimulation was performed via semipermanent needles (ASP®, Sedatelec, France). Four out of 20 preselected points were needled on the basis of the decrease in impedance measured via an ohmmeter (Pointoselect®, Jiajian, China). Two sessions were performed two weeks apart. The mean number of weekly migraine days decreased more significantly in the treatment group than in the placebo group. However, the results may be biased due to the lack of true blinding (as the control group was not needled) and the outcome criterion being based on a weekly rather than a monthly basis. Allais et al. studied the efficacy of ear acupuncture in an open-label study involving 16 patients [18]. Ear stimulation was performed via semipermanent needles (ASP®, Sedatelec, France). Three sessions were scheduled 3 weeks apart. The mean number of migraine days per month ranged from 21.9 ± 4.1 days before the study to 16.3 ± 6.3 days at the second month of the study. The small sample size and the absence of a control group reduced the scope of the study, as noted by the authors. Cherqui et al. conducted an open-label study comparing the efficacy of auriculotherapy in preventing episodic migraine in 90 women divided into two groups. The first group received auriculotherapy treatment in three sessions, one month apart, using ASP according to a preestablished protocol. The second group received standard treatment without auriculotherapy. The primary outcome, the number of migraine days, was identical in both groups, but triptan consumption was lower and the MIDAS score was improved in the auriculotherapy group. This study was limited by the lack of blinding.

This study has the following strengths. First, this study was designed to be double-blinded and has never been performed before when the efficacy of auriculotherapy or ear acupuncture in the preventive treatment of migraines was studied. Second, the primary outcome measure was that used in clinical trials evaluating the efficacy of anti-CGRP agents in the treatment of episodic migraine. This allowed for a direct comparison of the effects of auriculotherapy with those of established pharmacological treatments. Finally, this study is the first to investigate the efficacy of LLLT in the treatment of episodic migraine.

Authors’ contributions

ES Conceived the study, wrote the draft of the protocol. EK Contributed to conceiving the study. GG Contributed to conceiving the study. HF Contributed to designing the study. GP Provided statistical expertise and contributed to the design of the study. MB Contributed to designing the study and writing the draft of the protocol. CB Designing the study and writing the draft of the protocol.

Funding

This study was supported by a grant from the French Ministry of Health (ReSP-Ir 2022/N).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Informed and written consent will be obtained from all individual participants included in the study.

Consent for publication

Not applicable.

No data that could identify a participant will be published. Furthermore, no subject photographs will be disseminated.

Competing interests

The authors declare no competing interests.