NEUROSTIMULATION/NEUROMODULATION NEUROSTIMULATION/NEUROMODULATION UPDATEUPDATE

Andrew Charles, M.D.Andrew Charles, M.D.ProfessorProfessor

Meyer and Renee Meyer and Renee LuskinLuskin Chair in Migraine and Headache StudiesChair in Migraine and Headache StudiesDirector, Director, UCLA Goldberg Migraine ProgramUCLA Goldberg Migraine ProgramDavid Geffen School of Medicine at UCLADavid Geffen School of Medicine at UCLA

DISCLOSURESDISCLOSURESDISCLOSURESDISCLOSURES

•• AmgenAmgen –– ConsultantConsultant•• Amgen Amgen  ConsultantConsultant•• Eli Lilly Eli Lilly ‐‐ ConsultantConsultant

di l d idi l d i dd•• eNeuraeNeura –– Medical Advisory Medical Advisory BoardBoard•• Kimberly Clark Kimberly Clark ‐‐ ConsultantConsultant•• StSt. Jude Medical . Jude Medical –– Clinical trial steering Clinical trial steering committeecommittee

•• Takeda Takeda –– Research Grant SupportResearch Grant Support•• TrevenaTrevena ConsultantConsultant•• Trevena Trevena ‐‐ ConsultantConsultant

NEUROSTIMULATION/NEUROMODULATION NEUROSTIMULATION/NEUROMODULATION APPROACHESAPPROACHES

Supraorbital nerve stimulationCefaly Device - FDA Approved Transcranial magnetic stimulationCefaly Device - FDA Approved

for migraine prevention (also being investigated as acute therapy)

gSpring TMS Device

FDA Approvedfor acute therapy of migraine with aura

Vagal nerve stimulationSpenopalatine ganglion stimulationi iti ll i ti t d t Vagal nerve stimulation

Initially investigated as acute therapy for migraine and cluster, now being

studied as preventive therapy

initially investigated as acutetherapy for cluster headache, now being

investigated as preventive therapy

General Concepts of General Concepts of NeurostimulationNeurostimulation for Headachefor HeadacheGoal is to use peripheral stimulation toGoal is to use peripheral stimulation toGoal is to use peripheral stimulation to Goal is to use peripheral stimulation to provide input to both peripheral and central provide input to both peripheral and central sites that are involved in headachesites that are involved in headachesites that are involved in headachesites that are involved in headacheThe fact that input peripheral input may The fact that input peripheral input may modulate migrainemodulate migraine DOES NOTDOES NOT necessarilynecessarilymodulate migraine modulate migraine DOES NOT DOES NOT necessarily necessarily indicate that there is any pathology at the site indicate that there is any pathology at the site of inputof inputof input of input ? Inhibitory or excitatory  ‐‐‐May depend on f li d h h i i ffrequency, amplitude, other characteristics of stimulus 

PAIN PATHWAYS IN MIGRAINE“Pain Matrix”

DuraMeningealblood vessel

Thalamus

Pain Matrix

Trigeminal ganglion

Thalamus

Peri‐aqueductalgray

SupraorbitalNerve

Trigeminal cervical complex

Upper cervical nerveroots

Upper Neck and Head Pain are Referred to the Same N i th L B i tNeurons in the Lower Brainstem

Greater Greater occipital occipital nervenerve

SupratentorialSupratentorialduradura matermater

Electrical stimulationElectrical stimulation

Recording Recording electrodeelectrode

Trigeminal cervical Trigeminal cervical complexcomplex

ThalamusThalamus

BartschBartsch T, Goadsby PJ. Cur Pain Headache Rep 2003;7:371T, Goadsby PJ. Cur Pain Headache Rep 2003;7:371--376376

SUPRAORBITAL NERVE STIMULATIONSUPRAORBITAL NERVE STIMULATION•• Rationale:Rationale:

–– SupraorbitalSupraorbital nerves are branches of V1 that provide input nerves are branches of V1 that provide input i t t l t i i li t t l t i i l i tii ti ththinto central trigeminal into central trigeminal nociceptivenociceptive pathwayspathways

–– Many migraine patients experience pain in sensory Many migraine patients experience pain in sensory distribution of these nervesdistribution of these nerves

–– SupraorbitalSupraorbital nerve blocks are anecdotally helpful in some nerve blocks are anecdotally helpful in some patients with migrainepatients with migraine

–– Nerve stimulation may relief by stimulation of sensory Nerve stimulation may relief by stimulation of sensory fibers leading to “pain gating”, or may cause release of fibers leading to “pain gating”, or may cause release of endogenous opioidsendogenous opioidsendogenous opioidsendogenous opioids

1.Ashkenazi A, et al. Peripheral nerve blocks and trigger point injections in headache management 1.Ashkenazi A, et al. Peripheral nerve blocks and trigger point injections in headache management ‐‐ a a systematic review and suggestions for future research. Headache 2010; 50: 943systematic review and suggestions for future research. Headache 2010; 50: 943‐‐52.52.

2.Reed KL, et al. Combined occipital and 2.Reed KL, et al. Combined occipital and supraorbitalsupraorbital neurostimulationneurostimulation for the treatment of chronic for the treatment of chronic migraine headaches: initial experience. migraine headaches: initial experience. CephalalgiaCephalalgia 2010; 30: 2602010; 30: 260‐‐71.71.g pg p p gp g ;;

• Randomized, sham-controlled study (sham control – stimulation withreduced pulse width, frequency, intensity)

• 67 patients randomized• Primary outcome migraine days per month, 50% responder rate

•• 2573 patients who rented2573 patients who rented CefalyCefaly were surveyedwere surveyed2573 patients who rented 2573 patients who rented CefalyCefaly were surveyedwere surveyed•• 2313 who used 2313 who used triptanstriptans as acute therapy were selectedas acute therapy were selected•• AE reporting on all patientsAE reporting on all patients

--Discomfort with use of device causing reduced use (1.25%)Discomfort with use of device causing reduced use (1.25%)--Sleepiness during sessionSleepiness during session--Headache after sessionHeadache after session--Local skin irritationLocal skin irritationLocal skin irritationLocal skin irritation

•• At end of 40 day rental period:At end of 40 day rental period:--1077 (46.6%) were not satisfied and returned device1077 (46.6%) were not satisfied and returned device

Of these use was 48% of recommended timeOf these use was 48% of recommended timeOf these, use was 48% of recommended time Of these, use was 48% of recommended time --1236 (53.4%) were satisfied and purchased device1236 (53.4%) were satisfied and purchased device

TranscranialTranscranial Magnetic StimulationMagnetic Stimulationgg

•• Rationale:Rationale:–– Cortical Cortical hyperexcitabilityhyperexcitability may be an mechanism of may be an mechanism of migrainemigraine

–– TranscranialTranscranial magnetic stimulation can modulate magnetic stimulation can modulate the excitability of the cortexthe excitability of the cortex

–– TMS can inhibit cortical spreading depression in TMS can inhibit cortical spreading depression in animal modelsanimal models

–– Repetitive TMS is now FDA approved for Repetitive TMS is now FDA approved for treatment of medication refractory depression (10 treatment of medication refractory depression (10 Hz stimulation of leftHz stimulation of left dorsolateraldorsolateral prefrontalprefrontalHz stimulation of left Hz stimulation of left dorsolateraldorsolateral prefrontal prefrontal cortex)cortex)

Volume 9, Issue 4, Pages 373 - 380, April 2010 , , g , p

-267 patients intially enrolled, 201 patients randomized-Treatment during aura with 2 pulsesPrimary outcome pain free response at 2 hours-Primary outcome pain free response at 2 hours

• 119/164 patients reported reduction in acute medication use, average 8.5 +/- 7.7 days reductiong y

SphenopalatineSphenopalatine Ganglion Ganglion Stimulation Stimulation 

•• Rationale:Rationale:Rationale:Rationale:–– SPG is major SPG is major extracranialextracranial parasympathetic ganglion of the parasympathetic ganglion of the head and is involved in cranial autonomic symptoms of head and is involved in cranial autonomic symptoms of primary headaches primary headaches 

–– SPG block is helpful in some patients with  primary SPG block is helpful in some patients with  primary headache disorders including migraine and clusterheadache disorders including migraine and clusterheadache disorders including migraine and cluster headache disorders including migraine and cluster headacheheadache

–– SPG stimulation may interrupt parasympathetic outflow to SPG stimulation may interrupt parasympathetic outflow to inhibit pain and autonomic symptomsinhibit pain and autonomic symptoms

–– SPG stimulation may modulate sensory processing in the SPG stimulation may modulate sensory processing in the trigeminal nucleustrigeminal nucleus caudaliscaudalistrigeminal nucleus trigeminal nucleus caudaliscaudalis

32 patients enrolled, 28 completed randomized periodE hE h l t tt k t t d ith f ll b ti h ti l tiEachEach cluster attack treated with full, subperception, or sham stimulationPain relief and adverse events recorded at 15 minute time intervalsCluster attack frequency also recorded

Significant Adverse EffectsSignificant Adverse EffectsSignificant Adverse EffectsSignificant Adverse Effects•• Sensory disturbances (localized loss of Sensory disturbances (localized loss of sensation hypoesthesiasensation hypoesthesia paresthesiaparesthesiasensation, hypoesthesia, sensation, hypoesthesia, paresthesiaparesthesia, , dysesthesiadysesthesia, , allodyniaallodynia) ) –– 81%, resolved with 81%, resolved with time in 58%time in 58%time in  58% time in  58% 

•• Pain (face, cheek, gum, etc.) 38%, resolved in Pain (face, cheek, gum, etc.) 38%, resolved in 100%100%100%100%

•• Tooth pain/sensitivity, swelling, Tooth pain/sensitivity, swelling, trismus,headachetrismus,headache

‐‐More frequent attacks and sideMore frequent attacks and side‐‐switching switching reportedreported

VagalVagal Nerve StimulationNerve Stimulation•• Rationale:Rationale:

–– The The vagusvagus nerve innervates multiple anatomical structures nerve innervates multiple anatomical structures potentially involved in migrainepotentially involved in migraine

–– Branches of cervical nerves innervating the Branches of cervical nerves innervating the duradura may travel may travel with thewith the vagusvagus nervenervewith the with the vagusvagus nervenerve

–– VNS with implanted stimulators found to be effective as acute VNS with implanted stimulators found to be effective as acute therapy for migraine and cluster headachetherapy for migraine and cluster headache

–– VNS reduces VNS reduces allodyniaallodynia and glutamate release in response to and glutamate release in response to inflammatory soup applied to inflammatory soup applied to duradura in ratsin rats

Ma skopMa skop Va sVa s ner e stim lation relie es hroni refra tor mi raine and l sterner e stim lation relie es hroni refra tor mi raine and l sterMauskop. Mauskop. VagusVagus nerve stimulation relieves chronic refractory migraine and cluster nerve stimulation relieves chronic refractory migraine and cluster headache. headache. CephalalgiaCephalalgia,25:82,25:82‐‐86. 200586. 2005

OshinskyOshinsky et al., Noninvasive et al., Noninvasive vagusvagus nerve stimulation as treatment for trigeminal nerve stimulation as treatment for trigeminal allodyniaallodynia.. PainPain, 2014, 2014allodyniaallodynia. . PainPain, 2014, 2014

•• 27 patients 80 attacks27 patients 80 attacks•• 27 patients, 80 attacks27 patients, 80 attacks•• All attacks :  Moderate to severe pain at baseline All attacks :  Moderate to severe pain at baseline ‐‐ 12/54 12/54 

(22%) pain free at 2 hours, 23/54 (43%) pain relief at 2 hours; (22%) pain free at 2 hours, 23/54 (43%) pain relief at 2 hours; Mild pain at baseline Mild pain at baseline –– 10/26 (38%) pain free at 2 hours; 10/26 (38%) pain free at 2 hours; 

•• Relevant adverse effects Relevant adverse effects –– neck twitching (1), raspy voice (1)neck twitching (1), raspy voice (1)

FollowFollow‐‐up Studiesup StudiesnVNSnVNS for Prevention of Headachefor Prevention of Headache

-59 patients enrolled, 49 completed protocolprotocol->15 days of headache per month for previous 3 months3 t t t d 2 90 d-3 treatments per day – 2 90 second

administrations per treatment

Caloric Vestibular StimulationCaloric Vestibular StimulationCaloric Vestibular StimulationCaloric Vestibular Stimulation

Warm/cold stimulation of external ear canalWarm/cold stimulation of external ear canalWarm/cold stimulation of external ear canal Warm/cold stimulation of external ear canal with varying controllable waveformswith varying controllable waveformsRationale is that vestibular pathwaysRationale is that vestibular pathwaysRationale is that vestibular pathways Rationale is that vestibular pathways represent targets for neuromodulation in represent targets for neuromodulation in migrainemigrainemigrainemigraineData presented at this meetingData presented at this meeting

COMMON THEMES WITH COMMON THEMES WITH NEUROSTIMULATION/NEUROMODULATIONNEUROSTIMULATION/NEUROMODULATIONNEUROSTIMULATION/NEUROMODULATIONNEUROSTIMULATION/NEUROMODULATION

•• Multiple stimulation parameters:Multiple stimulation parameters:Multiple stimulation parameters:Multiple stimulation parameters:–– Amplitude, duration, frequency of stimulationAmplitude, duration, frequency of stimulation

•• Overlap between acute and preventive effectsOverlap between acute and preventive effects•• Overlap between acute and preventive effectsOverlap between acute and preventive effects•• Anatomical targets/mechanisms of action may Anatomical targets/mechanisms of action may be broader or different than those originally be broader or different than those originally proposedproposed

•• Further  rigorous studies are neededFurther  rigorous studies are needed