Pharmacotherapy of migraine.pptx

PHARMACOTHERAPY OF MIGRAINE
Dr Pramoda N
JR2, Dept of Pharmacology
GMC Nagpur
Guided by: Dr A.V.Turankar

OVERVIEW
 Introduction
 Pathophysiology and clinical features
 Treatment options for Acute Migraine Attack
 Prophylaxis of Migraine
 Recent advances
 Summary
11/16/2022
Pharmacotherapy of Migraine
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INTRODUCTION
 Migraine is a recurring syndrome of headache associated with
other symptoms of neurologic dysfunction in varying
admixtures.
 It is 2nd most common cause of headache.
 It afflicts 15% of women and 6% of men over a 1 year period.
 Classic form of migraine is characterised by aura (25%).
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DEFINITION
Migraine is a familial disorder characterized by
recurrent attacks of unilateral headaches variable in
intensity, frequency & duration and are usually
associated with anorexia, nausea, Vomiting and increased
sensitivity to light and sound.
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TRIGGERS FOR MIGRAINE
 Migraineurs are particularly
sensitive to environmental and
sensory stimuli.
 This Sensitivity is amplified in
females during menstrual cycle.
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PATHOPHYSIOLOGY- HYPOTHESES
 Abnormal dilatation of carotid arteriovenous
anastomoses leading to shunting of carotid arterial
blood flow which cause Hypoxia.
 Activation of cells in trigeminal nucleus results in the
release of vasoactive neuropeptides (particularly
CGRP), at the vascular terminals of trigeminal nerve and
also within the nucleus.
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CLASSIFICATION OF MIGRAINE
1. Migraine without aura
2. Migraine with aura
• Migraine with typical aura
• Migraine with brainstem aura
• Hemiplegic Migraine – Familial and Sporadic
3. Chronic Migraine- >15 days of headache/month.
4. Other Rare types
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CLINICAL FEATURES
Migraine typically presents in 3 phases:
 Prodromal phase: few hours to days
• Tiredness, Yawning, cognitive dysfunction, mood change, neck discomfort,
polyuria and food cravings.
 Headache Phase: few hours to 72 hrs
• Unilateral throbbing headache with associated features
 Postdrome phase: few hours to a day
• Feeling tired/weary, lack of concentration, mild neck discomfort.
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DIAGNOSTIC CRITERIA
Repeated attacks of headache lasting 4-72 hours in
patients with a normal physical examination, no other
detectable cause for the headache, and:
At least 2 of the following: Plus at least 1 of the following:
• Unilateral pain
• Throbbing pain
• Aggravation by movement
• Moderate or severe intensity
• Nausea/Vomiting
• Photophobia and phonophobia
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TREATMENT OPTIONS OF ACUTE MIGRAINE
 Simple Analgesics and NSAIDs
 5-HT Receptor agonists
• Ergot alkaloids
• Triptans
 Dopamine Receptor Antagonists (Adjunctive)
 Opioids
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NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
 Reduce both severity and duration.
 Less effective in Moderate to severe Attacks.
 Most effective when taken early.
 To start with, paracetamol is the preferred drug in
Simple Analgesics.
 Side effects of NSAIDs include dyspepsia and GI
irritation.
Ibuprofen
Naproxen
Diclofenac
Tolfenamic acid
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ERGOT ALKALOIDS
 Ergotamine preparations stimulate 5𝐻𝑇1 receptors non
selectively.
 GI absorption is erratic.
 Nasal formulations- Good tolerability and overcome
absorption problem.
 Dihydroergotamine reaches peak plasma concentration
in 3 mins by IV, 30 mins by IM and 45 mins by SC.
Ergotamine
Oral- 1mg
IV/IM- 0.25 to 0.5 mg
(for very severe attack)
Dihydroergotamine
Nasal Spray- 2mg
IV/IM/SC- 1 mg
(maximum 3mg/day
and 6 mg per week)
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ERGOT ALKALOIDS
 Vasoconstriction induced by ergotamine is long lasting and cumulative when
taken repeatedly.
 Main disadvantage is that they cause Nausea and vomiting.
 Orally not more than 6 mg per attack and 10 mg per week should be taken.
 Use should be restricted to frequent moderate or infrequent severe Migraine
attacks.
 Methysergide was used for prophylaxis but was withdrawn due to Inflammatory
fibrosis.
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TRIPTANS
 𝟓𝑯𝑻𝟏𝑩/𝟏𝑫 Receptor Agonists
 Activation of 5𝐻𝑇1𝐵/1𝐷 receptors may cause
constriction of intracranial blood vessels, including the
arterio-venous anastomoses, closing the shunts.
 Alternate hypothesis suggests that 5𝐻𝑇1𝐵/1𝐷
receptors serve as presynaptic autoreceptors that
block release of pro-inflammatory neuropeptides.
Sumatriptan- SC and Nasal
Rizatriptan- 5 to 10 mg
Eletriptan- 40 or 80 mg
Naratriptan- 2.5 mg
Frovatriptan- 2.5 mg
Almotriptan- 12.5 mg
Zolmitriptan- Oral- 2.5 mg
Nasal Spray- 5 mg
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TRIPTANS
 Nasal and injectable formulations are useful in
patients with early onset nausea and vomiting.
 Sumatriptan is given 6 mg SC and may be repeated once
within 24 hours.
 Nasal Spray- 5 to 20 mg, can be repeated after 2 hours
maximum upto 40 mg in 24 hours period.
 Orally 25 to 100 mg, repeatable after 2 hours maximum
upto 200 mg in 24 hours period.
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TRIPTANS
 Rizatriptan and Eletriptan are most efficacious of triptans.
 Sumatriptan and Zolmitriptan has advantage of multiple
formulations.
 Almotriptan, frovatriptan and naratriptan are better tolerated
but the latter two have slower onset of action comparatively.
 Triptans donot cause nausea like that seen with Ergot alkaloids.
 Recurrence of headache, within an attack, is a limitation of
triptans. 11/16/2022
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TRIPTANS
 Triptans can cause parasthesias, flushing, pain in chest, neck and
jaw, drowsiness and sweating.
 Contraindicated in patients with Coronary artery disease,
cerebrovascular and peripheral vascular disease.
 Naratriptan is Contraindicated and Rizatriptan should be used with
caution in Renal and hepatic impairment.
 All triptans are Contraindicated in patients who has taken ergot
alkaloids, other triptans, SSRIs and SNRIs.
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DOPAMINE RECEPTOR ANTAGONISTS
 Orally given as adjunctive therapy.
 Parental drugs can provide significant acute relief of
Migraine.
 Can be used with parenteral 5𝐻𝑇1𝐵/1𝐷 Receptor Agonists
 Mixture of 5 mg prochlorperazine and 0.5 mg
dihydroergotamine IV over 2 mins is a common IV
protocol used.
Oral:
Metoclopramide
Oral- 5-10 mg/d
IV- 10 mg
Prochlorperazine
Oral- 1-25 mg/d
IV- 10 mg
Chlorpromazine
IV- 0.1 mg/kg at 2
mg/min; max 35 mg/d
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OPIOIDS
 Opioids just alter the pain sensation and they are suboptimal
for recurrent headache.
 Usage recommended to be limited to Severe but infrequent,
Migraine that are unresponsive to other approaches.
 Evidence suggests that opioids may decrease the likelihood
for response to triptans in future.
 IV Meperidine (50-100 mg) is given frequently in emergency
room.
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HOW TO CHOOSE A DRUG FOR PATIENT?
 A standard approach for all patients is not possible.
 A regimen should be refined until one is identified that
provides rapid, complete and consistent relief with minimal
side effects.
 Triptans serve as the first tier drugs after NSAIDs fail.
 Injectables or Nasal spray formulations are used for early
vomiting, nausea, very severe cases and emergency setting.
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PREVENTIVE TREATMENT FOR MIGRAINE
Candidates for Preventive Treatment:
 Patients who have very frequent headaches (more than 2 per
week)
 Attack duration is > 48 hours
 Headache severity is extreme
 Migraine attacks are accompanied by prolonged aura
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PREVENTIVE TREATMENT FOR MIGRAINE
Candidates for Preventive Treatment:
 If unacceptable adverse effects occur with acute
migraine treatment
 Contraindication to acute treatment
 Migraine substantially interferes with the patient’s
daily routine, despite acute treatment
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PREVENTIVE TREATMENTS FOR MIGRAINE
 Identify and Avoid reliable triggers.
 Healthy diet
 Regular exercise
 Regular sleep patterns
 Avoidance of excess caffeine and alcohol
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 Avoidance of acute change in stress levels
 Decrease one’s response to stress by various techniques like
 Yoga
 Transcendental meditation
 Hypnosis
 Conditioning techniques such as biofeedback.
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 Pharmacological treatment for prophylaxis of migraine
include the following groups of drugs:
• Beta blockers
• Calcium channel blockers
• Antidepressants
• Anticonvulsants
• Onabotulinum toxin A
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DRUGS FOR PREVENTION OF MIGRAINE
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Beta blockers:
Propronalol – 40 – 120 mg BD
Metoprolol – 25 – 100 mg BD
Timolol
Antidepressants:
Amitriptyline – 10 – 75 mg HS
Dosulepin – 25 – 75 mg HS
Nortriptyline – 25 – 75 mg HS
Venlafaxine – 75 – 100 mg/day
Anticonvulsants:
Topiramate – 25 – 200 mg/day
Valproate – 400 – 600 mg/day
Calcium Channel blockers:
Flunarizine – 5 to 15 mg qd
Verapamil

 The mechanism seems likely that the brain sensitivity that
underlies migraine is modified.
 A lag of 2 to 12 weeks seen before the drug shows effect.
 Propronalol, Timolol, Sodium valproate and topiramate are
FDA approved.
 Propronalol and Flunarizine are the preferred drugs.
 The probability of success of any one of the drugs is 50%.
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 Once effective stabilization is achieved, the drug is continued for
around 6 months, then slowly tapered to assess continued need.
 Phenelzine is a MAOI, reserved for only very resistant cases.
 Most of these drugs cause drowsiness.
 Valproate and Flunarizine cause weight gain whereas topiramate
cause weight loss.
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 Beta blockers cause postural symptoms, reduced energy and
contraindicated in Asthma.
 Topiramate cause parasthesias, cognitive symptoms,
glaucoma.
 Valproate cause tremors, hairloss, fetal abnormalities,
Hematalogic or liver abnormalities.
 Flunarizine can cause depression and parkinsonism.
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 The choice of drug depends on the tolerability,
effectiveness and other conditions which may be benefited
by the drug.
 If these fail – Neuromodulation approach
• Single pulse transcranial magnetic stimulation (sTMS) is
FDA approved for Prophylaxis.
• Non invasive Vagal nerve stimulation can be tried.
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RECENT ADVANCES IN
MIGRAINE THERAPY
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MONOCLONAL ANTIBODIES
1. Erenumab (Human IgG2 mAb):
 Calcitonin gene-related peptide (CGRP) receptor antagonist.
 Approved by FDA for prophylaxis of migraine on 17 may 2018.
 Dose: 70 or 140 mg SC once a month.
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2.Fremanezumab:
 CGRP antagonist.
 Approved by FDA for prophylaxis of migraine on 14 sep
2018.
 Dose: 225 mg SC monthly or 675 mg SC every 3 months.
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3. Galcanezumab:
 CGRP Antagonist.
 Approved by FDA for prophylaxis of migraine on 27 sep
2018.
 Dose: 240 mg SC loading dose followed by 120 mg SC
monthly dose.
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4. Eptinezumab:
 CGRP antagonist
 Approved by FDA for prophylaxis of migraine on 21 feb
2020.
 Dose: 100 mg IV infusion (in 100 ml NS) over 30 minutes
every 3 months.
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GEPANTS
 CGRP receptor antagonists.
 Ubrogepant (Dec 2019) and Rimegepant (Feb 27 2020) are FDA
approved for treatment of acute Migraine in adults.
 Most common Adverse effects are Nausea and Somnolence.
 Contraindicated for use with strong CYP3A4 inhibitors.
 Dose: Ubrogepant- 50 or 100 mg orally
Rimegepant- 75 mg orally
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DITANS
 Lasmiditan is a Selective 𝟓𝑯𝑻𝟏𝑭 agonist.
 It is approved by FDA for acute treatment of migraine on 11
Oct 2019.
 Dose: 50 mg or 100 mg or 200 mg taken orally as needed.
 Not more than one dose in 24 hours.
 Can cause Driving impairment, serotonin syndrome, Medication
overuse headache.
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SUMMARY
 Migraine is a disabling condition and requires prompt treatment.
 Pathophysiology and mechanism of drugs in migraine is not clear.
 Both prophylaxis and treatment should be individualised.
 Lifestyle modification in many patients can give long migraine free period.
 Out of all the treatment options triptans are currently the preferred
drugs for an acute attack of migraine.
 CGRP antagonists including mAbs seems to be promising drugs for Migraine.
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REFERENCES
 Peter J.Goadsby, Migraine and Other Primary Headache Disorders,
Harrison’s priciples of internal medicine, 20th ed. p 3096-3103.
 David R. Silbley, Lisa A. Hazelwood, and Susan G.Amara, 5-
Hydroxytryptamine (Serotonin) and Dopamine, Goodman & gillman’s
13th edition, the pharmacological basis of therapeutics, p 225-241.
 Betram G. Katzung, Histamine, serotonin and the Ergot Alkaloids,
Bertram G. Katzung –basic & clinical pharmacology, p 277-298.
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