Non-invasive vagus nerve stimulation for prevention of migraine: The multicenter,randomized,double-blind,sham-controlled PREMIUM II trial

Abstract

Aim

Evaluate the efficacy and safety of non-invasive vagus nerve stimulation for migraine prevention.

Methods

After completing a 4-week diary run-in period, adults who had migraine with or without aura were randomly assigned to receive active non-invasive vagus nerve stimulation or sham therapy during a 12-week double-blind period.

Results

Of 336 enrolled participants, 113 (active, n = 56; sham, n = 57) completed ≥70 days of the double-blind period and were ≥66% adherent with treatment, comprising the prespecified modified intention-to-treat population. The COVID-19 pandemic led to early trial termination, and the population was ∼60% smaller than the statistical target for full power. Mean reduction in monthly migraine days (primary endpoint) was 3.12 for the active group and 2.29 days for the sham group (difference, −0.83; p = 0.2329). Responder rate (i.e. the percentage of participants with a ≥50% reduction in migraine days) was greater in the active group (44.87%) than the sham group (26.81%; p = 0.0481). Prespecified subgroup analysis suggested that participants with aura responded preferentially. No serious device-related adverse events were reported.

Conclusions

These results suggest clinical utility of non-invasive vagus nerve stimulation for migraine prevention, particularly for patients who have migraine with aura, and reinforce the well-established safety and tolerability profile of this therapy.

Trial Registration: ClinicalTrials.gov (NCT03716505).

Keywords

Neuromodulation preventive therapy migraine prophylaxis nonpharmacologic treatment clinical trial

Introduction

Migraine is a chronic headache disorder with an estimated worldwide 1-year prevalence of 15% (1). Despite the availability of numerous options for both acute and preventive treatment, migraine remains a substantial global burden and the leading cause of disability in individuals younger than 50 years of age (1). Oral and parenteral migraine preventive treatments, including calcitonin gene-related peptide–targeted agents, are not always effective and are associated with significant side effects in some people (2). Many patients seek non-pharmacologic options such as neuromodulation.

Non-invasive vagus nerve stimulation (nVNS) is an effective treatment for many primary headache disorders (3 –14) and is suggested in one review as a first-line acute treatment for cluster headache (15). In 2019, the PREMIUM I study evaluated the clinical utility of nVNS in migraine prevention, suggesting possible greater clinical benefit among patients with aura than those without aura (4). Certain limitations of PREMIUM I, including suboptimal therapeutic adherence and the use of a sham device that produced some level of vagal activation, likely contributed to the study’s failure to achieve significance on its primary endpoint. The current report presents the PREMIUM II study, which was designed to address the limitations of PREMIUM I while providing additional data to substantiate and complement its findings.

Methods

Study design

PREMIUM II was a multicenter, randomized, double-blind, sham-controlled study conducted between 8 November 2018 and 13 May 2020 at 27 US sites. It began with a 4-week diary run-in period with no study treatment, followed by randomized assignment to either nVNS or sham therapy during a 12-week double-blind period.

Standard protocol approvals, registrations, and patient consents

The study protocol, including the informed consent form, was approved by the institutional review board for each study site before the enrollment of any participants. All participants provided informed consent before undergoing any study-specific procedures. The trial is registered at ClinicalTrials.gov (NCT03716505).

Data availability

Any data not published in this article will be publicly available at ClinicalTrials.gov with the identifier NCT03716505. Individual participant data will not be shared.

Participants

Patients aged 18 to 75 years with a diagnosis of episodic or chronic migraine with or without aura according to International Classification of Headache Disorders, 3rd edition (ICHD-3) (16), criteria were eligible for participation. Eligible patients were ≤50 years of age at migraine onset and had experienced 8 to 20 headache days per month during the preceding 3 months, with at least 5 of them being migraine days (i.e. those on which headaches either lasted >4 hours or were treated with a migraine-specific acute treatment). Key exclusion criteria included a regimen of ≥2 migraine preventive therapies, injections of onabotulinumtoxinA or calcitonin gene-related peptide–targeting monoclonal antibody drugs within the last six months, a previous diagnosis of medication overuse headache that had reverted to migraine within the preceding three months, and a preceding history or suspicion of a secondary headache disorder. Complete inclusion and exclusion criteria are provided in Supplemental Table 1.

Participants were permitted to use prescribed or over-the-counter treatments to acutely treat migraine attacks. Changes in the type, dosage, or frequency of any preventive medication for indications other than migraine that, in the opinion of the investigator, might interfere with the study were not permitted. Participants were reassessed for eligibility at the end of the run-in period. Those who adjusted their preventive medications, no longer met all the inclusion criteria, or met any of the exclusion criteria were excluded from the double-blind treatment period.

Randomization and blinding

After the run-in period, participants were randomly assigned to receive nVNS or sham therapy (allocation 1:1) under a variable block design, stratified by study site. Site personnel entered the study and participant information into an interactive web response technology system, which then provided a participant randomization number and a device serial number. An unblinded trainer opened the box, used the study device to train the participant, and provided it to the participant after training. Participants, investigators, and study coordinators remained blinded to treatment assignments throughout the double-blind period.

Interventions and procedures

At the start of the run-in period, participants were trained on the use of an electronic diary, which was used to record information on migraine and headache attacks, medication use, adverse events (AEs), and use of the study device throughout the trial.

The nVNS device produces a proprietary low-voltage electric signal comprising five 5-kHz pulses repeated at a rate of 25 Hz. The waveform of the electric pulses is approximately a sine wave with a peak voltage of 24 V and a maximum output current of 60 mA. The sham device appeared identical to the nNVS device in appearance, weight, visible and audible feedback, user application, and control. To help maintain blinding, participants using the sham device were instructed that they might or might not hear an audible sound and/or experience muscle contractions while using the device.

Participants were instructed to administer treatments 3 times each day (upon waking, at midday, and before sleep) during the double-blind period. Each treatment comprised two consecutive 120-second stimulations delivered on the same side of the neck, ipsilateral to the side of predominate pain.

Outcomes

Efficacy endpoints used in the study were selected on the basis of existing recommendations for migraine pharmacologic treatments and align with those specified in the recently published International Headache Society position statement regarding the assessment of neuromodulatory devices for migraine (17). The primary efficacy outcome was the mean change in the number of migraine days from the run-in period to the last four weeks of the double-blind period (weeks 9–12). Secondary outcomes included the ≥50% responder rate for migraine days (i.e. the percentage of participants who recorded a reduction of ≥50% in migraine days from the run-in period to the last four weeks of the double-blind period) and mean changes in the number of headache days and acute medication days from the run-in period to the last four weeks of the double-blind period. A migraine day was defined as a 24-hour calendar period in which a migraine occurred, and a headache day was defined as a 24-hour calendar period in which any headache occurred. Other efficacy outcomes included scores on the Headache Impact Test-6 (HIT-6), the Migraine Disability Assessment (MIDAS), and participant satisfaction with treatment rated on a 5-point scale as extremely satisfied, very satisfied, satisfied, a little satisfied, or not at all satisfied. To assess blinding, at the end of the last week of the double-blind period, participants were asked which treatment group they thought they were in (nVNS, sham, or don’t know). Success of blinding was evaluated via the Bang Blinding Index (18). The primary safety outcome was the overall incidence of device-related serious adverse events (SAEs). Additional safety outcomes included rates of AEs, adverse device effects, and study discontinuations due to AEs.

Classification of evidence

The primary research aim of the study was to demonstrate the effectiveness and safety of nVNS as a therapy for prevention of migraine. The study was intended to provide class I evidence that nVNS is effective and safe for prevention of migraine in adults who have migraine with or without aura.

Statistical analysis

A sample size of 143 participants per treatment group was planned to yield at least 80% power to demonstrate a treatment difference of 1 day with a common standard deviation of 3.0 days for the primary efficacy endpoint. Assuming an attrition rate of 15% and <66% adherence in 15% of participants, a sample size of 409 participants, equally divided between the treatment arms, was determined.

Descriptive statistics were used to summarize data by study period and by treatment group. Partially completed data for the run-in period and the double-blind period were adjusted to reflect an estimated number of days with the outcome of interest per 28-day interval by using the formula (28/x)*y, where x is the number of days with observed data per 28-day period and y is the number of observed days with the outcome of interest. If <21 days of data were observed during the run-in period, the run-in value was not calculated and was considered missing, and the participant was not randomly assigned in the double-blind period. If <70 days of data were observed for the double-blind period, the month-3 value was imputed to the run-in value, implying no change between treatment periods.

The intention-to-treat (ITT) population comprised all randomly assigned participants with ≥1 verified posttraining treatment during the double-blind period. The primary efficacy analysis set was the prespecified modified intention-to-treat (mITT) population (participants from the ITT population who were ≥66% adherent with treatment each week and who were in the double-blind period for ≥70 days). Safety analyses were conducted on the safety population, which included all participants who entered the run-in period.

Changes in the number of migraine days, headache days, and acute medication days were compared between treatment groups using linear regression (analysis of covariance models) adjusted for treatment group; presence/absence of aura; and number of migraine, headache, or acute medication days (as appropriate) during the run-in period. Adjusted mean differences, 95% CIs, and p values for the adjusted mean differences were calculated. The ≥50% responder rates were compared between treatment groups using logistic regression adjusted for treatment group and number of migraine days in the run-in period. Adjusted proportions, odds ratios, 95% CIs, and p values were calculated. Changes in HIT-6 scores and MIDAS grades were compared between treatment groups using 2-sample t tests and chi-square tests, respectively. The percentages of patients who were satisfied with study treatment were compared between treatment groups using chi-square tests. Values of p<0.05 from 2-sided tests were considered statistically significant.

The primary efficacy analysis and key secondary efficacy analyses were repeated on the subgroup of participants from the mITT population who had aura, defined as those who had a diagnosis of migraine with aura according the ICHD-3 criteria in the medical history on their case report form.

Results

Participants

Among the 336 participants enrolled, 231 were randomly assigned to receive nVNS (n = 114) or sham (n = 117) therapy during the double-blind period (Figure 1). The mITT population of 56 participants (23 with chronic migraine, 33 with episodic migraine) in the nVNS group and 57 participants (23 with chronic migraine, 34 with episodic migraine) in the sham group was ∼60% lower than the target of 143 participants per treatment group owing to COVID-19. Restrictions imposed at many study sites suspended activity on clinical trials for non–life-saving therapies. Limited availability of clinical staff, along with other logistical and health concerns, also made it infeasible and inappropriate to continue the study. The emergence of the pandemic also caused concern among investigators that a potential shift in migraine load among participants enrolled after the start of the pandemic could confound the study results. These concerns have been borne out by findings that headache is a common neurologic symptom of COVID-19 (19) and by changes in migraine load (either increases or decreases) during the pandemic (20 –22). Ultimately, the pandemic prompted early closure of the study, which accounted for discontinuation of >20% of participants. Demographics and baseline characteristics were well balanced among participants in the nVNS and sham groups (Table 1). The most commonly used agents for migraine prevention included those that are US Food and Drug Administration approved for this purpose (e.g. topiramate, propranolol), those used off-label (e.g. zonisamide, gabapentin), and over-the-counter supplements (e.g. magnesium, riboflavin). Classes of medications most commonly used for acute treatment of migraines during the study included simple analgesics/nonsteroidal anti-inflammatory drugs, triptans, and combination agents.

Figure 1.

Participant disposition.

Table 1.

Participant demographics and baseline characteristics.

Characteristic^a	nVNS (n = 56)	Sham (n = 57)
Age, y	40.3 (13.9)	44.6 (10.7)
Age at migraine onset, y	18.1 (10.8)	18.7 (10.0)
Female, no. (%)	49 (87.5)	44 (77.2)
White or Caucasian, no. (%)	51 (91.1)	52 (91.2)
Migraine type, no. (%)
With aura	16 (28.6)	19 (33.3)
Without aura	40 (71.4)	38 (66.7)
No. of migraine days in the last 4 weeks	9.2 (4.6)	9.9 (3.5)
No. of headache days^b in the last 4 weeks	13.4 (4.0)	12.8 (3.7)
No. of acute medication use days per month^c	8.2 (3.5)	8.8 (4.0)
Preventive medication use, no. (%)	19 (33.9)	18 (31.6)
HIT-6^d	62.4 (5.1)	62.2 (5.8)
MIDAS grade, no. (%)^d
I (little/no disability)	4 (7.1)	6 (10.7)
II (mild disability)	6 (10.7)	4 (7.1)
III (moderate disability)	10 (17.9)	12 (21.4)
IV (severe disability)	36 (64.3)	34 (60.7)

^aData are mean (SD) unless otherwise indicated and are from the mITT population. ^bIncludes migraine days. ^cNo. of days participant typically takes acute treatments for migraine. ^dn = 56 for the sham group.

HIT-6, Headache Impact Test-6; MIDAS, Migraine Disability Assessment; mITT, modified intention-to-treat; nVNS, non-invasive vagus nerve stimulation.

Efficacy

The number of migraine days per month during weeks 9 through 12 (primary endpoint) decreased from baseline by a mean of 3.12 in the nVNS group and 2.29 days in the sham group (difference, −0.83; p = 0.2329; Figure 2a). The responder rate (i.e. the percentage of participants with a ≥50% reduction in the number of migraine days) was significantly greater in the nVNS group (44.87%) than in the sham group (26.81%; p = 0.0481; Figure 2b). The number of headache days decreased by a mean of 4.56 in the nVNS group and 3.00 in the sham group (difference, –1.56; p = 0.0530; Figure 3a). Acute medication days decreased by a mean of 2.53 in the nVNS group and 1.36 in the sham group (difference, –1.17; p = 0.1132; Figure 3b). nVNS was significantly better than sham at decreasing the headache impact, as measured by the HIT-6, and at decreasing migraine-related disability, as measured by the MIDAS (Figure 4). A greater percentage of participants in the nVNS group (53.8%) than in the sham group (21.8%) were very or extremely satisfied with study treatment (p = 0.0006). In the subgroup of patients who had migraine with aura, the number of monthly migraine days decreased from baseline by a mean of 4.04 in the nVNS group and 1.94 in the sham group (Figure 5a; difference, −2.10; p = 0.1004). A greater proportion of patients in the nVNS group (44.36%) than in the sham group (12.96%) had a ≥50% reduction from baseline in the number of migraine days (p = 0.0488; Figure 5b). Compared with the sham group, the nVNS group also had a greater decrease from baseline in the number of monthly headache days (p = 0.0411; Figure 5c).

Figure 2.

Mean change in number of migraine days (a) and percentage of participants with ≥50% reduction in migraine days (b) (mITT population).

Figure 3.

Mean change in number of headache days (a) and acute medication days (b) by treatment group (mITT population).

Figure 4.

Mean change in HIT-6 score (a) and MIDAS shift analysis (b) by treatment group (mITT population).

Figure 5.

Subgroup analysis: patients with aura; mean change in number of migraine days (a), percentage of participants with ≥50% reduction in migraine days (b), and mean change in of number of headache days (c) by treatment group (mITT population).

Blinding

At the conclusion of the double-blind period, 58% (32/55) of participants in the nVNS group and 62% (36/58) of participants in the sham group correctly guessed their treatment assignment. Bang Blinding Index estimates were 0.47 (95% CI, 0.31–0.63) for the nVNS group and 0.43 (95% CI, 0.26–0.59) for the sham group, indicating successful blinding.

Safety

Four SAEs were reported, two (cholecystitis and dyspnea) during the run-in period and two (hematoma and pyelonephritis) during the double-blind period. None were life-threatening or considered related to treatment. AEs were predominantly mild and considered unrelated to treatment (Table 2). The most common AEs across both study periods were nasopharyngitis, influenza, upper respiratory tract infection, muscle strain, arthralgia, and headache. Device-related AEs with >1 instance reported during the study were headache/procedural headache, migraine, application site pain, dysphonia, pain in jaw, palpitations and sensory disturbance.

Table 2.

Adverse event summary (double-blind period; safety population; N = 336)

	nVNS^a (n = 111)		Sham^a (n = 117)		Total (N = 336)
	Events	Participants (%)^b	Events	Participants (%)^b	Events	Participants (%)^b
Total	85	46 (41.4)	77	48 (41.0)	162	94 (28.0)
Severity
Mild	61	38 (34.2)	43	33 (28.2)	104	71 (21.1)
Moderate	21	12 (10.8)	32	22 (18.8)	53	34 (10.1)
Severe	3	3 (2.7)	2	1 (0.9)	5	4 (1.2)
SAEs	1	1 (0.9)	1	1 (0.9)	2	2 (0.6)
Related to device
No	56	34 (30.6)	58	37 (31.6)	114	71 (21.1)
Possibly	16	11 (9.9)	12	9 (7.7)	28	20 (6.0)
Probably	4	4 (3.6)	3	3 (2.6)	7	7 (2.1)
Definitely	9	7 (6.3)	4	3 (2.6)	13	10 (3.0)
ADEs	29	20 (18.0)	19	13 (11.1)	48	33 (9.8)

^aRandomized assignment in double-blind phase. ^bParticipants may have reported more than 1 event.

ADE, adverse device effect; nVNS, non-invasive vagus nerve stimulation; SAE, serious adverse event.

Discussion

Results from PREMIUM II facilitate a clearer understanding of the efficacy of nVNS for migraine prevention. Although statistical significance was not achieved for the primary endpoint (mean change in the number of migraine days from the run-in period to the last 4 weeks of the double-blind period), the magnitude of the treatment effect was within the expected range. In addition, statistically significant differences favoring nVNS were demonstrated for multiple endpoints, including the ≥50% responder rate (overall and for the subgroup of participants with aura), change in number of headache days (aura subgroup), as well as changes in HIT-6 (headache impact) and MIDAS (migraine-related disability) scores. Consistent with previous research (4), in PREMIUM II the migraine with aura subgroup had a more pronounced response than those without aura and appear to be particularly well suited to nVNS therapy. This clinical finding is consistent with mechanistic data from animal models, which suggest that nVNS inhibits susceptibility to and diminishes the frequency and propagation speed of cortical spreading depression, an electrophysiological phenomenon that is believed to be a major mechanism behind migraine aura (15,23,24). There is an opportunity for future research and analysis to determine whether the more prominent response of nVNS among patients with aura in this study is appreciated in other clinical settings.

Limitations in this trial include the impact of the COVID-19 pandemic and the difficulty in blinding during studies of devices. As was the case for many trials during the pandemic, non–life-saving research was suspended at several PREMIUM II sites. There was also concern among investigators that the emergence of the COVID-19 pandemic would influence migraine load and present a confounding factor. Subsequent reports have suggested that COVID-19 infection and other pandemic-related issues appear to affect migraine frequency, severity, and characteristics (25,26). Ultimately, the pandemic prompted early closure of the study, which also accounted for discontinuation of >20% of participants.

The sham device used in the PREMIUM I study was later shown to produce some degree of vagal activation (27); thus, a different, completely inactive sham device was employed in PREMIUM II. Nonetheless, a strong sham response was seen in PREMIUM II, which is a frequent challenge in device studies (28,29). Placebo/sham effects may vary depending on the type of placebo used, with injectable or topical preparations and sham devices or procedures having greater effects than inert pills. Other factors, such as treatment setting, perceived level of innovation, and regression to the mean have also been postulated to enhance placebo effects (30,31)

Conclusions

Results from PREMIUM II further refine the clinical utility of nVNS for the prevention of migraine, particularly for patients who have migraine with aura. The study findings also reinforce the well-established safety and tolerability profile of nVNS.

Article Highlights

This randomized, double-blind, sham-controlled trial demonstrated clinical utility of non-invasive vagus nerve stimulation (nVNS) for migraine prevention, with significant differences favoring nVNS noted on multiple endpoints, including responder rate, headache impact, and migraine-related disability, but not the primary endpoint

The COVID-19 pandemic led to early trial termination, and the population was ∼60% smaller than the statistical target for full power, which likely adversely impacted the study’s primary endpoint analysis

Patients who had migraine with aura responded preferentially to nVNS therapy

Study findings reinforce the well-established safety and tolerability profile of nVNS

Supplemental Material

sj-pdf-1-cep-10.1177_03331024211068813 - Supplemental material for Non-invasive vagus nerve stimulation for prevention of migraine: The multicenter, randomized, double-blind, sham-controlled PREMIUM II trial

Supplemental material, sj-pdf-1-cep-10.1177_03331024211068813 for Non-invasive vagus nerve stimulation for prevention of migraine: The multicenter, randomized, double-blind, sham-controlled PREMIUM II trial by Umer Najib, Timothy Smith, Nada Hindiyeh, Joel Saper, Barbara Nye, Sait Ashina, Candace K McClure, Michael J Marmura, Serena Chase, Eric Liebler and Richard B Lipton in Cephalalgia

Footnotes

Acknowledgments

Writing and editorial support was provided by Elizabeth Barton of MedLogix Communications, LLC, in cooperation with the authors, and was funded by electroCore, Inc. The authors have authorized the submission of this manuscript via a submitting agent and approved all statements of conflict of interest and provided final approval prior to submission. The authors would like to thank Danny Benmoshe, David True, Lazlo Mechtler, Deborah Friedman, Alexander Feoktistov, Abigail Chua, Christina Treppendahl, Ira Turner, Peter McAllister, Steve Meyers, Brian Plato, Maria Carmen Wilson, Cori Millen, Jack Schim, Deborah Reed, Carol Redillas, Nina Riggns, Artem Kaplan, and Thomas G. Ledbetter for contributing to data acquisition.

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Umer Najib is a consultant for and received honoraria from Abbvie. Timothy Smith is a consultant and advisor for Alder/Lundbeck, Amgen, Allergan/Abbvie, Biohaven, Impel Neurpharma, Lilly, Neurolief, and Nocira and has served on Speaker Bureaus for Amgen, Allergan/Abbvie, Biohaven, and Lilly. Nada Hindiyeh is a consultant and advisory board member for Lundback, Lilly, and Impel. Joel Saper received research grants from Allergan Pharmaceuticals, Amgen, Inc., Axsome Therapeutics, Inc, Biohaven Pharmaceuticals, Colucid Pharmaceuticals, Electrocore, Eli Lilly, Equinox Opthalmic, Inc., H. Lundbeck A/S, Impax Laboratories Inc., the FDA (NIH Grant), Novartis Pharmaceuticals Corp., Satsuma Pharmaceuticals Inc., Teva Branded Pharmaceutical & Upsher-Smith Laboratories, LLC., and Currax Pharmaceuticals. Barbara Nye serves on advisory boards for BioDelivery Sciences and Impel. Sait Ashina received honoraria for consulting from Allergan/AbbVie, Biohaven, Eli Lilly, Impel NeuroPharma, Theranica and Percept, is associate editor for Neurology Reviews and BMC Neurology, review editor for Frontiers in Neurology, serves on Advisory Board for Journal of Headache and Pain, and is a member of the Education Committee of the International Headache Society. Candace McClure declares no conflict of interest. Michael Marmura is on the Speaker Bureau of and a consultant for of Lilly. Consultant for Alder/Lumbeck and Theranica. Receives authorship and royalties of Medlink, Cambridge University Press, and Demos Medical. Serena Chase is a paid consultant of electroCore, Inc. Eric Liebler is an employee of electroCore, Inc. and receives stock ownership. Richard B. Lipton receives research support from the NIH, the FDA, the S&L Marx Foundation, the Migraine Research Foundation, and the National Headache Foundation. He holds stock options in Biohaven Holdings and CtrlM Health. He serves as consultant or advisory board member and has received honoraria from or research support from Abbvie (Allergan), American Academy of Neurology, American Headache Society, Amgen, Biohaven, Biovision, Boston, Dr. Reddy’s (Promius), Electrocore, Eli Lilly, eNeura, Equinox, GlaxoSmithKline, Grifols, Lundbeck (Alder), Merck, Pernix, Pfizer, Teva, Vector, and Vedanta.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by electroCore, Inc.

ORCID iD

Serena Chase

Supplemental material

Supplemental material for this article is available online.

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