Andrew H. Ahn, MD PhDDepartments of Neurology and Anatomy

University of California San Francisco

Advances in Internal MedicineMay 21, 2009

Headache Update

Overview

Migraine as systems neurobiology

Φ Clinical features

Φ Neurobiological mechanisms

Mechanisms of triptan action

Φ Triptan receptors in PNS and CNS

Φ Modulation of pain circuits

The near future of headache care

Φ CGRP receptor antagonists

France 400 BCNeolithic c. 7000 BC

Case study* (HIPAA compliant)

France 400 BCNeolithic c. 7000 BC

Case study* (HIPAA compliant)

* Headache is not an FDA-approved indication for trephanation

Why Migraine Matters

Migraine is a common disabling disorderYearly prevalence 36 million people (US 2005)18 % of women6 % of men19% of veterans of conflicts in Iraq and Afghanistan

Migraine has a high social cost$31 billion lost productivity

Migraine complicationsPain and disabilityOverdose and dependenceCo-morbid with other pain and medical disordersCo-morbid psychiatric disease

Migraine: A multi-system disorder

∴ Episodic, lasting hours to days

∴ PainModerate to severeUnilateralPulsating, throbbingAggravation with routine activityAllodynia

∴ Neurologic featuresAuraPhotophobia PhonophobiaNausea, vomitingVertigo Slurred speech, somnolence

Based on the Headache Classification Committee of the International Headache Society, 2nd Ed. Cephalalgia 2004

Theories of migraine: an overview

Cortical spreading depressionThe “vascular hypothesis”Central sensitizationBrainstem dysfunctionMigraine geneticsNeurochemical circuits

Environment

Theories of migraine: a theoretical framework

Neurogenicinflammation

Cortical hyperexcitability

Brainstem dysfunction

Trigeminal excitation(CGRP, glutamate) HEADACHE

+

+

Genetic predisposition

Initiation

Generation/perpetuation

Adapted from Pietrobon Neuroscientist. 2005

Centralsensitization

Peripheralsensitization

+

+

K.S. Lashley, 1941

Theories of migraine: a cortical disorder?

K.S. Lashley, 1941

Theories of migraine: a cortical disorder?

K.S. Lashley, 1941

Theories of migraine: a cortical disorder?

K.S. Lashley, 1941

Theories of migraine: a cortical disorder?

K.S. Lashley, 1941

Theories of migraine: a cortical disorder?

A.A.P. Leao, 1944 Neuronal correlate of aura?

1234567

Theories of migraine: cortical spreading depression

A.A.P. Leao, 1944

stimulus1234567

Neuronal correlate of aura?

Theories of migraine: cortical spreading depression

A.A.P. Leao, 1944

stimulus1234567

Neuronal correlate of aura?

Theories of migraine: cortical spreading depression

A.A.P. Leao, 1944

stimulus1234567

Neuronal correlate of aura?

Theories of migraine: cortical spreading depression

A.A.P. Leao, 1944

stimulus1234567

Neuronal correlate of aura?

Theories of migraine: cortical spreading depression

A.A.P. Leao, 1944

stimulus1234567

Neuronal correlate of aura?

Theories of migraine: cortical spreading depression

A.A.P. Leao, 1944

stimulus1234567

Neuronal correlate of aura?

Theories of migraine: cortical spreading depression

A.A.P. Leao, 1944

stimulus1234567

Neuronal correlate of aura?

Theories of migraine: cortical spreading depression

A.A.P. Leao, 1944

stimulus1234567

Neuronal correlate of aura?

Theories of migraine: cortical spreading depression

A.A.P. Leao, 1944

stimulus1234567

Neuronal correlate of aura?

Theories of migraine: cortical spreading depression

A.A.P. Leao, 1944

stimulus1234567

Neuronal correlate of aura?

Theories of migraine: cortical spreading depression

Woods et al, 1994

Perfusion disturbances in a spontaneous migraine

spreading oligemia

Graham and Wolff, 1938

BP systolic

BP diastolic

TA pulsations

headache

minutes0 10 20 30 40 50 60

Theories of migraine: the vascular hypothesis

FHM: Familial Hemiplegic Migraine

Disorder Gene ProteinFHM-I CACNA1A P/Q Ca2+ channel

FHM-II ATP1A2 Na+/K+-ATPase

FHM-III SCN1A Na+ channel

Theories of migraine: ion channel dysfunction

Substance P and CGRP are “pain” neurotransmitters

Theories of migraine: neuoromodulation

Venous CGRP may be a biomarker of headache

CGRP is a mediator of peripheral inflammation and painEdvinsson and Uddman Brain Res Rev 2005

- no change from before headache.↑ significant increase in neuropeptide level.

VIP Substance P CGRPMigraine without aura - - ↑

Migraine with aura - - ↑

Trigeminal neuralgia - - ↑

Cluster headache ↑ - ↑

Chronic paroxysmal headache

↑ - ↑

CGRP antagonists abort migraine attacks*

BIBN4096 BS reduces migraine pain* Not FDA approved for any clinical application

Olesen et al, NEJM 2004

Analgesics: ASA, APAP, ibuprofen, indomethacin

Opiates: morphine, codeine, meperidine

Phenothiazines: chlorpromazine

Acetazolamide

Ergots: ergotamine, DHE-45

Serotonin (5-HT) sub-selective agonists (triptans):5HT1B, 5HT1D, 5HT1F receptorssuma nara almo ele frova riza zolmi

Theories of migraine: follow the triptans

Triptans activate receptors at multiple sites

5HT = serotonin receptor subtypesGoadsby NEJM 2002

5HT1D Substance P

Bergerot Eur J Neurosci 2006

5HT1D receptors on “pain responsive” afferents

Ahn, unpublished

The classical pain pathway

From Fields Nature Rev Neurosci, 2004

Somatosensory cortex

Insular cortex

Thalamus

Anterolateral tract

Tissue injury

Functional imaging of pain

A distributed representation of painApkarian et al Eur J Pain 2005

Ascending and descending pain pathways

Opiates modulate both afferent and efferent responses to painAdapted from Fields Nature Rev Neurosci, 2004

Potential areas of triptan pain modulationAdapted from Fields Nature Rev Neurosci, 2004

Triptan actions on modulatory pathways

5HT1D receptor terminals within the central nucleus of the amygdala

5HT1D AChE

BLA

CeA

Ahn et al, in preparation

5HT1D receptor terminals within the central nucleus of the amygdala

5HT1D receptorSERT - 5HT vesicular transporter

Ahn et al, in preparation

5HT1D receptor terminals within the central nucleus of the amygdala

5HT1D receptor CGRP

Ahn et al, in preparation

CGRP

5HT1B

5HT1

D

5HT1F

5HT1D receptors in the rat thalamus after ICV colchicine

5-HT1D receptor CGRP

5-HT1D receptor in SPF and SPFFCAhn et al, in preparation

The central amygdala in pain processing

∴ Affective and nociceptive circuits through CeASpino-parabrachio-amygdaloid pathwayMulti-modal connections to lateral (LA) and basolateral (BLA)CGRP: nociceptive and enteroceptive input

∴ Amygdala plays a central role in nociceptive processingEmotional learning - Fear conditioning“Nociceptive amygdala” in arthritic painConditioned place aversion

∴ Modulation of mood and anxiety

CGRP receptor antagonists in amygdala reduce pain-evoked responses

Pain alters synaptic plasticity in CeA at post-synaptic sites blocked by CGRP antagonistsHan et al, J Neurosci 2005

Headache Treatment Horizon

υ CGRP receptor antagonists

υ Occipital nerve stimulation

Why Headache Treatment Fails

υ Diagnosis is incomplete or incorrect

υ Important exacerbating factors were missed

υ Pharmacotherapy is inadequate

υ Non-pharmacologic interventions are

inadequate

υ Other factors: co-morbidity, unrealistic

expectations, psychiatric disease

Lipton, Silberstein, Saper, Bigal, Goadsby. Neurology Apr 8;60(7):1064-70 (2003)

Re-evaluation of the diagnosis I

Lipton, Silberstein, Saper, Bigal, Goadsby. Neurology Apr 8;60(7):1064-70 (2003)

ν Secondary Headache Disordersυ Giant Cell Arteritisυ Carotid dissectionυ High- and low-pressure headachesυ Chronic sphenoid sinusitisυ Nasopharyngeal carcinomaυ Chronic infection (Lyme, HIV)υ Metabolic disorders (hepatic, renal,

endocrine)υ Mediastinal process (angina, lesion, SVC)υ Ocular disturbancesυ Dental, mandibular joint pain

Re-evaluation of the diagnosis II

Lipton, Silberstein, Saper, Bigal, Goadsby. Neurology Apr 8;60(7):1064-70 (2003)

ν Primary Headache Disorders υ Medication Overuse Headacheυ Chronic Tension Type Headacheυ Cluster-migraine disorder

ν Primary Headache Disorders (rare)υ Hemicrania continua (indomethacin)υ Paroxysmal hemicrania (short, frequent,

indomethacin)υ Hypnic headache (elderly, <30min, Li, mel, caff,

verap)υ New daily persistent headache

What is a Chronic Daily Headache?

ν The International Classification of Headache Disorders, second edition (2003)

υ Greater than 15 headache days per month

Medication Overuse Headache

υ The most common cause of chronic migrainous headache

υ Mixed migraine-like and tension-type-like headache

υ Associated with overuse of migraine drugs or analgesics

υ Highest risk in 3 or more treatment days per week

υ Applies to ergotamines, triptans, analgesics, opioids, combination medications

Exacerbating factors in CDH

Lipton, Silberstein, Saper, Bigal, Goadsby. Neurology Apr 8;60(7):1064-70 (2003)

υ Medication overuse headache (rebound)

υ Chronic cervical strain

υ Caffeine overuse

υ Other medications (NTG, retin-A)

υ Over-the-counter preparations (Valerian, Vit A, D)

υ Dietary, hormonal, psychosocial triggers

υ Visual correction / ocular disorder

υ Sleep apnea / poor sleep hygiene

υ High BMI

Migraine Prophylaxis

ν Medicationsυ Tricyclics, beta-blockersυ Ca-channel blockers (verapamil)υ Anticonvulsantsυ Adjustments to hormone therapy

ν Behavior modificationsυ Diet, hydration, caffeine/alcohol useυ Exercise, sleep hygiene, altitude

changesν Physical Therapy

υ Chronic cervical strain, posture trainingν Biofeedback and relaxationν Alternative/Integrative medicine

Medical Migraine Prophylaxis

ν Patient ready for a daily medication?

ν Starting medical prophylaxis depends on the level of disabilityυ Severity - interruption of critical activitiesυ Frequency - greater than 3 times per week

ν Start at low doses, increase slowly

ν Maintain a diary / journal of headaches

ν Reproductive considerations

Physical Treatments for Headache

Biondi, Headache: The Journal of Head and Face Pain 45 (6), 738-746 (2005)

ν Migraine: PT most effective when combined with:υ Exerciseυ Relaxation trainingυ Thermal biofeedback

ν Tension-type headache:υ physical therapy >> massage, acupuncture

ν Chiropractic manipulationυ Trend toward benefit, but data is weakυ Probably TTH > Migraineυ Probably not harmful (excl: high velocity neck manip)

UCSF - PT Health and Wellness Program

PT Health and Wellness CoordinatorSandra.Stefanuto@ucsfmedctr.orghttp://www.ptrehab.medschool.ucsf.edu/WellnessCenter/

Spine HealthRepetitive Strain InjuryWater Fit Stress Control and Relaxation