Migraine, it's types, pathophysiology and pharmacotherapy

Migraine and it's pharmacotherapy have been discussed in this powerpoint presentation.

1. DRUG THERAPY OF MIGRAINE Prepared by- Dr. Chitranshi Hyanki Department of Pharmacology & Therapeutics King George’s Medical University

2. Definition Migraine is a disorder characterised by a pulsating headache, restricted to one side, which comes in attacks lasting 4 - 48 hours and is often associated with nausea, vomiting, sensitivity to sound and light , flashes of light, vertigo.

3. Simplified Diagnostic Criteria for Migraine Repeated attacks of headache lasting 4-72 h in patients with a normal physical examination. No other reasonable cause for the headache, and: At Least 2 of the Following Features: Plus at Least 1 of the Following Features: Unilateral pain Nausea/vomiting Throbbing pain Photophobia and Phonophobia Aggravation by movement Moderate or severe intensity

4. Types - Migraine with aura (classical migraine) - headache preceded by visual or other neurological symptoms Migraine without aura (common migraine)

5. Stages - Prodrome Aura Headache Postdrome

6. Prodrome Vague premonitory symptoms that begin from 12 to 36 hours before the aura and headache. Symptoms: Yawning , Excitation , Depression , Lethargy , Craving or distaste of various foods. Duration : 15 to 20 minutes.

7. Aura Aura is a warning or signal before onset of headache. Symptoms : Flashing of lights Zig-zag lines Difficulty in focusing Duration : 15-30 minutes

8. Headache Headache is generally unilateral and is associated with symptoms like: Anorexia Nausea Vomiting Photophobia Tinnitus Duration : 4 – 72 hours

9. Postdrome Following headache, patient complains of – Fatigue Depression Severe exhaustion Some patients feel unusually fresh Duration : Few hours or up to 2 days.

10. MIGRAINE TRIGGERS

11. Causes Increased excitability of CNS Meningeal blood vessel dilation Activation of perivascular sensory trigeminal nerves Pain impulses

12.  Vasoactive neuropeptides contain: substance P calcitonin gene-related peptide (CGRP) neurokinin A Combination of increased pain sensitivity, tissue and vessel swelling, and inflammation.

13. Pathophysiology Vascular theory : It states that initial vasoconstriction or shunting of blood through carotid arterio-venous anastomoses produces cerebral ischemia and starts the attack. Neurogenic theory : Some triggering events appear to produce neurogenic inflammation of the affected blood vessel wall which is amplified by retrograde transmission in the afferent nerves and release of mediators like: 5-HT, CGRP, neurokinin, substance P etc.

14. Classification Mild Moderate Severe Less than one attack a month. One or more attacks per month 2-3 attacks or more every month Lasting upto 8 hours 6-24 hours 12-48 hours Throbbing but tolerable headache Intense throbbing headache with nausea and vomiting Intense throbbing headache with nausea and vomiting, vertigo, GIT instability, fatigue, photophobia

15. Drug therapy of migraine Severity Drug Therapy Mild Simple analgesics/NSAIDs or their combinations (+ antiemetic) Moderate NSAIDs combinations/ergot alkaloids/sumatriptan (+ antiemetic) Severe Ergot alkaloids sumatriptan/rizatriptan (+ antiemetic)

16. Mild migraine Simple analgesics- Paracetamol (0.5- 1 gm), Aspirin (300- 600mg), repeated 4-6 hourly NSAIDS- Ibuprofen (400-800mg 8 hourly), Naproxen, Diclofenac(50mg 6-8 hourly), Mefenaemic acid Antiemetics- Metoclopramide (10mg oral/ im ), Domperidone (10-20mg) Can be given in combination with Paracetamol/Diazepam/Diphenhydramine or another antihistaminic / caffeine

17. Moderate migraine Stronger NSAIDS or their combinations Ergot preparation or sumatriptan Severe migraine Ergot alkaloid, Triptans

18. Ergotamine Most effective ergot alkaloid for migraine, given early in attack Oral / sublingual route is preferred, 1 mg is given at half hours intervals till relief is obtained or total of 6mg is given Act by constricting the dilated cranial vessel or by specific constriction of carotid A-V shunt channels Reduce neurogenic inflammation and leakage of plasma in dura mater.

19. Why are triptans superior?  Ergotamine has Low bioavailability <1% - better after rectal or sublingual administration. Many adverse effects - Nausea, muscle cramps, coronary spasm etc. C/l in sepsis, IHD, pregnancy etc. Background and rebound headache.

20. Selective 5-HT 1b/1d agonists Sumatriptan - Selective 5HT 1B/1D receptor agonist Administered at the onset of attack of migraine Constriction of dilated cranial extra cerebral blood vessel, especially the arterio-venous shunt in carotid artery

21. Reduce 5-HT and inflammatory neuropeptide release around the affected vessels, reduce extravasation of plasma protein across dural vessel. Reduce Inflammatory mediators release- CGRP, NK, SP suppression of impulse transmission in Trigeminovascular pathway 3 dosage forms: oral, nasal, & parenteral (SC) Costlier

22. Advantages over ergotamine Better tolerated than ergotamine. Faster relief than ergotamine (2.5 hrs). Lesser rebound headache. Also able to take care of other related problems e.g.- nausea, photophobia etc.

23. Side effects Tightness in head and chest Feeling of heat, paresthesias in limbs D izziness, weakness Rare S/E:- Bradycardia, coronary vasospasm, MI, seizures, hypersensitivity reaction

24. Indication for prophylactic therapy Two or higher frequency of attacks / month. Migraine attacks not responding to acute drug treatment. Frequent , very long or uncomfortable auras.

25. Prophylaxis Start with low dose till therapeutic effect reached To be taken daily Takes atleast 2-6 weeks to act Course 5-6 months & gradually tapered down +/- discontinued

26. Beta Blocker: Propranolol is commonly used drug, reduces frequency as well as severity of attacks effect seen in 4 weeks dose - start with 40mg bd increased up to 160mg bd Tricyclic Antidepressants: A mitriptyline (25-50mg at bed time) Calcium channel blocker: 1. Verapamil 2. Flunarizine - weak Ca2+ channel blocker that also inhibits Na+ channels

27. Anticonvulsants: Valproic acid (400-1200mg/day), Gabapentin (300-1200mg/day) 5HT antagonists: M ethysergide , Cyproheptadine

28. Prophylaxis Drug Daily Dose Range(mg) Adverse Effects Beta Blockers Propranolol 40 – 320 mg Bronchospasm, bradycardia, hypotension fatigue, depression Nadolol 40 – 240 mg Same Tricyclic Antidepressants Amitriptyline 10 – 175 mg Sedation, xerostomia, weight gain, cardiac arrhythmias, urinary retention, constipation tremor Nortriptyline 10 – 125 mg Same Anticonvulsant Divalproex sodium 250 – 1500 mg Teratogenicity, nausea, hair loss, hepatotoxicity, weight gain, tremor, fatigue Calcium Channel Blocker Verapamil 240 – 480 mg Hypotension, edema, constipation

29. Reference Tripathi, K. D.  Essentials of Medical Pharmacology . 8th ed., Jaypee Brothers Medical, 2018.

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