This presentation on Migraine and Anti-Migraine Drugs provides a comprehensive description of migraine including its symptomatology and pathophysiology. On the basis of these aspects drugs used in the treatment of migraine are described with special emphasis on ergotamines and tryptans. Hopefully, students of pharmacology and medicine in medical and pharmacy colleges will find it useful. Marketing and sales teams of pharmaceutical companies may also find this presentation useful from the point-of-view of understanding their products in proper perspective.

1. Migraine & Anti-Migraine Drugs
Dr. Ashok Kumar Batham, M.B.,B.S., M.D., D.C.R.,
Chief Consultant, Dr Batham Pharma Consultants
Phone: +91 93280 18777
Email: ashokpharmacol@gmail.Com
Dr. Ashok Kumar Batham 1

2. Migraine - Epidemiology
Worldwide, nearly 15% or 1 billion people are migraine sufferers
More common in women (19%) than in men (11%)
Incidence of migraines is slightly lower in Asia and Africa than in Western
countries
Chronic migraines occur in approximately 1.4 to 2.2% of the population
Dr. Ashok Kumar Batham 2

3. Migraine – Symptoms (Phases)
Prodrome: which occurs hours or days before the headache
Aura: which immediately precedes the headache
Pain phase: also known as headache phase
Postdrome: the effects experienced following the end of a migraine
attack
Dr. Ashok Kumar Batham 3

4. Migraine - Symptoms
Migraine is a primary headache disorder characterized by recurrent
moderate to severe headaches
Typically, the headaches affect one half of the head, are pulsating in nature,
and last from 2 to 72 hours
Headache may be associated with nausea, vomiting, and sensitivity to
light, sound, or smell
Recurrent severe migraine headache is associated with autonomic
symptoms
Dr. Ashok Kumar Batham 4

5. Migraine - Symptoms
About 1/3rd of people experience migraines with an aura; typically a short period of visual
disturbance
Migraine ‘with aura’ also frequently occurs ‘without aura’ in the same person
Occasionally, an aura can occur with little or no ensuing headache
Severity of the pain, duration of the headache, and frequency of attacks are variable
Headache is worsened by physical activity
Migraine lasting >72 hours is termed status migrainosus
Dr. Ashok Kumar Batham 5

6. Migraine Aura
Confusing thoughts or experiences
Perception of strange, sparkling or flashing lights
Zig-zagging lines in the visual field
Blind spots or blank patches in the vision
Pins and needles in an arm or leg
Difficulty speaking
Stiffness in the shoulders, neck, or limbs
Unpleasant smells
Dr. Ashok Kumar Batham 6

7. Migraine - Causes
Migraines are believed to be due to a mixture of environmental and genetic factors
About 2/3 cases run in families
Changing hormone levels may also play a role, as migraines affect slightly more boys than
girls before puberty and two to three times more women than men
Risk of migraines usually decreases during pregnancy
Underlying mechanisms involve neural and vascular elements
Dr. Ashok Kumar Batham 7

8. Migraine – Co-morbidities
Following disorders are 2–5 times and 3-10 times more
common in migraine sufferers without and with aura,
respectively
•Major depression
•Bipolar disorder
•Anxiety disorders
•Obsessive compulsive disorder
Dr. Ashok Kumar Batham 8

9. Types of Migraine
Migraine without aura - 70-90% of patients with migraine
Migraine with aura - a common type of migraine featuring additional
neurological symptoms
Chronic migraine - headaches for more than 15 days per month
Menstrual migraine - migraine linked to menstrual period
Dr. Ashok Kumar Batham 9

10. Types of Migraine
Hemiplegic migraine – headache associated with one sided weakness of
body
Migraine with brain stem aura (basilar-migraine) – headache associated
with dizziness, vertigo, visual disturbances, difficulty in speaking, hearing
problem, tingling in hands and feet, ringing in ears
Abdominal migraine – headache with abnormal bowel movement and
abdominal symptoms
Dr. Ashok Kumar Batham 10

11. "5, 4, 3, 2, 1" Criteria To Diagnose Migraines Without Aura
(International Headache Society)
5 or more attacks with a duration of 4 hours in 3 days
At least 2 of following characteristics:
• occurring on one side of the head,
• pulsating quality,
• moderate-to-severe pain, and
• aggravation by routine physical activity
At least 1 additional symptom, such as,
• Nausea
• vomiting
• sensitivity to light or
• sensitivity to sound.
Dr. Ashok Kumar Batham 11

12. Symptoms indicating need for further clinical
investigations
Unusually severe headaches
Speech difficulty
Visual impairment
Motor weakness
Persistent tingling and numbness
Ataxia
Dr. Ashok Kumar Batham 12

13. Migraine Triggers
Hormonal changes: menstrual migraine
Emotional triggers: stress, depression, anxiety, excitement, and shock can
trigger a migraine.
Physical causes: tiredness and insufficient sleep, shoulder or neck tension,
faulty posture, and physical overexertion
Low blood sugar
Dr. Ashok Kumar Batham 13

14. Migraine Triggers
Jet lag
Certain foods and drinks: alcohol, caffeine, chocolate, cheese, citrus fruits,
and tyramine containing foods
Medications: Seeping pills, OCs, HRT,
Environmental triggers: loud noises, bright lights. flickering screens, strong
smells, second-hand smoke, stuffy rooms, and temperature changes
Dr. Ashok Kumar Batham 14

15. Pathogenesis of Migraine
Migraine pathogenesis is complex
Involves neural and vascular
elements
Dr. Ashok Kumar Batham 15

16. Serotonin as Key Mediator of Migraine Pathophysiology
Plasma & platelet concentrations of 5-HT vary with different phases of
migraine
Urinary concentrations of 5-HT and its metabolites are elevated during
most migraine attacks
Migraine may be precipitated by agents that cause release of 5-HT from
intracellular storage vesicles
5-HT receptor agonists successfully treat migraine attacks and have
become the mainstay of treatment of acute attacks
Dr. Ashok Kumar Batham 16

17. Drugs Used In Migraine
Ergotamines
Tryptans
Analgesics [Non-Steroidal Antiinflammatory Drugs (NSAIDs)]
Antiemetics
Anti-epileptics
Corticosteroids
Intranasal Lidocaine
Botulinum toxin
Dr. Ashok Kumar Batham 17

18. Ergotamines
Ergot/Ergotamines produced by a fungus Claviceps purpurea that grows on rye and other grains
Ergot caused gangrene of hands, arms, legs and feet & abortions – St. Anthony’s Fire
Ergot alkaloids (derivative of 6-methylergoline):
• Ergotamine (used in migraine either alone or with caffeine)
• Ergonovine (Ergometrine), Methylergonovine – used as uterotonic in PPH
Semisynthetic derivatives of ergot alkaloids
• Dihydroergotamine (DHE) - used in migraine
• Bromocriptine (dopamine agonist – used in Parkinson’s disease and hyperprolactinemia
• Lysergic acid diethylamide (LSD) – potent hallucinogen
• Methysergide (migraine prophylaxis)
• Ergoloids (Ergocriptine, Ergocristine and Ergocornine) - used as nootropic
Dr. Ashok Kumar Batham 18

19. Ergotamines (contd.)
Ergotamine and dihydroergotamine are older medications still prescribed for migraines,
the latter in nasal spray and injectable forms
As effective as triptans
Adverse effects are quite benign
Most effective treatment option – in most severe cases like status migrainosus
May cause vasospasm, leading to angina pectoris, therefore, contraindicated in patients
with coronary artery disease
Dr. Ashok Kumar Batham 19

20. Triptans
Developed in an attempt to find selective
vasoconstrictors of extracranial circulation based
on vascular theory of migraine
Sumatriptan introduced in 1992
Dr. Ashok Kumar Batham 20

21. Triptans - 2nd Generation
Second generation triptans having higher bioavailability
introduced subsequently, and include the following:
• Zolmitriptan
• Rizatriptan
• Naratriptan
• Frovatriptan
• Almotriptan
• Eletriptan
Dr. Ashok Kumar Batham 21

22. Triptans
Developed as selective vasoconstrictors for extracranial blood
vessels based on the earlier hypothesis of causation of migraine
by vasodilatation
Work as selective agonists at 5-HT1B and 5-HT1D receptors (have
no effects on other 5-HT receptors, alpha and beta adrenergic
receptors, cholinergic receptors, dopaminergic receptors, GABA
receptors).
Dr. Ashok Kumar Batham 22

23. Triptans - Actions
1. Cause vasoconstriction in intracerebral blood vessels and closure of carotid arteriovenous
anastomoses (shunt) leading to restoration of blood flow to the brain
2. 5-HT1B and 5-HT1D serve as autoreceptors and their activation by triptans modulate the release
of neuronal transmitters
3. Block the release of inflammatory peptides by nerve terminals in the perivascular space
accounting for efficacy in terminating acute migraine attacks
4. Control nausea and vomiting associated with migraine
[Ergot derivatives also produce above effects]
Dr. Ashok Kumar Batham 23

24. Triptans
Triptans such as sumatriptan are effective for both pain and nausea in up to 75% of people
Sumatriptan with naproxen works better
Recommended for moderate to severe pain or mild symptoms unresponsive to simple
analgesics
Available as oral, injectable, nasal spray, and oral dissolving tablets
All triptans appear equally effective, with similar side effects
Dr. Ashok Kumar Batham 24

25. Triptans
Triptans such as sumatriptan are effective for both pain and nausea in up to 75% of
people
Sumatriptan with naproxen works better
Recommended for moderate to severe pain or mild symptoms unresponsive to
simple analgesics
Available as oral, injectable, nasal spray, and oral dissolving tablets
All triptans appear equally effective, with similar side effects
Dr. Ashok Kumar Batham 25

26. Sumatriptan
Oral bioavailability is 14-17% Vs SC bioavailability ~ 97%
Therefore, Oral dose is 25-100 mg Vs SC dose of 6 mg (4 to 16 times lower);
may be repeated after 2-hours up to a total dose of 200 mg in 24-hour
Injection 6 mg S.C., may be repeated in 24 hours (if no relief)
Also administered as Nasal Spray in a dose of 5 - 20 mg, may be repeated after
2 hours with a maximum dose of 40 mg over 24-hours
Dr. Ashok Kumar Batham 26

27. Sumatriptan
Cmax after s.c. inj. oral dosing 1-2 hours
Elimination half-life ~ 1-2 hours
Predominantly metabolized by MAO-A
Sumatriptan Nasal Spray 5-20 mg,
Dr. Ashok Kumar Batham 27

28. Adverse Effects of Triptans
Generally an cause paresthesia, feelings of pressure, tightness or pain in chest, neck and jaw,
drowsiness, dizziness, nausea and sweating
Rarely may cause serious ADRs – coronary artery vasospasm, transient myocardial ischemia, atrial
and ventricular arrhythmias, and myocardial infarction in patients with pre-existing risk factors for
CAD
Injection site pain, burning and stinging
Bitter taste in mouth after nasal spray
Dr. Ashok Kumar Batham 28

29. Contraindications of Triptans
Ischemic vascular diseases:
• Ischemic Heart Disease
• Transient Ischemic Attacks
• Peripheral Vascular Disease
• Ischemic bowel disease
• Hemiplegic and basilar migraine
Uncontrolled hypertension
Use of MAO-Inhibitors in preceding 2 weeks
Exposure to ergot alkaloids or other 5-HT agonists in near term pregnancy
Dr. Ashok Kumar Batham 29

30. Contraindications of Triptans (contd.)
Naratriptan - contraindicated in hepatic and renal
insufficiency
Rizatriptan - to be used with caution in renal and hepatic
insufficiency
Eletriptan - contraindicated in hepatic insufficiency
Dr. Ashok Kumar Batham 30

31. Zolmitriptan
Used in a dose of 1.25 -2.5 mg repeated after 2-hours upto a
maximum of 10 mg in 24-hours
Oral bioavailability ~ 40%
Converted to active metabolite – N-desmethylzolmitriptan (several
fold more active)
Parent drug and the metabolite have t1/2. of 2-3 hours
Dr. Ashok Kumar Batham 31

32. Naratriptan
Used in a dose of 1-2.5 mg repeated after 4-hours up to a maximum of 5 mg in 24-hours
Bioavailability ~ 70%
Tmax 2-3 hours
T1/2 ~ 6 hours
50% of dose excreted unchanged in urine
30% excreted as oxidized metabolites
Dr. Ashok Kumar Batham 32

33. Rizatriptan
Used in a dose of 5-10 mg repeated after 2-hours up to a maximaum
of 30 mg in 24-hours
Bioavailability ~45%
Tmax 1-1.5 hours
Metabolized by MAO-A
Dr. Ashok Kumar Batham 33

34. Analgesics (NSAIDs) For Migraine
Analgesics (NSAIDs) – Aspirin, Paracetamol, Ibuprofen, Naproxen, Ketorolac,
Diclofenac are recommended as initial treatment for mild to moderate symptoms
Combination of Naproxen and Domperidone are now gaining poppularity
Aspirin can relieve moderate to severe migraine pain, with an effectiveness similar
to sumatriptan.
Combination of paracetamol, aspirin, and caffeine often prescribed.
Dr. Ashok Kumar Batham 34

35. Analgesics (NSAIDs) For Migraine
Ketorolac is available in an intravenous formulation is quite
suitable
Paracetamol alone or in combination with metoclopramide
is another option with a low risk of adverse effects
Paracetamol and metoclopramide are deemed safe in
pregnancy until the third trimester
Dr. Ashok Kumar Batham 35

36. Other Drugs For Acute Attacks
Intravenous - Metoclopramide
Intravenous - Prochlorperazine
Intranasal - Lidocaine
Intravenous – Dexamethasone
Dr. Ashok Kumar Batham 36

37. Anti-convulsants for Migraine
Divalproex-sodium (depakote, depakote ER)
Gabapentin (neurontin)
Levetiracetam (keppra)
Pregabalin (lyrica)
Tiagabine (gabitril)
Topiramate (topamax)
Valproate (depakene)
Zonisamide (zonegran)
Dr. Ashok Kumar Batham 37

38. Botulinum Toxin Type A
For Chronic Migraine
To be injected in the extracranial
muscles
Dr. Ashok Kumar Batham 38

39. Dr. Ashok Kumar Batham 39
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