This was a presentation for PG Teaching activity- seminar. It was presented to audience of faculty and PG students of MD pharmacology

1. Recent Advances:
Migraine
Guide: Dr Raakhi
Tripathi
JR-2: Dr Anup
Petare
20/09/2015 Department of Pharmacology & Therapeutics 1

2. Recent Advances:
Migraine
Guide: Dr Raakhi
Tripathi
JR-2: Dr Anup
Petare
20/09/2015 Department of Pharmacology & Therapeutics 2

3. Overview
• Definition
• Epidemiology
• Types/Classification/Grades
• Pathogenesis
• Current therapy
• Recent advances
20/09/2015 Department of Pharmacology & Therapeutics 3

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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.
Migraine
- World Federation of Neurology

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Migraine
Disabling Primary Headache disorder
Ranked 19th by the WHO among all diseases world-wide
causing disability
IHS: migraine constitutes 16% of primary headaches
In India, 15-20% of people suffer from migraine with M:F ratio
of 1:2
WHO: Severe migraine can be as disabling as quadriplegia

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Two major sub-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

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8. Grades of Migraine
Mild migraine: may be one attack per month throbbing
but tolerable headache lasting upto 8 hours which does not
incapacitate the individual
Moderate migraine: The throbbing headache more intense,
lasts for 6-24 hours, nausea/vomiting and other features
are more prominent patient is functionally impaired. One
or more attacks occur per month.
Severe migraine: 2-3 or more attacks per month of severe
throbbing headache lasting 12-48 hours, often accompanied
by vertigo, vomiting and other symptoms; the subject grossly
incapacitated during the attack.
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Pathogenesis
Vascular
theory
Neurogenic
theory
Neurogenic
inflammation
Aura results from
intracranial vaso-
constriction
Headache results
from subsequent
rebound
vasodilatation
Cortical spreading
depression of the
electrical activity
followed by vascular
phenomena
Triggered by
Trigeminal sensory
system mediated
by 5-HT,
neurokinin,
substance P,
calcitonin gene
related peptide
(CGRP), nitric
oxide, etc.

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Neurovascular Theory

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Signaling cascade

12. Current therapeutic option..
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

13. Acute/ Abortive therapy
Non-specific treatment:
NSAID’s
Specific treatment:
Ergot alkaloids
5-HT receptor agonist
(Triptans)

14. Acute therapy: Triptans
Selective 5-HT 1B/1D agonist
 Sumatriptan
 Almotriptan
 Eletriptan
 Frovatriptan
 Naratriptan
 Rizatriptan
 Zolmitriptan
Similar efficacy
Differing Pharmacokinetic
profile

15. Acute / Abortive therapy
Failed analgesics or NSAIDs
Oral Sumatriptan 50 mg or 100 mg, Rizatriptan 10mg
Almotriptan 12.5 mg, Eletriptan 40 mg, Zolmitriptan 2.5 mg
For slower effect or better tolerability:
Oral Naratriptan 2.5 mg, Frovatriptan 2.5 mg
Infrequent headache:
Ergotamine 1-2 mg oral, Dihydroergotamine nasal spray 2 mg
Headache recurrence
Ergotamine 2 mg (perhaps most effective taken rectally, usually
with caffeine)
Oral Naratriptan 2.5 mg and Eletriptan 80 mg

16.  Early nausea or difficulties taking tablets
Sumatriptan 20 mg nasal spray, Zolmitriptan 5 mg nasal
spray, Rizatriptan 10 mg dissolvable wafer,
zolmitriptan 2.5 mg dispersible tablet ± Anti-emetics
 Early vomiting
Sumatriptan 25 mg suppository,
Sumatriptan 6 mg subcutaneous injection ± Anti-emetics
 Rapidly developing symptoms
Sumatriptan 6 mg subcutaneous injection,
Dihydroergotamine 1 mg intramuscular injection
Acute / Abortive therapy

17. Contraindications to Triptans
 Coronary artery disease
 Hypertension
 Peripheral vascular disease
 Hemiplegic or Basilar migraine
 Avoid in those on Ergots, SSRI and TCA
 Pregnancy and Lactation
 Should not be used for more than 2 days a week to
decrease the possibility of rebound headache

18. Preventive therapy
Beta- blockers
 Propranolol
 Metoprolol
 Timolol
Calcium channel blockers
 Flunarizine
 Verapamil
Tricyclic antidepressants
 Amitryptiline
 Nortryptiline
Anti-epileptics/ Neurostabilizers
 Topiramate
 Divalproex sodium
 Gabapentin
Serotonin antagonists
 Pizotifen
 Methysergide
Serotonergic agents
 Dihydroergotamine

19. Recent advances
 New FDA approvals
 New uses of existing drugs
 Drugs in pipeline
 New devices

20. Recent Advances: In acute Treatment
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Brandes JL, Kudrow D, Stark SR, O'Carroll CP, Adelman JU, O'Donnell FJ, Alexander WJ, Spruill SE, Barrett PS, Lener SE. Sumatriptan-naproxen for acute treatment of
migraine: a randomized trial. JAMA. 2007;297:1443–54. doi: 10.1001/jama.297.13.1443.

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Reduction in migraine frequency in patients with chronic migraine with
analgesic overuse.
Silvestrini M, Bartolini M, Coccia M, Baruffaldi R, Taffi R, Provinciali L. Topiramate in the treatment of chronic migraine. Cephalalgia. 2003;23:820–4. doi: 10.1046/j.1468-
2982.2003.00592.x.
Silberstein SD, et L Topiramate Chronic Migraine Study Group Efficacy and safety of topiramate for the treatment of chronic migraline: a randomised, doubleblind, placebo-
controlled trial. Headache.
2007;47:170–80. doi: 10.1111/j.15264610.2006.00684.x.
Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ, TOPMATMIG201(TOP CHROME) Study Group Topiramate reduces headache days in chronic migrai
a randomised, doubleblind, placebocontrolled study. Cephalalgia. 2007;27:814–23. doi: 10.1111/j.14682982.2007.01326.x.

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 New FDA approvals

23. TOPAMAX
• March 28, 2014: 1st FDA approval for prophylaxis of
migraine headaches in adolescents ages 12 to 17
(100mg)
• ADR: paresthesia, upper respiratory infection, anorexia,
abdominal pain
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24. Treximet
• Treximet (Sumatriptan/Naproxen Sodium) Formerly
Known as TREXIMA,
• May 2012: Menstrual Migraine in Women With
Dysmenorrhea Phase 3 study was completed
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https://clinicaltrials.gov/ct2/show/NCT00329459?term=Imitrex+menstrual+migraine&rank=1

25. Zomig (Zolmitriptan)
• October 2008: USFDA approved Zomig (zolmitriptan)
Nasal Spray
• Jan 2015: Treatment of Acute Migraine Headache in
Adolescents (TEENZ) Phase 4 study was completed
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26. BOTOX®
(OnabotulinumtoxinA)
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• 15 Oct 2010 USFDA approved 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.
• Boxed warning: Botulinum toxin may spread from the area
of injection to other areas of the body, causing symptoms
similar to those of botulism

27. Transdermal patch:
Sumatriptan
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January 2013, FDA approved: acute
medication sumatriptan delivery by new
mechanism (transdermal patch)
ADR: Painful sensation at the patch application site, reddening

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• Otopoint-needle implant can effectively relieve
headache in migraine patients
• Upregulate plasma 5-HT level.
http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/654/CN-00778654/frame.html accessed on 3.4.2015.
Acupuncture:

29.  New uses of existing drugs

30. Dexamethasone addition to standard
acute therapy
 Proposed to prevent recurrence of migraine through its
prevention of neurogenic inflammation
 7 Randomized clinical trials (n = 742)
 Dexamethasone vs placebo (both + standard therapy):
Dexa group was less likely to experience recurrent
headache within 24 to 72 hours
 Conclusion:
Dexamethasone appears to be safe and modestly effective
addition to standard migraine abortive therapy for the
prevention of migraine recurrence
Giuliano C, Smalligan RD, Mitchon G, Chua M. Role of dexamethasone in the prevention of migraine recurrence in the acute care setting: a review. Postgrad Med. 2012
May;124(3): 110-5

31. Carvedilol
 Additional alpha-1 blocking and antioxidant properties
 A very favourable adverse event profile
 A prospective, open-label trial in 76 patients with doses
titrated from 3.125 mg/day to 6.25 mg twice daily over 2
weeks revealed,
 50% reduction in monthly migraine attack frequency at the
third month of treatment in 59% patients,
 But, 26% patients withdrew due to lack of efficacy or as a
result of adverse events
Bigal ME, Krymchantowski AV. Emerging Drugs for Migraine Prophylaxis and Treatment. Medscape General Medicine. 2006;8(2):31.

32. Tiagabine (TGB)
 Inhibits the neuronal and glial reuptake of GABA and therefore
enhances GABA-mediated inhibition
 Open-label study in 41 patients with refractory migraine using
a mean dose of 10 mg/day TGB revealed,
 5 patients experienced a remission of their migraine attacks
 33 patients had at least a 50% reduction in their attacks
 Side effects reported were dizziness, asthenia, tremor and
abdominal pain
 Safety alert issued in 2005: Risk of new onset seizures and
status epilepticus in patients without a history of epilepsy

33. Levetiracetam
 Promising drug for the treatment of transformed migraine
 Open label trial in 36 transformed migraine patients with 1000
mg/day of LCT revealed significant reduction in headache
frequency at 1 month and 3 months
 Efficacy and safety evaluated in 30 patients ( aged 6 – 19 years)
with paediatric migraine with 125 – 250 mg BD revealed,
 At least 50% reduction in headache frequency and severity in 17
patients with improved quality of life
 Used off-label for migraine prophylaxis
Brighina F, Palermo A, Aloisio A, Francolini M, Giglia G, Fierro B. Levetiracetam in the prophylaxis of migraine with aura: a 6-month open-label study.
Clin Neuropharmacol. 2006 Nov-Dec;29(6):338-42
Miller GS. Efficacy and safety of levetiracetam in pediatric migraine. Headache. 2004 Mar;44(3):238-43

34. Zonisamide
Unique combination of pharmacologic actions:
 Blocks voltage-dependent sodium and T-type calcium
channels
 Reduces glutamate-mediated excitatory neurotransmission
 Inhibits excessive nitric oxide (NO) production, scavenging
hydroxyl and NO radicals
 Inhibits carbonic anhydrase
All of these mechanisms may play a role in headache and pain
modulation possibly via neuronal stabilization
2 open-label trials:
One in 33 patients and second in 34 patients with refractory
migraine with 100 mg/day Zonisamide showed,
Significant reduction in frequency and severity of migraine
Side effects reported included paraesthesia, fatigue, anxiety,
and weight loss
Bermejo PE, Dorado R. Zonisamide for migraine prophylaxis in patients refractory to topiramate. Clin Neuropharmacol. 2009 Mar-Apr;32(2):103-6

35. Quetiapine
 Atypical antipsychotic drug with a high affinity for D4
receptors
 Also possesses,
 High affinity for 5-HT2 receptors
 Partial agonistic activity at 5-HT1A receptors
 Blocking activity at alpha1-adrenergic receptors
 In an open label pilot study in 34 pts with refractory
migraine, 75.9% presented > 50% headache reduction
Potential for
migraine
prophylaxis
Krymchantowski AV, Jevoux C. Quetiapine for the prevention of migraine refractory to the combination of atenolol + nortriptyline + flunarizine: an open pilot
study. Arq Neuropsiquiatr. 2008 Sep;66(3B):615-8.

36. Tizanidine hydrochloride
 Alpha-2-adrenergic presynaptic agonist that inhibits the
release of norepinephrine in the brainstem and spinal cord
 An open study of 220 patients demonstrated efficacy in
chronic migraine
 Evidence supports tizanidine as an effective prophylactic
adjunct for chronic daily headache
 Also, possible importance of an alpha2-adrenergic
mechanism underlying the pathophysiology of migraine is
suggested
Saper JR, Lake AE 3rd, Cantrell DT, Winner PK, White JR. Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled,
multicenter outcome study. Headache. 2002 Jun;42(6):470-82.

37. Petasites/Butterbur
 Extract from the plant Petasites hypridus (butterbur)
 Inhibits peptide-leukotriene biosynthesis, possibly through
calcium channel regulation
 efficacy in migraine prevention was studied in 2 trials,
 A small RCT reported: low dose of petasites, 50 mg twice daily,
significantly reduced the number of migraine attacks per month
and the number of migraine days per month
 A larger RCT over 5 month by Lipton and colleagues reported:
4-month mean attack count reduced by 48% in patients treated
with petasites 75 mg twice daily, by 34% with petasites 50 mg

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Holland PR, Akerman S, Andreou AP, Karsan N, Wemmie JA, Goadsby PJ. Acid-sensing ion channel 1: a novel therapeutic target for migraine with aura. Ann Neurol. 2012
Oct;72(4):559-63. doi: 10.1002/ana.23653. PubMed PMID: 23109150.
Acid-sensing ion channel 1
• Novel therapeutic target for migraine with aura.
• Amiloride: Shown to block cortical spreading depression
via this mechanism

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 Drugs in pipeline

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Phase 3: Completed
TARGET:A Randomized,
Double-Blind, Placebo-Controlled,
Parallel-Group Study Evaluating the
Efficacy and Safety of a Single 20 mg Dose of Sumatriptan Powder
Delivered Intra-nasally with the Bi-Directional Device in Adults
With Acute Migraine With or Without Aura
Head-to-Head Comparison Trial:
COMPASS: Efficacy and Safety of 20 mg Sumatriptan Powder
Delivered Intranasally With the Bi-Directional Device Compared
With 100 mg Sumatriptan Tablets in Adults With Acute Migraine
With or Without Aura
PG Djupesland, P Dočekal, the Czech Migraine Investigators Group Intranasal sumatriptan powder delivered by a novel breath-actuated bi-
directional device for the acute treatment of migraine: A randomised, placebo-controlled study Cephalalgia August 2010 vol. 30 no. 8 933-942

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NXN-188
• 20 July 2014 trial NXN 188 for the Treatment of
Migraine With Aura completed its Phase 2
• Immediate release oral product
• Novel mechanism, selective inhibition of
neuronal Nitric Oxide Synthase (nNOS), as well
as 5-HT1B/1D activation

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Levadex (Dihydroergotamine)
• Multi-center trial, FREEDOM-301, consisted of a
randomized, double blind, placebo-controlled
• 16 April 2013 USFDA issued Complete
Response Letter on NDA of Levadex raising
concern over manufacturing process for the
final filled canisters.

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• Glutamate receptors antagonist
• In 2007 Phase 2 was completed
https://clinicaltrials.gov/ct2/show/NCT00567086?term=tezampanel&rank=1
Tezampanel
(NGX424MIG2001)

45. Telcagepant (MK-0974)
• In 2010 merck terminated it study with Telcagepant
(0974-049)
• Terminated: Identification of two patients with significant
elevations in serum transaminases
• 27 Jan 2015: Phase 3 study of Telcagepant (MK-0974-011)
in Participants With Moderate to Severe Acute Migraine
With or Without Aura
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https://clinicaltrials.gov/ct2/show/NCT00442936?term=telcagepant&rank=1
• Antagonist of the receptor for CGRP

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Edvinsson L. CGRPreceptor antagonism in migraine treatment. Lancet. 2008;372:2089–90. doi:10.1016/S01406736(08)617109.
ADX10059

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 New devices

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• 13 December 2013: FDA allows marketing of first device to
relieve migraine headache pain (Cerena)
• Device delivers Pulse transcranial magnetic stimulation at
the onset of headache or aura
• Disrupts cortical spreading depression
www.accessdata.fda.gov/cdrh_docs/pdf13/den130022.pdf
Cerena

49. Cefaly
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http://www.accessdata.fda.gov/cdrh_docs/pdf12/k122566.pdf
• 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.

50. Conclusion
• <60% migraine patients respond & tolerate preventatives1
• Need for better options for the
symptomatic and preventative treatment of migraine
• future seems bright as understanding of the disease improving
newer and safer treatment are rising.
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1: Pascual J. Recent advances in the pharmacological management of migraine. F1000 Med Rep. 2009 May 8;1. pii: 39. doi: 10.3410/M1-39. PubMed PMID: 20948742;
PubMed Central PMCID: PMC2924709.