The word derives from the Greekἡμικρανία (hemikrania), "pain on one side of the head", from ἡμι- (hemi-), "half", and κρανίον (kranion), "skull".
Definition: Migraine - disorder characterized by recurrent attacks of headache variable in intensity, frequency and duration. Attacks are unilateral and are usually associated with anorexia, nausea and vomiting”
during pregnancy symptoms usually improve temporary when there are noncyclic high levels of estrogen at first trimester , Absence of migraine noted in second & third trimesters of pregnancy. during lactation Decreased estrogen production may trigger an exacerbation of migraine and make lactation difficultBirt control pills make headache worse specially in week off , stop pills may give some reliefin the climacteric phase Decreased estrogen production may trigger an exacerbation of migraineafter menopause when estrogen levels are noncyclic and low, there may be an improvement in migraine
Prodrome - Vague premonitory symptoms that begin from 12 to 36 hours before the aura and headache.Symptoms include – Yawning, Excitation, Depress, LethargyAURA- is the complex of neurological symptoms that occurs just before or at the onset of migraine headache.Visual disturbances – most common complaintOther symptoms - Flashing of light, Zigzag Lines, Difficulty in focusingFollowing headache, patient complains of (postdrome or resolution phase)FatigueDepressionSevere exhaustionSome patients feel unusually freshDuration: Few hours or up to 2 days
Migraine patients – ‘Migraine generator’ in dorsal rapheof midbrain.Cortical hyper excitability forms basis of migraine susceptibility.Triggers - lead to cortical spreading depression.Cortical spreading depression - depressing neuronal activity & reducing cerebral blood flowCortical spreading depression or spreading depression of Leão is bursts of neuronal activity followed by a period of inactivity,
Cortical spreading depression is further believed to stimulate the central nervous system and initiate a cascade of events, including the activation of trigeminal sensory fibers surrounding cerebral and meningeal blood vessels.1,2
During activation of trigeminal sensory fibers surrounding cerebral and meningeal blood vessels, the stimulated nerve fibers release a variety of inflammatory and vasodilatoryneuroactive substances, such as calcitonin gene related peptide (CGRP), substance P, NO, and cytokines.1,2
The release of the inflammatory neuroactive substances results in a secondary inflammatory response, which includes the production of prostaglandins through a conversion of arachidonic acid by cyclooxygenase
CGRP and the inflammation caused by prostaglandins in turn act upon local blood vessels causing vasodilation and edema.
These responses activate peripheral meningeal pain receptors called nociceptors, which then transmit the signals to the trigeminal ganglion and centrally to the trigeminal nucleus caudalis (TNC).
Peripheral sensitization is a reduction in threshold and an increase in responsiveness of the peripheral nociceptors.1Following peripheral sensitization, continuous stimulation of the trigeminal ganglion results in activation of the TNC and surrounding glial cells.2
Prolonged stimulation of the TNC results in continuous firing by the TNC independent of any signals coming from the periphery; this creates a self-sustaining loop called central sensitization.1 The presence of central sensitization is associated with more refractory, harder-to-treat migraines where a sustained pain-free response is harder to achieve.2
Headache. 2006 Mar;46(3):444-53.Acetaminophen, aspirin, and caffeine in combination versus ibuprofen for acute migraine: results from a multicenter, double-blind, randomized, parallel-group, single-dose, placebo-controlled study.Goldstein J, Silberstein SD, Saper JR, Ryan RE Jr, Lipton RB.SourceSan Francisco Headache Clinic, CA 94109, USA.Conclusion.—AAC and IB are safe, cost-effective treatments for migraine; AAC provides significantly superior efficacy and speed of onset compared with IB.
CGRP - Dilation of blood vessels and inflammatory changes in membrane around brain Calcitonin gene-related peptide (CGRP) blockedClinPharmacolTher. 2000 Oct;68(4):418-26.Vascular effects of 5-HT1B/1D-receptor agonists in patients with migraine headaches.de Hoon JN, Willigers JM, Troost J, Struijker-Boudier HA, Van Bortel LM.SourceDepartment of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, The Netherlands.
Migraine prophylaxis is recommended, when more than 3 attacks occur per month, if attacks do not respond to acute treatment or if side effects of acute treatment are severe. Substances with proven efficacy include the beta-blockers metoprolol and propranolol, the calcium channel blocker flunarizine, several 5-HT antagonists and amitriptyline. Recently antiepileptic drugs (valproic acid, gabapentin, topiramate) were evaluated for the prophylaxis of migraine. The use of botulinum-toxin is under investigation.
In 17 th century it is used for trating cough, asthma, and skin woundsIt is also reported to inhibit peptide-leukotrine biosynthesis
calcitonin gene related peptide (CGRP),
Pharmacotherapy of migraine
The word derives from the Greek (hemikrania) "pain on one side of the head” From (hemi-) "half" (kranion) "skull
DefinitionMigraine - Disorder characterized by recurrentattacks of headache variable in intensity, frequencyand duration. Attacks are unilateral and areusually associated with anorexia, nausea andvomiting” -World federation of Neurology
Burden Of Migraine Second most common cause of Headache World - 15-20% of women and 10-15% of men In India, 15-20% of people suffer from migraine Adults – Female: Male ratio is 2 : 1 Prevalence peaks in the 25-55 age group 25% women - age 18-49. More than 2/3 of migraine sufferers either have never consulted a doctor or have stopped doing soNEJM 2002:346(4):257-269;XI congress of the HIS,2004
Familial Common Classical Basilar Herditry Migraine Migraine Migraine Migraine Recurrent Recurrent Migraine with Aura including headache disorder, Aura aura symptoms motor weaknessattacks lasting develop over 5- originating and at least one 4-72 hours. 20 minutes and from the first- or second- last for less brainstem but degree relative than 60 no motor has migraine minutes. weakness. 75% patients 33% patients 1-2 % patients < 1% patientssuffer from this suffer this type Involvement of type the basilar artery territory Higher Less frequent Same as 1. FHM1 - Mutations in the CACNA1A gene ,average attack than Common Classical chromosome 19 frequency Migraine 2. FHM2 mutations occur in the ATP1A2 gene , chromosome 1 Has a strict AURA Mostly seen in Have basilar- menstrual young adults. type symptoms
FEMALE MIGRAINEAt the menarche the incidence rises because it isclearly linked to estrogen levelsBefore menses attacks may be precipitated by fallingestrogen levels (premenstrual migraine)Menstruation-associated migraine The fallingEstradiol level rather than the absolute level providesthe trigger for migraine (menstrual migraine)ovulation or mid cycle migraine is infrequent
DIAGNOSIS & CLINICAL FEATURES Simplified Diagnostic Criteria for MigraineRepeated attacks of headache lasting 4–72 h in patients with anormal physical examination, no other reasonable cause for theheadache, and: At Least 2 of the Following Plus at Least 1 of the Following Features: Features: Unilateral pain Nausea/vomiting Throbbing pain Photophobia and Phonophobia Aggravation by movement Moderate or severe intensitySource: Adapted from the International Headache Society Classification (Headache Classification Committee of the InternationalHeadache Society, 2004).
CORTICAL SPREADING DEPRESSION(CSD) Trigeminal nerve fibers in the meningeal blood vessel
ROLE OF INFLAMMATORY MEDIATORSRelease of CGRP, substance P & Inflammatory Cytokines Calcitonin gene related peptide(CGRP)
• Kinins facilitate the production of Cyclooxygenases• Cyclooxygenases convert arachidonic acid to prostaglandins
VASODILATION AND EDEMA IN LOCAL BLOOD VESSELSCGRP and prostaglandins cause inflammation andvasodilation of cerebral and meningeal blood vessels
ACTIVATION OF NOCICEPTORSThe inflammation and edema activate peripheralmeningeal pain receptors called nociceptorsNociceptors transmit signals to the trigeminalganglion and the TNC
QUICK REVIEW MULTIPLE MECHANISM IN PROCESS PRIOR TO PAIN PERCEPTION Release of neuroactive substances Initiation of arachidonic cascade Vasodilatation and edema Activation of nociceptors Signals transmit centrally to TNC Signals travel to higher brain centers, including the thalamus and cerebral cortex
CONSEQUENCES OFSUSTAINED PAIN TRANSMISSION Continuo us Activation stimulatio of the n of the TNC trigeminal ganglion Activation of the surroundi ng glial cells
PROLONGED TNC STIMULATIONMAY LEAD TO CENTRAL SENSITIZATION Cutaneous Allodynia - marker for central sensitization, when present during a migraine, make the migraine episode more difficult to treat • A sustained pain-free response is harder to achieve
HISTORY OF TREATMENT 1200 BC: Egyptians Herbal brews and – clay crocodile & folk practices magic herbs Mid-1600’s AD: Dr. 10th century AD: Thomas Willis – Arabian physicians enemas, blood – garlic or hot iron letting, leeches, and to incision at temple natural products 1870’s: cold bandage on head, quiet room, and sleep
GOALS OF THERAPY Treat migraine attacks rapidly and consistently without recurrence Restore the patient’s ability to function Optimize self-care for overall management Be cost-effective in overall management Cause minimal or no adverse effects
ANALGESICS Drugs of first choice for mild or moderate migraine attacks.Acetylsalicylic acid (ASA) Ibuprofen 200–800mgupto1000mgDiclofenac 50–100mg Phenazon 1000mgMetamizol 1000mg Tolfenamicacid 200mgParacetamol 1000mg Naproxen 220-550mg
ANALGESICS Effective early in the attack PG synthesis inhibition & prevention of neurogenic inflammation For MILD cases • Acetaminophen + Aspirin + Caffeine • Aspirin + Metoclopramide • S/E : Gastritis , DyspepsiaGoldstein J, Silberstein SD, Ryan RE Jr, Lipton RB Headache. Acetaminophen, aspirin, and caffeine in combination versusibuprofen for acute migraine: results from a multicenter, double-blind, randomized, parallel-group, single-dose, placebo-controlled study 2006 Mar;46(3):444-53.
ANTIEMETICSMetoclopramide 10–20 mg, 20mgsuppository,10 mg IM, IV, SC• Side effect: Dyskinesia• Contraindicated in childhood and in pregnancyDomperidon 20–30 mg• Side effects less severe than in metoclopramide,• Can be given to children
The overall results of the study suggest that the efficacy of naproxen for all the end points and improvement in QOL is equivalent to that of triptans. Naproxen was as well tolerated as, if not better than, the triptans. Naproxen is much more cost-effective than the triptans. Naproxen has long duration of action, so attainment of sustained headache relief is better compared to triptans. Considering all these facts, we suggest that naproxen be used as an alternative drug for treatment of moderate-to-severe migraine attack. Vol. 12 No. 4, Oct-December 2010 www.jkscience.org
ERGOTS 1868: Use of ergot in the treatment of one- sided headache Ergot: potent neurotoxin & vasoconstrictor found in a fungus that grows on rye 1925: Identified active chemical of ergot (ergotamine) 1940’s: Ergotamine tartrate became the preferred treatment for acute migraine
ERGOTAMINE Structurally similar to amines, serotonin, norepinephrine, and dopamine Interact with multiple receptors in these systems Cause constriction of the blood vessels Wide-range of effects Problems: Avoid if patient has coronary disease; safety margin is small.
1980’S… DISCOVERY OFRECEPTORS2 subtypes of serotonin receptors (For Migraine) 1. 5-HT1B 2. 5-HT1D Located in brain blood vessels – responsible for vasoconstriction
SUMATRIPTAN 1983: studied GR-43175 Vasoconstrictor effect on 5-HT GR-43175 effective and well tolerated in clinical trials (side-effects associated with the drug were mild and short lived)
SUMATRIPTAN Acts on receptors at smooth muscle cells of brain vessels (also in peripheral blood vessels like coronary artery = side effects) The first selective serotonin agonist approved for the treatment of migraine Rapid relief Sumatriptan oral bioavailability14%
SUMATRIPTAN Relieves pain of migraine and associated symptoms 3 dosage forms Oral Nasal Parenteral
NARATRIPTAN Oral bioavailability improved to ~60% Half-life of 5-6 hours Take orally at the onset of headache pain
ZOLMITRIPTAN Oral bioavailability improved to ~50% Half-life of 3 hours Take orally at the onset of headache pain
RIZATRIPTAN Oral bioavailability ~40% Half-life of 2.5 hours Shows the fastest time of onset
ADRS OF TRIPTANS Parasthesia Dry mouth Hot and cold sensations altered, Asthenia Dizziness headache, Dyspepsia Fatigue Palpitations Chest pain Somnolence
COMPARISON OF TRIPTANS Subcutaneous delivery of sumatriptan most rapid and complete pain relief beginning as early as 10 to 15 minutes A Triptan can be efficacious even if another triptan was not effective Naratriptan and frovatriptan (2.5mg) are less effective than sumatriptan 50 or 100 mg but have less side effects Eletriptan 80 mg is significantly more effective than sumatriptan 100 mg in the primary endpoint of all studies, pain relief in 2 hours
Triptans - Advantages Triptans- Disadvantages M , Ergot Alkaloids over over Ergot Alkaloids More incidence of Rebound Receptor specificity headache Good Bioavailability ExpensiveLess incidence of nausea and vomiting Well tolerated Less incidence of Coronary vasospasm
INDICATIONS FOR PROPHYLACTIC THERAPYPoor QOL•Business duties•School attendance, etc.Two or higher frequency of attacks / monthMigraine attacks not responding to acute drugtreatmentFrequent, very long, or uncomfortable auras.
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 +/- discontinue
DATA FROM TRIALSDepartment of Neurology, University Essen, Federal Republic of Germany. firstname.lastname@example.org, J Neural Transm Suppl. 2003;(64):35-63
CLINICAL STRATIFICATION OF ACUTE SPECIFIC MIGRAINE TREATMENT
CLINICAL STRATIFICATION OF ACUTE SPECIFIC MIGRAINE TREATMENTHarrisons™principles Of Internal Medicine Eighteenth Edition. E book
NEWER T/T STRATERGIES FOR MIGRAINEPREVENTION This is about drugs which are less frequently prescribed for migraine prevention. Some of them still require further investigation with larger RCT Double blind Placebo controlled trials
TOPIRAMATE US FDA Approval in 2004 for migraine prevention Exact MOA is not known Proposed Mechanism is by increasing inhibitory effect of GABA Blocking Na+ Channel Limiting repetitive firing reduces calcium channel activity Inhibiting carbonic anhydraseSilberstein S D, Neto W, Schmitt J, Jacobs D for the MIGR-001 Study Group,“Topiramate in migraine prevention: results of a large, controlled trial”, Arch Neurol (2004);61: pp. 490–495.
TOPIRAMATE The efficacy of topiramate in migraine prevention has been shown in more patient in controlled trials than any other migraine preventing agents The recommended daily dose is 100mg ,in divided doses At recommended doses it is well tolerated by patients Potential adverse events includes Cognitive dysfunction Parasthesias Weight lossSilberstein S D, Neto W, Schmitt J, Jacobs D for the MIGR-001 Study Group,“Topiramate in migraine prevention: results of a large, controlled trial”, Arch Neurol (2004);61: pp. 490–495.
ZONISAMIDE Zonisamide(ZNS) is sulfonamide derivative It has been used for adjunctive therapy of partial seizures It blocks voltage – Dependent Na+ and T- type of calcium channels ,reduces glutamate- mediated excitatory neurotransmission All of these mechanism play role in headache and pain modulation , possibly via neuronal stabilization. ZNS was studied for migraine prevention in 2 open label trials presented. It is seen that those who are refractory to other preventive therapies respond well to 100mg of ZNS daily, which was titrated as tolerated up to 400mg daily.Mohammadianinejad SE, Abbasi V, Sajedi SA, Majdinasab N, Abdollahi F et al. Zonisamide versus topiramate in migraine prophylaxis: adouble-blind randomized clinical trial. Clin Neuropharmacol 2011 Jul-Aug;34(4):174-7
LEVETIRACETAM Levetiracetam(LEV) is also anticonvulsant Rapidly and nearly absorbed by oral administration Peak Sr. conc. 2 hrs Its efficacy in migraine prevention may be related to possible effect on cortical spreading depression Which is an early pathophysiological process in a migraine attack.Krusz J C,“Levetiracetam as prophylaxis for resistant headaches”, Cephalalgia (2001);21: p.373 (Abstract).
LEVETIRACETAM Open – label trials have demonstrated the efficacy of LEV in the prevention of refractory migraine The minimally effective dose appears to be 1.500mg , and most patients need 2,000-2,500 mg daily.Krusz J C,“Levetiracetam as prophylaxis for resistant headaches”, Cephalalgia (2001);21: p.373 (Abstract).
PETASITES Petasites is in extract from the plant petasites hybridus (butterbur) Used since centuries and during middle ages used for t/t of fever & plague Efficacy of this is studied in two trials Seen that significantly reduces the number of migraine attack per month and the number of migraine days per monthAgosti R, Duke RK, Chrubasik JE.Effectiveness of Petasites hybridus preparations in the prophylaxis of migraine: a systematicreview.Phytomedicine 2006 Nov;13(9-10):743-746
PREGABALIN Is new drug having analgesic , anticonvulsant , and anxiolytic effect Recently approved for the treatment of neuropathic pain It modulates voltage gated calcium channels Is pharmacologically similar to gabapentin Which is found to be effective in migraine prevention ADRs Somnolence Dizziness But now a date no open label or placebo controlled trials evaluating this claim have been publishedChristina Sun, Alan Rapoport. New tretment stratergies for migraine prevention. Us Neurological Disease 2006
CANDESARTAN It is angiotensin receptor blocker Evaluated in a prospective ,randomized double blind crossover study with 60 pts. At dose of 16mg daily it was found that It reduces the mean no. of headache days Significantly decreased headache severity The mean no. of days of sick leave due to headacheTronvik E, Stovner L J, Helde G et al.,“Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomizedcontrolled trial”,JAMA (2003);289: pp. 65–69.
QUETIAPINE (QTP) It is Dibenzothizepine derivative classified as atypical antipsychotic drug It also posses high affinity for 5-HT2 receptors Partial agonistic action at 5-HT1A receptor Alpha 1 adrenergic blocking propertyo With a consequent potential for migraine preventiono According to one trial QTP represent a very importantresource for refractory migraine.Brandes JL, Roberson SC, Pearlamn SH. Quetiapine for migraine prophylaxis. Headache 2002; 42:450-51.
SPECIAL CONDITIONS Migraine treatment in childhood and adolescents Acute• Ibuprofen 10mg per kg body weight and paracetamol 15 mg per kg body weight• Domperidone only antiemetic licensed for the use in children upto 12 years• Sumatriptan nasal spray the recommended dose for adolescents from the age of 12 is 10mg. Prophylaxis • Flunarizine 10 mg and propranolol 40–80 mg per day
MIGRAINE & PREGNANCY Only Paracetamol is allowed during the whole period. NSAID can be given in the second trimester. Triptans in the first trimester of pregnancy - if the foetus is more at risk by severe attacks with vomiting than by the potential impact of the triptan.
FUTURE SCOPE CGRP1 antagonist Olcegepant –• Can only be given IV. Upto Phase II development Telcagepant• Orally available. Completed 6 Phase III trials with positive results• But – serious increased levels of liver transaminases
Tonabersat Gap junction inhibitor & CSD inhibitor Shown good results in prophylaxis Vanilloid TRPV1 receptor antagonists Activation of TRPV1 - release pro-nociceptive peptides. e.g. Capsaicin and Resiniferatoxin 5-HT1F receptor agonist - Lasmiditan phase II Nitric oxide synthase inhibitors