Stephen D Silberstein, MD · eNeura SpringTMS Post-Market Observational U.S. Study of Migraine (The...

transcript

Stephen D Silberstein, MD

Jefferson Headache Center

Thomas Jefferson University Hospital

Philadelphia, PA

Neurostimulation 2016

Neuromostimulation

• Occipital Nerve Stimulation (ONS)

• Transcranial Magnetic Stimulation (TMS)

• Frontal Nerve Stimulation

• Vagal nerve stimulation (VNS)

• Sphenopalatine ganglion stimulation (SPGS)

Central 2nd-order neuron

(trigeminal cervical complex)

Pain perception

Trigemino-Cervical Complex Anatomical Convergence

ONS: Randomized Sham-Controlled Studies

For Chronic Migraine: Design Elements

Study Control Trial Primary Endpoint

ONSTIM

Preset stim 1 min/day

Medical managed

None BUT intra-operative testing for

adequate paresthesia coverage

1 s on / 90 m off Yes; 5-10d active and sham trial

∆ Migraine days per month at week 12

St Jude

No stimulation Yes; only those with >50% pain relief

enrolled

Responder rate (>50% ↓ VAS)

ONSTIM: Mean Percent Reduction in Headache

Days Per Month From Baseline to Month 3

Adjustablestim

Presetstim

MedicalMgt

Ancillary

P=0.566

P=0.058

P=0.132

N=75Saper, JR et al. Cephalalgia 2010;31(3) 271–285

ONSTIM: Responder Rate

Responder rate = > 50% reduction in headache days/mo or >3 point reduction in overall pain intensity (VAS)

Adjustablestim

Presetstim

MedicalMgt

Ancillary

P=0.003*P=0.032*

Saper, JR et al. Cephalalgia 2010;31(3) 271–285

Silberstein SD, et al. Cephalalgia 2012;32(16) 1165–1179:

Primary Endpoint: Significant difference at 50% reduction in

pain AND 10% differential at the 95% CI

% reduction from baseline

Control Group %

responders (n=52)

Active Group % responders

(n=105)p-value1

met protocol objective

(>10% dif.)2

10,0% 30,8% 56,2% 0,003 Yes

20,0% 19,2% 40,0% 0,009 Yes

30,0% 17,3% 35,2% 0,020 Yes

40,0% 15,4% 25,7% 0,0143 No

50,0% 13,5% 17,1% 0,553 No

Silberstein SD, Dodick DW, Saper JR, et al. Cephalalgia 2012;32(16) 1165–1179:

Headache Days (Secondary Endpoint)

Visit Control Group (n=52) Active Group (n=105) P-Value

Baseline

Mean (± std) 20,1 (± 7,2) 22,4 (± 6,9) 0,049

Week 12

Mean Change1 -3,0 (14,9%) -6,1 (27,2%) 0,008

Difference (95% CI) -3,1 (-5,4, -0,8)

Silberstein SD, Dodick DW, Saper JR, et al. Cephalalgia 2012;32(16) 1165–1179:

Baseline [days/month] Baseline [days/month]

Intent-to-Treat (n=139) Modified ITT (n=125)

-3.6-3.9

-5.2-5.5-6

PRISM: Primary Endpoint: No Significant Change From

Baseline in Migraine Days/Month at 12 Weeks

P=0.26

±8.3±8.2

P=0.29

19.9±7.3

18.9±8.0

20.2±7.2

19.2±7.9

Control

Treatment

Lipton RB, et al. Presented at IHC 2009

ONS: Adverse Event Rate

Neuromostimulation

• low frequency : INHIBITS

• high frequency : EXCITES

Transcranial Magnetic Stimulation

Repetitive TMS

Single Pulse TMS (sTMS) Disrupts CSD

Modifies Cortical Excitability

Holland et al. Cephalalgia. 2009;29(Suppl 1):22.

Andreou et al. Headache. 2010;50(Suppl 1):58.

Single Pulse Transcranial Magnetic Stimulation for

Acute Treatment of Migraine With aura

• Portable device developed to

facilitate early self-treatment

at home

• 201 aura patients randomized in

double- blind, parallel group,

sham controlled study at 16 U.S.

headache centers

Lipton RB et al. Lancet Neurology 2010;9:373-380

• Multicenter, randomized, double-blind, sham-controlled

• sTMS N=82, sham N=82

– Migraine with aura

– 1-8 migraine attacks per month

• Instructed to treat as soon as possible after the onset of migraine aura

and always within 1 hour of aura onset

• 2 consecutive pulses per attack

• Rescue drugs permitted 2h after treatment

Pain-free Response at 2, 24 and 48 hours

29%27%

16%13%

10 outcome: 2 hour pain free

• 39% vs 22%, p< 0.0179

• Therapeutic gain 17%

AEs minimal and mild

• 5% sTMS vs. 2% sham

Adverse Event Type ShamN = 99 TMS

N = 102

Number of Patients With at least 1AE

9 (9.1%) 14 (13.7%)

Number of Patients With at least 1 TRAE

2 (2.0%) 5 (4.9%)

AEs Leading to Withdrawal 0 0

Serious Adverse Events (SAEs)

0 1 (1%) Optic Neuritis

Treatment-related SAEs 0 0

TMS Adverse Events

Lipton RB, Dodick DW, Silberstein SD et al. Lancet Neurol 2010; 9: 373–80

UK Pilot: Open Label Experience

(Demographics)

N= 98 patients prescribed

Migraine Features # of Patients # of Attacks Treated

Migraine with aura 26 387

Migraine without aura 18 188

Of these:

Episodic 26 334

Chronic 14 188

Daily 4 53

Goadsby PJ, et al. EHMTIS London, Sept 2012

sTMS Open Label Study: Pulsed BID and PRN

Bhola et al. AHS Scientific Meeting, June 2015.

Reduction Migraine Days

Time 0 wks 6 wks 12 wks / 0 wks 6 wks 12 wks

Reduction Acute Medicine Days

Migraine wo aura Migraine w/aura

patients

eNeura SpringTMS Post-Market Observational U.S. Study of Migraine

(The “ESPOUSE” Study)

MULTI-CENTER, PROSPECTIVE, NON-RANDOMIZED, SINGLE ARM, OPEN LABEL, POST-MARKET, OBSERVATIONAL STUDY TO EVALUATE THE USE OF THE ENEURA, SPRINGTMS SYSTEM IN REDUCTION OF MIGRAINE HEADACHE SYMPTOMS

SITE INVESTIGATOR

Mayo Clinic Arizona Amaal J. Starling, MD

Jefferson Headache Center Michael J. Marmura, MD

UCLA Headache Research and Treatment Program Andrew Charles, MD

Mid-Atlantic Permanente Medical Group (Kaiser) Ejaz A. Shamim MD

Stanford Headache Program Nada Ahmad Hindiyeh, MD

The Cleveland Clinic Center for Headache and Pain Stewart Tepper, MD

Montefiore Headache Center (MAB site) Matthew S. Robbins, MD

Patient Selection Criteria

Inclusion Criteria

• 18 to 65 years of age

• Migraine w/wo aura

• 4-25 headache days per

month; minimum of 5

completely headache-

free days/month)

• Headache Day: 4 hours

of headache which at

any point resulted in

moderate to severe pain

Exclusion Criteria

• Epilepsy or history of seizure.

• Metal-containing implants

• Concurrent use of other

neurostimulation devices

• No change in preventive

medications past 2 months

• Extracranial nerve blocks

within past 3 months

• Botox® within past 4 months

ESPOUSE Treatment Protocol

• Daily: 4 Pulses each morning and evening

– 2 consecutive pulses wait 15 minutes and repeat the 2 consecutive pulses.

• As needed: Treat an acute attack

– 3 consecutive pulses at the onset of migraine pain, wait 15 minutes

– If needed, treat with additional 3 pulses, wait 15 minutes

– If needed, treat with additional 3 pulses

• Patients may rescue with acute medication 30 minutes after the first three pulses

are delivered

ESPOUSE Study Subject Accountability Flow Chart

Patients consented to enroll in study

217Patients who were confirmed eligible to participate and

received a device

179Patients who began treatment

Deemed

Eligible

Safety Data

1321,2Patients eligible based on definition of headache day

117Patients who completed 3 months of treatment

95Patients who completed 3 months of treatment per

protocol

Full Analysis

Set (FAS)

Completed

Cases (CC)

Per Protocol

1 47 patients were not included in the Full Analysis Set because they

did not meet the inclusion criteria of at least 4 headache days2 Definition of Headache Day = 4 hours of pain which at any point during

the 4 hour period resulted in moderate to severe pain

229Patients completing baseline (BL) diaryCompleted

BL diary

-2.73 -2.98

Full Analysis Set (FAS)

Per Protocol (PP)Baseline = 9.07 Days

P< .0001

Performance Goal = -0.63

Primary Effectiveness Endpoint:

Mean Reduction in Headache Days

Safety: Adverse Events

Adverse Event n %

Lightheadedness 8/179 4.5

Tingling 7/179 3.9

Tinnitus 7/179 3.9

Dizziness 6/179 3.4

Headache 5/179 2.8

Worsened head pain 5/179 2.8

Scalp discomfort 5/179 2.8

Any reported adverse event 62/179 34.6

No Serious AEs

Practical Implications for Clinicians

• Promising non-drug treatment option that is safe

and well tolerated

• Acute and prophylactic studies in migraine

without aura underway

• FDA approved for acute treatment of migraine

with aura

Neuromostimulation

Schoenen J et al. Neurology 2013;80:697-704

Supraorbital TNS

3 months Verum Sham P-value

Decrease in mean

migraine days6.94 4.88 6.54 6.22

Verum 0.023*

Sham 0.608

50% responder rate 38.1% 12.1% 0.023*

Schoenen J et al, Neurology 2013

• Double-blind, sham-controlled trial, n=67

• Stimulation 250 µs, 60 Hz, 16 mA, 20 min / day

Supraorbital Transcutaneous

StimulationAEs Reported by >1 Patient (40-day trial period)Patients

Patients

Do not like the feeling and want to discontinue use 29 29.29 1.25

Sleepiness 12 12.12 0.52

Headache 12 12.12 0.52

Reversible forehead skin irritation 5 5.05 0.22

Insomnia 4 4.04 0.17

Feeling of fatigue 3 3.03 0.13

Forehead paresthesia for several minutes post-session 3 3.03 0.13

Feeling of stress during the session 3 3.03 0.09

Allergic skin reaction 2 2.02 0.09

Dental pain during the session or at the beginning 2 2.02 0.09

Inability to keep eyes open during sessions 2 2.02 0.09

Feeling of contusion on the forehead during a few days 2 2.02 0.09

Magis D et al. J Headache Pain. 2013

•2,313 renters

•Mean 58.2 day rental

•46.6% unsatisfied, returned device

Supraorbital TNS: AEs

Neuromostimulation

VNS: An Evolving Field

• Much I wanted to review

• But never enough time

• I have written what I would have said!

• Longest cranial nerve

• Innervates neck, thorax and abdomen

• Reaches colon

The Vagus Nerve (VN)

Cranial Nerve X

Latin: wandering

GammaCore® (ElectroCore® )

• Handheld, patient-controlled

• Uniform electric field

– Low-voltage 1-ms bursts of 5kHz sine waves repeated at 25hz.

– Maximum: 30 V and 60 mA

• Stimulates low-threshold A fibers, not high-threshold efferent C fibers

• Recommended preventive Rx:

– Two 120-second stimulations TID.

StudyPrincipal

Investigator

(N)Format Status

Royal Free Hospital Goadsby 21 patients

Open-label case series,

prevention

and acute use

Neurology 2015

GC-002 (PREVA) Gaul 97 patients

Open-label, SoC

comparator study;

prevention

Cephalalgia 2015

CH-US-01 (ACT 1) Silberstein 150 patientsDouble-blind, RCT,

active sham, acuteAHS 2015

GC-003 (ACT 2) Goadsby 102 patientsDouble-blind, RCT,

active sham, acuteIn Preparation

Abbreviations: RCT, randomized controlled trial; SoC, standard of care.

VNS Clinical Trial Overview: Cluster

PREVA Study Overview• Randomly assigned treatment groups had matched demographics and

baseline characteristics

• nVNS stimulations twice daily and as needed for rescue

2 weeks 4 weeks 4 weeks

Standard of CarePlus nVNS

(N=48)

Standard of Care(N=49)

Standard of Care Plus nVNS

(N=90)

Standard of Care(N=114)

BaselinePhase

RandomisedPhase

Open-label Phase

Demographics and Baseline Characteristics

CharacteristicSoC Plus nVNS

(n=48)Control(n=49)

Age, y, mean (SD) 45.4 (11.0) 42.3 (11.0)

Sex, n (%)

Male 34 (71) 33 (67)

Time since onset of chronic CH disorder, y, mean (SD)a 4.7 (3.9) 5.0 (3.7)

CH attack duration, min, mean (SD)

With acute pharmacologic medications/oxygenb 27.4 (19.8) 29.3 (29.9)

Without acute pharmacologic medications/oxygenc 95.2 (57.7) 103.3 (66.8)

Number of CH attacks in the 4 weeks before enrolment, mean (SD)c 67.3 (43.6) 73.9 (115.8)

Abbreviations: CH, cluster headache; nVNS, non-invasive vagus nerve stimulation; SD, standard deviation; SoC, standard of care. a Data were missing for 2 subjects in the control group. b Data were missing for 1 subject in the control group. c Data were missing for 1 subject in the SoC plus nVNS group.

Change in the Number of CH Attacks/ Week

SoC Plus nVNS (n=45) Control (n=48)

−5.9

Δ=3.9

−2.1

P=0.02

Abbreviations: CH, cluster headache; ITT, intent-to-treat; nVNS, non-invasive vagus nerve stimulation; SoC, standard of care.Values are presented as unadjusted means and were calculated from all subjects with evaluable data.P value corresponds to the difference in the change from baseline between treatment groups from an analysis of variance.

Baseline Versus the Last 2 Weeks of Randomised Phase (ITT)

8.3% 8.5%

n=37 n=47

Δ=−40.1%(p<0.001)

mITT Population

Δ=−31.7%(p<0.001)

ITT Population

n=45 n=48

%) SoC Plus nVNS Control

≥50% Treatment Response Rate

Abbreviations: ITT, intent-to-treat; mITT, modified intent-to-treat; nVNS, non-invasive vagus nerve stimulation; SoC, standard of care. Analysis of response rate was performed on the ITT population (defined as subjects who had ≥1 efficacy recording in the headache diary after randomization), the mITT population (defined as subjects who had measurable

observations across the study phases being compared); subjects with incomplete data were designated as treatment failures.

Small n values represent the number of observations included in the analyses.

Attack Frequency Over Time

Abbreviations: CH, cluster headache; CI, confidence interval; mITT, modified intent-to-treat; nVNS, non-invasive vagus nerve stimulation; SoC, standard of care.

* p<0.02 vs SoC alone

No. of Attacks

per Week (Mean ±95% CI)

Treatment Week

Expanded Response Rates

Abbreviations: ITT, intent-to-treat; nVNS, non-invasive vagus nerve stimulation; SoC, standard of care.a Proportion of patients with the specified percentage decrease in attack frequency from baseline to the end of the randomized phase.

Responder Ratea

Patients(%)

SoC Alone (n=48)

SoC+nVNS (n=45)

nVNS Conclusions

• Significant improvement compared with SoC

– Reduced frequency of CH attacks per week

– Associated with significantly higher proportion of patients who achieved ≥50% reduction in CH attacks per week versus SoC

– Reduced use of rescue medication, including sumatriptan and oxygen, compared with SoC

• Safe and generally well tolerated, with few reported device-related AEs

• Continued use of nVNS associated with sustained clinical effects

Study Overview

• Two-phase, randomized, sham-controlled prospective study of nVNSfor CH

– Double-blind phase (up to 1 month or until 5 CH attacks were treated)

– Open-label phase (3 months)

• Study population

– Episodic CH or chronic CH according to the International Classification of Headache Disorders criteria1

– 150 enrolled subjects; 133 subjects in the ITT population (ie, all randomly assigned subjects who treated ≥1 CH attack)

• Acute treatment

– Three consecutive 2-minute stimulations to the right side of the neck at the onset of premonitory symptoms or pain

– Only 1 CH attack could be treated during a 12-hour period

1. Headache Classification Subcommittee of the International Headache Society. Cephalalgia. 2004;24(suppl 1):9-160.

Study Design and Patient Disposition

a Some subjects failed screening for >1 reason.

14 Discontinuations

- 3 Nonadherence

- 8 No CH/CH ended

- 2 Lost to follow-up

- 1 Other

Subjects Enrolled

22 Subjects failed screeninga

- 16 Did not meet entry criteria

- 6 Declined to participate

- 2 Other

Open-label Phase

3 Months

Randomized Phase

1 Month

n=58End of Study

nVNS Group Sham Group

Assessed for Eligibility

8 Discontinuations

- 2 Nonadherence

- 1 No CH/CH ended

- 2 Other

17 Discontinuations

- 1 AEs

- 3 No CH/CH ended

- 8 Lack of efficacy

- 4 Other

11 Discontinuations

- 1 No CH/CH ended

- 6 Lack of efficacy

- 2 Other

Primary End Point: 1st Attack Response @ 15 Minutes (ITT)

All Subjects Episodic CH Chronic CH

Secondary End Point

Proportion of Subjects With a Sustained Treatment Response (60 Min/No Rescue)

All Subjects Episodic CH Chronic CH

Summary of Results (Double-blind Phase)

End PointAll Subjects

(n=150)eCH Cohort

(n=101)cCH Cohort

(n=49)

Response rateNS

(P=0.1)SIG

(P=0.008)NS

(P=0.48)

Sustained treatment response rateSIG

(P=0.04)SIG

(P=0.008)NS

(P=1.0)

Pain intensityNS

(P=0.4)NS

(P=1.0)NS

(P=0.2)

Responder for ≥50% of treated attacksNS

(P=0.41)SIG

(P=0.04)NS

(P=0.19)

Pain free for ≥50% of treated attacksNS

(P=0.33)SIG

(P=0.04)NS

(P=0.36)

Duration of first attackNS

(P=0.25)NS

(P=0.21)NS

(P=0.82)

Change in attack durationSIG

(P=0.03)SIG

(P=0.03)NS

(P=0.69)Rescue medication use in the first hour after the first attack

NS(P=0.15)

NS(P=0.53)

NS(P=0.13)

Safety and Tolerability

Incidence of AEs/ADEs (All Treated Subjects)

nVNS (n=73) Sham (n=77)

≥1 AE, No. (%) 18 (24.7) 31 (40.3)

≥1 Serious AE, No. (%) 1 (1.4)a,b 0

≥1 ADE, No. (%) 11 (15.1) 24 (31.2)

ADEs Occurring in ≥5% of Subjects in Any Treatment Group, n (%)

Application site reactions

Burning/tingling/soreness/stinging 2 (2.7) 7 (9.1)

Skin irritation/redness/erythema 0 9 (11.7)

Musculoskeletal disorders

Lip or facial drooping/pulling/twitching 8 (11) 0

Nervous system disorders

Dysgeusia/metallic taste 0 7 (9.1)

a Serious AE of cluster headache. b Serious AEs were not considered related to the study device. c Serious AEs included cluster headache (1 occurrence; 1 subject); cluster headache as well as multiple left extremity deep vein thromboses, abdominal aortic aneurysm, pneumonia, anasarca, acute respiratory failure, and urethral trauma (1 occurrence each in the same subject); mesenteric ischemia (1 occurrence; 1 subject); herniated disk (1 occurrence; 1 subject); and ureteral calculus (1 occurrence; 1 subject)

Conclusions

• Large RCT of a therapeutic intervention for cluster

• Examined acute response, sustained relief, safety and tolerability

• Significant and meaningful benefit in eCH(34.2% vs. 10.6%; p=0.008)

• Not significant in cCH (13.6% vs. 23.1%; p=0.48)

• Impacted total population (26.7% vs. 15.1%; p=0.1)

• Safe and well tolerated

• New treatment option with benefit profile in eCH

Clinical Trial Overview: Migraine

Study PI N/attacks Format Primary Findings Status

Acute Treatment

Episodic

MigraineGoadsby 27/80 OL, MC

33.3% PF, 62.9% PR (mild-severe)

Cephalalgia 2014

HFEM & CM Barbanti 18/131 OL, MC39.6% PF, 64.6% PR (mild-

severe)

Journal of Headache and Pain

CM Moscato 22/79 OL, SC44% improvement in mean

pain intensity @ 2 hr2014/2015 AHS, EHMTIC, IHS

CM & MOH Rainero 15/362 OL, SC 33.4% PF AAN 2014

EM Tassorelli ≈ 300DB, sham controlled

RCT> 200 enrolled, Sep. 16

Preventive Treatment

EM/CM (Acute

and Prev.)Kinfe 20/225 OL, SC

39.4% (p<0.001) reduction in

headache days;

Journal of Headache and Pain

CM (EVENT) Silberstein59/8

months

Double-blind, sham

controlled, pilot RCT

Met safety endpoint, 2 day

(ns) reduction in HA days at 2 months

Neurology 2016

MM/MRM Grazzi56/3

monthsOL, MC

33% decrease in monthly MM/MRM days per month

Journal of Headache and Pain,

In-Press

EM Diener ≈ 425DB, sham controlled

RCT>350 enrolled as of Sep. 16

Abbreviations: MOH, medication-overuse headache; RCT, randomized controlled trial. HFEM, high frequency episodic migraine; CM, chronic migraine; EM, episodic migraine; OL,

open label; DB, double blind; SC, single-center; MC, multi-center; PF, Pain Freedom (2hr); PR, Pain Relief (2hr); MM/MRM, menstrual/menstrually related migraine

Chronic Migraine Headache Prevention With Non-invasive Vagus Nerve Stimulation

The EVENT Study

Study Overview and Design

Run-innVNS

Sham controlOpen-label nVNS

Run-in Phase4 weeks

Randomized Phase8 weeks

Open-label Extension6 months

Randomization (1:1)

Abbreviation: nVNS, non-invasive vagus nerve stimulation.

• Patients had chronic migraine with or without aura• Prophylactic treatment (comparative and extension

phases)- Two 2-minute stimulations (nVNS or sham)

administered to the right side of the neck 3 times per day (6 stimulations total per day)

Demographics and Baseline Characteristics

CharacteristicnVNS(n=30)

Sham(n=29)

Age, mean (SD), y 40.5 (14.2) 38.8 (11.1)

BMI, mean (SD), kg/m2 28.6 (5.3) 31.6 (9.8)

Headache days reported during baseline, mean (SD) 20.8 (5.0) 22.3 (4.9)

Females, n (%) 26 (87) 27 (93)

Race, n (%)

Caucasian 26 (87) 25 (86)

Black 3 (10) 0

Other 1 (3) 4 (14)

Abbreviations: BMI, body mass index; SD, standard deviation.

Reduction in Number of Headache Days

a Imputation for missing data was performed using the last observation carried forward. ITT Population.b Received open-label nVNS after month 2.

Mean Change From Baseline in Number of Headache Days per 28 Daysa

-1.3-…

-2.5-1.4

-2.4-2.8

Sham (n=29)

nVNS (n=30)

Baseline Month 2 Month 4 Month 6 Month 8

*P<0.05 vs baseline

Open-labelRandomized

Treatment Response

Response was defined as a ≥50% decrease from baseline in the number of headache days per 28 days. Per Protocol Completer Population.a 2-, 4-, and 6-month completers were from the 59 subjects initially randomized to either nVNS or sham treatment. b 8-month completers were from the 30 subjects initially randomized to nVNS treatment.

Conclusions: nVNS Prophylactic Use

• Safe, well tolerated in chronic migraine(CM) patients

• Compared with sham device, nVNS had greater reductions in mean headache days

• Longer treatment duration associated with increased benefits: fewer headache days and improved treatment response– Improved outcomes with longer treatment may result from neuroplastic

change in the brain state; further research required to substantiate this

• nVNS may offer CM patients clinical benefit without exposure to additional pharmacologic Rx

• Health Canada approved, CE mark in the EU, approved by NICE in the UK, and currently under consideration by US FDA

Neuromostimulation

The Sphenopalatine Ganglion (SPG)

Edvinsson, Goadsby. Cephalalgia 1994;14:320-7.

Burstein,Jakubowski. J Comp Neurol 2005;493:9-14

SPG Stimulation with Implanted System

• Miniaturized implant stimulates SPG

• Wirelessly powers and controled: no external batteries or wires

• Implanted through mouth

• On-demand, patient-controlled therapy with remote controller

• Rechargeable through USB port, internet connected

• On / Off Button, Programmable Up / Down Buttons

(amplitude adjustment)

Schoenen et al. Cephalalgia 2013;33: 816–830.

SPG Stimulation Acute, Preventive, or Both In Large EU RCT

N=38 patients at end of experimental period, 769 attacks analyzed)

• Acute treatment: 55% of attacks with pain relief 15 minutes vs 6% sham

Schoenen et al. Cephalalgia 2013;33: 816–830.

Schoenen et al. Cephalalgia 2013; 33 (Supplement 8):101-102.

• Preventive effect: 42% of patients had 89%

decreased attack frequency

“Pain is a more terrible

lord of mankind than

even death itself.”

-Albert Schweitzer

Stephen D Silberstein, MD · eNeura SpringTMS Post-Market Observational U.S. Study of Migraine (The...

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