The word derives from the Greek (hemikrania) "pain on

one side of the head

From (hemi-) "half" (kranion) "skull


Definition
Migraine - Disorder characterized by recurrent
attacks of headache variable in intensity, frequency
and duration. Attacks are unilateral and are usually
associated with anorexia, nausea and vomiting

-World federation of Neurology
Second most common cause of Headache
World - 15-20% of women and 10-15% of men
In India, 15-20% of people suffer from migraine
Adults Female: Male ratio is 2 : 1
Prevalence peaks in the 25-55 age group
25% women - age 18-49.
More than 2/3 of migraine sufferers either have never consulted a
doctor or have stopped doing so
Burden Of Migraine
NEJM 2002:346(4):257-269;XI congress of the HIS,2004
TYPES OF MIGRAINE
Common Migraine Classical Migraine Basilar Migraine
Familial Herditry
Migraine
Recurrent
headache
attacks lasting
4-72 hours.
Recurrent
disorder, Aura
develop over 5-
20 minutes and
last for less than
60 minutes.
Migraine with
aura symptoms
originating from
the brainstem
but no motor
weakness.
Aura including
motor weakness
and at least one
first- or second-
degree relative
has migraine
75% patients
suffer from this
type
33% patients
suffer this type

1-2 % patients
Involvement of the
basilar artery
territory

< 1% patients
Higher average
attack frequency
Less frequent
than Common
Migraine
Same as
Classical
1. FHM1 - Mutations in the
CACNA1A gene ,
chromosome 19
2. FHM2 mutations occur
in the ATP1A2 gene ,
chromosome 1
Has a strict
menstrual
relationship
AURA Mostly seen in
young adults.
Have basilar-type
symptoms in 60%
of cases.
FEMALE MIGRAINE
At the menarche the incidence rises because it is
clearly linked to estrogen levels
Before menses attacks may be precipitated by falling
estrogen levels (premenstrual migraine)
Menstruation-associated migraine The falling
Estradiol level rather than the absolute level provides
the trigger for migraine (menstrual migraine)
ovulation or mid cycle migraine is infrequent
DIAGNOSIS & CLINICAL FEATURES
Simplified Diagnostic Criteria for Migraine

Repeated attacks of headache lasting 472 h in patients with a normal
physical examination, no other reasonable cause for the headache, and:
At Least 2 of the Following
Features:
Plus at Least 1 of the Following
Features:
Unilateral pain Nausea/vomiting
Throbbing pain Photophobia and Phonophobia
Aggravation by movement
Moderate or severe intensity
Source: Adapted from the International Headache Society Classification (Headache Classification Committee of the International Headache
Society, 2004).

4 STAGES OF MIGRAINE

1. Prodrome
2. Aura
3. Headache
4. Postdrome
Food
Disturbed
sleep
pattern
Hormonal
changes
Drugs
Physical
exertion
Visual
stimuli
Auditory
stimuli
Olfactory
stimuli
Weather
changes
Hunger
Psychologic
al factors
Pathopysiology
NEURO-VASCULAR THEORY
Migraine generator

Cortical hyper excitability
Cortical spreading depression
Triggers
Depressing neuronal activity &
reducing cerebral blood flow
CORTICAL SPREADING DEPRESSION(CSD)
Trigeminal nerve fibers in the
meningeal blood vessel

ROLE OF INFLAMMATORY MEDIATORS
Release of CGRP, substance P & Inflammatory Cytokines
Calcitonin gene related peptide(CGRP)
Kinins facilitate the production of Cyclooxygenases
Cyclooxygenases convert arachidonic acid to prostaglandins

VASODILATION AND EDEMA IN
LOCAL BLOOD VESSELS
CGRP and prostaglandins cause inflammation and
vasodilation of cerebral and meningeal blood vessels
ACTIVATION OF NOCICEPTORS
The inflammation and edema activate peripheral
meningeal pain receptors called nociceptors





Nociceptors transmit signals to the trigeminal ganglion
and the TNC


QUICK REVIEW MULTIPLE MECHANISM IN PROCESS
PRIOR TO PAIN PERCEPTION

Release of neuroactive
substances
Initiation of arachidonic
cascade
Vasodilatation and edema
Activation of nociceptors
Signals transmit centrally to
TNC
Signals travel to higher brain
centers, including the
thalamus and cerebral cortex

CONSEQUENCES OF
SUSTAINED PAIN TRANSMISSION
Continuou
s
stimulation
of the
trigeminal
ganglion
Activation
of the TNC
Activation
of the
surroundin
g glial cells
PROLONGED TNC STIMULATION
MAY LEAD TO CENTRAL SENSITIZATION
Cutaneous Allodynia -
marker for central
sensitization, when
present during a migraine,
make the migraine episode
more difficult to treat
A sustained pain-free response
is harder to achieve
ISTORY OF TREATMENT
Herbal brews and
folk practices
1200 BC: Egyptians
clay crocodile &
magic herbs
10th century AD:
Arabian physicians
garlic or hot iron to
incision at temple
Mid-1600s AD: Dr.
Thomas Willis
enemas, blood
letting, leeches, and
natural products
1870s: cold
bandage on head,
quiet room, and
sleep
Non-pharmacological Treatment
Identification of triggers
Meditation, Yoga
Relaxation training
Psychotherapy
Pharmacotherapy
Abortive therapy
Preventive therapy
GOALS OF THERAPY
Treat migraine attacks rapidly and
consistently without recurrence
Restore the patients ability to
function
Optimize self-care for overall
management
Be cost-effective in overall
management
Cause minimal or no adverse
effects
ACUTE ATTACK MANAGEMENT
Analgesics
Antiemetic
Ergot alkaloids
Triptans(5-HT1B/1D-agonists)
ANALGESICS
Drugs of first choice for mild or moderate migraine
attacks.
Acetylsalicylic acid (ASA)
upto1000mg
Ibuprofen 200800mg

Diclofenac 50100mg

Phenazon 1000mg

Metamizol 1000mg

Tolfenamicacid 200mg

Paracetamol 1000mg

Naproxen 220-550mg
ANALGESICS
Effective early in the attack
PG synthesis inhibition & prevention of neurogenic inflammation
For MILD cases
Acetaminophen + Aspirin + Caffeine
Aspirin + Metoclopramide
S/E : Gastritis , Dyspepsia
Goldstein J, Silberstein SD, Ryan RE Jr, Lipton RB Headache. Acetaminophen, aspirin, and caffeine in combination versus ibuprofen for
acute migraine: results from a multicenter, double-blind, randomized, parallel-group, single-dose, placebo-controlled study 2006
Mar;46(3):444-53.
ANTIEMETICS
Metoclopramide 1020 mg, 20mg suppository,10
mg IM, IV, SC
Side effect: Dyskinesia
Contraindicated in childhood and in pregnancy
Domperidon 2030 mg
Side effects less severe than in
metoclopramide,
Can be given to children



The overall results of the study suggest that the efficacy of naproxen
for all the end points and improvement in QOL is equivalent to that of
triptans.
Naproxen was as well tolerated as, if not better than, the triptans.
Naproxen is much more cost-effective than the triptans.
Naproxen has long duration of action, so attainment of sustained
headache relief is better compared to triptans.
Considering all these facts, we suggest that naproxen be used as an
alternative drug for treatment of moderate-to-severe migraine attack.
Vol. 12 No. 4, Oct-December 2010 www.jkscience.org
RGOTS
1868: Use of ergot in the treatment of one-
sided headache
Ergot: potent neurotoxin & vasoconstrictor
found in a fungus that grows on rye
1925: Identified active chemical of ergot
(ergotamine)
1940s: Ergotamine tartrate became the
preferred treatment for acute migraine
ERGOTAMINE
Structurally similar to amines,
serotonin, norepinephrine, and
dopamine
Interact with multiple receptors
in these systems
Cause constriction of the blood
vessels
Wide-range of effects
Problems: Avoid if patient has coronary disease; safety
margin is small.
5-HYDROXYTRIPTAMINE RECEPTORS
1980S DISCOVERY OF RECEPTORS
2 subtypes of serotonin receptors (For
Migraine)
1. 5-HT1B
2. 5-HT1D
Located in brain blood vessels
responsible for vasoconstriction

SUMATRIPTAN
1983: studied GR-43175
Vasoconstrictor effect on 5-HT
GR-43175 effective and well tolerated in clinical
trials (side-effects associated with the drug
were mild and short lived)
SUMATRIPTAN
Acts on receptors at smooth muscle cells of brain
vessels (also in peripheral blood vessels like
coronary artery = side effects)
The first selective serotonin agonist approved for
the treatment of migraine
Rapid relief
Sumatriptan oral bioavailability14%

SUMATRIPTAN
Relieves pain of migraine and associated symptoms
3 dosage forms
Oral
Nasal
Parenteral
NARATRIPTAN
Oral bioavailability improved to ~60%
Half-life of 5-6 hours
Take orally at the onset of headache pain
ZOLMITRIPTAN
Oral bioavailability improved to ~50%
Half-life of 3 hours
Take orally at the onset of headache pain
RIZATRIPTAN
Oral bioavailability ~40%
Half-life of 2.5 hours
Shows the fastest time of onset
ADRS OF TRIPTANS

Parasthesia

Dry mouth
Hot and cold sensations altered,
Asthenia
Dizziness
headache,

Dyspepsia

Fatigue

Palpitations
Chest pain

Somnolence
COMPARISON OF TRIPTANS
Subcutaneous delivery of sumatriptan most rapid
and complete pain relief beginning as early as 10 to
15 minutes

A Triptan can be efficacious even if another triptan
was not effective

Naratriptan and frovatriptan (2.5mg) are less effective
than sumatriptan 50 or 100 mg but have less side
effects

Eletriptan 80 mg is significantly more effective than
sumatriptan 100 mg in the primary endpoint of all
studies, pain relief in 2 hours

M ,
Triptans - Advantages over
Ergot Alkaloids

Triptans- Disadvantages
over Ergot Alkaloids

Receptor specificity

More incidence of Rebound
headache

Good Bioavailability

Expensive

Less incidence of nausea and
vomiting

Well tolerated

Less incidence of Coronary
vasospasm

INDICATIONS FOR PROPHYLACTIC THERAPY
Poor QOL
Business duties
School attendance, etc.
Two or higher frequency of attacks / month
Migraine attacks not responding to acute drug treatment
Frequent, very long, or uncomfortable auras.
PROPHYLAXIS
Start with low dose till therapeutic effect
reached
To be taken daily
Takes atleast 2-6 weeks to act
Course 5-6 months & gradually tapered +/-
discontinue
DATA FROM TRIALS
Department of Neurology, University Essen, Federal Republic of Germany. h.diener@uni-essen.de, J Neural Transm Suppl. 2003;(64):35-63

SUCCESSFUL PROPHYLAXIS
CLINICAL STRATIFICATION OF ACUTE SPECIFIC MIGRAINE
TREATMENT
CLINICAL STRATIFICATION OF ACUTE SPECIFIC MIGRAINE
TREATMENT
Harrison'sprinciples Of Internal Medicine Eighteenth Edition. E book


NEWER T/T STRATERGIES FOR MIGRAINE
PREVENTION
This is about drugs which are less frequently
prescribed for migraine prevention.
Some of them still require further investigation with
larger
RCT
Double blind
Placebo controlled trials


ANTICONVULSANTS FOR MIGRAINE
Topiramate
levetiracetam
Zonisamide

Other drugs
Pregabalin
Angiotensin receptor blockers
Candesertan
Atypical Antipsychotics
Quitiapine

TOPIRAMATE
US FDA Approval in 2004 for migraine prevention
Exact MOA is not known
Proposed Mechanism is by increasing inhibitory
effect of GABA
Blocking Na+ Channel
Limiting repetitive firing reduces calcium channel activity
Inhibiting carbonic anhydrase

Silberstein S D, Neto W, Schmitt J, Jacobs D for the MIGR-001 Study Group,Topiramate in migraine prevention: results of a
large, controlled trial, Arch Neurol (2004);61: pp. 490495.
TOPIRAMATE
The efficacy of topiramate in migraine prevention has
been shown in more patient in controlled trials than any
other migraine preventing agents
The recommended daily dose is 100mg ,in divided doses
At recommended doses it is well tolerated by patients
Potential adverse events includes
Cognitive dysfunction
Parasthesias
Weight loss

Silberstein S D, Neto W, Schmitt J, Jacobs D for the MIGR-001 Study Group,Topiramate in migraine prevention: results of a
large, controlled trial, Arch Neurol (2004);61: pp. 490495.
ZONISAMIDE
Zonisamide(ZNS) is sulfonamide derivative
It has been used for adjunctive therapy of partial seizures
It blocks voltage Dependent Na+ and T- type of calcium
channels ,reduces glutamate- mediated excitatory
neurotransmission
All of these mechanism play role in headache and pain
modulation , possibly via neuronal stabilization.
ZNS was studied for migraine prevention in 2 open label
trials presented.
It is seen that those who are refractory to other preventive
therapies respond well to 100mg of ZNS daily, which was
titrated as tolerated up to 400mg daily.
Mohammadianinejad SE, Abbasi V, Sajedi SA, Majdinasab N, Abdollahi F et al. Zonisamide versus topiramate in migraine prophylaxis: a double-
blind randomized clinical trial. Clin Neuropharmacol 2011 Jul-Aug;34(4):174-7

LEVETIRACETAM
Levetiracetam(LEV) is also anticonvulsant
Rapidly and nearly absorbed by oral administration
Peak Sr. conc. 2 hrs
Its efficacy in migraine prevention may be related to
possible effect on cortical spreading depression
Which is an early pathophysiological process in a
migraine attack.

Krusz J C,Levetiracetam as prophylaxis for resistant headaches, Cephalalgia (2001);21: p.373 (Abstract).
LEVETIRACETAM
Open label trials have demonstrated the efficacy
of LEV in the prevention of refractory migraine
The minimally effective dose appears to be
1.500mg , and most patients need 2,000-2,500 mg
daily.
Krusz J C,Levetiracetam as prophylaxis for resistant headaches, Cephalalgia (2001);21: p.373 (Abstract).
PETASITES
Petasites is in extract from the plant petasites hybridus
(butterbur)
Used since centuries and during middle ages used for t/t
of fever & plague
Efficacy of this is studied in two trials
Seen that significantly reduces the number of migraine
attack per month and the number of migraine days per
month


Agosti R, Duke RK, Chrubasik JE.Effectiveness of Petasites hybridus preparations in the prophylaxis of migraine: a systematic
review.Phytomedicine 2006 Nov;13(9-10):743-746

PREGABALIN
Is new drug having analgesic , anticonvulsant , and anxiolytic
effect
Recently approved for the treatment of neuropathic pain
It modulates voltage gated calcium channels
Is pharmacologically similar to gabapentin
Which is found to be effective in migraine prevention
ADRs
Somnolence
Dizziness
But now a date no open label or placebo controlled
trials evaluating this claim have been published
Christina Sun, Alan Rapoport. New tretment stratergies for migraine prevention. Us Neurological Disease 2006
CANDESARTAN
It is angiotensin receptor blocker
Evaluated in a prospective ,randomized double
blind crossover study with 60 pts.
At dose of 16mg daily it was found that
It reduces the mean no. of headache days
Significantly decreased headache severity
The mean no. of days of sick leave due to headache

Tronvik E, Stovner L J, Helde G et al.,Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled
trial,JAMA (2003);289: pp. 6569.
QUETIAPINE (QTP)
It is Dibenzothizepine derivative classified as atypical
antipsychotic drug
It also posses high affinity for 5-HT2 receptors
Partial agonistic action at 5-HT1A receptor
Alpha 1 adrenergic blocking property

o With a consequent potential for migraine prevention
o According to one trial QTP represent a very important
resource for refractory migraine.

Brandes JL, Roberson SC, Pearlamn SH. Quetiapine for migraine prophylaxis. Headache 2002; 42:450-51.
SPECIAL CONDITIONS
Migraine treatment in childhood and adolescents

Acute
Ibuprofen 10mg per kg body weight and paracetamol 15 mg per kg
body weight
Domperidone only antiemetic licensed for the use in children upto 12
years
Sumatriptan nasal spray the recommended dose for adolescents from
the age of 12 is 10mg.
Prophylaxis
Flunarizine 10 mg and propranolol 4080 mg per day

MIGRAINE & PREGNANCY
Only Paracetamol is allowed during the whole
period.

NSAID can be given in the second trimester.

Triptans in the first trimester of pregnancy - if the
foetus is more at risk by severe attacks with
vomiting than by the potential impact of the triptan.
FUTURE SCOPE
CGRP1 antagonist
Olcegepant
Can only be given IV. Upto Phase II development
Telcagepant
Orally available. Completed 6 Phase III trials with
positive results
But serious increased levels of liver transaminases


Tonabersat
Gap junction inhibitor & CSD inhibitor
Shown good results in prophylaxis
Vanilloid TRPV1 receptor antagonists
Activation of TRPV1 - release pro-nociceptive peptides.
e.g. Capsaicin and Resiniferatoxin
5-HT1F receptor agonist - Lasmiditan phase II
Nitric oxide synthase inhibitors