Recent Advances in Neurology 2020 Disclosures for Dr. Morris Levin

Difficult Headache Consultant in one-time advisory boards: Supernus, Upsher Smith, Amgen, Alder, Revance, Management Theranica, Currax, Biohaven, Allergan No speaker’s bureaus Decisions Consultant and stock in Percept Royalties: Oxford University Press, Anadem Publishing, Wiley Blackwell, Castle Connolly Publ, UCSF Office of Innovation Morris Levin, MD Research support Professor, Dept of Neurology, UCSF American Headache Society, Theranica, Electrocore Director, UCSF Headache Center

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CHALLENGING HA MANAGEMENT WHEN TO INITIATE CGRP MABS SITUATIONS • Case – • 45 year old executive began having HAs in • When to initiate mAb treatment and when to change to another Ab 30s, initially infrequent, now occurring at least 3x weekly leading her to use butalbital- • Treating migraines in elderly patients and in patients with vascular disease or other complicating factors acetaminophen-caffeine tablets (Fioricet ®) 2-6 tablets on many days, frequent NSAIDs, • Managing migraine in pregnancy and lactation occasional hydrocodone (Norco®) and • New options in acute migraine treatment other OTC meds. • Options in intractable Cluster Headache • Triptans have not helped, nor have a number • When inpatient HA treatment is appropriate of prophylactic medications.

Levin UCSF Levin UCSF 3 4 MANAGING MEDICATION OVERUSE MEDICATION OVERUSE HEADACHE HEADACHE Definition • Mechanisms are unclear but consensus holds • Headache occurring on >15 days/month that use of analgesic or abortive headache in a patient with a pre-existing (primary) medications >2x a week tends to worsen headache disorder migraine frequency and severity • Initially, reducing the use of medications will tend • Regular overuse (10 or 15 days per month to further worsen headaches, leading to an depending on the agent) for >3 months impasse. of one or more drugs that can be taken • Physical and psychological dependency may be for acute headache occurring simultaneously • Allowing MOH to continue seems to be associated with conversion of migraine to chronic migraine

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MANAGING MEDICATION OVERUSE HEADACHE MIGRAINE PROPHYLAXIS CURRENT OPTIONS Solution = “Bridge Therapy” • Steroid “burst” – prednisone 60 mg x 4 days reducing over the next 6 days to 0 Anticonvulsants – topiramate 100-200 mg hs • IV Dihydroergotamine x 5 d Beta blockers – propranolol 80 mg bid • IV Chlorpromazine x 4-5 d Cyclic antidep – nortriptyline 25-75 mg hs Coupled with • discontinuation of previous analgesics • replacement with less problematic rescue meds • preemptive treatment of withdrawal • Institution of new prophylactic program

Levin UCSF Levin UCSF 7 10 MIGRAINE PROPHYLAXIS MIGRAINE PROPHYLAXIS CURRENT OPTIONS CURRENT OPTIONS

Anticonvulsants – topiramate 100-200 mg hs At best, 50% pts are 50% Beta blockers – propranolol 80 mg bid better Cyclic antidep – nortriptyline 25-75 mg hs Multiple adverse effects Calcium channel bl – amlodipine 2.5-10 mg/d Med-med interactions Angiotensin receptor bl – candesartan 4-16 mg Tachyphylaxis Memantine 10 mg bid “I feel so much better since I stopped taking the pills you Noruzzadeh, R, et al. Memantine for prophylactic treatment or migraine w/o aura: a RDBPC study. Headache 2016, 56:95-103. prescribed”

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RATIONALE FOR CGRP MODULATION 4 anti-CGRP MABs to prevent IN MIGRAINE migraine

. CGRP levels elevated in migraineurs between • Aimovig®(Amgen erenumab) – Human anti GCRP receptor attacks and during (even higher) Ab – SC monthly; available since June 2018 . Triptans and Onabotulinum toxin block CGRP • Ajovy® (Teva fremanezumab) - humanized mAb anti CGRP release, thought to be a significant component of ligand - SC monthly their mechanisms of action • Emgality® (Lilly galcanezumab) – humanized mAb anti- . CGRP infusion induces migraine-like headache in susceptible individuals CGRP ligand - SC monthly • ALD403 (Alder eptinezumab)– humanized mAb anti-CGRP ligand - IV q3mo; submitted to the FDA for regulatory Buchanan T, et al. Expert Rev Neurotherapeutics 2004; evaluation Edvinsson L. Expet Opin Ther Targets 2003; Buzzi MG, et al. Cephalalgia 1995; Goadsby PJ, et al. Ann Neurol 1988; Edvinsson L, et al. J Auton Nerv Syst, 1998; Ashina M, et al. Pain 2000.

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13 15 CGRP MAbs – Routes and Doses Response to mAb over time

MAB target Antibody type Doses (mg) Route

erenumab receptor IgG2 70,140 SC (Amgen) Human galcanezumab ligand IgG4 120,240,300 SC control (Lilly) humanized

fremanezumab ligand IgG2 225,675 SC (Teva) humanized

eptinezumab ligand IgG1 100,300 IV (Alder) humanized

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CGRP MAbs – Best evidence to date CGRP MAbs – Best evidence to date generally very positive at high dose generally very positive at higher doses for EM

MAB target EM (12 wks) CM Route MAB target 50% RR at 12 wks* erenumab receptor P2 −3.4d v. −2.3 -6.6d v. -4.2d SC erenumab receptor 65% (Amgen) Human P3 -3.7 v. -1.8 galcanezumab ligand 70% (75% RR – 34%) galcanezumab ligand P2 -4.2 v. -3.0 -2.7 v. -4.8 SC (Lilly) humanized P3 -4.7 v. 2.8 -4.3 v. 2.3 fremanezumab ligand 48% fremanezumab ligand P2 -6.3 v. -3.5 -6.2 v. -4.2 SC P3 -3.7 v. -2.2 -5.0 v. -3.2 (Teva) humanized eptinezumab ligand 61% (75% RR – 30%) eptinezumab ligand P2 −5.6 v. −4.6 -8.2 v. -5.6 IV *50% responder rate – the % of patients who over a spec time (Alder) humanized P3 -4.3 v. -3.8 period experienced half as many (or less) than usual # HA days

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18 19 CGRP MAbs - Evidence to date Aimovig® (erenumab)

Potential strengths are significant • Autoinjector • highly target specific, so if no on-target AEs • 70 and 140 mg emerge, a very focused treatment • Monthly • Appear more effective than current prophylactic • Latex in needle cover meds – certainly for some patients (high 50% responder rates, impressive 75% responder rates) • When 70 is not effective, but AEs • long half life – infrequent dosing boosts compliance are mild or 0, increase to 140 • Might work in MOH, cluster, PTTHA • When effect wears off early, • Rapid onset – determination of benefit quick shorten interval

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Ajovy® (fremanezumab) Emgality® (galcanezumab)

• Syringe – to inject by nurse or self – 1.5 cc • Autoinjector • 225 mg monthly or 675 mg (3 injections) quarterly • 120 mg monthly (240 mg loading dose – 2 • Not an autoinjector; soon to be available injections) • Viscous – may take 10 sec to inject • Available in 100 mg to use 3 for cluster HA

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22 23 Eptinezumab Lingering questions about CGRP mAbs • Which patients will respond? • Intravenous • Are responses going to be as dramatic in real • 100 or 300 mg infusion life (i.e. did the high placebo rate confound) • quarterly • Will CGRP levels or other biomarkers help to predict response? • Are they really safe? • Will there be clinical differences between the 4 CGRP mAbs? Which to choose / when to switch • Will they be covered by insurance plans?

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Are anti-CGRP antibodies really safe? CGRP and its receptors

Observed adverse effects in clinical use: . GCRP receptors found in neural, respiratory, endocrine, gastrointestinal, immune and • Injection site swelling cardiovascular tissues. • Constipation . CGRP is a potent vasodilator and is considered • Nausea (area postrema - medulla) important in cardiovascular regulation, response to • Fatigue, several cases of overwhelming ischemia, gastrointestinal physiology and wound debilitation (Hypothal-Pit axis?) healing. • Arthralgias . CGRP MABs seem not to pose cardio- or cerebrovasc • risk but not adequately studied in people with Rashes underlying vascular disease or risks. • (No elevation of hepatic enzymes)

MaassenVanDenBrink, A, et al. Wiping out CGRP: Potential cardiovascular risks. Trends in Pharmacological Sciences 37.9 (2016): 779-788. Levin UCSF 27 28 Erenumab – “real world cardiac risk study”

Cardiac safety – Erenumab and Angina trial: 89 cardiac patients (36 had prev MIs) Endpoint – exercise time during treadmill not effected by pts pretreated with erenumab 140 mg IV; no diff in secondary endpoints of exercise induced angina or ST depression.

Depre C, Antalik L, Starling A, Koren M, Eisele O, Kubo Y, Lenz RA, Mikol DD. A randomized, double-blind, placebo-controlled study to evaluate the effect of erenumab on exercise time during a treadmill test in patients with stable angina. Cephalalgia 2017 37:340-341

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Might exercise caution in prescribing Which mAb? When to switch anti-CGRP antibodies for patients with:

• Erenumab – most data • GI illnesses with reduced motility • Fremanez – self inject v. autoinjector • Patients at risk for cardio and cerebrovascular • Galcanez – cluster HA; less constip? disease • Inflammatory diseases • Eren – if ineffective, change to Gal • Recent surgery or injuries or Frem; vise versa • Pregnancy • How long for a trial? 3 rounds? 6? • Children/adolescents (HPA) • Payment – All 3 have payment assistance but not for public insurance, and not forever

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31 32 TREATING MIGRAINES IN PATIENTS WITH TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS VASCULAR DISEASE OR RISK FACTORS

• Migraine often persists into old age – 3-10% of elderly have migraine. (Fasted growing Case – demographic) 72 year old woman with longstanding • Triptans are mildly vasoconstrictive and if risks are migraine, HLD, borderline DM and a high, should probably be avoided. But often risks lacunar stroke seen on MRI. She is using are exaggerated. sumatriptan 2-3x per week. • Risk factor stratification based on Framingham study data using gender, Total Chol, HDL, DM, HTN, and tobacco is more logical.

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TREATING MIGRAINES IN PATIENTS WITH TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS VASCULAR DISEASE OR RISK FACTORS

• Roberto et al - systematic review of observational • Migraine is associated with increased risk of data of use of triptans: stroke, and possibly with increased risk for • “…intense consumption of ergotamines may be cardiovascular disease associated with an increased risk of serious ischemic complications. As for triptans, available • Migraine with aura is assoc with an increased risk studies do not suggest strong CV safety issues”. of ischemic stroke (OR as high as 3) (Mig without aura – 1.8x) • Risk is particularly increased in women, especially women using oral contraceptives, peripartum period, younger than 45, and partic with smoking Roberto, G., Raschi, E., Piccinni, et al. (2014). Adverse cardiovascular events associated with • New evidence of increased risk in “late middle triptans and ergotamines for treatment of migraine. Cephalalgia 2014 age” Androulakis XM, Kodumuri N, Giamberardino LD, Rosamond WD, Gottesman RF, Yim E, Sen S. Ischemic stroke subtypes and migraine with visual aura in the ARIC study. Neurology. 2016 Dec 13;87(24):2527-32. Levin UCSF Levin UCSF 35 37 TREATING MIGRAINES IN PATIENTS WITH MANAGING MIGRAINE IN PREGNANCY VASCULAR DISEASE OR RISK FACTORS • Case – • All this should probably lead to more • 27 year old G1P2 with occasional menstrual and other aggressive migraine prophylaxis in pts headaches since her late teens began having more with cerebrovascular disease or risks. frequent and more severe HAs with nausea and • Good choices: vomiting in her 1st trimester. Her PCP told her: • Candesartan 4-8 mg daily • “All of our usual treatments are contraindicated in • Verapamil 80-240 mg daily pregnancy, including botulinum toxin, but your nd • Memantine 5-10 mg bid headaches will get better in your 2 trimester.” They • Botulinum toxin did not.

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MANAGING MIGRAINE IN PREGNANCY MANAGING MIGRAINE IN PREGNANCY

• First steps – Acute Medication FDA category TERIS risk rating • Rule out preechlampsia, gestational HTN, gestational diabetes, cerebral venous thrombosis, reversible Acetaminophen B No risk cerebral vasoconstrictive syndrome Ibuprofen cB (D in 3rd Trimester) Minimal • Follow BP, UA, Glu Naproxen B (D in 3rd Trimester) Undetermined • CVT usually produces persistent c severe HA often with increased ICP Oxycodone cB (D near term) or focal signs or both – fundoscopy Magnesium B Unlikely • MRV without gad & LP might be needed Metoclopramide B Unlikely C in 1st trimester; • Follow BP, UA, Glu Prednisone ?2nd/3rd trimesters Minimal Promethazine C None Levin UCSF

42 43 MANAGING MIGRAINE IN PREGNANCY MANAGING MIGRAINE IN PREGNANCY

Spielman, K, et al. Pregnancy outcome after anti- • Triptans are contraindicated in pregnancy – migraine triptan use: A prospective observational but very few reports of defects or other issues cohort study. Cephalalgia, Jan 2017 • Nezvalová-Henriksen, K, Spigset, O, and Hedvig 432 pregnant women exposed to triptans Nordeng, H. "Triptan safety during pregnancy: a Compared to a non-migraine cohort no increase in: Norwegian population registry study." European journal of epidemiology 28.9 (2013): 759-769. – major birth defects (ORadj 0.84; 95% CI 0.4–1.9) •  found no associations between triptan use – Spontaneous abortions (ORadj 1.20; 95% CI 0.9–1.7) during pregnancy and congenital malformations. – preterm delivery (ORadj 1.01; 95% CI 0.7–1.5), Second trimester use was associated with – preeclampsia (ORadj 1.33; 95% CI 0.7–2.5) postpartum haemorrhage (adjusted OR 1.5) Conclusion: Triptans are not major teratogens. (Sumatriptan - best studied triptan)

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MANAGING MIGRAINE IN PREGNANCY Non medicinal Tx

Prevention Lifestyle adjustment • Magnesium becoming controversial – Avoidance of triggers Fetal calcium depletion – small but real risk Exercise Respiratory distress in newborn – very small risk Sleep regulation • CoQ10 may be safe and can improve fertility Relaxation techniques and reduce the risk of preeclampsia Biofeedback, yoga • Memantine 5-10 mg bid is category B meditation, hypnotherapy Manual therapies Acupuncture

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48 49 Herbal Tx & Supplements MANAGING MIGRAINE IN PREGNANCY Ginger • Occipital and other nerve blocks – Lidocaine and Bupivicaine category C, Ropivicaine B CoQ10 • Evidence is anecdotal but some small studies support nerve block efficacy Riboflavin Butterbur Feverfew Start probiotics now before they are proven Magnesium worthless! Valerian

Aromatherapy – Peppermint, Eucalyptus Suproaorbital Greater and Lesser Auriculotemporal supratrochlear occipital

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MANAGING MIGRAINE MANAGING MIGRAINE DURING LACTATION DURING LACTATION

Acute meds which seem to be Proph meds which seem to be compatible compatible Riboflavin Acetaminophen Magnesium Ibuprofen Probably compatible – gabapentin, candesartan, Eletriptan verapamil, cyproheptadine, botulinum toxin Meperidine Caffeine Prednisone Hutchinson, S. et al. Use of Common Migraine Treatments in Breast- Feeding Women. Headache 2013;53:614-627 Probably compatible – other triptans, other NSAIDs, ondansetron, promethazine, Dilaudid, Lidocaine Davanzo, R, et al. Breastfeeding and migraine drugs. Eur J Clin Pharmacol (2014) 70:1313–1324

52 53 INEFFECTIVE ACUTE MIGRAINE NEW FORMS OF TRIPTANS AND TREATMENT ERGOT Case – 32 year old man with severe migraine attacks • Sumatriptan nasal including pounding bitemporal pain, nausea, Onzetra® vomiting, mental fog and lightheadedness. Headaches are often triggered by exercise. • Inhaled DHE (not yet Triptans, butalbital, prochlorperazine, and Cefaly® approved) were ineffective; the only effective intervention is 3-4 Excedrin tablets • Needle microarray zolmitriptan patch

Kellerman DJ, et al. Rapid systemic delivery of zolmitriptan using an adhesive dermally applied microarray. Pain management. 2017 7:559-67 Spierings EL, Brandes JL, Kudrow DB, et al. Randomized, double-blind, placebo- controlled, parallel-group, multi-center study of the safety and efficacy of ADAM Levin UCSF Levin UCSF 54 55

A new class – Serotonin 1F A new class of (not-)triptans – receptor blockers - lasmiditan Serotonin 1F receptor Kuca, et al. Lasmiditan is an effective acute treatment for migraine: A phase 3 RCT. Neurology 2018 agonists - lasmiditan Methods - 1856 adult patients with migraine were randomized (1:1:1) to a double-blind dose of oral lasmiditan 200 mg, • Lasmiditan, Reyvow®, the first “ditan”, approved Jan lasmiditan 100 mg, or placebo for their next migraine attack 2020 within 4 hours of onset. • It is non-vasoconstrictive Results - Of the 1,856 patients who treated an attack, 77.9% had • Can serve as an option for patients with ≥1 cardiovascular risk factors in addition to migraine. Compared cardiovascular and cerebrovascular disease. with placebo, more patients dosed with lasmiditan 200 mg were free of headache pain at 2 hours after dosing, 32.2% vs 15.3%; (similar with lasmiditan 100 mg.)

Adverse events were mostly mild or moderate in intensity – Dizziness 16%, Paresthesia 8%, Somnolence 5%, Nausea 5%, Fatigue 3%, Lethargy 2%

56 57 Calcitonin gene related peptide (CGRP) receptor antagonists

 Telcagepant, olcegepant – abandoned because of liver enzyme elevations • Double-blind, phase 3 multicenter study in patients with  ubrogepant (Ubrelvy®)– just approved; rimegepant, soon to be available migraine with and without aura treated with oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo.  Trugman, et al. Efficacy, Safety, and Tolerability of Ubrogepant for the Acute Treatment of Migraine: • Most patients (79.2%) had a cardiovascular risk factor at Results From a Single-Attack Phase 3 Study, baseline, in addition to migraine. Lasmiditan was ACHIEVE II associated with significantly more pain freedom at 2 h -  Croop, et al. Efficacy, safety, and tolerability lasmiditan 200 mg: 38.8%; 100 mg: 31.4%; 50 mg: of rimegepant orally disintegrating tablet for the 28.6%, versus placebo 21.3% acute treatment of migraine: a randomized, • Most adverse events were CNS-related and included phase 3, double-blind, placebo-controlled dizziness, somnolence and paresthesia.

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Gepants TMS FOR MIGRAINE

Acute Treatment • 3 pulses wait  Tfeldt Hansen – The Emperor’s New 15mins, 3 more Gepants Headache 2019 pulses. RENTAL: $450/3mo for first 3  “…ubrogepant and rimegepant...appear to • Max 24 stims/day months, then $750 /3-months have far lower efficacy than the triptans, and are not more effective than simple analgesics that can be purchased without Proph Treatment a prescription. Their purported safety or tolerability advantages over triptans are • 4 pulses BID daily. speculative and likely to be relevant for Max 24 stims/day. only a small proportion of migraineurs.

60 61 TMS FOR MIGRAINE Distant electrical stim: “Nerivio Migra” Rationale – magnetic pulses disrupt cortical spreading depression. A wireless wearable battery-operated Acute treatment RCT – N=167, 39% pain free at 2h v. 22% with stimulation unit with a smartphone software application. The active device produces a sham device proprietary electrical signal comprising a Preventive treatment open label studies N=249 modulated symmetrical biphasic square pulse FDA approved in 2017 as “non-significant risk device for preventive with a modulated frequency of 100-120 Hz, and acute tx pulse width of 400 us, generating up to a maximum of 40 mA output current (adjusted by the participant).

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Distant electrical stim: “Nerivio Migra” Principle of operation of Nerivio Migra In a RCT, the control group used a sham device which produced a signal with a pulse Activating the continuous pain modulation (CPM) system frequency of ~0.083 Hz and pulse width of 40- (DNIC in animal models) – “Pain modulates pain” 550 us, aimed to be perceptible, presumably A descending without inducing a CNS response. pain modulating Active group achieve pain relief 67% v. 39% at system in the 2 h and pain freedom 37% v 18% placebo. lower brainstem In animals: DNIC - diffuse Yarnitsy et al. Remote Electrical Neuromodulation (REN) noxious Relieves Acute Migraine: A Randomized, Double-Blind, inhibitory Placebo-Controlled, Multicenter Trial. Headache 2019 control 59(8):1240-1252

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TL45 I changed the tile - from Nerivio Migra to current devices for pain relief Tamar Lin, 12/4/2018 EXTERNAL VAGAL NERVE MANAGING INTRACTABLE CLUSTER STIMULATION FOR ACUTE MIGRAINE HEADACHE • Case – • 48 year old accountant has had yearly cluster cycles since his 20s. This cycle began 2 months ago and has not responded to the usual 1 stim on each side/affect side, may repeat after 20 interventions min. If needed, may repeat again (a 3rd time) after 2hrs from start of Tx . Max 24 stims/day. Initial step: Establish diagnosis with certainty • R/o hemicranias continua, intracranial pathology (especially pituitary region neoplasms), sinus or ocular pathology, and chronic paroxysmal hemicrania

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MANAGING INTRACTABLE CLUSTER HEADACHE

Severe or very severe unilateral orbital, • Chronic supraorbital and/or temporal pain lasting paroxysmal 15–180 minutes (when untreated) hemicrania 2-30 min Either or both of the following: 1. at least one of the following ipsilateral to the headache: a) conjunctival • Trigeminal • Methods: 193 cluster headache patients were asked about injection and/or lacrimation b) nasal neuralgia, their suicidality during and between attacks, specifically congestion and/or rhinorrhoea c) SUNCT – about passive suicidal ideation, active suicidal ideation, eyelid oedema d) forehead and seconds suicide plan, and suicide attempt. 175 cluster headache patients participated in the full study. facial sweating e) miosis and/or ptosis 2. a sense of restlessness or agitation • Factors associated with high ictal suicidality were longer • Hemicrania disease duration, the Headache Impact Test score, and the Occurring with a frequency between one continua – Patient Health Question 9 score. every other day and eight per day constant with exacerbations • Conclusions: Cluster headache attack carries a high suicidality compared to the interictal or between-bouts state.

68 69 MANAGING INTRACTABLE CLUSTER MANAGING INTRACTABLE CLUSTER HEADACHE HEADACHE Traditional approach to CH • Break cycle: Prednisone 10d; 80 mg to start • Break cycle: Prednisone • Prophylaxis: • Prophylaxis: . Verapamil – consider up to 480 mg . Calcium channel blockers – Verapamil . Antiepileptics - higher doses Valproate; . Lithium Consider Lamotrigine (up to 50 mg bid), . Antiepileptics – Valproate Galcanezumab mAb • Acute treatment . Acute treatment . Oxygen 8-10 L/min . Oxygen 8-10 L/min  25 L/min . Sumatriptan subcutaneous . Sumatriptan subcutaneous, IV . Occipital nerve blocks with steroid . Sphenopalatine ganglion block . Sphenopalatine ganglion stim . Vagal nerve stimulation

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MANAGING INTRACTABLE CLUSTER MANAGING INTRACTABLE CLUSTER HEADACHE HEADACHE Sphenopalatine ganglion Sphenopalatine stimulation ganglion block

Jürgens TP, Barloese M, May A, Láinez JM, Schoenen J, Gaul C, Goodman AM, Caparso A, Jensen RH. Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia. 2017 Apr;37(5):423-34. Significantly reduces numbers of cluster headaches in refractory patients.

Levin UCSF Levin UCSF 72 73 MANAGING INTRACTABLE CLUSTER HEADACHE External vagal nerve stimulation

• Goadsby PJ, Dodick DW, Leone M, et al. Trial of galcanezumab in prevention of episodic cluster headache. NEJM 2019 Jul 11;381(2):132-41. • 106 enrolled patients, 49 randomly assigned to receive galcanezumab and 57 to receive placebo. The mean reduction in the weekly frequency of cluster headache attacks across weeks 1 through 3 was 8.7 attacks in the galcanezumab group, as compared with 5.2 in the placebo group (difference, 3.5 attacks per week. The percentage of patients who had a Goadsby PJ, de Coo IF, Silver N, Tyagi A, Ahmed F, Gaul C, Jensen RH, Diener HC, Solbach K, Straube A, Liebler E. Non-invasive vagus nerve stimulation for the acute treatment of episodic and reduction of at least 50% in headache frequency at week 3 was 71% in the chronic cluster headache: A randomized, double-blind, sham-controlled ACT2 study. Cephalalgia. galcanezumab group and 53% in the placebo group. 2017 Jan 1:0333102417744362. • CONCLUSIONS: Galcanezumab administered subcutaneously at a dose of Gaul C, Diener HC, Silver N, Magis D, Reuter U, Andersson A, Liebler EJ, Straube A, PREVA 300 mg once monthly reduced the weekly frequency of attacks of episodic Study Group. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of cluster headache across weeks 1 through 3 after the initial injection, as chronic cluster headache (PREVA): A randomised controlled study. Cephalalgia. 2016 compared with placebo. (Funded by Eli Lilly) May;36(6):534-46. Levin UCSF 74 75

WHICH INTRACTABLE MIGRAINE PATIENTS WILL BENEFIT FROM INPATIENT TX INPATIENT TREATMENT OF REFRACTORY HEADACHES Case – • Intravenous Dihydroergotamine (DHE) 45 year old woman has had nearly daily nauseating and disabling headaches since her 20s. “Everyone • Intravenous Chlorpromazine in my family has them”. • Intravenous Divalproex She is demoralized and intensely frustrated as the • Safe discontinuation of pain medications headaches have led to job loss and break-up of her marriage. No prophylactic medication has worked for her and triptans and other pain meds “are just bandaids”

Levin UCSF 76 77 Inpatient treatment of refractory IV Medication headache - When? • Numerous treatment failures and high pain Dihydroergotamine (D.H.E.) and disability Chlorpromazine The stages of life • Comorbid medical conditions Lidocaine • Risk of serious withdrawal Dexamethasone • Unable to withdraw from acute meds Valproate Sodium • Psychiatric or impending psych complications Propofol

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DHE IV Medication – DHE Why does DHE work when triptan fails? sumatriptan serotonin • Mechanism – Serotonin agonist • DHE speed of onset: IV 2–11 min, IM 30 min, SC 60 • Efficacy – observational studies min, Nasal 60–90 min • AE’s – hypertension, venoconstriction, nausea, • DHE works even after HA has progressed to include muscle cramping cutaneous allodynia • Contraindications – Coronary or cerebrovascular disease • Binds to brainstem serotonergic centers like dorsal • Dose – 1 mg IV or IM repetitively (12 infusions – raphe nuclei total 11.25 mg) • Prolonged effect of active metabolite 8–hydroxy-DHE

Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986 36(7):995 Silberstein, SD et al. Chronic daily headache: long-term prognosis following inpatient treatment with repetitive IV DHE. Headache. 1992 32:439-45.

80 81 IV Medication – DHE IV Chlorpromazine Can it work even with past failure? • Side Effects - Sedation, dystonia, akathisia, orthostatic hypotension, prolonged QT interval • Incorrect dosing in past - Dose must be 1 mg tid • Contraindications - prolonged QT, pregnancy • Course needs to be at least 3 days (UCSF - 5 days) • Dosage - 12.5-50 mg IV q6 h to maintain light sedation • Nausea which may have prevented effectiveness can • Watch for hypotension, akathisia, dystonia be easily prevented (metoclopramide, etc) • Combine with diphenhydramine (Benadryl) – 25 mg po prior to each dose • Keep pt in bed during course of tx to prevent falls • Monitor ECG for QT interval

Lu, SR, et al. Repetitive Intravenous Prochlorperazine Treatment of Patients With Refractory Chronic Daily Headache. Headache 2000, 40:724-729

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Dexamethasone Cortisol IV Corticosteroids IV Valproate

• Dexamethasone - 2 mg Q8H for 2-3 days DOSE - 250 mg diluted in 20 ml normal saline I.V. • Can combine with DHE Drip over 30-60 min, Q8H for 4 days • Followed by tapering doses orally Possible AE’s: dizziness (5.2%), headache (4.3%), injection-site reactions (2.4%), injection-site pain • Other options - (2.6%), taste perversion (1.9%), and somnolence Methylprednisolone, Hydrocortisone (1.7%) • Limited evidence Category X in pregnancy Do not use in pts with hepatic dysfunction

Riggins, N, Ehrlich, A, Levin, M. Retrospective Chart Review of Intravenous (IV) Valproate Sodium as a Preventive Treatment for Patients with Chronic Migraine. Headache 2020

86 87 IV Propofol IV Lidocaine

• Lidocaine 4 mg/ml in D5W start infusion at 1 mg min • Intravenous sedative-hypnotic • AE’s – hypotension, bradycardia, arrhythmia, resp • Side effects – dyspnea, apnea depression, apnea, dizziness, drowsiness, confusion, visual disturbances, tinnitus, tremor, paresthesias. • Use sub-anesthetic doses – 20-30 mg I.V. push, • Continuous cardiac monitoring required repeat q 5 mg • BP syst betw 90-160, diast betw 45-95, P 50-120 • Average dose used 100-400 mg • Regular diet, no grapefruit (inhibits P450 system which • Close monitoring of respiration is essential metabolizes Lido) Williams DR, Stark RJ. Intravenous lignocaine (lidocaine) infusion for the Krusz and Belanger 1999 treatment of chronic daily headache with substantial medication overuse. Cephalalgia. 2003 23:963-71. 63 patients - 25.4% had a complete response, Mendes et al 2002 57.1% had a partial response, 3.2% worsened, and 14.3 had no change.

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Improving Inpatient treatment Pitfalls in inpatient HA treatment outcomes • Unlimited stays • Pre hosp education about goals (limited) of • Psychiatric flares in hosp without support hospitalization • • Pain flares while hospitalized Assure psych services in hosp if necessary • Improve psychosocial support in home env; Rethink • Lack of good psychosocial post-hospital support lifestyle issues that may have been overlooked – caffeine, • Lack of good follow up in clinic sleep, alcohol, drugs, exercise, nutrition, stress • Lack of pt education re post hosp treatment plan • Arrange psych services at home • Lack of acute HA treatment plan with limits (ER trips, • Assure clinic follow up as well as f/u with PCP MOH recurrence) • During stay: Education about use of medications and their AEs and toxicity • Plan for HA rescue at home

92 93 UCSF Inpatient HA Unit SOLUTIONS IN CHALLENGING HA MANAGEMENT SITUATIONS • 4-5 day stays • When to use mAb treatment, how to choose and • DHE, Chlorpromazine, Divalproex when to change to another Ab • Expedited intake visits available: • Treating migraines in elderly patients and in patients with vascular disease or other complicating factors – Refractory chronic migraine, tension-type, cluster, • Managing migraine in pregnancy and lactation post-traumatic HA • New options in acute migraine treatment – Referred by neurologist • Options in intractable Cluster Headache – Neurologically and Psychiatrically stable • When inpatient HA treatment is appropriate – Not currently on regular opioids • Headachecenter.ucsf.edu • THE END Levin UCSF

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