Chronic migraine headache prevention with noninvasive ... · chronic migraine (CM; headache...

Stephen D SilbersteinMD

Anne H Calhoun MDRichard B Lipton MDBrian M Grosberg MDRoger K Cady MDStefanie Dorlas BMath

BEdKristy A SimmonsChris Mullin MSEric J LieblerPeter J Goadsby MD

PhDJoel R Saper MDOn behalf of the EVENT

Study Group

Correspondence toDr Silbersteinstephensilbersteinjeffersonedu

Supplemental dataat Neurologyorg

Chronic migraine headache preventionwith noninvasive vagus nerve stimulationThe EVENT study

ABSTRACT

Objective To evaluate the feasibility safety and tolerability of noninvasive vagus nerve stimula-tion (nVNS) for the prevention of chronic migraine (CM) attacks

Methods In this first prospective multicenter double-blind sham-controlled pilot study of nVNSin CM prophylaxis adults with CM ($15 headache dmo) entered the baseline phase (1month) andwere subsequently randomized to nVNS or sham treatment (2 months) before receiving open-label nVNS treatment (6 months) The primary endpoints were safety and tolerability Efficacyendpoints in the intent-to-treat population included change in the number of headache days per28 days and acute medication use

Results Fifty-nine participants (mean age 392 years mean headache frequency 215 dmo)were enrolled During the randomized phase tolerability was similar for nVNS (n 5 30) and shamtreatment (n 5 29) Most adverse events were mildmoderate and transient Mean changes in thenumber of headache days were 214 (nVNS) and 202 (sham) (D 5 12 p 5 056) Twenty-sevenparticipants completed the open-label phase For the 15 completers initially assigned to nVNSthe mean change from baseline in headache days after 8 months of treatment was 279 (95confidence interval 2119 to 238 p 001)

Conclusions Therapy with nVNSwaswell-tolerated with no safety issues Persistent prophylacticuse may reduce the number of headache days in CM larger sham-controlled studies are needed

ClinicalTrialsgov identifier NCT01667250

Classification of evidence This study provides Class II evidence that for patients with CM nVNS issafe is well-tolerated and did not significantly change the number of headache days This pilotstudy lacked the precision to exclude important safety issues or benefits of nVNS Neurologyreg

201687529ndash538

GLOSSARYAE5 adverse event CI5 confidence interval CM5 chronic migraine ITT5 intent-to-treat LOCF5 last observation carriedforward nVNS5 noninvasive vagus nerve stimulation PP5 per-protocol SAE5 serious adverse event VNS5 vagus nervestimulation

Migraine is a disabling neurologic headache disorder with symptoms including nausea and sen-sitivity to lightsound1 Compared with episodic migraine (headache occurring 15 dmo)chronic migraine (CM headache occurring $15 dmo) leads to greater disability and lowerproductivity12 Although preventive b-blockers tricyclic antidepressants and anticonvulsantsare used off-label in CM23 onabotulinumtoxinA is the only approved prophylactic CMmedication45

From Jefferson Headache Center (SDS) Philadelphia PA Carolina Headache Institute (AHC) Chapel Hill NC Montefiore Headache Centerand Albert Einstein College of Medicine (RBL) Bronx NY Hartford HealthCare Headache Center (BMG) West Hartford CT ClinvestHeadache Care Center (RKC) Springfield MO MedLogix Communications LLC (SD) Schaumburg IL electroCore LLC (KAS EJL)Basking Ridge NJ NAMSA (CM) Minneapolis MN University of California San Francisco (PJG) Kingrsquos College London (PJG) UK andMichigan Headache and Neurological Institute (JRS) Ann Arbor BMG was affiliated with Montefiore Headache Center Bronx NY at thetime of study completion

Coinvestigators are listed on the Neurologyreg Web site at Neurologyorg

Go to Neurologyorg for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the articleThe Article Processing Charge was paid by electroCore LLC

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CCBY-NC-ND) which permits downloading and sharing the work provided it is properly cited The work cannot be changed in any way or usedcommercially

copy 2016 American Academy of Neurology 529

ordf 2016 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Neuromodulation using implanted vagusnerve stimulation (VNS) devices has demon-strated efficacy for the treatment of epilepsy6

and depression7 and potential efficacy formigraine prophylaxis89 Case reports and smallstudies of patients who received implantedVNS devices for epilepsy showed reductionsin migraine attack frequency and severity8ndash12

Epilepsy and depression studies of VNS suggestthat efficacy improves with time on therapy67however this association has not been investi-gated in migraine prophylaxis

Despite the potential benefits of implantedVNS therapy the high risks and costs of surgicalimplantation have hindered its clinical evalua-tion A patient-controlled handheld noninvasiveVNS (nVNS) device (gammaCorereg electro-Core LLC Basking Ridge NJ) has beenCE-marked for the treatment of primary head-ache disorders (including migraine) Here wedescribe preliminary experience with nVNS forCM prophylaxis These data were first reportedat the 56th annual meeting of the AmericanHeadache Society (June 26ndash29 2014 LosAngeles CA)13

METHODS Primary objective The objective of this studywas to assess the feasibility safety and tolerability of nVNS it

was not powered to assess efficacy

Standard protocol approvals and patient consents Theprotocol was approved by site-specific institutional review

boards for 2 of the 6 participating sites and by the Biomedical

Research Alliance of New York institutional review board for

the remaining 4 sites All participants provided signed informed

consent before enrollment

Study design This prospective pilot study of nVNS for CM

prophylaxis was conducted at 6 US tertiary care headache centers

between October 2012 and April 2014 (EVENT ClinicalTrials

gov NCT01667250) The study comprised 3 consecutive phases

a 1-month baseline phase to collect pretreatment data and medical

history a 2-month double-blind randomized sham-controlled

phase during which participants received prophylactic treatment

with nVNS or a sham device and a 6-month open-label phase

during which all participants received nVNS treatment For the

total 8-month treatment period the end of the 2-month

randomized phase was denoted as month 2 and the three

2-month evaluation points during the 6-month open-label phase

were denoted as months 4 6 and 8

Study population Participants were aged 18ndash65 years and

previously diagnosed with CM withwithout aura according

to the revised International Classification of Headache Disorderssecond edition criteria1415 had migraine onset before 50 years of

age and had $15 headache dmo during the previous

3 months

Key exclusion criteria were a history of aneurysm intracranial

hemorrhage brain tumor or head trauma a lesion dysesthesia

previous surgery or abnormal anatomy at the treatment site

known or suspected cardiovascular disease uncontrolled hyperten-

sion abnormal ECG results recent myocardial infarction an im-

planted electricalneurostimulator device a metallic implant

metal cervical spine hardware near the stimulation site previous

surgery for migraine prevention onabotulinumtoxinA injections

for migraine prevention during the previous 6 months and prophy-

lactic migraine medication during the previous 30 days Modifica-

tions in prophylactic medication typedose for indications other

than CM that could interfere with the study were not permitted

Randomization and blinding An independent statistician

generated a randomization schedule to assign participants 11

(variable block design stratified by study center) to prophylactic

treatment with nVNS or sham treatment The study sponsor (elec-

troCore LLC) prelabeled the devices according to each sitersquos ran-

domization scheme a third-party distributor provided the devices

to study sites An unblinded trainer provided participants with the

devices and instructions on device features proper use and

treatment schedules Participants investigators and study

coordinators were blinded to treatment assignment during the

randomized phase

Interventions The nVNS device produced a proprietary electri-

cal signal that delivered a low voltage (peak 24 V) and a maxi-

mum output current of 60 mA Users adjusted the stimulation

amplitude within a preset range Two stainless steel contact sur-

faces coated with a conductive gel enabled delivery of stimulations

to the neck in the vicinity of the vagus nerve (figure e-1 on the

Neurologyreg Web site at Neurologyorg) The sham device was

identical in appearance weight visual and audible feedback

and user application and control but did not deliver electrical

stimulations Each treatment consisted of two 2-minute self-

administered stimulations delivered 5ndash10 minutes apart to the

right side of the neck at 3 prespecified times every day (1) within

1 hour of awakening (2) 6ndash8 hours after the first treatment and

(3) 6ndash8 hours after the second treatment Acute headache

medication use was permitted throughout the study

Assessments and endpoints Participants used diaries to recordsafety and tolerability (primary endpoints) efficacy and satisfac-

tion data Investigators categorized the onset type severity (mild

moderate severe) and frequency of adverse events (AEs) accord-

ing to treatment relatedness Serious AEs (SAEs) were defined by

the International Conference on Harmonization of Technical Re-

quirements for Registration of Pharmaceuticals for Human Use

Guidance for Good Clinical Practice

The number of reported headache days per month was nor-

malized to the number of headache days per 28 days which

was the primary efficacy measure A headache day was defined

as any day on which a participant recorded a headache The mean

change from baseline in the number of headache days was eval-

uated at the end of the randomized phase (month 2) and through

the end of the open-label phase (at 4 6 and 8 months of treat-

ment) Post hoc efficacy analyses assessed the effect of treatment

duration on the number of headache days and determined the

percent treatment response defined as the proportion of partici-

pants who demonstrated $50 reduction from baseline in the

number of headache days

The rate of patient-reported acute medication use and treat-

ment adherence satisfaction and ease of use were evaluated

throughout both phases Treatment adherence ([actual number

of administered treatments][total number of scheduled treat-

ments]3 100) was calculated as the average daily adherence Treat-

ment satisfaction was assessed on a 5-point scale (extremely satisfied tonot at all satisfied) Ease of use was rated on a 4-point scale (very easy

530 Neurology 87 August 2 2016


to very difficult) One week into the randomized phase and at its end

study blinding effectiveness questionnaires were completed

Statistical methods No formal sample size calculations were

performed the sample size was selected to facilitate initial assess-

ment of feasibility and tolerability in a clinically relevant number

of participants All analyses were conducted on the intent-to-treat(ITT) population which included all participants who were

randomly assigned to treatment and provided data for each

outcome Missing data were imputed using last observation

carried forward (LOCF) To assess the effect of protocol

deviation and discontinuations sensitivity analyses were

performed on the per-protocol (PP) population which included

only participants who completed each phase with no major

protocol violations Pooled participants from both treatment

groups in the PP population (ie the PP completer population)were stratified and analyzed by the total duration of nVNS

treatment completed throughout the study (2- 4- 6- or 8-month

completers) Specifically 2-month completers comprised

participants in the nVNS group who completed the 2-month

randomized phase and participants in the sham group (controls)

who completed 2 months of open-label nVNS treatment

There were no formal a priori statistical analyses exploratory

post hoc analyses were conducted to determine the effect of

nVNS treatment duration on the mean change in number of

headache days and to compare treatment responses for nVNS

and sham Categorical variables were compared using the Fisher

exact test (if $1 cell had an expected frequency 5) or x2 anal-

yses Continuous variables were compared using the Student t testand the Wilcoxon rank sum test for normal and non-normal

distributions respectively Blinding questionnaire results were

analyzed using the Bang index16 and corresponding 95 confi-

dence intervals (CIs)

RESULTS Participants Fifty-nine of the 73 partici-pants in the baseline phase were eligible for random-ization and constituted the ITT population (nVNSn 5 30 sham n 5 29) (figure 1) A total of 51participants (nVNS n 5 26 sham n 5 25) fromthe ITT population and 49 participants (nVNS n 5

26 sham n 5 23) from the PP population (ie noviolations) completed the randomized phase and 48participants (nVNS n5 24 sham n5 24) from theITT population and 47 participants (nVNS n 5 24sham n5 23) from the PP population continued intothe open-label phase Twenty-seven participantscompleted the study (nVNS n 5 16 sham n 5 11)Safety analyses were performed on all 59 participantsfrom the ITT population Demographic and baselinecharacteristics were similar to those reported in othermigraine studies (table 1)17 Participants (mean age 39years mean headache frequency 20 dmo) werepredominantly Caucasian women

Safety and tolerability The tolerability profile of nVNSwas satisfactory and generally similar to that of shamtreatment (table 2) Most AEs were mild or moderateand transient The most commonly reported AEswere upper respiratory tract infections and gastrointesti-nal symptoms During the randomized phase 6nVNS-treated participants reported 12 AEs that were

related or possibly related to the device whereas 5controls reported 8 such AEs No SAEs occurredduring the randomized phase During the open-labelphase 5 participants reported 8 AEs that were relatedor possibly related to the device Two participantsreported SAEs during the open-label phase (ieappendicitis and worsening headache) both wereunrelated to the device No discontinuations due todevice-related AEs occurred

Number of headache days The mean number of head-ache days in the nVNS group (n 5 30) was 208(95 CI 189ndash226) at baseline and 194 (95 CI166ndash221) at month 2 (end of the randomizedphase) representing a mean change of 214 (95CI 237 to 077 p 5 044) (figure 2A) The meannumber of headache days in controls (n 5 29) was223 (95 CI 204ndash241) at baseline and 220 (95CI 195ndash246) at month 2 demonstrating a meanchange of 202 (95 CI 215 to 11 p 5 072)(figure 2A) The mean change from baseline was notstatistically different between groups (p5 056) Thedifference between groups was slightly more pro-nounced in the PP population with mean changesof 220 (95 CI 244 to 04) for nVNS and201 (95 CI 216 to 14) for sham (p 5 035)

Persistent prophylactic nVNS use was associatedwith continued reductions in the number of headachedays After the open-label phase participants initially as-signed to nVNS had a mean of 172 (95 CI 138ndash205) headache days and a mean change from baselineof 236 (95 CI 263 to 2087 p 5 002) after 8months of treatment (figure 2A) Participants initiallyrandomized to sham treatment had a mean of 197(95 CI 165ndash230) headache days and a mean changefrom baseline of 225 (95 CI 250 to 2004 p 5006) after 6 months of nVNS (figure 2A) To investi-gate the effect of treatment persistence mean changes inthe number of headache days were analyzed withoutLOCF imputation More pronounced and clinicallymeaningful reductions from baseline at months 4 6and 8 (237 261 and 280 headache days respec-tively) were observed in the nVNS group (month 4p 005 months 6 and 8 p 001) The meanchange of 260 headache days for controls reachedstatistical significance at month 8 (p 005)

In the PP completer population longer durationwas associated with greater reductions in headache daysfrom study baseline (nVNS) and from month 2 (sham)(figure 2B) These mean reductions were 16 (95 CI01ndash31 p 5 006) for 2-month completers (n 5 44)39 (95 CI 14ndash63 p 5 0004) for 4-month com-pleters (n 5 32) 62 (95 CI 32ndash93 p 00001)for 6-month completers (n 5 26) and 79 (95CI 119ndash38 p 5 00009) for 8-month completers(n 5 15) (figure 2B) In contrast with 2-month

Neurology 87 August 2 2016 531


completers 4- 6- and 8-month completers each expe-rienced significant reductions at 2- 4- 6- and 8-monthtimepoints except for the 8-month completers at the2-month timepoint (p 5 006) (figure 2B)

Treatment response At month 2 100 (330) of par-ticipants from the nVNS group had a$50 responseand 33 (130) experienced a $75 response Nocontrols experienced a$50 response In the PP pop-ulation 115 (326) of participants from the nVNSgroup had a$50 response 38 (126) experienceda $75 response No controls experienced a $50response In the PP completer populations the propor-tion of participants who achieved a $50 responseincreased with longer duration of treatment throughoutthe open-label phase (figure 3)

Acute medication use Rates of acute medication use werecomparable between groups and remained stable frombaseline (898) through the open-label phase (815)

Table 1 Participant demographics and baselinecharacteristics

nVNS (n 5 30) Sham (n 5 29)

Age y mean (SD) 405 (142) 388 (111)

BMI kgm2 mean (SD) 286 (53) 316 (98)

Headache days reportedduring baseline mean (SD)

208 (50) 223 (49)

Sex n ()a

Female 26 (87) 27 (93)

Male 4 (13) 2 (7)

Race n ()a

Caucasian 26 (87) 25 (86)

Black 3 (10) 0

Other 1 (3) 4 (14)

Abbreviations BMI 5 body mass index nVNS 5 noninva-sive vagus nerve stimulationa Percentage totals in some columns are either 100 or100 because of rounding

Figure 1 Participant disposition

nVNS 5 noninvasive vagus nerve stimulation



Treatment adherence satisfaction and ease of useMeantreatment adherence for both groups was$95 dur-ing the randomized phase and $92 during theopen-label phase At month 2 583 (1424) ofnVNS-treated participants and 417 (1024) ofsham-treated participants were at least a little satisfiedwith treatment (p5 025 x2 test) Among participantswho completed the open-label phase 885 (2326)were satisfied with treatment Most participants foundthe device somewhat easy or very easy to use (nVNS 2024 833 sham 2224 917)

Blinding evaluation At the beginning of the randomizedphase a similar number of participants in each arm(nVNS 379 [1129] sham 393 [1128]) cor-rectly identified their treatment The groups had similarBang index values (nVNS 031 [95 CI 015ndash047]sham 032 [95 CI 015ndash049]) each indicating thatblinding was not achieved At month 2 Bang indexvalues of 004 (95 CI 00ndash025) for nVNS and 054

(95 CI 031ndash077) for sham suggest blinding wasachieved in the nVNS group but not in controls

DISCUSSION We demonstrated that nVNS for CMprevention was well-tolerated and identified no safetyissues preliminary efficacy results showed that thereduction in headache days during the 2-monthrandomized phase among participants receivingnVNS compared with controls was not significantWe assessed whether longer treatment duration wasassociated with clinically meaningful results aspreviously reported in a study of neuromodulationin CM18 Participants originally randomized tonVNS and who continued open-label treatment for6 months had a significant reduction from baseline inthe number of headache days Longer treatmentdurations were associated with greater reductions innumber of headache days and higher$50 responserates recognizing that the 27 participants whocompleted the open-label phase of the trial and

Table 2 Incidence of adverse events

Randomized phase (2 months) n () Open-label phase (6 months) n ()

nVNS (n 5 30) Sham (n 5 29) nVNS (n 5 48)

Participants with Dagger1 AE 17 (57) 16 (55) 30 (62)

Participants with Dagger1 device-related AEa 6 (20) 5 (17) 5 (10)

Participants with Dagger1 AE of severe intensity 1 (3) 4 (14) 10 (21)

Participants with Dagger1 SAE 0 0 2 (4)

AEs occurring in Dagger2 participants inany treatment arm

Randomized phase (2 months) Open-label phase (6 months)


Events n Participants n () Events n Participants n () Events n Participants n ()

Back pain 1 1 (3) 0 0 1 1 (2)

Cervicalgia 0 0 2 2 (7) 0 0

Dental infectiontooth pain 1 1 (3) 1 1 (3) 1 1 (2)

Eye twitch 2a 2 (7) 1 1 (3) 0 0

Facial painnumbness 3a 3 (10) 2 1 (3) 0 0

Gastrointestinal symptoms 4a 3 (10) 4 4 (14) 5 5 (10)

Head pain 0 0 0 0 3a 2 (4)

Influenza 1 1 (3) 0 0 1 1 (2)

Low back pain 1 1 (3) 1 1 (3) 5 5 (10)

Paresthesia 1a 1 (3) 0 0 1 1 (2)

Pharyngitis 0 0 3a 2 (7) 0 0

Streptococcal infection throat 1 1 (3) 0 0 1 1 (2)

Treatment site skin reaction 1a 1 (3) 1a 1 (3) 4a 2 (4)

Upper respiratory tract infection 3 3 (10) 6 6 (21) 15 11 (23)

Vaginitis 2 2 (7) 2 1 (3) 0 0

Worsening migraine 1a 1 (3) 3a 2 (7) 5a 5 (10)

Abbreviations AE 5 adverse event nVNS 5 noninvasive vagus nerve stimulation SAE 5 serious adverse eventa Includes AEs that were deemed possibly related or related to the device



received longer treatment (16 and 11 of whom wereinitially randomized to nVNS and sham respectively)may have been self-selected

Among study completers the $50 response rateincreased with time on treatment which supports the

slow accrual of clinical benefits over time reported inVNS studies of epilepsy and depression67 Loss tofollow-up cannot explain this result however regressiontoward the mean may be a confounding factor Theassociation between longer nVNS treatment duration

Figure 2 Effects of noninvasive vagus nerve stimulation (nVNS) on the change in number of headache daysper 28 days

(A) Mean change in headache days per 28 days from baseline through the open-label phase (intent-to-treat population)Imputation for missing data was performed using the last observation carried forward aReceived open-label nVNS aftermonth 2 p 005 vs baseline (B) Mean change in headache days per 28 days from baseline through the duration of nVNStreatment (per-protocol completer population) aThe 2- 4- and 6-month completers were from the 59 participants initiallyrandomized to either nVNS or sham treatment bThe 8-month completers were from the 30 participants initially randomizedto nVNS treatment cOne participant who completed 8months of nVNS initiated gabapentin treatment during the study andwas therefore excluded from 8-month completer analyses p 005 vs baseline p 001 vs baseline



and a gradual reduction in headache days suggests thatparticipants who discontinued the study might havebenefited from continued treatment consistent withother findings in the literature6719 Conversely partic-ipants who continued treatment may represent self-identified responders for whom the device is effective

Study limitations included the small sample sizeblinding challenges and high discontinuation rateBlinding in device studies is challenging especially incomparison with drug studies20 Our sham devicewas identical to the nVNS device but did not deliveran active signal A sham device should mimic the func-tionality and sensation of active treatment without pro-ducing treatment effects or device-related AEs Missingdata and high discontinuation rates occurring dispro-portionately across treatment groups can affect studyoutcomes In this study discontinuation rates werehigher in controls than in the nVNS group howeverno discontinuations stemmed from device-related AEs

The emergence of noninvasive neuromodulationdevices has sparked interest in their application inmigraine therapy Two short-term double-blind ran-domized controlled trials have examined prophylactictherapy for migraine using noninvasive neuromodula-tion devices2122 One multicenter sham-controlledstudy reported a significant reduction in the meannumber of headache days following transcutaneoussupraorbital stimulation for 3 months in participantswith migraine however the proportion of participants

with CM was unknown21 A single-center controlledstudy of prophylactic transcutaneous auricular VNStherapy in CM showed that the reduction in numberof headache days was significantly greater at a stimula-tion frequency of 1 Hz than at 25 Hz however nosham arm was available for comparison22 EVENT isthe first multicenter double-blind randomizedsham-controlled trial to demonstrate the long-term(8-month) tolerability and preliminarily evaluate theefficacy of prophylactic nVNS therapy in a clinicallydefined CM population Stimulation parameters usedin EVENT (ie 2-minute stimulations administered 3times per day on the right side of the neck) were basedon both previous open-label clinical studies in migraineand cluster headache2324 and preclinical models ofmigraine and airways disease25ndash27 but bilateral stimu-lations are currently being used in ongoing studieswhich may affect efficacy results observed in theseand future trials Findings from the animal migrainemodels suggest that nVNS may exert beneficial effectsvia the suppression of glutamate levels and corticalspreading depression a key factor in migraine patho-physiology2527 Prophylactic nVNS has been shown tobe clinically beneficial19 and cost-effective28 in chroniccluster headache Findings from EVENT expand theevidence regarding the potential role of noninvasiveneuromodulation in headache therapy Given the needfor novel prophylactic therapies for CM and the highcost of the currently approved medication2930 nVNS

Figure 3 Participants who achieved a Dagger50 treatment response with noninvasive vagus nerve stimulation(nVNS) (per-protocol completer population)

aThe 2- 4- and 6-month completers were from the 59 participants initially randomized to either nVNS or sham treatmentbThe 8-month completers were from the 30 participants initially randomized to nVNS treatment cOne participant whocompleted 8 months of nVNS initiated gabapentin treatment during the study and was therefore excluded from 8-monthcompleter analyses



may serve as a well-tolerated and potentially cost-effective alternative for patients with CM

nVNS is a highly feasible well-tolerated and con-venient therapy Although self-selection bias is associ-ated with the long-term findings the continuedreduction in headache days over the 6-month open-label phase suggests that nVNS may offer a clinicalbenefit to patients with CM Longer-term use ofnVNS in treatment responders would be reflectiveof clinical practice31 On the basis of the lack of a pla-teau in effects seen during the open-label phase largerstudies using modified stimulation parameters andlonger open-label periods may validate the use ofnVNS in migraine therapy a study with a 9-monthopen-label period is currently planned

AUTHOR CONTRIBUTIONSThis study was sponsored by electroCore LLC Professional writing and

editorial support (ie technical editing copyediting preparation of tables

and figures and clerical assistance) from MedLogix Communications

LLC funded by electroCore LLC was based on author direction

throughout draft development and revisions Data analysis support from

NAMSA was funded by electroCore LLC Dr Stephen D Silberstein

Dr Peter J Goadsby Eric J Liebler and Kristy A Simmons contributed

to the EVENT study design and provided detailed input into the devel-

opment of the manuscript Stefanie Dorlas is responsible for drafting

revising the manuscript for content including medical writing for con-

tent All primary investigators were involved in participant recruitment

and treatment for the EVENT study All authors participated in data col-

lection interpretation and validation Kristy A Simmons Eric J Liebler

and NAMSA were involved in data analysis All authors reviewed critiqued

and contributed to revision of the manuscript content and provided

approval of the final manuscript draft to be submitted to Neurologyreg

The corresponding author Dr Stephen D Silberstein had full access to

all the study data and had final responsibility for the decision to submit the

manuscript for publication

ACKNOWLEDGMENTThe authors thank the investigators and study sites (coinvestigator appen-

dix at Neurologyorg) the EVENT study investigators thank the nurses

and study coordinators professional writing and editorial support (ie

technical editing copyediting preparation of tables and figures and cler-

ical assistance) for this manuscript was provided by MedLogix Commu-

nications LLC (Schaumburg IL) under the direction of the authors

STUDY FUNDINGThis study was sponsored by electroCore LLC

DISCLOSURES Silberstein has received honoraria as a consultant andor advisory panel

member from Alder Biopharmaceuticals Allergan Inc Amgen Inc Avanir

Pharmaceuticals Inc Depomed Inc Dr Reddyrsquos Laboratories Ltd elec-

troCore LLC eNeura Inc Ipsen Biopharmaceuticals Medscape LLC

Medtronic Inc Mitsubishi Tanabe Pharma America Inc NINDS St

Jude Medical Supernus Pharmaceuticals Inc Teva Pharmaceuticals and

Trigemina Inc A Calhoun has participated as an advisory board member

for Allergan Inc Depomed Inc and Teva Pharmaceuticals Dr Calhoun

has received honoraria from and participated as a speakerrsquos bureau member

for Depomed Inc Merck amp Co Inc and Teva Pharmaceuticals She has

also received research support from Autonomic Technologies Inc electro-

Core LLC and Scion NeuroStim LLC B Grosberg reports no disclosures

relevant to the manuscript R Lipton receives research support from the

National Headache Foundation and the NIH PO1AG003949 (program

director) RO1AG025119 (investigator) RO1AG022374-06A2 (investiga-

tor) RO1AG034119 (investigator) and RO1AG12101 (investigator)

serves on the editorial board of Neurology and as senior advisor to Headache

has reviewed for the National Institute on Aging and NINDS holds stock

options in eNeura Inc and serves as a consultant or advisory board

member or has received honoraria from Alder Biopharmaceuticals Allergan

Inc American Headache Society Amgen Inc Autonomic Technologies

Inc Avanir Pharmaceuticals Inc Boston Scientific Corporation CoLucid

Pharmaceuticals Inc Dr Reddyrsquos Laboratories Ltd electroCore LLC Eli

Lilly and Company eNeura Therapeutics Informa Merck amp Co Inc

Teva Pharmaceuticals and Vedanta Biosciences R Cady has participated as

a consultant advisory board member and speakerrsquos bureau member for

Allergan Inc Depomed Inc and Teva Pharmaceutical Industries Ltd Dr

Cady has also participated as an advisory board member for Aerocrine Inc

Amgen Inc Autonomic Technologies Inc Avanir Pharmaceuticals Inc

Boston Scientific Corporation Dr Reddyrsquos Laboratories Ltd electroCore

LLC Novartis and Suda Ltd He has served as a consultant and speakerrsquos

bureau member for Impax Pharmaceuticals as a consultant for Becker

Pharmaceuticals Consulting and Zosano Pharma Corporation and as

a speakerrsquos bureau member for Merck amp Co Inc Dr Cady has also

received research support from Alder Biopharmaceuticals Allergan Inc

Amgen Inc AstraZeneca Autonomic Technologies Inc Boston Scientific

Corporation Capnia Daiichi-Sankyo Dr Reddyrsquos Laboratories Ltd elec-

troCore LLC Eli Lilly and Company Labrys Biologics Inc OptiNose

Pharmalyte Solutions LLC Questcor Pharmaceuticals Inc Tian Medical

and Vivid Pharmaceuticals P Goadsby has received honoraria from

CommentNoninvasive vagus DBSmdashPreliminary study encouraging forchronic migraine

Headache disorders are the most common among the most disabling and themost treatable of all neurologic conditions Despite numerous available therapiespatients with refractory migraine cluster headache and other headache types are inneed of effective treatment Neurostimulation utilized for decades to treat pain orig-inating from the spinal cord is gaining momentum for treating cephalalgic pain

Surgical procedures investigated to date include occipital and supraorbital nervestimulation for migraine and cluster deep brain stimulation (DBS) of the posteriorhypothalamus and sphenopalatine ganglion (SPG) stimulation for chronic clusterWhile DBS is fraught with surgical complications some serious both DBS andSPG stimulation showed a long-term reduction in cluster attack frequency suggestinga disease-modifying effect1 Transcutaneous supraorbital nerve stimulation and trans-cranial magnetic stimulation are available noninvasive options

Noninvasive vagus nerve stimulation (nVNS) was studied in a small (n 5 27)open-label study of acute migraine treatment showing modest benefit (22 painfreedom at 2 hours for moderate to severe attacks 38 for mild attacks) withoutcardiac side effects2 EVENTwas a pilot study of nVNS to assess safety tolerabilityefficacy and satisfaction data for the prevention of chronic migraine3 Tolerabilitywas similar to sham treatment The study was underpowered to assess efficacy withno difference between treatment groups at the end of the randomized phase Amongthose participants who completed the open-label phase of the trial there wasa greater reduction in headache days similar to previous stimulation studies

Further studies with a larger sample size and a longer treatment phase areneeded to determine the role of nVNS in the therapy of migraine An effective non-invasive neurostimulation device is an attractive treatment alternative for patientswith medically refractory migraine and for those who are unable to take currentlyused oral prophylactic treatments

1 Goadsby P Grosberg B Mauskop A Cady R Simmons K Effect of noninvasivevagus nerve stimulation on acute migraine an open label pilot study Cephalalgia201434986ndash993

2 Schwedt TJ Vargas B Neurostimulation for treatment of migraine and cluster head-ache Pain Med 2015161827ndash1834

3 Silberstein SD Calhoun AH Grosberg BM et al Chronic migraine headache pre-vention with noninvasive vagus nerve stimulation the EVENT study Neurology201687529ndash538

Deborah I Friedman MD MPH FAAN

From the Department of Neurology amp Neurotherapeutics and Ophthalmology University of TexasSouthwestern Medical Center DallasStudy funding No targeted funding reportedDisclosure The author reports no disclosures relevant to the manuscript Go to Neurologyorg for fulldisclosures



Ajinomoto Pharmaceuticals Co Ltd Akita Pharmaceuticals Ltd Amgen

Inc Alder Biopharmaceuticals Allergan Inc Autonomic Technologies Inc

Avanir Pharmaceuticals Inc Cipla Ltd CoLucid Pharmaceuticals Inc Dr

Reddyrsquos Laboratories Ltd Eli Lilly and Company eNeura Inc WL Gore

amp Associates Inc Heptares Therapeutics Ethicon Inc NEJM Journal

Watch NuPathe Inc Pfizer Inc Promius Pharma LLC Teva Pharmaceu-

tical Industries Ltd UptoDateregcom (outside the submitted work) Wells

Fargo and Zosano Pharma Corporation He has also received honoraria for

medicolegal work in headache and grants from Allergan Inc and Amgen

Inc and has a pending patent for magnetic stimulation for headache

K Simmons was an employee of electroCore LLC at the time of study

completion C Mullin is an employee of NAMSA E Liebler is an employee

of electroCore LLC and receives stock ownership Stefanie Dorlas is em-

ployed by MedLogix Communications LLC as a medical writer J Saper has

received research grants from Achelios Therapeutics Inc Alder Biopharma-

ceuticals Allergan Inc Amgen Inc Astellas Pharma Inc Autonomic Tech-

nologies Inc Cerephex Corporation Daiichi-Sankyo Dr Reddyrsquos

Laboratories Ltd GlaxoSmithKline Labrys Biologics Inc Lilly Merck amp

Co Inc Pfizer Inc Scion NeuroStim LLC Vanda Pharmaceuticals and

Winston Laboratories Inc and has received honoraria as a consultant for

Alder Biopharmaceuticals Allergan Inc Johnson amp Johnson (Ethicon Inc)

the Migraine Research Foundation NuPathe Inc Purdue Pharma Supernus

Pharmaceuticals Teva Pharmaceutical Industries Ltd and Tian Pharmaceu-

tical Co Go to Neurologyorg for full disclosures

Received November 30 2015 Accepted in final form April 22 2016

REFERENCES1 Headache Classification Committee of the International

Headache Society The International Classification of Head-

ache Disorders 3rd edition (beta version) Cephalalgia

201333629ndash808

2 Schwedt TJ Chronic migraine BMJ 2014348g1416

3 Goadsby PJ Sprenger T Current practice and future di-

rections in the prevention and acute management of

migraine Lancet Neurol 20109285ndash298

4 Aurora SK Dodick DW Turkel CC et al Onabotuli-

numtoxinA for treatment of chronic migraine results from

the double-blind randomized placebo-controlled phase of

the PREEMPT 1 trial Cephalalgia 201030793ndash803

5 Diener HC Dodick DW Aurora SK et al Onabotuli-

numtoxinA for treatment of chronic migraine results

from the double-blind randomized placebo-controlled

phase of the PREEMPT 2 trial Cephalalgia 201030

804ndash814

6 Murphy JV Left vagal nerve stimulation in children with

medically refractory epilepsy The Pediatric VNS Study

Group J Pediatr 1999134563ndash566

7 Aaronson ST Carpenter LL Conway CR et al Vagus

nerve stimulation therapy randomized to different

amounts of electrical charge for treatment-resistant

depression acute and chronic effects Brain Stimul

20136631ndash640

8 Lenaerts ME Oommen KJ Couch JR Skaggs V Can

vagus nerve stimulation help migraine Cephalalgia

200828392ndash395

9 Mauskop A Vagus nerve stimulation relieves chronic

refractory migraine and cluster headaches Cephalalgia

20052582ndash86

10 Cecchini AP Mea E Tullo V et al Vagus nerve stimu-

lation in drug-resistant daily chronic migraine with depres-

sion preliminary data Neurol Sci 200930(suppl 1)

S101ndashS104

11 Hord ED Evans MS Mueed S Adamolekun B

Naritoku DK The effect of vagus nerve stimulation on

migraines J Pain 20034530ndash534

12 Sadler RM Purdy RA Rahey S Vagal nerve stimulation

aborts migraine in patient with intractable epilepsy Ceph-

alalgia 200222482ndash484

13 Silberstein SD Da Silva AN Calhoun AH et al Non-

invasive vagus nerve stimulation for chronic migraine pre-

vention in a prospective randomized sham-controlled

pilot study (the EVENT study) report from the double-

blind phase Headache 201454LBP19

14 Headache Classification Subcommittee of the Interna-

tional Headache Society The International Classification

of Headache Disorders 2nd edition Cephalalgia 200424

(suppl 1)9ndash160

15 Olesen J Bousser MG Diener HC et al New appendix

criteria open for a broader concept of chronic migraine

Cephalalgia 200626742ndash746

16 Bang H Flaherty SP Kolahi J Park J Blinding assessment

in clinical trials a review of statistical methods and a pro-

posal of blinding assessment protocol Clin Res Reg Aff

20102742ndash51

17 Silberstein SD Lipton RB Dodick DW Operational

diagnostic criteria for chronic migraine expert opinion

Headache 2014541258ndash1266

18 Dodick DW Silberstein SD Reed KL et al Safety and

efficacy of peripheral nerve stimulation of the occipital

nerves for the management of chronic migraine long-

term results from a randomized multicenter double-

blinded controlled study Cephalalgia 201535344ndash358

19 Gaul C Diener HC Silver N et al Non-invasive vagus

nerve stimulation for prevention and acute treatment of

chronic cluster headache (PREVA) a randomized con-

trolled study Cephalalgia 201636534ndash546

20 Broadbent HJ van den Eynde F Guillaume S et al Blind-

ing success of rTMS applied to the dorsolateral prefrontal

cortex in randomised sham-controlled trials a systematic

review World J Biol Psychiatry 201112240ndash248

21 Schoenen J Vandersmissen B Jeangette S et al

Migraine prevention with a supraorbital transcutaneous

stimulator a randomized controlled trial Neurology

201380697ndash704

22 Straube A Ellrich J Eren O Blum B Ruscheweyh R

Treatment of chronic migraine with transcutaneous stim-

ulation of the auricular branch of the vagal nerve (auricular

t-VNS) a randomized monocentric clinical trial J Head-

ache Pain 201516543

23 Goadsby PJ Grosberg BM Mauskop A Cady R

Simmons KA Effect of noninvasive vagus nerve stimulation

on acute migraine an open-label pilot study Cephalalgia

201434986ndash993

24 Nesbitt AD Marin JC Tompkins E Ruttledge MH

Goadsby PJ Initial use of a novel noninvasive vagus nerve

stimulator for cluster headache treatment Neurology

2015841249ndash1253

25 Chen SP Ay I Lopes de Morais A et al Vagus nerve

stimulation inhibits cortical spreading depression Pain

2016157797ndash805

26 Hoffmann TJ Simon BJ Zhang Y Emala CW Low

voltage vagal nerve stimulation reduces bronchoconstric-

tion in guinea pigs through catecholamine release Neuro-

modulation 201215527ndash536

27 Oshinsky ML Murphy AL Hekierski H Jr Cooper M

Simon BJ Noninvasive vagus nerve stimulation as treat-

ment for trigeminal allodynia Pain 20141551037ndash1042

28 Gaul C Straube A Reuter U Morris J Walker S

Diener HC Cost-effectiveness analysis of non-invasive



vagus nerve stimulation for the treatment of chronic clus-

ter headache in Germany Cephalalgia 20153581

29 Botulinum toxin for chronic migraine Med Lett Drugs

Ther 2011537ndash8

30 Khalil M Zafar HW Quarshie V Ahmed F Prospective

analysis of the use of onabotulinumtoxinA (BOTOX) in

the treatment of chronic migraine real-life data in 254

patients from Hull UK J Headache Pain 20141554

31 Moscato D Moscato FR A survey of patient perceptions

of non-invasive vagus nerve stimulation (nVNS) therapy

for acute migraine attacks Cephalalgia 201535(suppl 6)

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Expand your world view at Neurologyorgwoborders



DOI 101212WNL0000000000002918201687529-538 Published Online before print July 13 2016Neurology

Stephen D Silberstein Anne H Calhoun Richard B Lipton et al EVENT study

Chronic migraine headache prevention with noninvasive vagus nerve stimulation The

This information is current as of July 13 2016

rights reserved Print ISSN 0028-3878 Online ISSN 1526-632X1951 it is now a weekly with 48 issues per year Copyright copy 2016 American Academy of Neurology All

reg is the official journal of the American Academy of Neurology Published continuously sinceNeurology

ServicesUpdated Information amp

httpnneurologyorgcontent875529fullincluding high resolution figures can be found at

Supplementary Material

918DC2httpnneurologyorgcontentsuppl20160713WNL0000000000002

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This article cites 31 articles 3 of which you can access for free at

Citations httpnneurologyorgcontent875529fullotherarticles

This article has been cited by 5 HighWire-hosted articles

Subspecialty Collections

httpnneurologyorgcgicollectionvagus_nerve_stimulationVagus nerve stimulation

httpnneurologyorgcgicollectionmigraineMigraine

led_consort_agreementhttpnneurologyorgcgicollectionclinical_trials_randomized_controlClinical trials Randomized controlled (CONSORT agreement)

httpnneurologyorgcgicollectionclass_iiClass II

httpnneurologyorgcgicollectionall_headacheAll Headachefollowing collection(s) This article along with others on similar topics appears in the

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Neuromodulation using implanted vagusnerve stimulation (VNS) devices has demon-strated efficacy for the treatment of epilepsy6

and depression7 and potential efficacy formigraine prophylaxis89 Case reports and smallstudies of patients who received implantedVNS devices for epilepsy showed reductionsin migraine attack frequency and severity8ndash12

Epilepsy and depression studies of VNS suggestthat efficacy improves with time on therapy67however this association has not been investi-gated in migraine prophylaxis

Despite the potential benefits of implantedVNS therapy the high risks and costs of surgicalimplantation have hindered its clinical evalua-tion A patient-controlled handheld noninvasiveVNS (nVNS) device (gammaCorereg electro-Core LLC Basking Ridge NJ) has beenCE-marked for the treatment of primary head-ache disorders (including migraine) Here wedescribe preliminary experience with nVNS forCM prophylaxis These data were first reportedat the 56th annual meeting of the AmericanHeadache Society (June 26ndash29 2014 LosAngeles CA)13

METHODS Primary objective The objective of this studywas to assess the feasibility safety and tolerability of nVNS it

was not powered to assess efficacy

Standard protocol approvals and patient consents Theprotocol was approved by site-specific institutional review

boards for 2 of the 6 participating sites and by the Biomedical

Research Alliance of New York institutional review board for

the remaining 4 sites All participants provided signed informed

consent before enrollment

Study design This prospective pilot study of nVNS for CM

prophylaxis was conducted at 6 US tertiary care headache centers

between October 2012 and April 2014 (EVENT ClinicalTrials

gov NCT01667250) The study comprised 3 consecutive phases

a 1-month baseline phase to collect pretreatment data and medical

history a 2-month double-blind randomized sham-controlled

phase during which participants received prophylactic treatment

with nVNS or a sham device and a 6-month open-label phase

during which all participants received nVNS treatment For the

total 8-month treatment period the end of the 2-month

randomized phase was denoted as month 2 and the three

2-month evaluation points during the 6-month open-label phase

were denoted as months 4 6 and 8

Study population Participants were aged 18ndash65 years and

previously diagnosed with CM withwithout aura according

to the revised International Classification of Headache Disorderssecond edition criteria1415 had migraine onset before 50 years of

age and had $15 headache dmo during the previous

3 months

Key exclusion criteria were a history of aneurysm intracranial

hemorrhage brain tumor or head trauma a lesion dysesthesia

previous surgery or abnormal anatomy at the treatment site

known or suspected cardiovascular disease uncontrolled hyperten-

sion abnormal ECG results recent myocardial infarction an im-

planted electricalneurostimulator device a metallic implant

metal cervical spine hardware near the stimulation site previous

surgery for migraine prevention onabotulinumtoxinA injections

for migraine prevention during the previous 6 months and prophy-

lactic migraine medication during the previous 30 days Modifica-

tions in prophylactic medication typedose for indications other

than CM that could interfere with the study were not permitted

Randomization and blinding An independent statistician

generated a randomization schedule to assign participants 11

(variable block design stratified by study center) to prophylactic

treatment with nVNS or sham treatment The study sponsor (elec-

troCore LLC) prelabeled the devices according to each sitersquos ran-

domization scheme a third-party distributor provided the devices

to study sites An unblinded trainer provided participants with the

devices and instructions on device features proper use and

treatment schedules Participants investigators and study

coordinators were blinded to treatment assignment during the

randomized phase

Interventions The nVNS device produced a proprietary electri-

cal signal that delivered a low voltage (peak 24 V) and a maxi-

mum output current of 60 mA Users adjusted the stimulation

amplitude within a preset range Two stainless steel contact sur-

faces coated with a conductive gel enabled delivery of stimulations

to the neck in the vicinity of the vagus nerve (figure e-1 on the

Neurologyreg Web site at Neurologyorg) The sham device was

identical in appearance weight visual and audible feedback

and user application and control but did not deliver electrical

stimulations Each treatment consisted of two 2-minute self-

administered stimulations delivered 5ndash10 minutes apart to the

right side of the neck at 3 prespecified times every day (1) within

1 hour of awakening (2) 6ndash8 hours after the first treatment and

(3) 6ndash8 hours after the second treatment Acute headache

medication use was permitted throughout the study

Assessments and endpoints Participants used diaries to recordsafety and tolerability (primary endpoints) efficacy and satisfac-

tion data Investigators categorized the onset type severity (mild

moderate severe) and frequency of adverse events (AEs) accord-

ing to treatment relatedness Serious AEs (SAEs) were defined by

the International Conference on Harmonization of Technical Re-

quirements for Registration of Pharmaceuticals for Human Use

Guidance for Good Clinical Practice

The number of reported headache days per month was nor-

malized to the number of headache days per 28 days which

was the primary efficacy measure A headache day was defined

as any day on which a participant recorded a headache The mean

change from baseline in the number of headache days was eval-

uated at the end of the randomized phase (month 2) and through

the end of the open-label phase (at 4 6 and 8 months of treat-

ment) Post hoc efficacy analyses assessed the effect of treatment

duration on the number of headache days and determined the

percent treatment response defined as the proportion of partici-

pants who demonstrated $50 reduction from baseline in the

number of headache days

The rate of patient-reported acute medication use and treat-

ment adherence satisfaction and ease of use were evaluated

throughout both phases Treatment adherence ([actual number

of administered treatments][total number of scheduled treat-

ments]3 100) was calculated as the average daily adherence Treat-

ment satisfaction was assessed on a 5-point scale (extremely satisfied tonot at all satisfied) Ease of use was rated on a 4-point scale (very easy













































nVNS (n 5 30) Sham (n 5 29)

Age y mean (SD) 405 (142) 388 (111)

BMI kgm2 mean (SD) 286 (53) 316 (98)


208 (50) 223 (49)

Sex n ()a

Female 26 (87) 27 (93)

Male 4 (13) 2 (7)

Race n ()a

Caucasian 26 (87) 25 (86)

Black 3 (10) 0

Other 1 (3) 4 (14)





















Back pain 1 1 (3) 0 0 1 1 (2)



Eye twitch 2a 2 (7) 1 1 (3) 0 0



Head pain 0 0 0 0 3a 2 (4)

Influenza 1 1 (3) 0 0 1 1 (2)

Low back pain 1 1 (3) 1 1 (3) 5 5 (10)

Paresthesia 1a 1 (3) 0 0 1 1 (2)





Vaginitis 2 2 (7) 2 1 (3) 0 0
































































































































201333629ndash808













804ndash814








20136631ndash640



200828392ndash395



20052582ndash86




S101ndashS104















(suppl 1)9ndash160







20102742ndash51




















201380697ndash704





ache Pain 201516543




201434986ndash993




2015841249ndash1253



2016157797ndash805















Ther 2011537ndash8








PO016 Abstract


Look Whatrsquos New
































Reprints














































nVNS (n 5 30) Sham (n 5 29)

Age y mean (SD) 405 (142) 388 (111)

BMI kgm2 mean (SD) 286 (53) 316 (98)


208 (50) 223 (49)

Sex n ()a

Female 26 (87) 27 (93)

Male 4 (13) 2 (7)

Race n ()a

Caucasian 26 (87) 25 (86)

Black 3 (10) 0

Other 1 (3) 4 (14)





















Back pain 1 1 (3) 0 0 1 1 (2)



Eye twitch 2a 2 (7) 1 1 (3) 0 0



Head pain 0 0 0 0 3a 2 (4)

Influenza 1 1 (3) 0 0 1 1 (2)

Low back pain 1 1 (3) 1 1 (3) 5 5 (10)

Paresthesia 1a 1 (3) 0 0 1 1 (2)





Vaginitis 2 2 (7) 2 1 (3) 0 0
































































































































201333629ndash808













804ndash814








20136631ndash640



200828392ndash395



20052582ndash86




S101ndashS104















(suppl 1)9ndash160







20102742ndash51




















201380697ndash704





ache Pain 201516543




201434986ndash993




2015841249ndash1253



2016157797ndash805















Ther 2011537ndash8








PO016 Abstract


Look Whatrsquos New
































Reprints



















Back pain 1 1 (3) 0 0 1 1 (2)



Eye twitch 2a 2 (7) 1 1 (3) 0 0



Head pain 0 0 0 0 3a 2 (4)

Influenza 1 1 (3) 0 0 1 1 (2)

Low back pain 1 1 (3) 1 1 (3) 5 5 (10)

Paresthesia 1a 1 (3) 0 0 1 1 (2)





Vaginitis 2 2 (7) 2 1 (3) 0 0
































































































































201333629ndash808













804ndash814








20136631ndash640



200828392ndash395



20052582ndash86




S101ndashS104















(suppl 1)9ndash160







20102742ndash51




















201380697ndash704





ache Pain 201516543




201434986ndash993




2015841249ndash1253



2016157797ndash805















Ther 2011537ndash8








PO016 Abstract


Look Whatrsquos New
































Reprints































































































































201333629ndash808













804ndash814








20136631ndash640



200828392ndash395



20052582ndash86




S101ndashS104















(suppl 1)9ndash160







20102742ndash51




















201380697ndash704





ache Pain 201516543




201434986ndash993




2015841249ndash1253



2016157797ndash805















Ther 2011537ndash8








PO016 Abstract


Look Whatrsquos New
































Reprints







Ther 2011537ndash8








PO016 Abstract


Look Whatrsquos New
































Reprints



























Reprints




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