migraine pathophysiology, treatment,

1. Pharmacotherapy of Migraine
Dr Manukumar
Post graduate
Dept of Pharmacology
VMMC & Safdarjung hospital

2. • Outline
• Migraine
• Pathophysiology
Theories
Vascular theory
Neurogenic theory
Neurovascular theory
• Acute treatment of migraine
Non-specific treatment
Specific treatment
• Preventive treatment of migraine
• Newer targets and drugs

3. Migraine headache
First description of migraine with visual aura.
• Second most common type of primary headache
• Migraine is chronic neurological disorder
characterized by episodic attacks of headache
and associated symptoms.
• Migraine prevalence is approximately 18% in
females and 6% in males.
• The brain of the migraineur is particularly
sensitive to environmental and sensory stimuli.

4. • A recent economic model estimated that losses due
to decreased productivity are roughly $1.9 million for
a company with 10,000 employees

5. Pathophysiology of migraine
• Vascular theory-attributes the phenomenon of
vasodilatation.
• Neurogenic theory- neuronal events, cortical
spreading depression.
• Third theory - accommodate vascular
modifications with neuronal dysfunction.

6. Vascular theory
• Harold G Wolff first one to explain
• Vasoconstriction and ischemia accounts for
symptoms of migraine aura,
• Reactive vasodilatation activate primary
sensory neurons.
• Therapies provides evidence for this theory.

7. Cortical spreading depression
• NMDA receptors involved in the genesis and propagation of
CSD. CSD was blocked by NMDA receptors antagonists in
various experimental models
Long lasting depression of
neuronal activity.

8. Cortical spreading depression
perivascular trigeminal and
parasympathetic nerve activation, release
of vasodilator mediators, CGRP,
neurokinen A, substance P
(pain signal)trigeminal ganglion 
trigeminal nucleus caudalis
trigeminocervical complex

10. General diagnostic criteria of migraine.

12. Pharmacological treatment of
migraine includes
Acute (abortive) treatment
Preventive (prophylaxis) treatment

14. Goals for acute treatment
1. Treat attacks rapidly and consistently without
recurrence.
2. Restore the patient’s ability to function.
3. Minimize the use of back-up and rescue
medications.
4. Be cost-effective for overall management.
5. Have minimal or no adverse events.

15. Non-specific Rx of migraine
“NSAIDs”
• PGE2 and PGI2 reduce the threshold to
stimulation of nociceptors, causing peripheral
sensitization
• CGRP release from the terminals of the
trigeminal sensory neurons is modulated by
PGE2
• Blockade cyclooxygenase (COX) and hence
reduced synthesis of PG

16. Forest plot of comparison: Ibuprofen
400 mg versus placebo
26% 12%
• Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.:
CD008039

18. • Postgrad Med J 2004;80:720–723.

19. Anti-emetics/caffeine – combination
with NSAIDs
• Metoclopramide effective for nausea and
vomiting associated with certain types of
headaches.
• D2 antagonistic action might be responsible
for relieve of migraine
• Caffeine, Block the adenosine receptor,
Vasoconstricting action.

20. Efficacy and Safety of Acetaminophen, Aspirin, and Caffeine in
Alleviating Migraine Headache Pain: Double-blind,
Randomized, Placebo-Controlled Trials
• Arch Neurol. 1998;55(2):210-217

21. Specific acute treatment
• Triptan-Sumatriptan, naratriptan,
rizatriptan, eletriptan, zolmitriptan,
almotriptan & frovatriptan
• Selective activity on 5-HT1B/1D agonist.
• Mechanisms of action
Cranial vasoconstriction
Modulating neurotransmitter release from
neuronal terminals.

23. • The triptans -preventing the peripheral release of
vasoactive peptides (CGRP), reduce PPE.
• Also inhibit the abnormal activation of peripheral
nociceptors.
• The 5-HT1D receptor-selective agonist PNU-
142633 showed greater potency than
sumatriptan in blocking electrically induced PPE,
and had little to no detectable vascular activity in
carotid, meningeal arteries

24. Adverse Effects and Contraindications
• coronary artery vasospasm, transient myocardial
ischemia, atrial and ventricular arrhythmias, MI
• Irritation at the site of injection. The most
common side effect of sumatriptan nasal spray is
a bitter taste.
• Contraindicated- coronary artery disease ,
history of stroke or transient ischemic attacks,
cerebrovascular or peripheral vascular disease,

25. • J Manag Care Pharm. 2005;11(5):394-402

27. Ergot alkaloids
• The pharmacological effects of the ergot
alkaloids are varied and complex; partial
agonists or antagonists at serotonergic,
dopaminergic, and adrenergic receptors
• Ergot alkaloids at 5-HT1B/1D receptors likely
mediate their acute anti-migraine effects

28. Selection of patients – ergot
• Which patients?
Patients requiring migraine-specific therapy
Patients established on ergotamine
• Special cases
Patients with very long attacks
Patients with frequent headache recurrence

29. Adverse Effects and Contraindications
of Ergot Alkaloids
• Nausea and vomiting, due to a direct effect on
CNS emetic center.
• contraindicated in pregnant, peripheral vascular
disease, coronary artery disease, hypertension,
impaired hepatic or renal function
• In contrast to triptans, the contractile effect of
ergotamine in the human isolated coronary
artery is long- lasting and persists even after
repeated washings

30. • Comparison of vasoconstriction action of
ergotamine and triptan
• MaassenVanDenBrink et al., 1998

31. Preventive treatment of
migraine

32. Indications
1. Two or more attacks per month that
significantly interfere with the patient’s daily
routine activity
2. An unsatisfactory response to acute therapy
3. contraindication to acute treatments and
adverse effects (AEs) related to them.
4. Uncommon migraine conditions, including
hemiplegic migraine, migraine with
prolonged aura or migrainous infarction.

33. The potential mechanisms of migraine
preventive medications
• Raising the threshold to migraine activation by
stabilizing a more reactive nervous system
• Enhancing antinociception
• Inhibiting CSD
• Inhibiting peripheral and/or central
sensitization
• Blocking neurogenic inflammation

34. Preventive medication

35. Antidepressants
• Amitriptyline alters the 5-HT synthetic rate at
the dorsal raphe nucleus.
• Enhancement of the pain threshold produced
by AMT seems to be mediated by sodium
channels, L-type calcium channels inhibition.
• Chronic daily administration of AMT
suppresses CSD, whereas acute treatment is
ineffective.

36. 50% reduction in migraine headaches
TCA Vs placebo
Jackson, JE., et al. (2010). Tricyclic antidepressants and headaches: systematic review and
meta-analysis. Bmj, 341(oct20 1)

37. • SSRI- In a recent review, SSRIs resulted as
efficacious as placebo for preventing migraine
and less effective than TCA.
• In a randomized controlled study fluoxetine,
venlafaxine, duloxetine versus placebo,
reduced frequency of migraine attacks, but
not significant.

38. Beta blocker
• Clinical findings support the efficacy of
propranolol, timolol, atenolol, nadolol and
metoprolol in migraine preventive treatment.
• Exhibit high affinity for 5-HT receptor( 1a,
1b/d,2a)
• propranolol blocked CSD in rats, without
altering regional cerebral blood flow and
systemic arterial blood pressure

39. Cont…
• 53 studies including meta-analysis involving
2403 patients who are treated with either
propranolol and/or placebo , propranolol
yielded 44% reduction in migraine attack.
• Two clinical trials valproic acid compared with
propranolol, in both trials efficacy is identical.

40. Anti-epileptics
• An unbalanced activity b/w excitatory
glutamatergic transmission and GABAnergic
inhibition, abnormal activation of voltage-
operated ionic channels; Na , Ca channels ,
has been postulated in these two pathological
condition.
• “Valproate, topiramate”, gabapentin,
lamotrigine are best for prophylaxis.

41. Cont..
• VPA, TPM, Effect on voltage gated Na channels
modify the neuronal excitability(CSD), role of
Na channels are proved in FHM.
• VPA reduces the neurogenic inflammation,
plasma extravasation (Cutrer et al., 1997),
possibly through a GABA-mediated
mechanism

42. Calcium channel blockers
• In an experimental model of neurogenic
inflammation, blockade of L-type channels
attenuates dural vasodilatation.
• flunarizine could exert its antimigraine effect
by reducing neural NO synthase (NOS) activity
• In a double- blind study, flunarizine 5 mg/day
was as effective as propranolol 160 mg/day in
reducing the attack frequency.

43. Newer targets and drugs
• Non-triptan 5-HT1 agonist,
5-HT1D agonists (PNU-109291 and PNU- 142633)
are potent inhibitors of dural plasma protein
extravasation (PPE)
LY334370, which is a selective 5-HT1F agonist,
inhibits single cell firing in the trigeminal nucleus
caudalis (TNC)

44. CGRP antagonist-
BIBN4096BS(olcegapant)
• CGRP mediates dilation of cerebral
vasculature and increases in cerebral blood
flow.
• CGRP-induced vasodilation can activate
nociceptors on cerebral vessels.
• In humans, intravenous human CGRP
administration induces migraine-like headache
in susceptible migraineurs

46. CGRP Antagonist BIBN 4096
BS(olcegapant) Vs placebo
• N Engl J Med. 2004 Mar 11;350(11):1104-10

47. Nitric oxide synthase inhibitor
• An intravenous infusion of nitroglycerin (NTG)
releases NO, causes migraine in more than 60%
of migraineurs , and activates trigeminal neurons
in experimental animals.
• In a small RCT, 546C88, a non-selective NOS
inhibitor, was administered intravenoulsy to
migraineurs during an acute attack (Lassen et al.,
1998). The 2-hr headache response rate was 67%
(10/15) on 546C88 versus 14% (2/14) on placebo

48. compound Treatment class Clinical phase
Telcagepant [MK0974)- CGRP receptor antagonist Phase 111
Olcegepant [BIBN4096BS)- CGRP receptor antagonist phase II
B144370- CGRP receptor antagonist phase II
Lasmiditan 5-HT 1F receptor agonist Phase 111
Tezampanel (LY-293558) AMPA and kainate receptor antagonist phase 111