65
Stephen D Silberstein, MD Jefferson Headache Center Thomas Jefferson University Hospital Philadelphia, PA Neurostimulation 2016
Stephen D Silberstein, MD
Jefferson Headache Center
Thomas Jefferson University Hospital
Philadelphia, PA
1
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
stop
PAG
ONS: Randomized Sham-Controlled Studies
For Chronic Migraine: Design Elements
Study Control Trial Primary Endpoint
ONSTIM
N=60
Preset stim 1 min/day
Medical managed
None BUT intra-operative testing for
adequate paresthesia coverage
None
PRISM
N=139
1 s on / 90 m off Yes; 5-10d active and sham trial
∆ Migraine days per month at week 12
St Jude
N=157
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=1.0
P=0.003*P=0.032*
0%
N=75
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
-5
-4
-3
-2
-1
0
PRISM: Primary Endpoint: No Significant Change From
Baseline in Migraine Days/Month at 12 Weeks
P=0.26
±8.7
±8.3±8.2
±8.7
Mig
rain
e d
ays/
mo
nth
[ch
ange
fro
m b
asel
ine]
P=0.29
12
-We
ek
Ou
tco
me
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
• Occipital Nerve Stimulation (ONS)
• Transcranial Magnetic Stimulation (TMS)
• Frontal Nerve Stimulation
• Vagal nerve stimulation (VNS)
• Sphenopalatine ganglion stimulation (SPGS)
• low frequency : INHIBITS
• high frequency : EXCITES
Transcranial Magnetic Stimulation
sTMS
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
Lipton RB et al. Lancet Neurology 2010;9:373-380
Pain-free Response at 2, 24 and 48 hours
39%
22%
29%27%
16%13%
Lipton RB et al. Lancet Neurology 2010;9:373-380
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
MO MA
N=29
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
.
263
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
Set
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
(PP)
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
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
0.5
1
Me
an R
ed
uct
ion
of
He
adac
he
Day
s fr
om
Bas
eli
ne
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
• Occipital Nerve Stimulation (ONS)
• Transcranial Magnetic Stimulation (TMS)
• Frontal Nerve Stimulation
• Vagal nerve stimulation (VNS)
• Sphenopalatine ganglion stimulation (SPGS)
Schoenen J et al. Neurology 2013;80:697-704
Supraorbital TNS
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
(N)
AEs
(%)
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
• Occipital Nerve Stimulation (ONS)
• Transcranial Magnetic Stimulation (TMS)
• Frontal Nerve Stimulation
• Vagal nerve stimulation (VNS)
• Sphenopalatine ganglion stimulation (SPGS)
VNS: An Evolving Field
• Much I wanted to review
• But never enough time
• I have written what I would have said!
35
• 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
Size
(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
37
PREVA Study Overview• Randomly assigned treatment groups had matched demographics and
baseline characteristics
• nVNS stimulations twice daily and as needed for rescue
39
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
-7
-6
-5
-4
-3
-2
-1
0
SoC Plus nVNS (n=45) Control (n=48)
Me
an C
han
ge in
th
e N
um
be
r o
f C
H A
ttac
ks p
er
We
ek
−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)
40.0%
48.6%
8.3% 8.5%
0
10
20
30
40
50
60
70
80
n=37 n=47
Δ=−40.1%(p<0.001)
mITT Population
Δ=−31.7%(p<0.001)
ITT Population
n=45 n=48
≥50
% T
reat
me
nt
Re
spo
nse
Rat
e (
%) 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
45
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.
2
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
N=150
nVNS
n=73
Sham
n=77
nVNS
n=59
nVNS
n=69
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
nVNS
n=42
nVNS
n=58End of Study
nVNS Group Sham Group
Assessed for Eligibility
N=172
8 Discontinuations
- 2 Nonadherence
- 1 No CH/CH ended
- 3 Lost to follow-up
- 2 Other
17 Discontinuations
- 1 AEs
- 3 No CH/CH ended
- 8 Lack of efficacy
- 1 Lost to follow-up
- 4 Other
11 Discontinuations
- 1 No CH/CH ended
- 6 Lack of efficacy
- 2 Lost to follow-up
- 2 Other
ITT
n=60
ITT
n=73
ITT
n=45
ITT
n=59
3
Primary End Point: 1st Attack Response @ 15 Minutes (ITT)
8
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
9
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)
12
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)
13
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
14
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
2015
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
2015
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
-0.2
-1.3-…
-2.5-1.4
-2.4-2.8
-3.6
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
1
Sham (n=29)
nVNS (n=30)
b
Ch
an
ge
Fro
m B
ase
line
in
th
e #
of H
ea
da
ch
e D
ays
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
• Occipital Nerve Stimulation (ONS)
• Transcranial Magnetic Stimulation (TMS)
• Frontal Nerve Stimulation
• Vagal nerve stimulation (VNS)
• Sphenopalatine ganglion stimulation (SPGS)
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
65
“Pain is a more terrible
lord of mankind than
even death itself.”
-Albert Schweitzer
