Therapy of Migraine

8/7/2019 Therapy of Migraine

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Therapy ofTherapy ofMigraine:Migraine:

An OverviewAn Overview

By-

Parul Dixit

IInd Trimester, M.Pharm

(Pharmacology),SPTM,NMIMS


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What is migraine?What is migraine?

A debilitating neurobiological disorder charaterised by:

Pounding unilateral headache

Preceded by altered body perceptions, visual or otheraura, schotomas, phonophobia

Nausea, vomiting

Light and sound sensitivity

Lasting Mainly 4-72 hours


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DiagnosisDiagnosis depends on patient historyNo specific tests or clinical markers are there

Differentiating Migraine from tension type head-ache and other head aches:

Positive diagnosis if attack history fulfils IHS (International Head achesociety) criteria for migraine which is:

The attack should last for 4-72 hours

Atleast 5 episodes

Atleast 2 unilateral loactions, pulsating moderate to severe, aggravated byactivity

Atleast 1 : nausea or vomittiing, photophobia or phonophobia

History and exam do not show othet diagnosis


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Migraine with Aura:

Migraine aura fulfills criteria for typical aura or hemiplegic aura

Typical Aura Includes:

Fully reversible visual, sensory or speech symptoms.

Visual symptoms includes positive features like:

Flickering of lights, spots, lines, scotomas

Or negative features like :

Loss of vision, numbness

Each of the symptom gradually develops over a minimum of 5 minutes and lasts

for atleast 5 minutes or not longer than 60 minutes

Atleast 2 attacks fulfilling before mentioned criterias


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Visual Disturbances Seen in Migraine


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WORRISOMEHEADACHERED FLAGS

SNOOP

Older: new onset and progressive headache, especially in

middle-age >50 (giant cell arteritis)

Systemic symptoms (fever, weight loss) orSecondary risk factors (HIV, systemic cancer)

Neurologic symptoms or abnormal signs (confusion, impaired

alertness, or consciousness)

Onset: sudden, abrupt, or split-second

Previous headache history: first headache or different (change in

attack frequency, severity, or clinical features)


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World prevalence of migraine:

A disorder of First World

11--year prevalence ratesyear prevalence rates

PopulationPopulation--based studiesbased studies

IHS criteria (or modified)IHS criteria (or modified)

USA 12%USA 12%

Chile 7%Chile 7%

Japan 8%Japan 8%Italy 16%Italy 16%

Denmark 10%Denmark 10%

France 8%France 8%

Switzerland 13%Switzerland 13%

Rasmussen and Olesen (1994); Rasmussen (1995);Rasmussen and Olesen (1994); Rasmussen (1995);

LiptonLipton et al (et al (1994); Lavados and Tenhamm (1997);1994); Lavados and Tenhamm (1997);Sakai and Igarashi (1997)Sakai and Igarashi (1997)Prevalence measured over a few yearsPrevalence measured over a few years


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EcomomicEcomomic Impact of MigraineImpact of MigraineIn addition to being a major cause of pain and suffering, chronic migraine

attacks are a significant source of both medical costs and lost

productivity:

In theEuropean Community, costs are more than 27 billion per year.

Medical costs per migrainer averaged $107USDover six monthsincluding lost productivity averaging $313.

Annual employer cost of lost productivity due to migraines was

estimated at $3,309 per sufferer.

Total medical costs associated with migraines in the United Statesamounted to one billion dollars in 1994, in addition to lost productivity

estimated at thirteen to seventeen billion dollars per year.

The workplace model of 95, 5 days a week may not be viable for a

migraine sufferer


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Phases of Migraine

The prodrome which occurs hours or days before the headache.occur in 4060% of migraineurs may consist of altered mood,irritability, depression or euphoria, fatigue, yawning, excessivesleepiness, craving for certain food (e.g. chocolate), stiff muscles

(especially in the neck), constipation or diarrhoea, increasedurination, and other visceral symptom

The aura which immediately precedes the headache.Comprises focal neurological phenomena that precede or

accompany the attack. They appear gradually over 5 to 20 minutes

and generally last fewer than 60 minutes.. Symptoms of migraineaura can be visual, sensory, or motor in nature.

The painphase, also known as headache phase.


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Co-Morbidities

Renauds Disease

Mitral Valve Prolapse

Depression

Sleep Disorders

Stroke

Epilepsy

Irritable Bowel Syndrome

Anxiety + Pain Disorders


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EtioEtio--pathogenesis:Theoriespathogenesis:Theories of Migraineof Migraine

Following theories have been postulated which

explain how migraine is developped:

Vascular Theory: Role of Serotonin Nuerological Theory:Depolarisation Theory

Nuerogenic Theory

Allodynia Unifying theory


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The cranial cavity is innervated by nociceptive

sensory nerve fibres of the trigeminal pathway.,

which leads to sensitisation if pain receptors

Compensatory Dilation of blood arteries supplying

blood to the cranial cavity

The reduced flow of blood from t

he occipital

lobe triggers aura because the visual cortex

is in the occipital area.

Blood vessels in the brain contract and expand

inappropriately. Imbalanced serotonin levels

have been held responsible

Starts in the occipital lobe, in the back of the

brain, as arteries spasm.Vasoconsctriction

Vascular Theory : Role of SerotoninVascular Theory : Role of Serotonin

Dilation causes increase in vascular

permeability and leaking out of flui

occurs, chemical mediators of

inflammation are released

With Eachheart beat, blood passes throug

sensitised area and a throbbing head ach

produced


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Release of Nitric oxide

Release of Atrio-nueretic peptide

spread of astrocutic calcium waves

subsequent activation of intradural

nociceptive receptors

NuerologicalNuerological Theory: Cortical DepressionTheory: Cortical Depression

Nueronal Activation occurs The

nueronal activation may be due toabnormal firing of nuerons

Visual Phenomenon that spreads over

surface of brain like

shimmering C Epileptic like

phenomenon that spreads over Cortex

This is followed by progressive

suppression of the corticoid region.In

this the brain activity is suppressed

over a large area of th

e brain


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Mechanism ofTreatment

CGRPCGRP

NKNK

SPSP

55--HTHT1F1F

55--HTHT1D1D

55--HTHT1B1B

Blood vesselBlood vessel

TrigeminalTrigeminal

nervenerve

Adapted from Goadsby (1997)Adapted from Goadsby (1997)

CGRPCGRP calcitonin genecalcitonin gene

related peptiderelated peptide

NKNK neurokinin Aneurokinin A

SPSP substance Psubstance P

triptantriptan

CONSTRICTIONCONSTRICTION

INHIBITIONINHIBITION


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Acute Treatment: Drug Therapy

Analgesics/combination analgesics NSAIDs

Opioids

Neuroleptics/antiemetics

Anti-depressants Anti-convulsants

Migraine specific Triptans E

rgotamines

Drugs Acting on Calcium channels

Drugs Acting on Adernergic System


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Analgesics

NSAIDS:MOA:Inhibit PG synthesis

They are used for treatment of an acute attack, releive pain,but are mild

Ketorolac

Aspirin

Lornoxicam

Naproxen

Tolfenamic Acid

Fenoprofen


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Drugs acting on Serotonergic receptors and related targets:

Serotonin identified as a key player in the generation of amigraine attack

Plays a role through :5-HT-1B/1D , 5-HT-1F, 5-HT-2B, 5-HT-7 Receptors

5-HT metabolism in migraine patients is disturbedDrugs:

Triptans: 5HT-1D Agonists

Pizotifen: 5HT-2 Antagonist

Cyproheptadiene: 5HT-2 Antagonist

Methysergide: 5HT-2 Antagonist (Not used because of risk ofretroperitoneal fibrosis)

Migraine specific drugs


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Triptans

Sumatriptan- generic name

imigraine (glaxo)

Contraindicated in pateints

with coronary disease.

Zolmitriptan- zomig (astra-zeneca)

Almotriptan- Pharmacia

Naratriptan- Naramig (glaxo)

Rizatriptan- maxalt (merck)

MOA: Vasoconstrictor effect mediated by 5-HT -1 B ReceptorActs onreceptors at smooth muscle cells of brain vessels (also in peripheral blood

vessels like coronary artery = side effects)The first selective serotonin agonists approved for the treatment of migraine

Rapid reliefTriptans are an advance over ergots .Sumatriptan discovered in 1983, received

a huge success.

Effective in 70% patients


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Calcium Channel Blockers for Migraine

MOA: They block brain specific voltage gated ionchannels.

Verapamil

Nimodipine

Diltiazem

Nifedipine

Flunarizine


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Anticonvulsants used

They prevent nueral firing which initiates cortical

depression.

Drugs Used: Divalproex Sodium

Topiramate

Gabapentin


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Antidepressants

Anti-depressants act on the serotonergic system, hence are of use inmigraine

Drugs used

Tricyclic Antidepressants:

Amitriptyline Nortriptyline Doxepin

MAO Inhibitors:

Selegelline, Moclobemide

SSRIs: Fluoxetine,

5-HT-2A,2C Antagonist: Nefazodone


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Drugs Acting on Adrenergic System

adrenergic receptors:

MOA:-2a receptors play a role in constriction of carotid

vasculature.

The affinity of ergotamine and dihydroergotamine may be the

possible reason for the therapeutic application of this receptor

Adrenergic receptors :

The B- bloclers are the most widely used class of drugs inprophylactic migraine treatment. Majorly used drug is

propranolol, metoprolol

MOA: Interfering with the vigilance enhancing pathway

Cross modulation on serotonin system


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Co-enzyme Q10:

Role of Mitochondria in pathogeneis.

This co-enzyme is responsible for electron transportin side mitochondria and has antioxidant actions

If mitochondrial dysfunction plays an important

role, then this enzyme can be used to treat migraine

NK-1 Receptors

Lanepitant is a non-competitive NK-1 Receptor

antagonist that acts both periferally and centrally

and has shown to be effective in treating duralinflammation in guinea pig


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THANK YOU

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Therapy of Migraine