The Northern Neuroscience Centre

Chiang Mai University

NNC CMU

Effective Migraine
Management
Surat Tanprawate, MD, MSc(Lond), FRCPT
Headache specialist, Division of Neurology
Chiang Mai University
https://www.wfneurology.org/world-brain-day-2019
The Northern Neuroscience Centre
Chiang Mai University
NNC CMU
Migraine Subtypes
Migraine

Migraine without aura Chronic migraine

Migraine with aura
- Migraine with typical aura
- Migraine with brainstem aura
- Hemiplegic migraine
- Retinal migraine
Complication of migraine
- Status migranosus
- Persistent aura without infarction
- Migrainous infarction
- Migraine aura-triggered seizure

Episodic syndromes that may be associated with migraine

- Recurrent gastrointestinal disturbance (Cyclical vomiting syndrome, Abdominal
migraine )
- Benign paroxysmal vertigo
- Benign paroxysmal torticollis
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Migraine Situtation in Thailand
ระดับของไมเกรน
• Estimated migraine in
Thailand = 10.12 Million
4%
24%
• 7 Million need help
2.5 Million Need
Prevention
72%
• ในคลินิกโรคปวดศีรษะ
มช. พบไมเกรนเรื้อรังสูงถึง > 1 Migraine/Week
20% < 1 Migraine/Week
> 15 days/Month
The Northern Neuroscience Centre
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NNC CMU
Disease Course
ยาแก้ปวด ยาแก้ปวด ยาแก้ปวด

Co-morbidities

MOH

ไมเกรนความถี่ต่ำ ไมเกรนความถี่สูง ไมเกรนเรื้อรัง

The Northern Neuroscience Centre
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NNC CMU
Migraine is a disorder of sensory processing
Phases of Acute Migraine Attack

Prodromal Aura Headache Resolution

phase phase phase phase
 Serotonin receptor in the
Trigeminovascular System

• 5-HT1B: constricts the pain-

producing intracranial,
extracranial blood vessel in
the meninges

• 5-HT1D: presynaptically
inhibits trigeminal peptide
release and interfere with
central trigeminal nucleus
caudalis
Karsan N, Goadsby PJ Nature Review (2018)
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Functional change
Central sensitization
Sensitization: altered
perception of stimuli by
peripheral or central Dorsolateral pontine activity features prominently
in the pathophysiology of episodic migraine
considered as adaptive Weiller C, May A, Limmroth V, et al Nat Med. 1995;1:658-660

mechanism of neuronal plasticity

There is persistence of rostral pontine activation without any change on

MRI in chronic migraine Matharu MS, et al. Brain 2004; 127(1): 220-230
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NNC CMU
The Northern Neuroscience Centre
Headache Diagnosis and Clinical patterns in
Chiang Mai University

Chiang Mai Headache Clinic using EHR (2016-2017)

NNC CMU
Surat Tassanasorn M.D., Surat Tanprawate M.D.

Journal of Thai Neurology Meeting (2018)

The Northern Neuroscience Centre
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ประเมินระดับของไมเกรน • Severity

• Mild น้อย
• 1-4 วัน/เดือน ไมเกรนเป็นครั้งคราว
Episodic Migraine Low Frequency • Moderate ปานกลาง

• 5-10 วัน/เดือน ไมเกรนเป็นครั้งคราว • Severe มาก

Episodic Migraine Moderate Frequency

• 11-14 วัน/เดือน ไมเกรนเป็นครั้งคราว

Episodic Migraine High Frequency

• > 15 วัน/เดือน ไมเกรนเรื้อรัง

 3 Pillars of Migraine
The Northern Neuroscience Centre
Chiang Mai University
NNC CMU
Management

ความถี่และความรุนแรง

Migraine Level

Tr Layer I r
ig i o
ge a v
rs e h
B
สิ่งกระตุ้น พฤติกรรม
 3 Pillars of Migraine Management
The Northern Neuroscience Centre

NNC CMU
Chiang Mai University

ระวัง Medication overuse

Acute Medication
management

Co Layer II /
-m ci ry
or n
o to
b h r c
id C fr a
ity e
โรคร่วม R
ไมเกรนเรื้อรังและ
ดื้อยา
The Northern Neuroscience Centre
Chiang Mai University
NNC CMU
7 migraine types: Classified Headache
Depend on Complexity of Therapy
1. Migraine - Low frequency, Low impact

•Acute medication treatment

2. Migraine - Moderate to high frequency, Moderate to High impact

•Preventive medication need

3. Migraine - Chronic migraine - Very high frequency, High impact

• Preventive medication needs and conversion to EM need, anti-

CGRP?
The Northern Neuroscience Centre
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NNC CMU
7 migraine types: Classified Headache
Depend on Complexity of Therapy
4. Migraine - Chronic migraine with Medication overused

• Preventive medication, Detoxification need, Botulinum toxin?, anti-CGRP

5. Migraine - EM or Chronic Migraine with Comorbidity +/- MOH

• Preventive medication, Treatment Comorbidity, Botulinum toxin ?, anti-

CGRP?

6. Migraine - Refractory migraine +/- Comorbidity +/- MOH

• Advance therapy (Infusion therapy, Botulinum toxin, Nerve Block), anti-

CGRP?

7. Migraine who can not tolerate to Preventive Medication ??

• anti-CGRP?
Tools

Headache Impact
Test (HIT-6)

น้อย (< 49)

ปานกลาง (50-55)
มาก (56-59)
มากที่สุด (>60)
Tools

Headache diary
 Headache
follow up form
Headache day

Acute med used

HIT-6 scale

Treatment response
Headache Education is Still Important
Acute therapy
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NNC CMU
Rationale to use acute migraine medication
• what, when, to start initial treatment, back up
treatment and rescue treatment

• consider the patient’s age, any co existent illness

• consider the migraine type, severity, disability,

associated features (N/V)

• consider the previous drug response

• consider the potential for drug overuse

The Northern Neuroscience Centre
Chiang Mai University
NNC CMU
Migraine medication
Non-specific medication Specific medication

• analgesics (NSAIDs, • ergotamine

combination
analgesics) • DHE

• selective 5-HT1 agonist

• anti-emetics
(triptan)
• opioids

• corticosteroids

• DA antagonists
 Acute migraine pharmacotherapy
The Northern Neuroscience Centre

NNC CMU
Chiang Mai University

Migraine non-specific drug Migraine specific drug

• Dihydroergotamine

• Ergotamine

• Triptan

DHE injection form

Ergotamine tartrate+ Caffeine

Triptan in Thai market

Evers, S et al. European Journal of Neurology 2009, 16: 968–981 Eletriptan Zolmitriptan Sumatriptan
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Risk of Progress to CM Based on Acute Treatment
Efficacy
n t
Progressed
re ve
Treatment N from EM to OR
n p 95% CI
CM,%(n)
c a
n t
m e
Very poor 369 6.8(25)
a t i o n 1.42,4.61

re
t res s
s
k og
Poor 1007 4.4(44)
t a c r
1.02,2.81

a t e p
u t e a i n
Moderate 2657
a c
2.7(73)
i g r 0.81,1.97

s s m
c e
u c
S
Maximum 1648 1.9(32) 0.81,1.97

0 1 2 3 4 5

Lipton RB, et al. Neurology 2015;84:688-695

 When to start?
Treatment early vs late
 Third order
neuron

Second order
neuron
The Northern Neuroscience Centre
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NNC CMU

• 491 pt. migraine: Almotriptan 12.5 mg (n=198)-> mild/early vs moderate/

severe
Mild/early Moderate/severe
60

53.5
45
46
37.5
30
30
24
15

6
0
%2-h pain free %24-h sustain pain free %24-h headache recurrence
PJ Goadsby Cephalalgia 2008,26(Suppl):36-41
The Northern Neuroscience Centre
Chiang Mai University
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How to treat migraine

attack?
Step vs Strategic approach?
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NNC CMU

• MIDAS were evaluated before enrolled

• 6 migraine attacks

• Stratified care: take medication based on severity

• MIDAS II - NSAIDs (aspirin 1000 mg) x 6 attacks

• MIDAS III/IV - Tritan (zolmitriptan, 2.5 mg) x 6 attacks

• Step care across attacks

• first 3 attacks with aspirin if not satisfy -> step up to zolmitriptan next 3 attacks

• Step care within attacks

• aspirin initial treatment -> if not satisfied response -> zolmitriptan

Headache response at 1, 2 and 4 hours between
stratified care vs step care
The Northern Neuroscience Centre
Chiang Mai University
NNC CMU
Conclusion: US Headache
Consortium recommendation

• Acute treatment choice should be based on attack-

related disability, which encompasses the severity,
duration, and frequency of migraine attacks and
the presence of associated symptoms

• Stratified care specifically matches illness severity

to treatment need

Silberstein et al. 2007

Drug choices
The Northern Neuroscience Centre
Chiang Mai University

Non-specific
NNC CMU
migraine
medication:

Analgesics with
evidence of efficacy
EFNS migraine
treatment guideline
2009 Evers, S et al. European Journal
of Neurology 2009, 16: 968–981
The Northern Neuroscience Centre
Chiang Mai University
NNC CMU
Options
• Fixed combination ASA + Paracetamol + caffeine
more effective than single substance

• selective COX-2 inhibitors

• Valdecoxib 20-40 mg

• Celecoxib 400 mg

• Rofecoxib 25-50 mg
Migraine specific medication

- Drugs modulate serotonin in

migraine
Possible Sites of Action of Triptans in
the Trigeminovascular System
Ergot
Cock spur The ergot of Rye

The word “ergot” is derived from “argot”,

old French for “cock spur”

Fungus “Claviceps purpurea”

400 BC: ergotism was reported 1862: ergot use to

- vasospasm treat migraine
- gangrene
- abortion
 A 42 Thai woman with
ergotamine overuse (15 tab/
day) with rebound
vasodilatation
“The Beggars” by Pieter Bruegel the Elder, a painting believed to show
victims of ergotism.
Triptan
 Ergotamine/ 1 mg/100 mg
B
Caffeine Caffeine

Migraine- specific
medication
Ever S, Afra J. Eur J Neurol 2009, 16:968-981
 The Northern Neuroscience Centre
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NNC CMU
Side effect of triptan
• Triptan sensations – paraesthesias, sensations of
warmth, heaviness, pressure or tightness in
different parts of the body including the throat,
neck and chest.

• The chest symptoms in clinical trials were transient,

mild and never attributable to ischaemia

• The frequency of CNS adverse effects with some

triptans (fatigue, somnolence, dizziness, difficulty
concentrating, etc.)
The Northern Neuroscience Centre
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NNC CMU

Abstinence vs
Non-abstinence
(Caffeine < 200 mg/
d or > 200 mg/d)

Lee et al. The J of Headache and Pain 2016;17:71

Preventive Medication
Headache frequency associated with onset of CDH:
a study on episodic headache (2-104 day/year)

Frequency of migraine attacks > 1 / wk

n=798

4.33 / month
Estimated 1-year incidence rate of: (a) chronic daily headache (180+ HA day/
year); or (b) increased HA (105-179) in an episodic headache population

Scher A.I. et al. Pain 106 (2003) 81–89

 The major group of
preventive medication
• Anticonvulsants
Drug choice?
1. Migraine condition
• Antidepressants
(EM, CM, RM, MOH)
• B-adrenergic blockers 2. Efficacy
3. Adverse events
• Calcium channel antagonists 4. Comorbidity
5. Cost
• NSAIDs

• Serotonin antagonists

• Other (including riboflavin, minerals, herbs, botulinum toxin)

 AAN/AHS 2012

S.D. Silberstein, et al. Neurology 2012;78;1337

The Northern Neuroscience Centre
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Relative
Drugs Relative indications Adverse effect
contraindication
Amytriptiline (TCA) Other pain disorders, Mania, urinary Drowsiness, dry
depression, anxiety, retention, heart mouth, increase
insomnia blocks, glaucoma appetite, weight gain

Propranolol (B- Hypertension, angina Asthma, depression, Fatique, lethargy,

blocker) CHF, Raynaud’s nausea, depression,
disease dizziness

Flunarizine (CCB) Vertigo Obesity, depression, Drowsiness, weight

PD gain, depression, PD

Valproic acid (AED) Epilepsy, mania, Liver disease, Nausea dyspepsia,

anxiety bleeding disorder sedation, increase
appetite, weight gain

Topiramate (AED) Epilepsy, mania, Renal calculosis, liver Paresthesia, weight

anxiety disease loss, alter taste,
language disturbance
The Northern Neuroscience Centre
Chiang Mai University
NNC CMU
Patient-reported reasons for discontinuation of preventive
treatments for migraine (IBMS-II study; n=1,165)

Blumenfeld AM, et al. Headache. 2013;53:644–55.

 The Retrospective Study to Evaluate 

Migraine Treatment by BONT-A Injection in
Chiang Mai Headache Clinic
100 and 150 U
Tittaya Prasertpan M.D., Surat Tanprawate M.D.

65

64.27 26 cases with CM treated with BTx from 2014-2017

63.25
No significant different between 100 vs 150 U
HIT-6 Score

61.5

p = 0.038* p = 0.034* p = 0.087

59.75

58.89 59.11
58.86
58
0 1 3 6
Month Poster presentation, Annual Thai
Neurology Meeting(2018)
 The Northern Neuroscience Centre
Chiang Mai University

NNC CMU

• Decrease in migraine induced

disability (HIT-6 scale, MIDAS scale)

• % of patients with > 50% reduction

in attack frequency

• Treatment duration - 4-6 months (but

also depended on several factors)
 Issue on preventive
medication?
1 month 4-6 months
Drug titration Duration

Start Evaluation Stop

When should we start? When should we When should we

severity evaluate? stop?
frequency
acute med use 2 wks- 2 mo-4 mo-6 mo 4-6 months

What should we start? What should we How to stop?

type of migraine evaluate? slow tapering off with
efficacy frequency maintain lowest dose if
comorbidity impact headache occurs
 The Northern Neuroscience Centre
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NNC CMU

New Era in Migraine

Management
Surat Tanprawate, MD, MSc(Lond), FRCPT
Headache specialist, Division of Neurology
Chiang Mai University
Neuromodulator
FDA approved Neurostimulator for migraine

Transcranial magnetic stimulator (eNeura TMS)

Transcutaneous supraorbital neurostmulation (tSNS) (CEFALY)
Non-invasive vagal nerve stimulator (nVNS, gammaCore)
Searching for Specific
Migraine Therapy
The Northern Neuroscience Centre
Chiang Mai University
NNC CMU
CGRP story: 1988

“Edvinsson found that stimulating

TNG increase CGRP”

PJ Goadsby, UCL, UK

“Goadsby demonstrated CGRP level

were elevated during migraine”
L Edvinsson, Lund University, Sweden
The Northern Neuroscience Centre
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NNC CMU
Three evidences to support CGRP in migraine

• During spontaneous attack,

the level of CGRP rise in the
blood

• After being treat with triptan

and the pain relieve, the level
of CGRP decline in the blood

• Individual with migraine,

intravenously infuse of CGRP
induce attack undistingisable
from spontaneous attack
Goadsby PJ et al. Ann Neurol 1990;28:183-7.
The Northern Neuroscience Centre
Calcitonin Gene-Related Peptide:
Chiang Mai University

What is it role in Migraine

NNC CMU
Pathophysiology?

CGRP receptor in Trigeminal Ganglia

Tso AR, Goadsby PJ. Curr Treat Optons Neurol 2017;19:27
Radant AC, Russo AF Expert Rev Mol Med 2011;13:13:e36
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CGRP Receptor Antagonists
• Potent blockade of
CGRP-induced
vasodilation

• Do not cause
vasoconstriction

• Modulate sensory
signaling within
trigeminal pathway
The Northern Neuroscience Centre
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NNC CMU

Components of CGRP transmission and sites of action for

CGRP-related migraine therapies.
Edvinsson L et al. Nature 2018;14: 338-350
The Northern Neuroscience Centre
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Timeline drug discovery
1982 Discovery of CGRP

CGRP Ab made to measure and localize CGRP in the TVS, it found

1984
potent vasodilator

1985 CGRP first proposed to play a role in migraine

Discovery of the trigeminovascular reflex: a physiological role for

1986
CGRP

1988 First measure release by trigeminal stimulation in human

First demonstration in patients that CGRP is released during an acute

1990
migraine attack

1993 Sumatriptan shown to normalize CGRP during acute migraine attack

Edvinsson L et al. Nature 2018;14: 338-350

The Northern Neuroscience Centre
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Timeline drug discovery
Characterization of the multicomponent CGRP receptor that consists
1998
of CALCRL, RAMP1, and RCP
CGRP receptor blocker intravenous olegepant shown to alleviate
2000
headache during migraine attack
Clinical trials begin to test telcagepant and other repaints in acute
2006
migraine
Antibodies against CGRP shown to block CGRP responses in vitro
2007
and in vivo

2010 Merck halt : Telcagepant-> liver toxic

2013-
Galcanezumab, eptinezumab, fremanezumab, erenumab - shown
2016 efficacy for migraine prevention
Ubrogepant, an orally active gepant, shown to be effective in acute
2016
migraine attack without adverse side effect
Review with guideline of antibody migraine therapy by FDA, and
2018
release in the Market
Edvinsson L et al. Nature 2018;14: 338-350
-mab -gepant
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Trigeminal ganglion and
CGRP target therapy

Messlinger The Journal of Headache and Pain (2018) 19:22

The Northern Neuroscience Centre
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Nomenclature for therapeutic monoclonal antibodies

Silberstein S et al. , Headache 2015;55:1171.

The Northern Neuroscience Centre

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Chiang Mai University
CMU
CGRP-target therapies for Migraine
Dosing and
CGRP target Rx Company Target Indication
administration
Eptinezumab
1 IV dose every 3
Alder peptide or ligand Prevention (EM, CM)
(humanized) mo
Erenumab

Amgen receptor Prevention (EM, CM) 1 SC dose monthly

(fully human)
Fremanezumab
Prevention (EM, CM, 1 SC dose monthly
Teva peptide or ligand
(humanized) EC, CC, PPTH) or every 3 mo
Galcanezumab
Prevention (EM, CM,
Eli Lilly peptide or ligand 1 SC dose monthly
(humanized) EC, CC)

Remegepant Biohaven Receptor Acute therapy Oral as need

Ubrogepant Allergan Receptor Acute therapy Oral as need

Prevention of Oral once or twice

Atogepant Allergan Receptor
migraine (EM) daily

BHV-3500 Biohaven Receptor Acute therapy Intranasal as need

Giamberardino MA et al. Intern Emerg Med 2016;11:1045-1057

DolginE, Nature Biotech 2018; 36(3): 207-208
The Northern Neuroscience Centre
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Safety of Anti-CGRP mAbs: Similar to Placebo

Erenumab in Episodic Migraine

Erenumab 70 mg
Erenumab 140 mg
Placebo

AEs Through to week 12

(n=314%) (n=319) (n=319)

All AEs 180 (57.3%) 177 (55.5%) 201 (63%)

Serious AEs 8 (2.5%) 6 (1.9%) 7 (2.2%)

AEs leading to
7 (2.2%) 7 (2.2%) 8 (2.5%)
discontinuation

Fremanezumab in Chronic Migraine

Fremanezumab Monthly
Fremanezumab Quarterly
Placebo

AEs through to week 12

(n=379) (n=376) (n=375)

1 or more AEs 270 (71%) 265 (70%) 240 (64%)

Serious AEs 5 (1%) 3 (<1%) 6 (2%)

AEs leading to
7 (2%) 5 (1%) 8 (2%)
discontinuation

Goadsby et al. N Eng J Med 2017;377:2123-2132

Silberstein SD, et al. N Eng J Med 2017;377:2113-2122
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