Migraine1

Pathophysiology
and Management
of Migraine
Presenter: Dr Srikanth
Chairperson: Dr Pooja.M

OUTLINE
• Introduction
• Pathophysiology
• Management

Introduction
• The term migraine derived from Greek word, hemikranios, means
“half head,”
the unilateral distribution of head pain that is present in about
60%–75% of people with migraine
• Migraine ranks as the second most disabling neurologic condition
globally in terms of years lost to disability.
Neurology clinics 2019(headache)

Introduction
One-year prevalence of 12% in the general population
 Afflicts prepubescent boys and girls with a similar frequency.
 After puberty, girls are preferentially more effected nearly 3:1 ratio
 Peak prevalence for both sexes is between the ages of 25 and 55 years

Bradley’s neurology-7th edition

ICHD -3 criteria for migraine

The Migraine Attack
Bradley’s Neurology-7th Edition)

Pathophysiology
Theories of Migraine
Vascular theory:
Neuronal theory
Neurovascular theory

Pathophysiology
Vascular theory:
• Harold Wolff et al
Cerebral vasoconstriction
Cerebral vasodilation
Aura
headache
Points against vascular theory:
functional MRI studies ---phase of focal
hyperemia precedes the phase of oligemia
during the migraine aura
Oligemia does not conform to discrete
vascular territories
Headache may begin while cortical blood
flow remains reduced
MRA done during migraine showed no
meningeal vasodilation
Drugs which do not constrict vessels abort
migraine(Eg:Asprin)
VIP-vasodilator do not precipitate headache
Wolff HG et al 1963

Pathophysiology
Neurovascular theory:
Brain dysfunctional areas are wide spread
Areas responsible for processing pain,
visual stimuli, auditory stimuli, olfactory
stimuli, regulating sleep and wakefulness,
and awareness are involved
Atypical activity and atypical interaction
within these network areas are responsible
for migraine symptomatology
Primary brain dysfunction
with
secondary vascular effects
Goadsby -2017

Pathophysiology –Neurovascular theory
1)Migraine genetics
2)Migraine generator
3)Cortical spreading depression
4) Trigeminovascular system
5)Hyperexcitable migraine brain
Goadsby 2017

Pathophysiology
Migraine genetics:
 Genetically mediated disease
Evidence:
Genetic epidemiological surveys and large
national registry-based twin studies
A meta-analysis of 29 genome-wide
association studies identified 12 loci
associated with migraine susceptibility(
involved in sensing hot and cold,neuronal
excitability,glutamate regulation)
Goadsby -2017
Stewart WF et al(1997)
Annals of Neurology

Pathophysiology
A Migraine Generator :
“Either Hypothalamus or Brainstem are
considered the migraine generators”
Symptoms of the premonitory phase are
suggestive of hypothalamic dysfunction
(e.g., mood changes, thirst, food cravings,
excessive yawning, and drowsiness)
A PET study of NTG triggered migraine
attacks found premonitory phase
activations in
1. posterolateral hypothalamus,
2. several brainstem regions (e.g.,
midbrain tegmental area,
periaqueductal gray, dorsal pons), and
3. several cortical areas
Co-occurrence of multiple different types
of symptoms during migraine attacks point
to possibility of parallel alteration in
functional activity of several different
brain regions/networks
Maniyar et al. 2014 BRAIN

Pathophysiology
Cortical Spreading
Depression/depolarisation:
electrophysiological correlate of
the migraine aura.
Described by Leao
Depolarisation
oligemiaHyperemia
Hyperpolarisation
Lashley KS. Et al 1941

CSD and headache
Sonu Bhaskar et al(2013-EJN)

Pathophysiology: Sterile neurogenic inflammation
vasoactive Neuropeptides are released
from trigeminal afferents due to Either
CSD or from any cause and result in
vasodilation,
plasma protein extravasation
 inflammation
Neuropeptides implicated
 Calcitonin gene related peptide
(CGRP),
 Substance P
 Vasoactive intestinal polypeptide (VIP),
 Nitric oxide (NO)
 Pituitary adenylate cyclase- activating
peptide (PACAP)
Roshini R -2018(seminars in immunopathology)

Pathophysiology: peripheral and central
sensitization
BursteinR, et al 1998

Pathophysiology
Hyperexcitable brain:
Responsible for
 Photophobia
 Phonophobia
 Olfactory hypersensitivity
Mechanisms in photophobia
Boulloche et al 2010

Pathophysiology The Trigeminocervical System and migraine :
ASCENDING-TRIGEMINOVASCULAR PAIN
PATHWAYS
DESCENDING-TRIGEMINOVASCULAR
PAIN PATHWAYS
Goadsby -2017

In summary of pathophysiology….
• No single migraine generator
• Diffuse brain dysfunction
• Genetic Predisposition
• Aura- CSD
• Headache--trigeminal afferents activation----Neurogenic inflammation
• Throbbing nature /movement sensitivity---Peripheral sensitization
• Allodynia----Central sensitization
• Chronification of headache---- Central sensitization
• Photo/phonophobia/olfactory hypersensitivity-----Hyperexcitability of
brain

Management
• Acute treatment
 Principles
 Options available- drugs and devices
• Preventive treatment
 Principles
 Options available- drugs and devices
• Specific Scenarios
 Migraine in women(Menstrual /pregnancy)
 Pediatric migraine
 Refractory migraine
 Chronic migraine
 Status Migrainosus

1)
2)
 Opioids >2 times per week
 Triptans and combination analgesics >10 days per month
( Evidence regarding NSAIDs use is inconclusive)
Neurology clinics 2019(Headache)
Need for Optimal Acute treatment :
Suboptimal dosing high frequency migraine
(10-14 episodes per month ) chronic migraine
Excessive usage Medication overuse
headache

Choosing drug based on attack characteristics
1)Time of attack onset:
Up to 50% migraines occur in mornings
with progression of an attack from moderate to
severe during sleep
Hence this type is difficult to treat ,as most
medications work best when given early in
attack
eg: Triptans-which hence are not recommended
in this type
2) Time to peak intensity :
If is < 30 minutes, non oral alternatives
should be considered.
3) Severe nausea and vomiting:
non oral alternatives
4) Long-duration attacks with multiple
recurrence:
eg: Menstrually related migraine
4) Status migrainous :
Attack lasting for more than 72 hours

Acute Treatment of Migraine
Three approaches to selecting acute
treatment
1) Step care across attacks:
step up to Triptan for 4th attack
2) Step care within attacks:
stepping up to triptan in 2 hours if the
nonspecific treatment failed
3) Stratified care:
• Based on MIDAS scale (Disability scale)
• If low disability give nonspecific
treatment and if higher disability Triptan.
• It is considered better of three
approaches.

Patient-reported outcome tools for acute migraine treatment
assessment
Score < 2 : indication to switch acute
medication
Scored as
never / rarely (0),
<half the time (1),
≥half the time (2).
 4 categorizes of treatment
efficacy:
 very poor treatment efficacy (0),
 poor treatment efficacy (1–5),
 moderate treatment efficacy (6–
7),
 maximum treatment efficacy (8)
(Migraine-ACT)
(MTOQ -4)

The American Headache society (AHS) published an evidence
assessment of acute treatments for migraine in 2015.
Level A: established as effective
Level B: Probably effective
Level C: Possibly effective
Level U: Evidence is conflicting or inadequate
Level B negative: probably ineffective
Level C negative: possibly ineffective
American headache society 2015

Triptans:
Mechanism of action :
 Selective agonists of 5-HT1B/1D
receptors
5-HT1B receptor- mediates cranial vessel
constriction,
5-HT1D receptor-leads to inhibition of the
release of sensory neuropeptides from
perivascular trigeminal afferents.
Experiments show that activation of 5-
HT1B/5-HT1D receptors can attenuate the
excitability of cells in the TNC, which
receives input from the trigeminal nerve.
Also shown to reduce CGRP Levels

Triptans available in India
Cost:Rs-313
Cost:Rs-43
(Sun pharma)
Cost:Rs-456
(Cipla)
(Sun pharma)
Cost:Rs-36
Cost:Rs-63 for 2 tabs (Sunpharma)
Cost:Rs-48 per
tablet

Triptans – Contraindications
1)Untreated hypertension
2)Ischemic or vaso-occlusive
cerebrovascular disease,
3)Peripheral vascular disease
4)Those using ergot preparations
5)Pregnant women
6) hemiplegic migraine or migraine with
brainstem aura
7)Coronary artery disease
Side effects :
Tingling, flushing, and a feeling of fullness
in the head, neck, or chest
Triptans are generally not effective in
migraine with aura unless given after
the aura is completed and the
headache initiated .
coadministration of a longer-acting
NSAID, naproxen 500 mg, with
sumatriptan will augment the initial
effect of sumatriptan and,
importantly, reduce rates of
headache recurrence
Addition of metoclopramide helps to
improve gastric emptying and
increases bioavailability
More about triptans….

REASONS:
 Headache sufferers might
not seek doctoral advice
until headache intensity
and/or frequency change
significantly
 prescription of triptans is
still not widely accepted in
general practitioners.
 In contrast to triptans, non-
steroidal anti-inflammatory
medication is available over-
the-counter

Ergots:
Mechanism of action:
• They are both vasoconstrictors
and vasodilators, depending on
the dose and the resting tone of
the target vessels,
• Probably exert their effects on
migraine via agonist activity at
5-HT receptors
Two preparations
1) Ergotamine tartrate - oral
 Very habituating and can lead to both
medication/ergot overuse headache
 Fibrotic complications
2) Dihydroergotamine (DHE) – IV, IM, SQ, Nasal.
 Terminate Status Migrainosus
 Aid in wean from overuse of other acute
medications.
reversing central sensitization deep in attacks,

Contraindications: ergots
Hypertension
Peripheral vascular disease.
Coronary artery disease
Pregnant women
Prolonged aura

Non-invasive neuromodulation
Considered for patients with
Sensitivity to acute medications,
Multiple acute medication contraindications,
Overuse of acute medications
 Inadequate benefit from standard acute migraine medications.
• They can be used alone or adjunctive
• Four non-invasive neuromodulation devices are FDA approved for
acute treatment of migraine

1) External trigeminal neurostimulation:
transcutaneous supraorbital neurostimulation
(Cefaly)
• Stimulates the supraorbital and supratrochlear
nerve
• Likely modulates central trigeminocervical
pathways
• It can be used both acutely and in prevention
Acute: e-TNS is activated for 60 minutes
Prevention: 20 minutes as a nightly dose, with
benefits manifested in migraine prevention by the
third month of steady usage
Chou DE et al 2017(Cephalalgia)

2) Single-pulse transcranial
stimulation (sTMS):
• Delivers magnetic pulses to the
occiput.
FDA approved for both acute and
preventive migraine
• Acute treatment :pulsing the
magnet several times (maximum of
17 pulses per day ) at onset of an
aura or a migraine attack with or
without aura.
• Preventive treatment: protocol calls
for 4 pulses to be administered
twice daily
Lipton et al Lancet 2019

3) Non-invasive vagal nerve stimulation
(nVNS) :
• Hand-held device that modulates and
inhibits vagal afferents while not
activating vagal efferents that cause
bradycardia and bronchospasm.
• Mechanism of action:
Suppression of cortical spreading
depolarization,
Inhibition of thalamocortical pathways,
Modulation of central trigeminovascular
and trigeminocervical pathways.
FDA-approved protocol :
2 cycles of 2 minutes each and the option of 2 more 2-
minute cycles 15 minutes later if pain has not yet resolved
Tassorelli C et al Neurology 2018

4)Peripheral electrical stimulation(
Nerivio Migra/Theranica):
FDA approved for adults >18 yrs
Only in acute management
Works on principle that
”pain inhibits pain”
(Conditioned pain modulation)
pulse stimulates C and Aδ noxious
sensory fibers above their
depolarization thresholds but is low
enough to maintain the overall sensory
experience below perceptual pain
threshold
Applied for 45 min after attack of
migraine
Yarnitsky et al
headache 2019

Greater occipital nerve Block:
Injection site-at junction of medial 1/3 and
lateral 2/3
 Arises from fibers of the dorsal primary ramus
of the second cervical nerve
 Sensory input from the GON and the
ophthalmic branch of the trigeminal nerve
converges into the trigeminal nucleus
caudalis.
 GON block decreases afferent input to the
trigeminal nucleus caudalis, resulting in central
pain modulation and reducing neuronal
hyperexcitability at the level of second-order
neurons.
Greater occipital nerve block in migraine prophylaxis:
Narrative review -Levent et al 2018 (Cephalgia)

Greater occipital nerve Block:
GON block is used acutely and prevention of migraine.
Involves injecting local anesthetic + corticosteroid
Either unilateral (or) Bilateral GON block is done.
Frequency of injections depends on response
( Single injection can last 3 months )
Adverse effects:
Local-infection/hematoma
Systemic-
Vertigo, nausea
rarely cardiac arrhythmia, seizure, respiratory depression and hypersensitivity
reaction
Greater occipital nerve block in migraine prophylaxis: Narrative review -
Levent et al 2018 (Cephalgia)

NEED FOR NEW TREATMENTS. :
1)Triptans are the only migraine specific treatment available for
acute management
2) Triptans have vasoconstrictive properties which make them
contraindicated in CAD,Uncontrolled HTN,Cerebrovascular
disease,peripheral artery disease.
3)Only about 1/3 of patients are pain free at 2 h after taking
triptan
4) Headache recurrence occurs in the 30–40% of treated patients
5)Increased chance of chronic migraine if ill controlled or
excessive drug use (MOH)

Lasmiditan (REYVOW)
• Agonistic action at 5 HT -
1F receptor ,which are
noted centrally on
trigemino cervical
complex( TCC) ,trigeminal
ganglion and peripherally
in trigeminal afferents of
dural vessels
• Results in decreased
neuropeptides release and
neuroinflammation
Advantages:
No vasoconstrictive effects
and hence is useful in CAD
patients,raynauds disease.
Tessa de Vries et a l(2020

• Completed 2 phase 3 trials (
SAMURAI and SPARTAN) and
has met the efficacy end
points-2 hr pain freedom
about 30%
• On October 2019, the FDA
approved it for acute
treatment of migraine with
and without aura in adults
Dosage : 50,100 and 200 mg
(oral)
Side effects:
Dizziness,somnolence
,parasthesias.
Tessa de Vries et a l(2020

CGRP and migraine:
• CGRP is a 37-amino acid
peptide
• Exists in two forms in humans:
alpha and beta CGRP
• Alpha CGRP is responsible for
migraine
• Alpha CGRP receptor is a G
protein coupled receptor
Lars Edvinsson (2018)-Nature

CGRP and Alpha CGRP
receptors are present at all
sites involved in migraine
pathogenesis:
Cortex
Thalamus
Hypothalamus
Periaqueductal grey and
locus coeruleus
Trigeminal
ganglia,TCC(trigeminocephal
ic complex)
Dorsal root ganglia
Cerebral arteries,sinuses
Dura matter

CGRP release in the meninges leads
• vasodilation,
• mast cell degranulation,
• neurogenic inflammation,
At the level of cortex CGRP receptor
activation leads to
Cortical spreading depolarisation or
depression (CSD)
CGRP also contribute to Peripheral and
central sensitization
Migraine
headache
Aura

Main location for CGRP blocking drugs (also
triptans)seems to be at trigeminal ganglia and
at peripherally at trigeminal afferent endings
as the drugs cannot access central sites due to
BBB
Action at sites that lack BBB –Area Postrema may result
in decrease nausea and vomitings
CGRP as target of new therapies-Lars
Edvinsson (2018)-Nature

Evidence for role of CGRP in
migraine:
• CGRP levels rise during
migraine attacks(noted in
cranial vasculature and
saliva)
• CGRP infusion precipitates
migraine in migraineurs
• Blocking or removing CGRP
terminates migraine acutely
and prevents migraine
CGRP as target of new therapies-Lars
Edvinsson (2018)-Nature

Agonistic activity at 5HT 1B/1D results in decreased CGRP
release
Tessa de Vries et al(2020)
Pharmacology and Therapeutics

Small molecule CGRP Receptor
antagonists ( Gepants):
First generation gepants:
1)Olcegepant
2)Telcagepant.
Trials discontinued in view of
liver toxicity,short half life
Tessa de Vries(2020)

Second generation Gepants:
Gepant Type of treatment Study and stage of
development
Formulation No liver toxicity
Safe in cardiac
andcerebrovascular
disease patients
(NO vasocontriction)
2Hr pain free
freedom comparable
to Triptans
Useful in medication
overuse headache
Patients don’t
develop medication
overuse headache
Ubrogepant- Acute
50mg and 100 mgh
ACHIEVE 1 and 2
FDA approved
Oral
Rimegepant Acute and prophylaxis 3 trials(acute)
completed
FDA approved
Trial prophylaxis
ongoing
oral
Vazegepant acute Phase 2 intranasal
Atogepant prophylaxis Phase 3 Oral
Tessa de Vries(2010)

CGRP Monoclonal antibodies
Name
Type of Mab
Trial Ab against Dosing Route Approval Effects *
(Aims)
Adverss effects
Nasopharyngiti
s
Sinusitis
Nausea,dizzine
ss
UTI
Injection site
pain
Episod
ic
Chroni
c
Eptinezumab
Humanized
PROM
ISE 1
PROM
ISE2
PREVA
IL
CGRP monthly iv FDA Feb 2020 +
Erenumab
Human
STRIV
E
ARISE
LIBERT
Y
NCT
02066
415
CGRP
Receptor
monthly sc FDA and EMA
2018
+
Fremanezumab
Humanized
HALO
FOCUS
HALO CGRP Monthly or
quarterly
sc FDA and EMA
2018 and 2019
+
Galcanezuma
b
Humanized
EVOL
VE 1
EVOL
VE 2
REGAI
N
CGRP monthly sc FDA and EMA
2018
+
* 1)reduction in mean MMD(days) 2)>50%reduction in MMD 3)Reduced acute migraine medication use

Advantages of mAbs:
Specificity
Wide therapeutic use- Episodic & Chronic Migraine, Medication Overuse
Headache
Convinence-monthly/quarterly
Quick onset of action-(1-2 days –IV and 5-7 days –s/c)
Large absolute effect of treatment->75 % responder rates
Tolerability similar to placebo, low discontinuation rates
No major adverse effects
Pharmacological treatment of migraine: CGRP and 5-HT
beyond the triptans –Tessa de Vries(2010)

Preventive therapy in migraine
Indications:
1) > 4 headaches per month or headaches that last longer than 12 hours
2) Migraine attacks that cause significant disability or diminished quality of life
despite appropriate acute treatment
3) Contraindication to acute therapies
4) Failure of acute therapies
5) Serious adverse effects of acute therapies
6) Risk of medication overuse headache
7) Menstrual migraine
8) Special circumstances, such as hemiplegic migraine or migraine attacks with
a risk of permanent neurologic injury
9) Patient preference, or patient desire to have as few acute attacks as possible.

Reduce attack frequency, severity, and duration
Improve responsiveness to treatment of acute attacks
Improve function and reduce disability
Prevent progression or transformation of episodic migraine
to chronic migraine
 Prevent medication overuse headache and daily headache
Neurology Clinics 2019
Goals of preventive therapy

Principles of preventive therapy:
1) Choose drug according to patient
comorbidities
Eg
HTN- Betablockers( <60 yrs) and Flunarizine or
Verapamil (>60 yrs)
Depression : Amitriptyline/Venlafaxine
Epilepsy: Topiramate/Valproate
Insomnia: Amitriptyline
Obesity: topiramate /Zonisamide
Raynaud phenomenon: Verapamil/Flunarizine

Principles of preventive therapy:
2) Start the drug at a low dose. Increase the dose gradually until
therapeutic benefit develops, the maximum dose of the drug is reached,
or side effects become intolerable.
3) Give the chosen medication an adequate trial in terms of duration and
dosage
(may need upto 3-6 months )
3)Avoid valproate and topiramate if woman is planning for pregnancy

Options available for preventive therapy:
1)Non - pharmacological
management
2)Pharmacological therapy

Beta blockers:
 Reduction of neuronal firing of noradrenergic neurons
in vigilance-enhancing pathways and GABA-mediated
regulation of neuronal firing in the periaqueductal gray
matter
 inhibits nitric oxide production by blocking inducible
nitric oxide synthase
 inhibits kainate-induced currents and is synergistic with
N-methyl-D-aspartate blockers, which reduce neuronal
activity and have membrane-stabilizing properties.
Contraindications:
history of asthma
severe depression
Caution:Diabetics
Adverse effects:
Decreased exercise tolerance,
Orthostatic hypotension, Bradycardia
Impotence

Mechanism of action
 inhibition of norepinephrine and
serotonin reuptake
 modulate dopamine production
 enhances the body’s own pain-
modulating pathways and opioid effect
at the opioid receptors
Adverse effects:
TCA use:.
Sedation
Anticholinergic SE-
dry mouth, a metallic taste, epigastric distress, constipation, dizziness, mental confusion, tachycardia,
blurred vision, and urinary retention.
Other SEs include weight gain, orthostatic hypotension, and reflex tachycardia
can exacerbate glaucoma.
Older patients may develop confusion or delirium. And cardiac conduction abnormalities,

Zonisamide –comparable efficacy to topiramte
Carbamazepine-possibly effective (LEVEL-Cat C)
Lamotrigine not effective

Topiramate
modulation of
 voltage-gated sodium
channels,
high voltage-gated calcium
channels,
GABA receptors
AMPA/kainate receptors.
Neurology Clinics
2019
Adverse effects:
neurocognitive SEs –
mood changes including suicidal ideation
concentration/attention
memory difficulty
Due to inhibition of carbonic anhydrase:
risk for renal calculi,
metabolic acidosis,
hypokalemia
• Acute angle closure
• weight loss
TERATOGENIC

FLUNARIZINE:
Dosing:5mg (6-17 yrs age)
10mg/day(adults)
• Efficacy is comparable to other antimigraine
drugs (proved in clinical trials)
Useful in:
Vestibular /hemiplegic/abdominal migraine
and childhood migraine
Side effects:
1)Weight gain
2)Extrapyramidal symptoms-avoid use in
elderly>60years, drug holiday
3)Depression and mood swings
4)Drowsiness-night time dosing
Mechanism of action
UK-NICE guidelines 2014

Flunarizine to give or not….
It has been recommended as first line drug or drug with Class A
evidence by
Danish Headche society
European Federeation of Neurological Sciences Guidelines 2009
Italian guideline for primary headaches
German Society for Neurology and the German Migraine and
Headache Society
But is Not listed in AAN/AHA guidelines and is unavailable in US in part
due to tendency to cause parkinsonism.

Sodium valproate
Mechanism of action
Increase neuroinhibitory GABA
activity
inhibits NMDA-evoked
neuroexcitatory signals
increase extracellular serotonin
and dopamine
Adverse effects:
Tremor and alopecia
Hyperandrogenism,
ovarian cysts,
Weight gain
TERATOGENIC

Zonisamide
Mechanism of action
similar to Topiramate
Dosage:
started at 50 or 100
mg/d
titrated by 50 or 100 mg
weekly
up to 400 mg/d
Adverse effects:
 weight reduction,
 memory and concentration
impairment,
 paraesthesias,
 Drowsiness
 Anemia;
 risk of Stevens-Johnson
syndrome.
 Teratogenic

Complementary and Alternate therapies in migraine:
1. Acupunture
2. Massage
3. Yoga
4. Aerobic exercise
1. Biofeedback
2. Cognitive behavioral therapy
3. Meditation
4. Relaxation Training
5. Hypnosis
Migrende Tamamlayıc et al 2013

Acute severe migraine/Status Migrainosus
 AntiDopaminergic drugs are the
first line medications.
 They have to be given with
Anticholinergics like
Diphenhydramine to prevent
extrapyramidal symptoms.
 Steroids prevent recurrence of
migraine
 GON block can be used

Pediatric Migraine:
• Estimated prevalence : 7.7 %
• Children’s behavior during attacks :
preference to lie down in a quiet, dark room suggests photophobia and
phonophobia
decreased appetite during attacks may suggest nausea.
• Compared to adults headaches in paediatric population differs in
Duration: as short as 2 hrs ( 2hrs-72 hrs)
Location: > 80 % have bilateral pain
• Cranial autonomic features and osmophobia are common

Pediatric Migraine:
• Presence of episodic syndromes support the diagnosis of migraine

Management of Pediatric Migraine:
Acute treatment:
1. Acetaminophen (15
mg/kg)
2. Ibuprofen (7.5–10
mg/kg)
3. Naproxen (5–10
mg/kg)
4. Four triptans are
now FDA approved
for use in
adolescents aged 12-
17 years

Management of Pediatric Migraine:
1)Lifestyle changes
2)Behavioral interventions
Cognitive behavior therapy
Biofeedback
3)Pharmacologic preventives:
Amitriptyline
Propranolol
Flunarizine
Topiramate
Valproate
Preventive therapy:
Supplements :
1)Riboflavin: 100mg or 50 mg/day
2)Magnesium
decreases neuronal excitability
3)Melatonin
4)Coenzyme Q 10
5) Vitamin D
CGRP antagonists have not been studied in children but can
be considered in selected patients

1)Pure menstrual migraine (PMM ):
Attacks that occur between days −2
and +3 of the menstrual cycle .
Prevalence of PMM :7%
2) Menstrually-related migraine (MRM)
migraine attacks occur throughout the cycle but
increase in frequency or intensity at the time of
menstruation
Occurs in up to 60% of female migraineurs
Menstrual Migraine:
Tendency to be more severe, disabling, and treatment-refractory.
Aura is uncommon
Differential diagnosis :
Premenstrual syndrome( headache associated with depression
,irritability,breast tenderness,bloating,backache etc)
Bradley’s neurology -7th edition

Menstrual Migraine: Management
Menstrually related
migraine: (MRM)
standard prophylactic
medication
Pure menstrual
migraine(PMM)
perimenstrual use of a
prophylactic agent IF regular
cycles
Headache diary for at least 3 consecutive months
Acute management: NSAIDS/Triptans
Bradley’s neurology -7th edition

Menstrual Migraine
Prophylactic
Therapy
Nonhormonal
Cyclic or
perimenstrual
Noncyclic or
continuous
Hormonal
Nonhormonal prophylaxis:
Cyclic(Days -3 to +3)
(predictable regular cycles)
NSAID
Triptans and Ergots
Continuous
(for irregular cycles with PMM
and MRM)
Tricyclic antidepressants
Beta blockers
Calcium channel blockers
Verapamil(4—240mg/day)
Anticonvulsants:
Dopamine agonist:
Bromocriptine(2.5-5mg TID)
Magnesium:360-600mg /dayBradley’s neurology -7th edition

Menstrual Migraine•
Hormonal Therapy
Estrogen
supplementation
( Stabilizing Estrogen Levels )
Depleting estrogen
throughout cycle
 Transdermal estradiol (1 × 100 μg
days −3/−1/+2)
 Combined oral contraceptive or
transdermal patch (3–4 mo)
 Tamoxifen
 Danazol
 Goserlin
Used for resistant menstrual migraine
Bradley’s neurology-7th edition

Migraine and Pregnancy:
70% of women experience
improvement or remission esp
those with menstrual migraine
Worsening is more common in
those with a history of migraine
with aura
New onset migraine can occur in
pregnancy
No significant correlation between
improvement or worsening of
migraine and a specific trimester.
Management:
• Mild –moderate attacks:
Relaxation therapy/biofeedback/rest
Acetaminophen
• Severe Attacks/Status Migrainosus:
• (Risk to developing fetus+)
• Any one of following:
 Chlorpromazine or prochlorperazine (10
mg)
 Methylprednisolone (50–250 mg)
 Intravenous magnesium sulfate (1 g)
• Prophylaxis:
Amitriptyline or Propranolol are safe
Bradley’s neurology-7th Edition

Chronic migraine
Definition:
Headache on >15 days per month
(includes tension type and migraine)
With prior migraine history
with
Atleast 8 days per month being
migraine headaches
for at least 3 months
 2% of the general population has
“chronic migraine
 On average, people with chronic
migraine have 22 headache days per
month.
 About 2.5% of people with episodic
migraine transform to chronic
migraine each year
Neurology Clinics-2019 (headache)

Chronic migraine
Preventive therapy:
Beta blockers-propranolol
Antidepressants: Amitriptyline/Nortriptyline
Antiepileptics: Topiramate
Valproate
Calcium channel blockers: Flunarizine
ARB: Candesartan
 Onabotulinum Toxin A
Specifically studied in
chronic migraine via
controlled trials
Neurology Clinics-2019 (headache)

Chronic Migraine
FDA approved for chronic migraine in 2011.
Evidence for efficacy comes from PREEMPT
1 And 2 Studies(Phase III Research
Evaluating Migraine Prophylaxis Therapy )
Useful even in patients with concomitant
medication overuse
(some studies support use of 195 MU of
botox rather than 155 MU if associated
Medication overuse)
UK NICE guidelines recommend
Botox to patients of chronic
migraine who
1)Did not respond to atleast 3
prior pharmacologic prophylaxis
2)Appropriately managed for
medication overuse
Onabotulinum Toxin A:
Therapeutic advances in neurological disorders-
Claus et al 2017 review article(Botulinum toxin
management of chronic migraine)

Chronic Migraine
Onabotulinum Toxin A- Mechanism of
action:
Prevents release of neurotransmitters
(eg :CGRP and Substance P) from
presynaptic nerve endings
Via binding and cleaving SNAP-25 ,a
protein required for fusion of NT
containing vesicle to cell membrane.
This leads to inhibition of peripheral
sensitization and indirectly central
sensitization .
Therapeutic advances in neurological disorders-Claus et al 2017 review
article(Botulinum toxin management of chronic migraine)

Chronic Migraine
Onabotulinum Toxin A
Dosage/sites/frequency of injections:
 7 muscles
 31 sites
 Dose:155 MU
 Interval
between
doses-12
Weeks
Therapeutic advances in neurological disorders-Claus et al 2017 review
article(Botulinum toxin management of chronic migraine)
Benefit seen within
7-10 days and
effect lasts upto 3
months

Refractory Migraine:
AHA(RHSIS)-2008(Shulman et al)
2014-Martelletti et al

Refractory migraine Rule out common,serious and potentially
remediable causes of symptomatic
secondary headache
Modifiable
factors
Non modifiable
factors
1)Genetic heterogeneity
2)Drugs targeting single receptor
type whereas migraine involves
multiple NT”s
Reflections and Speculations on Refractory Migraine: Dodick
2008,Headache

Modifiable factors :
1) Minimizing and Educating About Side Effects:
start low and increase and educate prevents discontinuing
drugs prematurely
2) Reaching the Optimal Dose:
3) Adequate duration of treatment
4) Expectations for Success
5) Maximize Patient Compliance, Adherence, and Self-Efficacy:
Data suggests 25-50% patients are noncompliant with prophylactic and
70% donot use abortive medications as per instructions
Taking patient preferences into account makes them compliant
Refractory Migraine
2008,Headache

6)Being aware of Trap of Tachyphylaxis:
Loss of pharmacological response to a drug may be due to
Natural fluctuation in disease severity
Emergence of particular trigger
Rather than reflexly removing drug ,increase dose or add new medication
for limited period.
Refractory Migraine
Increased frequency or
severity of attacks
2008,Headache

7)Combination, Alternative, and Complementary Therapy:
Add drugs with different Mechanisms of action if partial response to one drug
or side effects noted
Add complementary medications with evidence in placebo- controlled trials
like: Riboflavin,Coenzyme Q10,Magnesium
8) Identifying and managing comorbid psychiatric diseases :
9)Management of obesity:
Refractory Migraine
2008,Headache

Barriers to headache care in India
Headache is overlooked because of other problems.
Dr Ravishankar –Lancet 2004

Barriers to headache care in India
Dr Ravishankar –Lancet 2004Triggers peculiar to India

Summary….
• Migraine pathogenesis is poorly understood but it is a neurologic disorder
with secondary vascular effects.
• Appropriate drug selection and use of drug for minimum period along
with proper education helps in patient compliance.
• Adequate treatment of episodic migraine decreases conversion to chronic
and refractory migraine

References
• Bradely’s Neurology -7th Edition
• Neurology Clinics-2019
• Continuum Journal-2018
• Review article by Goadsby-2017(Pathophysiology of migraine: a
disorder of sensory processing –American physiology society)
• Reflections and Speculations on Refractory Migraine: Why Do Some
Patients Fail to Improve With Currently Available Therapies? By David
Dodick 2008
• Pharmacological treatment of migraine: CGRP and 5-HT beyond the
triptans Tessa de Vries1 (Pharmacology and Therapeutics )-2020

Migraine1

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Similar to Migraine1

Similar to Migraine1 (20)

Recently uploaded

Recently uploaded (20)

Migraine1