Migraine - From Molecules to Medicine

Migraine From Molecules to Medicine David W. Dodick, MD, FRCP-C, FACP

Disclosure ď ą Advisory Boards/Consultant/Independent Contractor:

Allergan, Autonomic Technologies, Boston Scientific, Bristol Myers Squibb, CogniMed, Coherex, Colucid, Ferring, GlaxoSmithKline, Impax Laboratories, Inc., Lilly USA LLC, MAP Pharmaceuticals, Medtronic Inc., Merck, Nautilus, Neuralieve, Neuraxon, Neurocore, Novartis, NuPathe, Inc., Pfizer Inc., SmithKlineBeecham, Zogenix, Inc. ď ą Honoraria: CogniMed, Intramed, SAGE Publishing,

Lippincott Willams and Wilkins, Oxford University Press, Cambridge University Press, Miller Medical

Learning Objectives  Describe the physiological and structural

remodeling that may lead to frequent attacks and persistent symptoms  Review current management strategies to reduce the frequency and severity of migraine attacks  Describe the mechanism of action of emerging migraine therapeutics

Migraine 1/10th of the World’s Population

120 million lost work/school days each year

~48 million Americans

Up to 9 million experience headache almost daily ~900,000 Americans will suffer a migraine attack today 1.Natoli JL et al. Cephalalgia. 2010;30:599-609.

2.Silberstein SD et al. Neurology. 1996;47:871-875.

3.Katsarava Z et al. Cephalalgia. 2011;31:520-529.

6

Severe Migraine is Ranked in the Highest Disability Class by WHO Severe migraine Active psychosis Dementia Quadriplegia

Increasing disability

7 Unipolar major depression Blindness Paraplegia

6

5

4

Below-the-knee amputation Deafness

Disability Class 4

Mild mental retardation Down syndrome

Disability Class 5

Disability Class 6

Disability Class 7 Menken M. Arch Neurol 2000; 57: 418−20.

Overview Migraine Pathophysiology and Emerging Therapies

 What we thought we knew  What we’ve learned  How this translates into

new treatments

What We Thought We Knew 

Migraine is a vascular headache disorder



Serotonin depletion results in loss of cerebrovascular tone



Effective treatment: serotonin receptor agonists that constrict cerebral blood vessels

Harold Wolff

Aura Vasoconstriction

Headache Vasodilation

The Serotonin Club

The selective carotid arterial vasoconstrictor action of GR43175 in anaesthetised dogs Feniuk W, et al. Br J Pharmacol. 1989;96:83-90.

Sir Patrick Humphrey (2001)

5HT1B immunoreactivity

Middle meningeal artery

“All triptans are vasoconstrictive drugs and clinical efficacy appears Coronary artery

to be inherently dependent upon this property.�

What We’ve Learned 

Migraine is an inherited neurological disorder; attacks begins in the brain, not vessel or primary afferent



Cortical/sub-cortical mechanisms result in sensitization of peripheral and/or central trigeminal sensory afferents



Triptan efficacy depends on binding to peripheral afferents and central 5HT1B/D/F targets

Triptans 2 Decades Later . . .

Nelson D L et al. Cephalalgia 2010;30:1159-1169

Goadsby PJ, et al. NEJM. 2002;346:257-270.

Triptans Central Modulation dihydroergotamine

Naratriptan thalamus

60

Spikes per bin

*

40

20

0 0.00

0.01

0.02

0.03

0.04

0.05

Time (s)

Ann Neurol 1991;21:91-94

Bartsch T et al. Ann Neurol 2004;56:371-81

Cephalalgia 1997;17:153

zolmitriptan

Migraine: Pathophysiology of the Headache Meningeal blood vessel Sensitized peripheral afferent

Dura

Pain perception Activated central neuron (Thalamus)

Cutaneous allodynia Sensitized central neuron (trigeminal cervical complex)

Muscle tenderness

The Genetic Substrate for Migraine

Na-HCO3

EEAT1

TRESK K+ Channel

Ophoff RA, et al. Cell 1996;87: 543-552 De Fusco M, et al; Nature Genetics 2003; 33: 192-196 Dichgans M, et al. Lancet. 366(9483):371-7, 2005 Ligthart et al. Eur J Hum Genet 2011;19(8): 901–907 Antilla et al. Nat Genetics 2010 Suzuki et al. PNAS 2010 Nature Med Oct 2010;16(10):1157-1161

Cortical Spreading Depression The Biological Basis of the Migraine Aura

Lauritzen M, et al. Ann Neurol.1983;13:633-641

N. Hadjikhani PNAS 2001

CSD is a Nociceptive Stimulus The Link between Aura and Headache?

Zhang, XC et al. J Neurosci 2010;30(26):8807– 8814

The Phases of Migraine

75%

30% Headache

Time Premonitory phase

Aura

Headache phase

Postdrome

Adapted from Linde M. Acta Neurol Scand. 2006;114:71–83.

Where Does Migraine Without Aura Start?

Denuelle M et al. Cephalalgia 2008;28:856-62

Woods et al. N Engl J Med 331: 1689-1692 1994

Where Does Migraine Without Aura Start?

100

Enhanced sensory processing autonomic

Cognitive Affective

allodynia

VAS rating of state of health

vegetative 80

60 premonitory

40

20 headache

0 -100

-50

0

50

Time (hours) Giffin et al., Neurology 2003;60:935-940

100

Where Does Migraine Without Aura Start?

Denuelle M, et al. Headache 2007;47:1418-1426

Altered descending modulation of trigeminal nociception

Stankewitz A et al. J. Neurosci. 2011;31:1937-1943

Regulate cortical neuron. glial excitability and CBF

Hamel E. J Appl Physiol 100: 1059–1064, 2006

How This Translates Into New Treatments  Emerging acute and preventive

therapies target  neuronal receptors/ peptides involved in trigeminal sensory transmission  Cortical spreading depression  Descending modulation networks

Current and Future Treatments Where triptans were designed to work

Pain

Cerebral artery

Trigeminal nerve

Where CGRP receptor antagonists ‘GEPANTS’ Were designed to work

CGRP Smooth muscle cell

Where old and new drugs likely work

Brain synapse

Targeting Central Neurotransmitters and their Receptors Pain

Monoclonal antibodies Thalamus

NMDA (mGluR2; GluA3) receptor

CGRP Glutamate ASIC- 3

PAC TG

LC

OR1 5HT1F

CGRP receptor

Brainstem nNOS

All Effective Migraine Prevention Drugs Inhibit Cortical Spreading Depression 16 15

Saline Gabapentin 100 mg/kg IV Gabapentin 200 mg/kg IV

CSD frequency (/h)

14

Negative controls: D-propranolol, oxcarbazepine Ayata et al. Ann Neurol 2006

13 12 11 10 9 8

Peeters M, et al. JPET 2007;321:564-572

27

Migraine Progression

No migraine

Low-frequency episodic migraine

High-frequency episodic migraine

Chronic migraine

1. Lipton RB. Neurology. 2009;72:S3-S7.

2. Bigal ME, Lipton RB. Curr Opin Neurology 2008;21:301-308.

Enhanced Cortical Sensory Processing Sensorimotor network

Auditory network

Visual network

Affective pain network

Sprenger et al. AHS Washington 2011.

Riedl et al. Neuroimage 2011;57(1):206-13

Attack Frequency Dependent Functional and Structural Remodeling of Pain Matrix

Maleki N, et al. Cephalalgia 2012. In press Kim JH et al. Cephalalgia. 2008;28:598-604.

Dose dependent functional and structural remodeling of S1 and ACC Pain Memory and altered descending modulation

Risk Factors for Progression from Episodic to Chronic Migraine Not Modifiable by Health Interventions Female gender

Modifiable by Health Interventions Obesity

Low socioeconomic status

Medication overuse

Head trauma

Stressful life events

Genetic/epigenetic?

Snoring

Caffeine overuse

Depression Modifications Can Result in: Headache burden Migraine progression Rate of remission

Anxiety Attack frequency

Scher AI, et al. Headache 2008;48:16-25.

Bigal ME, Lipton RB. Curr Opin Neurol. 2009;22:269-76.

Botulinum Toxin Type A

Matak I, et al. Neurosci 2011;86:201–207

Peripheral and Central Neurostimulation Deep brain stimulation

Transcranial magnetic (TMS)

Extracranial (occipital, supraorbital) nerve

Sphenopalatine ganglion

ONS May Restores Central Descending Opioidergic Tone But Does Not Deactivate ‘Generator’

Matharu et al. Brain 2003;127:220-30

Progressive deactivation after ONS in pain matrix except hypothalamus ONS does not de-activate ‘generator’ Perigenual ACC selectively activated in responders Magis et al. BMC Neurology 2011, 11:25

Chronic Migraine Disease Management Model Biobehavioral therapy, lifestyle modification Risk factor modification

Preventive therapy

Dodick DW. N Engl J Med. 2006;354:158-165.

Judicious acute therapy

Chronic migraine management

Neuromodulation

350 years

20 years

Today

Summary 

Migraine is an inherited neurological disorder characterized by enhanced cortical and subcortical sensory processing



Physiological and structural remodeling may lead to frequent attacks and persistent symptoms



Current management must involve aggressive risk factor modification, bio-behavioral therapy, judicious acute therapy and aggressive prevention



Emerging therapeutics target trigeminal sensory neuropeptides/receptors, CSD, and descending modulation circuits