Dr.B.V.Venkataraman Professor in Pharmacology Faculti Perubatan, Shah Alam, Malaysia Ph: / Drugs used in Migraine

What is a migraine? A migraine is a throbbing, intense headache in one half of the head. Affect people of all ages. Associated with anorexia, nausea and vomiting Dilatation of cranial blood vessels causes the pain.

Migraine Triggers Food Changes in wake-sleep pattern Hormonal changes (e.g.menopause) Drugs Physical exertion Stress Sensory stimuli Environmental changes Hunger Psychological factors

Phases of Acute Migraine PRODROME AURA HEADACHE POSTDROME

PRODROME Vague premonitory symptoms that begin from 12 to 36 hours before the aura and headache Symptoms include Yawning Excitation Depression Lethargy Craving or distaste for various foods Duration – 15 to 20 min

AURA (absent in some people) Aura is a warning or signal before onset of headache Symptoms Flashing of lights Zigzag lines Difficulty in focussing Duration : min

HEADACHE Headache is generally unilateral and is associated with symptoms like: Anorexia Nausea Vomiting Photophobia (fear of light) Phonophobia (fear of sound) Tinnitus Duration is 4-72 hrs

POSTDROME (RESOLUTION PHASE) Following headache, patient complains of Fatigue Depression Severe exhaustion Some patients feel unusually fresh Duration: Few hours or up to 2 days

MIGRAINE – CLASSIFICATION According to Headache Classification Committee of the International Headache Society, Migraine has been classified as: Migraine without aura (common migraine) Migraine with aura (classic migraine) Complicated migraine

Migraine Without AuraMigraine With Aura No aura or ProdromeAura or prodrome is present Unilateral throbbing headache may be accompanied by nausea and vomiting Unilateral throbbing headache and later becomes generalised During headache, patient complains of phonophobia and photophobia Patient complains of visual disturbances and may have mood variations MIGRAINE: CLINICAL FEATURES

MIGRAINE - PATHOPHYSIOLOGY VASCULAR THEORY Intracerebral blood vessel vasoconstriction – aura Intracranial/Extracranial blood vessel vasodilation – headache

Vascular Theory

MIGRAINE - PATHOPHYSIOLOGY Serotonin Theory Decreased serotonin levels linked to migraine Specific serotonin receptors found in blood vessels of brain Present Understanding Neurovascular process, in which neural events result in activation of blood vessels, which in turn results in pain and further nerve activation

Arterial Activation Release of Neurotransmitter Worsening of Pain

calcitonin gene-related peptide /Nitric oxide

MIGRAINE MANAGEMENT Non-pharmacological treatment Identification of triggers Meditation Relaxation training Psychotherapy Pharmacotherapy non-specific Abortive therapy specific Preventive therapy

DrugDoseRoute Aspirin mgOral Paracetamol500 mg-4 gOral MIGRAINE: ABORTIVE THERAPY Non-specific treatment Ibuprofen mgOral Diclofenac mgOral/IM Naproxen mgOral

NSAIDs Relieve mild migraines Inhibition of PG Chronic use leads to ulcers, gastrointestinal bleeding and rebound headaches.

ABORTIVE THERAPY FOR MIGRAINE DrugDoseRoute Ergot alkaloids Ergotamine1-2 mg/d; max-6 g/d Oral Dihydroergotamine mgSC 5-HT receptor agonists Sumatriptan mg 6 mg Orally SC nasal Rizatriptan10 mgOrally Specific treatment

ERGOTS Ergotamine alkaloid from the fungus, claviceps purpurae Non-selective 5HT agonist & alpha blocker Constriction of cranial arteries Caffeine added to increase the absorption from GIT Nausea, vomiting, diarrhoea – common side effect Dihydroergotamine – more effective with lesser side effect – also available as nasal drops

TRIPTANS Severe attack Relieve pain, nausea, phonophobia, photophobia that are associated with attack 5-HT1B (blood vessels) and 5-HT1D (trigeminal) receptors agonist Sumatriptan: nasal, sc preparation avoid Gastric irritation rizatriptan, naratriptan, zolmitriptan, almotriptan, frovatriptan, eletriptan Side effects: nausea, dizziness, muscle weakness. Coronary vasoconstriction, heart attack and rarely stroke

DrugDose (mg)/dRoute Domperidone mgOral Metoclopramide 5-10 mgOral/IV Promethazine mgOral/IM Chlorpromazine mgOral/IV ANTI-NAUSEANT DRUGS FOR MIGRAINE TREATMENT

Anti-nausea medications Attacks usually accompanied by nausea, vomiting Medication for these symptoms appropriate combined with other medication

WHY THE NEED FOR PROPHYLAXIS ? Abortive drugs should not be used more than 2-3 times a week Long-term prophylaxis improves quality of life by reducing frequency and severity of attacks 80% of migraineurs may require prophylaxis

DrugsDose (mg/d) 1.Betablockers –Propranolol Calcium Channel Blockers –Flunarizine –Verapamil TCAs –Amitriptyline SSRIs –Fluoxetine PREVENTIVE THERAPY FOR MIGRAINE

PROPRANOLOL – MECHANISMS OF ACTION Mechanisms proposed Vasoconstriction Anxiolytic action Decrease sympathetic activity

CALCIUM CHANNEL BLOCKERS Flunarizine, Verapamil Vasodilatation due to calcium channel blocking Common side effects: constipation and postural hypotension.

ANTI DEPRESSANTS Tricyclic antidepressants: effective Amitriptyline, nortriptyline, protriptyline: commonly used All types of headache including migraine Patient need not have depression

DrugsDose (mg/d) 5.Anti-convulsant –Sodium valproate Anti-histaminic –Cyproheptadine4-8 PREVENTIVE THERAPY FOR MIGRAINE (CONTD.)

ANTI SEIZURE DRUGS Drugs with dual property (anti-seizure and bipolar depression): useful 5HT Antagonist Cyproheptadine: antihistaminic, Calcium antagonist Methysergide: rarely used because of risk of retroperitoneal fibrosis and renal failure. Anti-hypertensive Clonidine: Alpha-2 agonist Botulinum toxin type A Used in wrinkles