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MIGRAINE:TRENDS IN

TREATMENTR H O N D A C O L E M A N - J A C K S O N D N P, A P R N - C N S

O U N E U R O L O G Y

A P R I L 1 2 , 2 0 1 9

LEARNING OBJECTIVESLEARNING OBJECTIVESLEARNING OBJECTIVESLEARNING OBJECTIVES

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By the end of the lecture, participants will be able to:

• Verbalize understanding of the role of Calcitonin Gene Related Peptide (CGRP) in migraine;

• Describe the mechanism of action for CGRP inhibitors, along with adverse reactions;

• Discuss other preventives and abortives in treatment of migraine;

• Identify neuromodulation treatment devices for migraine;

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TYPES OF MIGRAINE

• Episodic-at least 4-14 migraine days/month

• Chronic-over 14-16 migraine days/month

• Cluster

• Hemiplegic

• With and without aura

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TRIGEMINAL VASCULAR SYSTEM

� Activation of nociceptive trigeminal nerves by stimuli →

release of vasoactive peptides;

�Hyperemia followed by reduced cerebral blood flow is what happens with cortical spreading depression.

�20-40% reduction in cerebral blood flow spreads at 2-3 mm/min, which prevents the

ability for neurons to return to baseline

�Due to cytokine and neuropeptide involvement, inflammatory

processes are also implicated.

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SEROTONIN 5HT RECEPTORS

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NEUROTRANSMITTERS

� Serotonin (5-HT)

�CGRP (calcitonin gene-related

peptide)

�Norepinephrine (NE)

�Histamine

�Substance P

�Nitric oxide (NO)

�Pituitary adenylate cyclase-

activating polypeptide (PACAP)

�Vasoactive intestinal peptide (VIP)

�Arachidonic acid metabolites

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SEROTONIN

• 5 hydroxytryptamine (5-HT)

• Also involved in memory, mood, and sleep

• Migraine attack → increases serotonin acutely

�Increase CGRP, glutamate, NO release

�Increase in anxiety

�Increase in nausea (via 5-HT3)

�Increase GI motility (via 5-HT4)

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NEUROTRANSMITTERS

NOREPINEPHRINE

NE produced in the pons and influences thalamocortical projections

�NE prolongs activation of thalamic neurons

�Acts on alpha and Beta

�↑ in wakefulness and attention

SUBSTANCE P

• Acts as a potent vasodilator

• Triggers release of histamine from mast cells

• Likely contributes to neurogenic inflammation

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HISTAMINE

• Produced in posterior hypothalamus � project to entire CNS

• Histamine receptors H1, H2, H3 expressed in CNS

�Excitatory for neurons, mostly via H1

�Histamine also contributes to vasodilation

• Migraineurs have ↑histamine levels ictally and interictally

�Sleep deprivation further ↑CSF histamine

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CGRPC A L C I T O N I N G E N E - R E L AT E D P E P T I D E

• Pronociceptive effects

� In inflammation and neurogenic pain, CGRP is upregulated

�Found in C and Aδ sensory fibers

• CGRP also acts as a potent arterial vasodilator

�Alpha (α) and beta (β)- CGRP receptors expressed in many body systems

� In cardiac disease, may serve a protective role

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MIGRAINEPREVENTION

• Anti-Hypertensives

• Anti-Depressants

• Anti-Epileptics

• Botox

• CGRP Inhibitors

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ANTIANTIANTIANTI----HYPERTENSIVESHYPERTENSIVESHYPERTENSIVESHYPERTENSIVES

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Beta Blockers

• Poorly understood. Likely ↑ interictal serotonin levels through weak 5-HT antagonism.

• Inderal (Propranolol) Toprol (Metoprolol) Timolol, Tenormin (Atenolol) Corgard (Nadolol)

Calcium Channel Blockers

• Inhibits calcium ion influx into vascular smooth muscle

• Calan (Verapamil)

ACE Inhibitors

• (Prinivil) Lisinopril

Angiotensin Receptor Blockers (ARBs)

• Atacand (Candesartan)

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ANTI-DEPRESSANTS

Serotonin and Norepinephrine Uptake Inhibitors (SNRIs) �

� Effexor (Venlafaxine)-inhibits NE, serotonin,, and dopamine reuptake

� Cymbalta (Duloxetine)

Tricyclic Antidepressants �

� Elavil (Amitriptyline)-inhibits NE and serotonin reuptake

� Pamelor (Nortriptyline)

� Silenor (Doxepin)

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ANTI-EPILEPTICSMOA

• Topamax (Topiramate) → extended release products Trokendi XR or

Qudexy XR

• Depakote (Valproic Acid/Sodium)

• Neurontin (Gabapentin)

• Zonegran (Zonesimide)

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OTHER PREVENTIVE MEDICATIONS

�Melatonin

�Magnesium

�B2 (Riboflavin)

�Namenda (Memantine)

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ONABOTULINUMTOXIN A (BOTOX) INJECTIONS

Administered for various treatments with multiple systems: antispasmodics (urinary) cosmetic (dermatologic) dystonia (Parkinson disease) migraine and ophthalmologic.

Mechanism of Action: inhibits acetylcholine release from nerve endings, reducing neuromuscular transmission and local muscle activity (neurotoxin).

• Up to 200 units every 12 weeks, usual dose is 155 units IM

• 31 injection sites

• Effects of botulinum toxin products may spread beyond treatment areas and produce muscle weakness, dysphagia, ptosis, and blurred vision.

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SITES FOR BOTOX INJECTIONS

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Corrugator10 Units divided in 2 sites

Procerus5 Units in 1 site

Frontalis20 Units divided in 4 sites

Temporalis40 Units divided in 8 sites

Occipitalis30 Units divided in 6 sites

Trapezius30 units in 6 sites

MIGRAINE ABORTIVES• NSAIDs: Naproxen is the only medication that does not cause

medication overuse headache (MOH). Cambia is diclofenac powder that

is readily absorbed at onset of head pain (may cause MOH if used > 2

days per week.

• Triptans: Imitrex (Sumatriptan) Maxalt (Rizatriptan, Eletriptan,

Zolmitriptan)� cannot use if history of MI or stroke, due to

vasoconstriction. **Do not use > 2 days per week to avoid MOH**

• Anti-emetics: Vistaril (Hydroxyzine) Compazine (Prochlorperazine)

Phenergan (Promethazine)

• Dihydroergotamine (DHE-45) Do not use within 24 hours of a

triptan. Must be monitored as an inpatient prior to outpatient use.4/4/2019 18

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MIGRAINE ABORTIVES

Triptans

�Imitrex (Sumatriptan) oral, IM, nasal

�Maxalt (Rizatriptan) oral, oral disintegrating tablet

�Relpax (Eletriptan) oral

�Axert (Almotriptan) oral

�Frova (Frovatriptan) oral→ longer acting, used for menstrual

migraines

�Amerge (Naratriptan) oral

�Zomig (Zolmitriptan) oral, nasal spray

�Treximet (Naproxen/sumatriptan) oral4/4/2019 19

NON STEROIDAL ANTI INFLAMMATORY DRUGS

� Naproxen –ONLY NSAID that doesn't cause Medication Overuse

Headache (MOH)

� Indocin (Indomethacin)

� Cambia (Diclofenac Potassium)

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ANTIEMETICS/ANTIHISTAMINES

�Phenergan (Promethazine)

� Compazine (Prochlorperazine)

�Vistaril, Atarax (Hydroxyzine)

� Periactin (Cyproheptadine)

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DIHYDROERGOTAMINE (DHE)

Dosing: 1 mg subcutaneous/IM/IV x 1. Max=3 mg/24 hours. May

repeat dose every 1 hour.

Black Box warning: life-threatening peripheral ischemia, ↑risk for

vasospasm leading to cerebral ischemia.

Contraindications: pregnancy/breastfeeding, renal or liver

impairment, coronary vasospasm, hemiplegic migraines.

Monitor CV periodically.

MOA: activates vascular serotonin 5-HT1D receptors, constricting

cranial and peripheral blood vessels.

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OTHER TREATMENTS

• Thera Specs

• Migraine Cryohelmet

• Implanted pain pump

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ERENUMAB ((((AIMOVIGAIMOVIGAIMOVIGAIMOVIG))))

• Released in May 2018

• Blocks CGRP activity (monoclonal antibody) at the receptor

• Autoinjector

• Once per month injection

• 70 mg SQ or 140 mg SQ (70 mg x 2)→now available in one 140 mg

syringe

• Side effect: constipation

• $5 co-pay

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GALCANEZUMAB (EMGALITY)

• Released in October 2018

• Blocks CGRP activity (monoclonal antibody)

• Auto-injector and pre-filled syringe

• Loading dose= 120 mg SQ x 2 initially, then 120 mg SQ monthly

• $0 co-pay

• Side effects: none

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FREMANEZUMAB ((((AJOVYAJOVYAJOVYAJOVY))))

• Released in October 2018

• Pre-filled syringe 225 mg/1.5 ml→ No autoinjector

• 225 mg SQ monthly or 225 mg x 3 every 3 months

• Same MOA as galcanezumab

• No side effects

• $0 co-pay card available for commercial insurers

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GEPANTS

In the 2000’s caused liver toxicity-never approved by FDA

• Rimegepant

• Ubrogepant

• Atogepant

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DITANS

• Lasmiditan

• Phase III trials

• No vasoconstriction effects

• Take at onset of head pain

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NEUROSTIMULATORS

• Cefaly®-prevent and abort

• gammaCore®-clusters and episodic

• eNeura®

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Cefaly

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Cefaly Use• Non-drug, non-invasive migraine treatment;

• Used for migraine with and without aura;

• Acute treatment x 1 hour→ significant relief in 8 out of 10

patients;

• Preven%on→ 20 minutes daily → 54% reduc%on in migraine a*acks

• Side effects: allergy to electrode adhesive and inability to tolerate

sensation

• Contraindicated in those with metallic implants, pacemakers

• Covered by Flex Spending accounts

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gammaCore (nVNS)

• Non-invasive vagus nerve stimulator

• Use for prevention of cluster and episodic

• Avoids side effects of oral, injectable, or inhaled medications

• Co-pay assistance program

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e Neura device

• Non drug option for treating and prevention of migraine

• For adolescents (12 +) and adults

• sTMS mini (Transcranial magnetic stimulation)

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SUMMARY

• Migraine treatment has new medications for prevention and

treatment with less adverse reactions.

• Many available preventives and abortives for migraineurs.

CGRP inhibitors are a safe alternative to daily oral medications.

• Patient assistance programs available.

• Neuromodulation devices available for prevention and treatment.

• Botox injections for chronic migraines > 16 episodes per month.

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REFERENCES:Bianca Raffaelli, Heike Israel, Lars Neeb & Uwe Reuter (2017) The safety and efficacy of the 5-HT

1F receptor agonist lasmiditan in the acute treatment of migraine, Expert Opinion on Pharmacotherapy, 18:13, 1409-1415, DOI: 10.1080/14656566.2017.1361406Matilde

Capi, Fernando de Andrés, Luana Lionetto, Giovanna Gentile, Fabiola Cipolla, Andrea Negro, Marina Borro, Paolo Martelletti & Martina Curto (2017) Lasmiditan for the treatment of migraine, Expert Opinion on Investigational Drugs, 26:2, 227-234, DOI: 10.1080/13543784.2017.1280457

Vila-Pueyo M. Targeted 5-HT1F Therapies for Migraine. Neurotherapeutics. 2018;15(2):291–303. doi:10.1007/s13311-018-0615-6

Lasmiditan is an effective acute treatment for migraine. Bernice Kuca, Stephen D. Silberstein, Linda Wietecha, Paul H. Berg, Gregory Dozier, Richard B. Lipton, on behalf of the COL MIG-301 Study Group Neurology Dec 2018, 91 (24) e2222-e2232; DOI: 10.1212/WNL.0000000000006641

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