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