management decisions difficult headache management … · lipton, richard b., et al....

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Difficult Headache Management DecisionsMorris Levin, MDProfessor of Neurology, UCSFDirector, UCSF Headache Center

Recent Advances in Neurology 2017 DIFFICULT HEADACHE MANAGEMENT DECISIONS

• Challenges in headache diagnosis• Some common management impasses• New treatment options

Disclosures for Dr. Morris Levin

Consultant: Supernus, Amgen, Allergan, Pernix

Royalties:Oxford University Press, Anadem Publishing, Wiley Blackwell, Castle Connolly, Publ, UCSF Office of Innovation

Grants:American Headache Society

INTERNATIONAL CLASSIFICATION OF HEADACHE DISORDERS 2013

Primary HA1. Migraine2. Tension-type HA3. Cluster headaches relatives (TAC)4. Exertional and other headaches

Secondary HA5. Posttraumatic6. Vascular disease7. Abnormal ICP, Neoplasm9. CNS infection10. Metabolic disturbances11. Cervicogenic, Eyes, Sinuses, Jaw12. Psychiatric 13. Neuralgias >200 HA types

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1. Migraine without auraHeadache attacks lasting 4-72 h (untreated or

unsuccessfully treated)Headache has ≥2 of the following

1. unilateral location2. pulsating quality3. moderate or severe pain intensity4. aggravation by or causing avoidance of routine

physical activity (eg, walking, climbing stairs)During headache ≥1 of the following:

1. nausea and/or vomiting2. photophobia and phonophobia

1.2 Migraine with aura≥1 of the following fully reversible aura symptoms:

1. visual; 2. sensory; 3. speech and/or language; 4. motor ; 5. brainstem; 6. retinal≥2 of the following 4 characteristics:

1. ≥1 aura symptom spreads gradually over ≥5 min, and/or ≥2 symptoms occur in succession2. each aura symptom 5-60 min3. ≥1 aura symptom is unilateral4. aura accompanied or followed

in <60 min by headache

Migraine with Aura ICHD III

Migraine with aura Migraine with

brainstem aura

Migraine with hemiplegia

Retinal migraine

Migraine with typical aura

With headache

Without headaches

1.3 Chronic migraineA. Headache (TTH-like and/or migraine-like) on ≥15 d/mo

for >3 mo and fulfilling criteria B and CB. In a patient who has had ≥5 attacks fulfilling criteria B-D

for 1.1 Migraine without aura and/or criteria B and C for 1.2 Migraine with aura

C. On ≥8 d/mo for >3 mo fulfilling any of the following:1. criteria C and D for 1.1 Migraine without aura2. criteria B and C for 1.2 Migraine with aura3. believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative

D.Not better accounted for by another ICHD-3 diagnosis

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Is Chronic migraine different than intermittent migraine?

Imaging studies – PET, DTI - may begin to differentiate

Maniyar, FH et al. Functional imaging in Chronic Migraine. Curr Headache and Pain Reports, 2013. Increasing frequency of migraine attacks is associated with changes in key brainstem areas, basal ganglia and various cortical areas involved in pain.Schwedt, T, et al Headache 2015 Accurate subclassification of individuals into lower and higher frequency subgroups via measurements of cortical thickness (and other measurements in temporal pole, anterior cingulate cortex, superior temporal lobe, entorhinal cortex, medial orbital frontal gyrus, and pars triangularis. Threshold = 15 days per month

Episodic Migraine

Chronic Migraine

Transformation: 2.5% per yearRisk increased by

High HA frequency, high use of acute meds, poor success with acute tx, obesity, depression, asthma)

Bigal, ME., et al. "Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population‐based study."Headache 48.8 (2008): 1157-1168.Lipton, Richard B., et al. "Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine." Neurology 84.7 (2015): 688-695.Martin, Vincent T., et al. "Asthma is a risk factor for new onset chronic migraine: Results from the American migraine prevalence and prevention study." Headache (2016).

3. Trigeminal autonomiccephalalgias (TACs)3.1 Cluster headache3.2 Paroxysmal hemicrania3.3 Short-lasting unilateral

neuralgiform headache.3.4 Hemicrania continua

All are unilateral, and accompanied by cranial autonomic sx

3. Trigeminal autonomiccephalalgias (TACs)3.1 Cluster headache3.2 Paroxysmal hemicrania3.3 Short-lasting unilateral

neuralgiform headache.3.4 Hemicrania continua

All are unilateral, and accompanied by cranial autonomic sx

a) conjunctival injection and/or lacrimation; b) nasal congestion and/or rhinorrhoea; c) eyelid edema; d) forehead and facial sweating; e) forehead and facial flushing; f) sensation of fullness in the ear; g) miosisand/or ptosis

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TAC’s:• Duration decreases with name length

Cluster15-180 min Paroxysmal

Hemicrania2-30 min

Short-lasting unilateral neuralgiform headaches 1-600 sec

HCYears

4. Other primary headachesExertional headaches

Cough headache Exercise headache Orgasmic headachePre-orgasmic headacheThunderclap headache

HA related to stimulationHA attributed to cold stimulusExternal compression headache

EpicraniasNummular HAEpicrania fugaxStabbing Headache

Other HAsHypnic HANDPH

New daily persistent headache (NDPH)

A. Persistent headache fulfilling criteria B and CB. Distinct and clearly-remembered onset, with pain

becoming continuous and unremitting within 24 hC. Present for >3 mo

The secondary headaches5. Headache attributed to trauma or injury to the head

and/or neck6. Headache attributed to cranial or cervical vascular

disorder7. Headache attributed to non-vascular intracranial

disorder8. Headache attributed to a substance or its withdrawal9. Headache attributed to infection10. Headache attributed to disorder of homoeostasis 11. Headache or facial pain attributed to disorder of

cranium, neck, eyes, ears, nose, sinuses, teeth, mouth12. Headache attributed to psychiatric disorder

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The secondary headaches5. Headache attributed to trauma or injury to the head

and/or neck6. Headache attributed to cranial or cervical vascular

disorder7. Headache attributed to non-vascular intracranial

disorder e.g. mass8. Headache attributed to a substance or its withdrawal9. Headache attributed to infection10. Headache attributed to disorder of homoeostasis 11. Headache or facial pain attributed to disorder of

cranium, neck, eyes, ears, nose, sinuses, teeth, mouth12. Headache attributed to psychiatric disorder

Headache attributed to traumatic injury to the head

• If persistent, a key component of the post-concussive syndrome

• Can resemble other headache types including migraine• Resistant to treatment• Divided by causative mild or severe head injury

Mild Head Trauma: Definition

Injury tosomeoneelse's' head

Headaches due to vascular disorders

• Stroke• Hemorrhage• Arteritis• Cerebral venous thrombosis• Reversible cerebral vasoconstriction synd• AVM• Aneurysm• Post endarterectomy• CADASIL• MELAS

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Headaches due to vascular disorders

Cerebral Venous Thrombosis RCVS

Intracranial HypertensionIncidence of IIH 1/100,000In obese young women as high as 20/100,000

Best treatment – weight loss if overweightClues to tx: Headache worse in recumbent, pulsatile tinnitus, papilledema

CSF pressure >250 mm CSF

IIH – Pseudotumor CerebriPapilledema Bilat enlarged blind spots

IIH – Pseudotumor CerebriOptical coherence tomography

Nerve fiber layer outside nl rangeNormal

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Intracranial HypotensionHA MUCH worse upon arising Antecedent LP, surgery, barotraumaCSF pressure <60 mm CSFGoal – Find the sight of leak and perform targeted blood patch

IMAGING CLUES TO SIH

Brain sag

Subdural collections

Dural enhancement

DIAGNOSING SIH Tools:• Spinal gad enhanced MR T1 with fat

suppression• MRI myelography• CT myelography• Radioisotope cysternography

DIAGNOSING SIH

MR myelogram demonstrating

myeloceles and leak

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DIAGNOSING SIH

Radioisotope Cisternography in SIH• Early bladder tracer• Paraspinal tracer

Medication-overuse headache (MOH)

A.Headache occurring on ≥15 d/mo in a patient with a pre-existing headache disorder

B.Regular overuse for >3 mo of one or more drugs that can be taken for acute and/or symptomatic treatment of headache

C. Not better accounted for by another ICHD-3 diagnosis

• Overuse is >2d/week usage • But overuse does not imply MOH

RED FLAGS IN HA

New or Change in patternOnset in middle age or laterEffort induced or PositionalFebrile or Systemic illness - AIDS, CancerChange in personality or cognitionNeurological findings

Secondary Headaches -When to look for them

RED FLAGS IN HA

ChangeSickFocal

Secondary Headaches -When to look for them

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CHALLENGING HA MANAGEMENT SITUATIONS

• Treating migraines in patients with vascular disease or risk factors

• Managing migraine in pregnancy• Managing medication overuse headache• Treating intractable cluster headache• New daily persistent headache• Migrainous vertigo• ED approach to treatment of acute severe headache

Levin UCSF

TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS

Case –72 year old woman with longstanding migraine, HLD, borderline DM and a lacunar stroke seen on MRI. She is using sumatriptan 1-2x per week.

Levin UCSF


• Migraine usually begins in early adulthood but not always; migraine often persists into old age –3-10% of elderly have migraine. (Fasted growing demographic)

• Triptans are mildly vasoconstrictive and if risks are high, should probably be avoided. But often risks are exaggerated.

• Risk factor stratification based on Framingham study data using gender, Total Chol, HDL, DM, HTN, and tobacco is more logical.

Levin UCSF


• Roberto et al - systematic review of observational data of use of triptans:

• “…intense consumption of ergotamines may be associated with an increased risk of serious ischemic complications. As for triptans, available studies do not suggest strong CV safety issues”.

Levin UCSF

Roberto, G., Raschi, E., Piccinni, et al. (2014). Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine. Cephalalgia 2014

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Alternatives to triptans include• NSAIDs and acetaminophen which can become more useful as pts age• Magnesium 200 mg• Short acting barbiturate butalbital – caution in elderly• Occipital nerve blocks• Low dose opioids – hydrocodone 5 mg• Neuroleptics – metoclopramide 10 mg, prochlorperazine 25 mg• Hydroxyzine 25-50 mg

Levin UCSF


• Use of triptans in “basilar migraine” (migraine with brainstem aura), and hemiplegic migraine (migraine with motor aura – contraindicated?

• Mathew, PG., et al. "A retrospective analysis of triptan and DHE use for basilar and hemiplegic migraine." Headache: 56.5 (2016): 841-848. – no incidents

• Also - no clear evidence that BM and HM carry an actual elevated risk for vascular events compared with migraine with aura.

Levin UCSF


• Migraine is associated with increased risk of stroke, and possibly with increased risk for cardiovascular disease

• Migraine with aura is associated with an increased risk of ischemic stroke (OR approx. 3)

• (Mig without aura – 1.8x)• Risk is particularly increased in women, especially women using oral contraceptives, peripartum period, younger than 45

• Especially in smokers

Levin UCSF

STRUCTURAL BRAIN LESIONS IN MIGRAINEMigraine particularly in women is associated with an increased risk of brain lesions, mostly in white matter (1,2,3)These tend to increase although can disappear (more likely in low frequency headaches) (4)

1. Kruit, MC et al. JAMA 2004;291:4272. Kruit, MC et al. Brain 2005;128:20683. Scher, AI et al. JAMA 2009;301:25634. Erdélyi-Bótor, S et al Headache 2015;55:55-70.

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STRUCTURAL BRAIN LESIONS IN MIGRAINEManagement of WML’s in migraine patientsIf asymptomatic – no workupMay follow imaging...

MANAGING MIGRAINE IN PREGNANCY

• Most proph meds contraindicated in pregnancy, including botulinum toxin

• Case –• 29 year old with migraine since her late teens is now having more frequent and more severe HAs with nausea and vomiting in her 2nd trimester.

Levin UCSF


• First steps –• Rule out preechlampsia, gestational HTN, gestational diabetes, cerebral venous thrombosis, reversible cerebral vasoconstrictive syndrome • Follow BP, UA, Glu• CVT usually produces persistent severe HA often with increased ICP or focal signs or both –• MRV without gad & LP – will also help to R/O RCVS

Levin UCSF

MANAGING MIGRAINE IN PREGNANCYMedication FDA category TERIS risk rating

Acetaminophen B No riskIbuprofen B (D in 3rd Trimester) Minimal Naproxen B (D in 3rd Trimester) UndeterminedOxycodone B (D near term)Magnesium B UnlikelyMetoclopramide B UnlikelyPrednisone C in 1st trimester;

? 2nd/3rd trimesters Minimal

Promethazine C None

ccc

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• Triptans are contraindicated in pregnancy –but very few reports of defects or other issues

• Nezvalová-Henriksen, K, Spigset, O, and Hedvig Nordeng, H. "Triptan safety during pregnancy: a Norwegian population registry study." European journal of epidemiology 28.9 (2013): 759-769.

• � found no associations between triptan use during pregnancy and congenital malformations. Second trimester use was associated with postpartum haemorrhage (adjusted OR 1.5)

Levin UCSF


• Magnesium becoming controversial –• Fetal calcium depletion – small but real risk• Respiratory distress in newborn – very small risk

• Herbal supplements also risky –Butterbur, Feverfew not safe

Levin UCSF

1438050943351_bob1.png

Lifestyle adjustmentAvoidance of triggersExerciseSleep regulation

Relaxation techniquesBiofeedback, yogameditation, hypnotherapy

Manual therapies Acupuncture

Non medicinal Tx MANAGING MIGRAINE IN PREGNANCY• Occipital and other nerve blocks – Lidocaine and Bupivicaine category C, Ropivicaine B• Evidence is anecdotal but some small studies support its efficacy

Greater and Lesser occipital

Auriculotemporal Suproaorbital supratrochlear

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MANAGING MEDICATION OVERUSE HEADACHE

• Case –• 45 year old executive began having HAs in 30s, initially infrequent, now nearly daily leading her to use butalbital-acetaminophen-caffeine tablets (Fioricet ®) 2-6 tablets most days, frequent NSAIDs, occasional hydrocodone (Norco®) and other OTC meds.

• Triptans have not helped, nor have a number of prophylactic medications. “I am not addicted! I only take enough medication to function!”

Levin UCSF


• Mechanisms are unclear but consensus holds that use of analgesic or abortive headache medications >2x a week tends to worsen migraine frequency and severity

• Reducing the use of medications will tend to further worsen headaches, leading to an impasse.

• Physical and psychological dependency may be occurring simultaneously

• Allowing MOH to continue seems to be associated with conversion of migraine to chronic migraine

Levin UCSF


Solution = “Bridge Therapy” • Steroid “burst” – prednisone 60 mg x 4 days reducing over the next 6 days to 0

• IV Dihydroergotamine x 5 d• IV Chlorpromazine

Coupled with discontinuation of previous analgesicsReplacement with rescue meds which are less likely to cause MOHPreemptive treatment of withdrawal

Levin UCSF


Analgesic hierarchy –• Opioids (hydrocodone, oxycodone)• Ergotamine• Barbiturates (Fioricet®)• Caffeine containing combination meds (Excedrin®)

• Triptans• NSAIDS, acetaminophen• Antihistiminics

Levin UCSF

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Preemptive treatment of withdrawal• Opioids – clonidine .1 mg – titrate dose to sx• Barbiturates – lorazepam .5-1 mg on a schedule titrated to sx

• Triptans – DHE, NSAIDs

Levin UCSF

DOES OVERUSE OF TRIPTAN MEDICATION REALLY CAUSE MOH?

• Yes.• Katsarava, Z, et al. Clinical features of withdrawal headache following overuse of triptans and other headache drugs Neurology 2001 57: 1694-1698

• Pathophysiology of medication overuse headache: Insights and hypotheses from preclinical studies Cephalalgia 2011 31:851-860

• Triptan overuse in the Dutch general population: A nationwide pharmaco-epidemiology database analysis in 6.7 million people Cephalalgia 2011 31: 943-952

MANAGING INTRACTABLE CLUSTER 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 interventions

Initial step: Establish diagnosis with certainty • R/o hemicranias continua, intracranial pathology (especially pituitary region neoplasms), sinus or ocular pathology, and chronic paroxysmal hemicranias

Levin UCSF


Traditional approach to CH• Break cycle: Prednisone• Prophylaxis:

� Calcium channel blockers – Verapamil � Lithium� Antiepileptics – Valproate

• Acute treatment� Oxygen 8-10 L/min � Sumatriptan subcutaneous

Levin UCSF

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• Break cycle: Prednisone• Prophylaxis:

� Verapamil – consider high dose – up to 480 mg and avoid SR

� Antiepileptics - also high dose Valproate; Consider Lamotrigine, remembering to up-titrate the dose gradually

• Acute treatment� Oxygen 8-10 L/min � 25 L/min� Sumatriptan subcutaneous, IV� Occipital nerve blocks with steroid� Sphenopalatine ganglion blockade� Sphenopalatine ganglion stimulation

Levin UCSF


Levin UCSF


Levin UCSF

NEW DAILY PERSISTENT HEADACHE• Case –• 25 year old grad student has unremitting headaches which she distinctly recalls having begin one day during a “flu” and have been essentially constant since then. The pain is diffuse, not associated with much nausea, photosensitivity or phonosensitivity, and there are no other features. Exam and MRI are normal.

Levin UCSF

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NEW DAILY PERSISTENT HEADACHE

• Definition – an unremitting headache that began at a clearly recalled time, unassociated with typical migraine features.

• Perhaps not a homogeneous group –Postinfectious, posttraumatic, migrainous, etc –

• Therefore treatment responses may vary.• Step 1 – exclude secondary causes – mass, inflammation, thrombosis, IIH, intracranial hypotension, etc. MRI, LP, Screening labs incl TSH, Lyme.

• When NDPH confirmed – attempt migraine proph; but often fails

Levin UCSF

The way we treat NDPH here is to divert your attention to

something else

CHOICES IN MIGRAINEPROPHYLAXIS – GOOD OPTIONS

�Anticonvulsants – topiramate 100-200 mg hs�Beta blockers – propranolol 80 mg bid �Cyclic antidep – nortriptyline 25-75 mg hs

CHOICES IN MIGRAINEPROPHYLAXIS – GOOD OPTIONS

�Anticonvulsants – topiramate 100-200 mg hs�Beta blockers – propranolol 80 mg bid �Cyclic antidep – nortriptyline 25-75 mg hs�Calcium channel bl – amlodipine 2.5-10 mg/d�Angiotensin receptor bl – candesartan 4-16 mg�Memantine 10 mg daily

Noruzzadeh, R, et al. Memantine for prophylactic treatment or migraine w/o aura: a RDBPC study. Headache 2016, 56:95-103.

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OTHER CHOICES IN MIGRAINEPROPHYLAXIS

�B2�Magnesium, �Feverfew�Co Q 10�Melatonin�Ginger�Boswellia

NEW DAILY PERSISTENT HEADACHE

• Botulinum toxin• Inpatient DHE or chlorpromazine• Nerve blockade• Address MOH• Address depression • Persistence

Levin UCSF

MIGRAINOUS VERTIGO AKA VESTIBULAR MIGRAINE

• Case –• 39 year old teacher who had recurring headaches during her. They improved during her 2 pregnancies and she is now having only rare headaches. She does not remember auras.

• Over the past 3 years she has had many episodes of nausea and a sensation of being pulled to the side along with some sensation of movement. These can last for hours.

Levin UCSF


Definition:

• Current or previous history of migraine with or without aura

• One or more migraine features with at least 50% of the vestibular episodes

• Vestibular migraine affects up to 1% of the generalpopulation*

• 7% of patients in specialized dizziness clinics;• 9% of patients in HA Centers

Levin UCSF

*Neuhauser, et al. Migrainous vertigo: prevalence and impact on quality of life, Neurology 67 (2006), 1028–1033.

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Migraine with Aura ICHD III

Migraine with aura

Migraine with brainstem aura

Migraine with hemiplegia

Retinal migraine

Vestibular migraine

Migraine with typical aura

With headache

Without headaches

DDX VESTIBULAR MIGRAINE

• Mal de Debarquement• Benign Paroxysmal Vertigo of Childhood• Benign Positional Vertigo• Meniere’s Disease• Migraine with brainstem aura• Vestibular pathology

Levin UCSF

CHRONIC VERTIGOBPPV Meniere’s Vestib

MigraineMdeD

Positionality + + +Hearing loss +Ear Fullness + +Tinnitus + +Photo/Phonoph + +Vestib testing +

Levin UCSF


Acute treatmentZolmitriptan RCT 38% relief v 22% placeboRizatriptan prevented motion sickness in the VM group better than placebo

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Pharmacologic Prophylaxis – best evidence• Flunarizine • Propranolol• Lamotrigine

Lepcha A, et al. (2014) Flunarizine in the prophylaxis of migrainous vertigo: a randomized controlled trial. Eur Arch Otorhinolaryngol 271:2931–2936Van Ombergen A, et al. (2015) Vestibular migraine in an otolaryngology clinic: prevalence, associated symptoms, and prophylactic medication effectiveness. Otol Neurotol 36(1):133–138Bisdorff AR (2004) Treatment of migraine related vertigo with lamotrigine, an observational study. Bull Soc Sci Med Luxemb 2:103–108


Other options:• caffeine cessation, nortriptyline and topiramate• Vestibular rehabilitation• Even less evidence – though suggested -

prophylaxis: benzodiazepines, cinnarizine, SSRIs, pizotifen, dothiepin, acetazolamide, and behavioral modification

Levin UCSF

Mikulec AA, et al (2012) Evaluation of theefficacy of caffeine cessation, nortriptyline, and topiramate therapy in vestibular migraine and complex dizziness of unknown etiology. Am J Otolaryngol 33:121–127Vitkovic J, et al (2013)Vestibular rehabilitation outcomes in patients with and without vestibular migraine. J Neurol 260:3039–3048


Pharmacologic Symptomatic TxAnticholinergic

Meclizine 12.5-25 mg po tid Scopalamine patch 1q3d

Anti-DAPromethazine (phenergan) 12.5-25 mg po tid, 25 mg IM for acute attack

SedativeDiazepam 2-5 mg po tid prn

“I went round and round with my neurologist about whether I have vestibular migraine”

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EMERGENCY DEPT APPROACH TO ACUTE SEVERE HEADACHE

Case –52 year old man rapidly developed the worst headache of his life while hiking. 2 hours later in the ED he is in a great deal of pain.He has had migraine headaches in the past.Exam is normal, but he complains of some “neck stiffness”CT of the head is normal

Levin UCSF

ED APPROACH TO ACUTE SEVERE HASTEP 1 - DDX

• Intracerebral hemorrhage• Subarachnoid hemorrhage• Pituitary Apoplexy • Cerebral Venous Thrombosis• Arterial Dissection• CNS Vasculitis, RCVS• Intracranial hypotension• Primary Thunderclap Headache• Sex related Headache• Meningitis • Acute Sinusitis

Levin UCSF

ED APPROACH TO ACUTE SEVERE HAR/O SAH, DISSECTION, INFECTION

• 2-5% of SAH may be missed by CT• LP may not finalize dx

• In the 6 hours following subarachnoid hemorrhage, fluid may not be xanthochromic• Traumatic tap leads to uncertainty

Typical approach:• If CT is normal, LP should be done• If LP is not conclusive, or concerned about dissection – head and neck vessel imaging (CTA)

Levin UCSF

Edlow JA, Caplan LR. Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N Engl J Med 2000;342:29–36.Ditta et al, Lumbar puncture and the diagnosis of CT negative subarachnoid haemorrhage: time for a new approach Br J of Neurosurgery 2013; 27:599-602

ED APPROACH TO ACUTE SEVERE HAKetotolac15-60 mg IM, IVChlorpromazine – 25 mg IV with Benadryl[Opioids – avoid – particularly meperidine]

Triptans - sumatriptan injectable 6 mgErgots – DHE – 1 mg IV with antinauseant

Other options:Valproate 250 mg IVMagnesium 1-4 g IVLevin, M. "Approach to the Workup and Management of Headache in theEmergency Department and Inpatient Settings." Seminars in neurology. Vol.35. No. 6. 2015.

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NEW DEVELOPMENTS IN MIGRAINE MANAGEMENT

“I’m looking for something slightly more perfect”

DO WE NEED NEW INTERVENTIONS IN MIGRAINE?

• Abortive migraine tx’s relieve pain in 60% pts (in 2 h) and eradicate pain completely in only 30%

• Prophylactic migraine tx reduce HA freq by 50% in only 20-40% of patients

• Abortive tx of cluster headache works about 75% of the time in 15 min (pain free in 50%)

• Proph tx of cluster reduce HA freq by 50% in 70% of patients

NEW TREATMENT OPTIONS IN HEADACHE

• New forms of triptans & other older meds• CGRP as a target• Monoclonal antibodies• Neurostimulation

NEW FORMS OF TRIPTANS AND ERGOT

• Sumatriptan nasal Onzetra®

• Inhaled DHE

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A NEW CLASS OF TRIPTANS –SEROTONIN 1F RECEPTOR

BLOCKERS

• lasmiditan, the first “ditan”, has clear proof of principle in 2 studies

• It is nonvascular so safer

CALCITONIN GENE RELATED PEPTIDE – CGRP – A NEW TARGET IN

MIGRAINE• Small molecule antagonists were developed but not finalized due to adverse effects

• Humanized and fully human monoclonal antibodies against CGRP and its receptor now in development

RATIONALE FOR CGRP MODULATION IN MIGRAINE

� Released from trigeminovascular afferents� Causes perivascular plasma protein extravasation and nociceptive pain

� CGRP levels elevated in migraineurs between attacks and during (even higher)

� Triptans and Onabotulinum toxin block CGRP release� CGRP induces migraine-like headache in susceptible individuals

� CGRP enhances transmission of pain signals in CNS

Buchanan T, et al. Expert Rev Neurotherapeutics 2004; 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.

4 MABS BEING DEVELOPED FOR MONTHLY INJECTION TO

PREVENT MIGRAINE• LY2951742 (Lilly galcanezumab) – humanized mAb anti-CGRP – aimed at preventing episodic migraine - SC monthly

• ALD403 (Alder fremanezumab)– humanized mAb anti-CGRP – aimed at preventing episodic migraine - IV q3mo

• TEV 48125 (Labrys LBR-101� Teva) - humanized mAb aimed at preventive treatment of chronic migraine - SC monthly

• AMG 334 (Amgen erenumab) – Human anti GCRP receptor Ab – SC monthly

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CGRP MABS - EVIDENCE TO DATEGENERALLY VERY POSITIVE AT HIGH DOSE

MAB target EM (12 wks) CM Other

LYhumanized

ligand -4.2 d v -3.0

ALDhumanized

ligand −5.6d v −4.6

AMGhuman

receptor −3.4 d−2.3 -6.6 v -4.2 d-75h v -57 h

TEVhumanized

ligand -6 d v -3.5 -67h v -37h

NEUROSTIMULATION IN HANon-invasive

Supraorbital n stim

Vagal n stim

TMS

Key Challenge in Studying Neuromodulation in Headache

• Placebo response rate high in migraine studies – 30% in adults and higher in pediatric population

• Stimulation devices impart high placebo effect• Sham treatment very difficult to hide,

therefore blinding almost impossible

NEURAL STIMULATIONinvasive

SPG

GON

DBS

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“I think I have the placebo.”

THE UCSF HEADACHE CENTER

• Intractable migraine, cluster headaches, post-traumatic headaches and other unusual or difficult headache disorders

• Outpatient treatment• Nerve blocks• Neurostimulation• Inpatient treatment• Telemedicine• Research

INPATIENT TREATMENT OF REFRACTORY HEADACHES• Intravenous Dihydroergotamine (DHE)• Intravenous Chlorpromazine• Intravenous Lidocaine• Safe discontinuation of pain medications

Headache diagnosis and treatmentAn interesting game

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UCSF HEADACHE MEDICINE

management decisions difficult headache management … · lipton, richard b., et al....

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