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
9. General diagnostic criteria of migraine.
10. Pharmacological treatment of migraine includesAcute (abortive) treatmentPreventive (prophylaxis) treatment
11. Goals for acute treatment1. Treat attacks rapidly and consistently without recurrence.2. Restore the patients 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.
12. 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
13. Forest plot of comparison: Ibuprofen 400 mg versus placebo 26% 12% Cochrane Database of Systematic Reviews 2010, Issue 10. Art. No.: CD008039
14. Postgrad Med J 2004;80:720723.
15. 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.
16. 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
17. 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.
18. 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
19. 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,
20. J Manag Care Pharm. 2005;11(5):394-402
21. 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
22. 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
23. 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
24. Comparison of vasoconstriction action of ergotamine and triptan MaassenVanDenBrink et al., 1998
25. Preventive treatment of migraine
26. Indications1. Two or more attacks per month that significantly interfere with the patients daily routine activity2. An unsatisfactory response to acute therapy3. 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.
27. The potential mechanisms of migraine preventive medications Raising the threshold to migraine activation by stabilizing a more reactive nervous