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1997 Clinical pharmacology By Duy Thai

MIGRAINE Definition • Common migraine • No aura • Attacks last 4 - 72 hours • The first indication that you are going to have a migraine is the pain • Diagnosed as migraine if there is: • At least 2 of: • Unilateral pain • Pulsating pain • Moderate/severe pain • Pain is aggravated by movement • And 1 of: • Nausea • Photophobia and phonophobia (excessive sensitivity to external stimuli) • Classic migraine • Aura present • 2 attacks per month with at least 3 of: • 1 or more aura symptoms • 1 aura symptom developing more than 4 min or 2 successive aura symptoms • Symptoms lasting less than 1 hour • Headaches start less than 1 hour after the aura • The first indication that you are going to have a migraine is the aura • An aura is a change in perception (sometimes people see lights) Mechanism of migraine • Still unclear • Vascular cause • Neural cause • Both? • Evidence for vascular cause: 1. During the aura phase, there is a decrease in cerebral blood flow (indicating that ischaemia may be causing the aura) 2. During a throbbing headache, there is cerebral vascular dilation (the stretch of the vessels triggers nerve endings around the vessels) 3. Headache can be triggered by vasodilators (e.g.. GTN) and reversed by vasoconstrictions • Evidence for neural causes: 1. Pain sensitive trigeminal nerves innervate cerebral vessels 2. Trigeminal nerves release a peptide CGRP (calcium gene related peptide) 3. CGRP is elevated during a migraine 4. Sumatriptan inhibits the release of CGRP (also acts as a 5HT1D agonist) • Carbamazapine: • Anti epileptic • Anti depressant (bipolar depression) • Can be useful in the treatment of migraine due to trigeminal neuralgia • What triggers the pain? • Don’t know • One potential mediator: • Serotonin • Plasma levels of serotonin (housed in platelets) are decreased during a migraine attack and levels of serotonin metabolites are increased in the urine • Serotonin is stored in platelets • There is a massive release of serotonin, causing vasoconstriction (aura) • When serotonin has been depleted, there is vasodilation (headache) • Giving serotonin stops the headache
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1997 Clinical pharmacology By Duy Thai

Therapy • Designed to: 1. Prevent an attack 2. Reduce the symptoms of an acute attack Preventing a migraine attack • Adjust the lifestyle to avoid triggering factors, e.g. Avoiding: • Certain foods (cheese, wine, chocolate) • The type of food depends on the individual (the foods often contain tyramine) • Changes in temperature, humidity, altitude • Vasodilator drugs • Stress • Irregular sleep patterns • Too little or too much • Pharmacological measures: • Only used if the attacks are frequent and very severe Pizotifen • 5HT2 antagonist • Adverse effects: • Drowsiness • The drug is introduced slowly and at nighttime • Weight gain • The drug causes hypoglycemia, and hence an increased appetite Propranolol • β antagonist • Has some 5HT2 antagonist activity • Usual contraindications and side effects • Used to prevent the vasodilation which causes the pain Methysergide • Most effective at preventing an attack • 5HT2 antagonist (partial agonist) • Not terribly selective. May have effects on 5HT1 • Use is limited by a range of adverse effects: • Nausea, drowsiness • Vasoconstriction • Especially in the coronary vessels, leading to cardiac ischaemia • Should not be used in people with any pre existing coronary artery disease or in hypertensive patients • Retroperitoneal fibrosis • Fibrosis of pleura and cardiac valves with prolonged use • In order to avoid this, a drug free period is required • In the drug free period, there is a rebound effect, with the headaches being more severe. However, this is necessary to avoid these potentially life threatening side effects Amitriptyline • Not used alone • A tricyclic antidepressant (e.g. imiprimine, desiprimine) • 5HT and NA uptake inhibitor • Used in combination with propranolol, pizotifen or methysergide • All these drugs have a slow onset of action (effects are seen only after a couple of months)

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1997 Clinical pharmacology By Duy Thai

Treatment of an acute migraine attack • Aims: 1. To reduce the pain 2. To prevent the nausea and vomiting which accompanies the pain 3. Best to treat as early as possible (during the aura phase for classic migraine) • Non pharmacological techniques: • Reduce external stimuli (sensitivity to movement, light, sound) • Pharmacological techniques: • Aspirin, NSAIDs (e.g. Naproxen) • The doses tend to be higher than for a normal headache • 1st line of defence • Metaclopromide • D2 antagonist • Anti emetic • If there is vomiting, it is difficult to give any drug orally • Ergotamine • Ergot alkaloid • Partial agonist at α receptors and 5HT receptors • Effects vary at different vascular beds • Main action is to constrict the cerebral vessels • Adverse effects: • Myocardial ischaemia in pre existing CAD • Hypertension • Only used acutely, never for an extended period of time • Sumatriptan • Save the best for last!!!!! • Specifically developed for the treatment of migraine • 5HT1D agonist • Constricts cerebral vessels • Also inhibits the release of CGRP • Can be administered subcutanously (useful if there is nausea) or orally • Not given IV because it can cause coronary vasoconstriction • Adverse effects: • Coronary vasoconstriction (contraindicated in people with CAD) • The coronary vasculature has 5HT1D receptors causing vasoconstriction. OTHER FORMS OF PERIPHERAL VASCULATURE DISEASES • Fixed obstruction: • Atherosclerosis • Berger’s disease • An inflammatory disorder of peripheral arteries, leading to fixed obstruction to flow • If there is a fixed obstruction, the vessel lumen will already be maximally dilated (like in angina) and so a vasodilator agent will not be useful • Vasospasm: • Raynaud’s disease • Spasm of the vessels of the extremities, especially in cold conditions, causing pain.

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1997 Clinical pharmacology By Duy Thai

Treatment: • α antagonist • Phentolamine • Tolazoline

Oppose vasoconstriction

• Can be applied topically to the site of vasoconstriction in a cold environment • Vasodilators • Isoxsuprine • β agonist • Nicotinic acid • A vasodilator in cutaneous vessels • Causes flushing of the face and neck • Feeling of warmth due to the flushing • No doing much to the peripheral vasospasm

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