Migraine, Pharmacology

1. Recent Advances in
Pharmacotherapy of Migraine
25/03/17
Capt. Htet Wai Moe

2. Migraine
• Migraine is a chronic neurological disorder
characterized by recurrent attacks of
headache widely variable in intensity,
frequency and duration
• Attacks are commonly unilateral and are
usually associated with anorexia, nausea and
vomiting

3. Simplified Diagnostic Criteria for
Migraine
• ≥5 attacks lasting 4-72 hrs
• ≥2 of the following
– Unilateral
– Throbbing
– Moderate or severe intensity
– Aggravation by routine physical activity
• ≥1 of the following
– Nausea/vomiting
– Photophobia and phonophobia
• Not attributable to another disorder

4. Two major types
Migraine without aura (common migraine)
• Headache with specific features and
associated symptoms
Migraine with aura (classic migraine)
• Focal neurological symptoms that usually
precede or sometimes accompany the
headache.
• Some experience premonitory phase,
occurring hours or days before the headache,
and a headache resolution phase

5. Classification depending on severity
Mild Moderate Severe
Attack 1 ≤ per month ≥1 per month
≥2-3 per
month
Headache
Throbbing but
tolerable
More intense
& Throbbing
Severe
throbbing
Duration Upto 8 hrs 6-24 hrs 12-48 hrs
Incapacitation No
Functionally
impaired
Incapacitated
Other features
Nausea/
vomiting
Prominent
Nausea/
Vomiting
Vomiting &
Vertigo

6. Pathogenesis
Vascular theory
Initial vasoconstriction or shunting of blood
through carotid arteriovenous anastomoses
cerebral ischemia
Migraine attack

7. Pathogenesis
Neurogenic theory
Spreading depression of cortical electrical
activity
Vascular phenomena
• Neurogenic inflammation of affected blood
vessel wall
• Amplified by retrograde transmission in
afferent nerves and release of mediators like
5-HT, neurokinin, substance P, calcitonin gene
related peptide (CGRP), nitric oxide

8. Current Therapeutic Options
Acute
treatment
Preventive
treatment
Behavioural
treatment
To reduce pain and
duration of attack
To reduce frequency of
attacks and disability
 Identification of triggers
 Meditation
 Psychotherapy

9. Acute Attack Therapies
• Anti-inflammatory agents
• 5HT1B/1D receptor agonists
• Dopamine receptor antagonists
• Must be individualized: standard approach for
all patients is not possible

10. Treatment of Acute Migraine
Simple Analgesics
• Acetaminophen, aspirin, caffeine
NSAIDs
• Naproxen, Ibuprofen, Tolfenamic acid

11. Treatment of Acute Migraine
5-HT 1 Agonists
Oral
• Ergotamine, Naratriptan, Rizatriptan,
Sumatriptan, Frovatriptan, Almotriptan,
Eletriptan, Zolmitriptan
Nasal
• Dihydroergotamine, Sumatriptan, Zolmitriptan
Parenteral
• Dihydroergotamine, Sumatriptan

12. Treatment of Acute Migraine
Dopamine Antagonists
Oral
• Metoclopramide, Prochlorperazine
Parenteral
• Chlorpromazine, Metoclopramide,
Prochlorperazine

13. Treatment of Acute Migraine
Other
Oral
• Acetaminophen + dichloralphenazone +
Isometheptene
Nasal
• Butorphanol
Parenteral
• Narcotics

14. Acute Specific Migraine Treatments
Failed NSAIDs/analgesics
First tier
• Sumatriptan, Almotriptan, Rizatriptan,
Eletriptan, Zolmitriptan (Per oral)
Slower effect/ better tolerability
• Naratriptan, Frovatriptan (PO)
Infrequent headache
• Ergotamine (PO), Dihydroergotamine (Nasal
Spray)

15. Acute Specific Migraine Treatments
Early Nausea or difficulties taking tablets
• Zolmitriptan, Sumatriptan (Nasal spray),
Rizatriptan (Wafer)
Headache recurrence
• Ergotamine (PR), Naratriptan, Almotriptan,
Eletriptan (PO)
Tolerating acute treatments poorly
• Naratriptan, Almotriptan (PO)

16. Acute Specific Migraine Treatments
Early Vomiting
• Zolmitriptan (Nasal spray), Sumatriptan (PR,
SC)
Menses-related headache
• Prevention – Ergotamine (PO)
• Treatment – Triptans, Dihydroergotamine
(Nasal spray)
Very rapidly developing symptoms
• Zolmitriptan (Nasal spray), Sumatriptan (SC),
Dihydroergotamine (IM)

17. Preventive Treatments
Beta blocker
• Propranolol
Tricyclics
• Amitriptyline, Dosulepin, Nortriptyline
Anticonvulsants
• Topiramate, Valproate, Gabapentin
Serotonergic drugs
• Methysergide, Flunarizine

18. Recent Advances
• Novel acute and preventive treatments
• New uses of existing drugs
• New devices

19. Calcitonin gene-related peptide
antagonists (gepants)
• Calcitonin gene-related peptide (CGRP) is a
neuropeptide implicated in pathophysiology
of migraine
• CGRP blockers known as gepants or
monoclonal antibodies
• First non-serotoninergic, migraine-specific
drugs without a vasoconstrictor action
Novel acute and preventive treatments

20. Calcitonin gene-related peptide
antagonists (gepants)
• Suitable for patients with vascular disease
• Telcagepant, Olcagepant, MK-3207, BMS-
927711, BI44370TA, NCT01613248 showed
proof of efficacy for the treatment of migraine
• Trials discontinued due to risk of liver toxicity
• ALD-403, LY-2951742, LBR-101 – phase I and II
studies show efficacy in episodic and chronic
migraine

21. Serotonin 5HT1F agonists (ditans)
• Lasmiditan (COL-144) – selective 5-HT1F
agonist
• Good efficacy and tolerability as an acute
treatment
• Now in Phase III trials

22. Glutamate receptor antagonist
• Glutamate released from neurons expressing
5-HT1B/1D/1F receptors in trigeminal ganglia,
is implicated in aspects of both migraine and
migraine aura pathophysiology
• Tezampanel (LY-293558), Raseglurant
(ADX10059) showed effectiveness in acute
treatment of migraine without aura
• Phase II trials discontinued due to the
observation of possible predictive signs of
hepatotoxicity

23. Orexin receptor antagonists (rexants)
• Orexin A & B – neuropeptides synthesized in
hypothalamus are thought to play a role in
nociception
• Filorexant – dual orexin receptor antagonist
• Completed phase II trials

24. BOTOX® (OnabotulinumtoxinA)
• OnabotulinumtoxinA inhibits the release of
excitatory neurotransmitters from both motor
and sensory neurons
• Botox inj: prevent headaches in adult patients
with chronic migraine.
• Every 12 weeks as multiple injections around
the head and neck
• ADR: neck pain and headache.

25. BOTOX® (OnabotulinumtoxinA)

26. Transdermal patch: Sumatriptan
• In January 2013, FDA approved acute
medication sumatriptan delivery by new
mechanism (transdermal patch)
• Temporarily suspended due to reported cases
of serious application site reactions
(burn/scar)

27. New uses of existing drugs
Dexamethasone addition to standard acute
therapy
• Proposed to prevent recurrence of migraine
through its prevention of neurogenic
inflammation
• Less likely to experience recurrent headache
within 24 to 72 hours
• Appears to be safe and modestly effective
addition to standard migraine abortive therapy
for the prevention of migraine recurrence

28. Carvedilol
• Additional alpha-1 blocking and antioxidant
properties
• A very favourable adverse event profile
• 50% reduction in monthly migraine attack
frequency at the third month of treatment

29. Tiagabine (TGB)
• Inhibits the neuronal and glial reuptake of
GABA and therefore enhances GABA-
mediated inhibition
• At least a 50% reduction in their attacks
• Risk of new onset seizures and status
epilepticus in patients without a history of
epilepsy

30. Levetiracetam
• Promising drug for the treatment of
transformed migraine
• At least 50% reduction in headache frequency
and severity with improved quality of life
• Used off-label for migraine prophylaxis

31. Zonisamide
• Significant reduction in frequency and severity
of migraine in patients with refractory
migraine
• Side effects reported included paraesthesia,
fatigue, anxiety, and weight loss

32. Tizanidine hydrochloride
• Alpha-2-adrenergic presynaptic agonist that
inhibits the release of norepinephrine in the
brainstem and spinal cord
• Effective prophylactic adjunct for chronic daily
headache

33. Medical Devices
Cerena
• 13 December 2013: FDA allows marketing of
first device to relieve migraine headache pain
(Cerena)
• Device delivers single pulse transcranial
magnetic stimulation
• Disrupts cortical spreading depression (CSD),
the underlying cause of migraine aura and pain

34. Cefaly
• 11 March 2014: USFDA approved
device for preventing migraine
• Transcutaneous electrical nerve stimulator to
treat Headache
• Warnings: Indicated for use by adults and
should only be used for 20 minutes/day,
• ADR: Tingling or massaging sensation where
electrode applied

35. Gamma core
• Delivers transcutaneous
vagal nerve stimulation
(VNS) by generating an electrical signal
• Suppress high glutamate levels
• For acute and preventive treatment of
migraine

36. Thank you!