2.  The word derives from the Greek (hemikrania)
"pain on one side of the head”
 From (hemi-) "half" (kranion) "skull

3. 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

4. Burden Of Migraine
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
NEJM 2002:346(4):257-269;XI congress of the HIS,2004

5. Differential Diagnosis

6. TYPES OF MIGRAINE

7. Familial
Common Classical Basilar
Herditry
Migraine Migraine Migraine
Migraine
Recurrent Recurrent Migraine with Aura including
headache disorder, Aura aura symptoms motor weakness
attacks lasting develop over 5- originating and at least one
4-72 hours. 20 minutes and from the first- or second-
last for less brainstem but degree relative
than 60 no motor has migraine
minutes. weakness.
75% patients 33% patients 1-2 % patients < 1% patients
suffer from this suffer this type Involvement of
type the basilar
artery territory
Higher Less frequent Same as 1. FHM1 - Mutations in
the CACNA1A gene ,
average attack than Common Classical chromosome 19
frequency Migraine 2. FHM2 mutations
occur in the ATP1A2
gene , chromosome 1
Has a strict AURA Mostly seen in Have basilar-
menstrual young adults. type symptoms

8. 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

9. DIAGNOSIS & CLINICAL FEATURES
Simplified Diagnostic Criteria for Migraine
Repeated attacks of headache lasting 4–72 h in patients with a
normal physical examination, no other reasonable cause for the
headache, and:
At Least 2 of the Following Plus at Least 1 of the Following
Features: 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).

10. 4 STAGES OF MIGRAINE
1. Prodrome
2. Aura
3. Headache
4. Postdrome

12. Migraine Triggers
Food Olfactory Weather
stimuli changes
Disturbed
sleep Auditory
Hunger
pattern stimuli
Hormonal Visual Psychologic
changes stimuli al factors
Physical
Drugs
exertion

13. Pathopysiology

14. NEURO-VASCULAR THEORY
Migraine generator
Cortical hyper excitability
Triggers
Cortical spreading depression
Depressing neuronal activity &
reducing cerebral blood flow

15. CORTICAL SPREADING DEPRESSION(CSD)
 Trigeminal nerve fibers in the
meningeal blood vessel

16. ROLE OF INFLAMMATORY MEDIATORS
Release of CGRP, substance P & Inflammatory Cytokines
Calcitonin gene related peptide(CGRP)

17. • Kinins facilitate the production of Cyclooxygenases
• Cyclooxygenases convert arachidonic acid to prostaglandins

18. VASODILATION AND EDEMA IN
LOCAL BLOOD VESSELS
CGRP and prostaglandins cause inflammation and
vasodilation of cerebral and meningeal blood vessels

19. ACTIVATION OF NOCICEPTORS
The inflammation and edema activate peripheral
meningeal pain receptors called nociceptors
Nociceptors transmit signals to the trigeminal
ganglion and the TNC

20. 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

21. CONSEQUENCES OF
SUSTAINED PAIN TRANSMISSION
Continuo
us
Activation
stimulatio
of the
n of the
TNC
trigeminal
ganglion
Activation
of the
surroundi
ng glial
cells

22. 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

24. HISTORY OF TREATMENT
1200 BC: Egyptians
Herbal brews and
– clay crocodile &
folk practices
magic herbs
Mid-1600’s AD: Dr.
10th century AD:
Thomas Willis –
Arabian physicians
enemas, blood
– garlic or hot iron
letting, leeches, and
to incision at temple
natural products
1870’s: cold bandage
on head, quiet room,
and sleep

25. Non-pharmacological Treatment
• Identification of triggers
• Meditation, Yoga
• Relaxation training
• Psychotherapy
Pharmacotherapy
• Abortive therapy
• Preventive therapy

26. GOALS OF THERAPY
Treat migraine attacks rapidly
and consistently without
recurrence
Restore the patient’s ability to
function
Optimize self-care for overall
management
Be cost-effective in overall
management
Cause minimal or no adverse
effects

27. ACUTE ATTACK MANAGEMENT
Analgesics
Antiemetic
Ergot alkaloids
Triptans(5-HT1B/1D-agonists)

28. ANALGESICS
Drugs of first choice for mild or moderate migraine
attacks.
Acetylsalicylic acid (ASA) Ibuprofen 200–800mg
upto1000mg
Diclofenac 50–100mg Phenazon 1000mg
Metamizol 1000mg Tolfenamicacid 200mg
Paracetamol 1000mg Naproxen 220-550mg

29. 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.

30. ANTIEMETICS
Metoclopramide 10–20 mg, 20mg
suppository,10 mg IM, IV, SC
• Side effect: Dyskinesia
• Contraindicated in childhood and in
pregnancy
Domperidon 20–30 mg
• Side effects less severe than in
metoclopramide,
• Can be given to children

31.  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

32. ERGOTS
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)
1940’s: Ergotamine tartrate became the
preferred treatment for acute migraine

33. 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.

34. 5-HYDROXYTRIPTAMINE RECEPTORS

35. 1980’S… DISCOVERY OF
RECEPTORS
2 subtypes of serotonin receptors (For
Migraine)
1. 5-HT1B
2. 5-HT1D
 Located in brain blood vessels –
responsible for vasoconstriction

37. 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)

38. 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%

39. SUMATRIPTAN
 Relieves pain of migraine and associated
symptoms
 3 dosage forms
 Oral
 Nasal
 Parenteral

40. NARATRIPTAN
 Oral bioavailability improved to ~60%
 Half-life of 5-6 hours
 Take orally at the onset of headache pain

41. ZOLMITRIPTAN
 Oral bioavailability improved to ~50%
 Half-life of 3 hours
 Take orally at the onset of headache pain

42. RIZATRIPTAN
 Oral bioavailability ~40%
 Half-life of 2.5 hours
 Shows the fastest time of onset

43. ADRS OF TRIPTANS
 Parasthesia
 Dry mouth
 Hot and cold sensations altered,
 Asthenia
 Dizziness
 headache,

Dyspepsia

Fatigue

Palpitations
 Chest pain
 Somnolence

44. 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

45. Triptans - Advantages Triptans- Disadvantages
M , Ergot Alkaloids
over over Ergot Alkaloids
More incidence of Rebound
Receptor specificity
headache
Good Bioavailability Expensive
Less incidence of nausea and
vomiting
Well tolerated
Less incidence of Coronary
vasospasm

46. 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.

47. 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

49. 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

50. SUCCESSFUL PROPHYLAXIS

51. CLINICAL STRATIFICATION OF ACUTE SPECIFIC
MIGRAINE TREATMENT

52. CLINICAL STRATIFICATION OF ACUTE SPECIFIC
MIGRAINE TREATMENT
Harrison's™principles Of Internal Medicine Eighteenth Edition. E book

53. 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

54. ANTICONVULSANTS FOR MIGRAINE
 Topiramate
 levetiracetam
 Zonisamide
Other drugs
Pregabalin
• Angiotensin receptor blockers
• Candesertan
• Atypical Antipsychotics
• Quitiapine

55. 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. 490–495.

56. 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. 490–495.

57. 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

58. 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).

59. 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).

60. 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

61. 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

62. 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. 65–69.

63. 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.

64. 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 40–80 mg per day

65. 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.

66. 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

67.  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

68. Thank you