RECENT ADVANCES IN MIGRAINE THERAPY

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Dr. Abialbon Paul

M.D. Pharmacology, Junior Resident

Migraine, just a headache

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“ Each day that I have a migraine,

it is a struggle to work, to move, sometimes even to breath.

That day, it began with stiffness in my neck and

an ache around my temples and brow bone.

I found it difficult to focus on the screen or on the words that

I was hearing. I began to see spots in front of my eyes.

I staggered across the hall to my room, not knowing whether

I would make it to my bed. In my room, I shut out all the light,

closed my laptop and hid myself under the covers. Even the

whirring of my laptop caused an annoying resonance in my

ears. I covered my head with my pillow and soon I found the

relief of sleep. I slept for the next fifteen hours, waking up

refreshed and new the next morning.”

3A day in the life of a migraineur

Migraine, just another headache?

• Yawning• Low mood• Irritability• Fatigue• Anorexia• Nausea & Vomiting• Throbbing headache• Photophobia & phonophobia• Hemiplegia• Blindness• Migranous infarction• Death

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Phases of migraine

• Prodrome

• Aura

• Headache

• Postdrome

• Resolution 5

Outline

• Introduction• Current understanding of migraine pathogenesis• Newer neuronal targets• Newer approaches to old drugs• Need for prophylaxis• Newer drugs for prophylaxis• Migraine genetics• Conclusion

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Introduction• Migraine is a complex heterogeneous neurovascular

disease

• Affects 15% general population, 3 times more common in females

• Varied clinical manifestations

• Lack of awareness among physicians as well as patients

• Changing paradigms in understanding of migraine pathophysiology

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Migraine with aura

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Diagnostic criteria:• A. At least 2 attacks fulfilling criteria B–D• B. Aura consisting of at least one of the

following, but no motor weakness:• 1. fully reversible visual symptoms including positive

features (eg, flickering lights, spots or lines) and/or negative features (ie, loss of vision)

• 2. fully reversible sensory symptoms including positive features (ie, pins and needles) and/or negative features (ie, numbness)

• 3. fully reversible dysphasic speech disturbance

• C. At least two of the following:• 1. homonymous visual symptoms and/or unilateral

sensory symptoms• 2. at least one aura symptom develops gradually

over ≥5 minutes and/or different aura symptoms occur in succession over ≥5 minutes

• 3. each symptom lasts ≥5 and <60 minutes

• D. Headache fulfilling criteria B–D for Migraine without aura begins during the aura or follows aura within 60 minutes

• E. Not attributed to another disorder. 9

Migraine without aura

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• Diagnostic criteria:• A. At least 5 attacks fulfilling criteria B–D• B. Headache attacks lasting 4–72 hours • C. Headache has at least two of the following

characteristics:• 1. unilateral location• 2. pulsating quality• 3. moderate or severe pain intensity• 4. aggravation by or causing avoidance of routine physical

activity (eg, walking or climbing stairs)

• D. During headache at least one of the following:• 1. nausea and/or vomiting• 2. photophobia and phonophobia

• E. Not attributed to another disorder

Migraine pathogenesis

• Cortical Spreading Depression (CSD)• Trigeminovascular System (TGVS)• Peripheral & Central sensory dysmodulation

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Figure1. Pathogenesis of migraine

Cortical Spreading Depression

TGVS

Central sensory areas

Current therapies

Specific migraine treatment• Triptans

Sumatriptan

Rizatriptan

Naratriptan

Zolmitriptan

Eletriptan

Almotriptan

Frovatriptan• Ergot and its derivatives

Ergotamine + caffeine

Dihydroergotamine13

Current therapies

• . Nonspecific pharmacological treatment• Anti-emetics (metoclopramide)• NSAIDs and nonnarcotic analgesics• Narcotics – Opiate analgesics

• Miscellaneous medications:• Steroids, isometheptene, intranasal lidocaine

Valproic acid IV• Non-pharmacological treatment

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Limitation of current therapies

• Pharmacokinetics – Variable oral bioavailability• Nausea & vomiting of migraine• Less effective after initiation of headache phase of

the attack• 50-70% efficacy in terminating acute attacks• Side effect profile, concern on ischemic adverse

events• Contraindication in vascular diseases• Medication overuse headache and chronicization of

migraine 15

Newer neuronal targets

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CGRP receptor antagonists

• Calcitonin Gene Related Peptide• Alternative splicing of calcitonin gene in ch11• αCGRP & βCGRP• Potent vasodilator & neurotransmitter in

nociceptive pathways

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Why CGRP receptor antagonists?

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• Location of receptors• Levels of CGRP were found elevated in the

external jugular vein in migraineurs during an acute attack

• CGRP levels normalised after treatment of the acute migraine attack.

• Infusion of human CGRP precipitated migraine attacks in susceptible individuals.

• Olcegepant - first CGPR receptor antagonist to be studied.

• Found effective in phase II trails.• Intravenous administration • Telcagepant, a potent orally active CGRP

receptor antagonist • Phase III• Similar efficacy to sumatriptan with better

tolerability19

Telcagepant

• Phase II trial studying Telcagepant in migraine prophylaxis resulted in elevation of liver enzymes after 300 mg twice a day for 3 months

• Off-target effect or CGRP antagonism??

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Figure 2. Efficacy and adverse effect profile of triptans and telcagepant in different RCTs (8)

Dose strengths are plotted along X-axis and %efficacy/ADR events in Y-axis

Newer drugs in the pipeline

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• BMS-927711 – Phase I

• BI 44370 TA - Phase II

• “gepants” will be of major use in treating migraine patients with contraindications for triptans & those not tolerating triptans

5HT1F receptor agonists

• 5HT1F receptors activation inhibits the trigeminal nucleus fos activation which is a marker for neuronal activation and firing

• Triptans also have agonist action on the 5HT1F

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• LY-334370, a potent 5HT1F agonist was found to be effective but with adverse actions on the central nervous system unrelated to its anti-migraine action.

• COL-144, another 5HT1F agonist has been found to be effective in phase II trial and is under further investigations.

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Glutamate receptor antagonists

• Glutamate is one of the important excitatory neurotransmitters in the central nervous system involved in sensory and nociceptive pathways

• Ionotropic glutamate receptors (comprises of NMDA, AMPA & Kainate receptors)

• G protein coupled metabotropic receptors

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• Central nociceptive dysmodulation may involve aberrant glutaminergic transmission

• Glutamate neurons in the trigeminal ganglia mostly

express 5-HT1B/1D/1F receptors, which have been proposed to modulate glutamate release.

• Glutamate is also implicated in trigeminovascular activation and cortical spreading depression

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• Currently three drugs are in phase II clinical trials:• BGG492 - AMPA receptor antagonist • Tezampanel (LY-293558) - AMPA and kainate

receptor antagonist• LY466195a - GLUK5 and kainate receptor

antagonist

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Transient receptor potential vanilloid (TRPV1) receptor antagonists

• TRPV1 receptors are cation channels activated by capsaicin and are present in nociceptive neurons of the central and peripheral nervous system.

• These receptors are present in the human trigeminal neurons with a sub group being co-localised along with the CGRP receptors.

• Sumatriptan is also known to block these receptors

• SB-705498 is a TRPV1 receptor antagonist and is in Phase II of clinical testing.

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Nitric oxide synthesis inhibition

• Glyceryl trinitrate infusion causes an acute attack of migraine. The vasodilation of cranial vessels were implicated in the trigger of migraine attacks

• Magnetic Angiography studies revealed that vasodilation caused by glyceryl trinitrate resolved before the attack of headache

• NO has been proposed to activate trigeminovascular fibres and thus release CGRP

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• NXN-188, a nNOS inhibitor with additional 5HT1B/1D

agonist activity is currently in phase II trials.

• GW274150 is an inducible NOS inhibitor in phase II of clinical trials.

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Prostanoid receptor antagonists

• Prostaglandin E2 is one of the important mediators of inflammation and pain.

• EP1 and EP3 mediate smooth muscle contraction

• EP2 and EP4 induce smooth muscle relaxation.

• EP4 are present on the cerebral vasculature and are thought to mediate anti-nociceptive action

• Currently BGC20-1531, a prostaglandin EP4 competitive antagonist is in clinical trials 31

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Table1: Drugs for acute management in clinical trials

Newer approach to older drugs

• Orally inhaled dihydroergotamine • Phase III clinical trial (FREEDOM-301) has been

completed and it is currently undergoing FDA review• rapidly and completely absorbed and reaches

Cmax in 12 minutes

• provide a quicker relief

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• Novel iontophoretic sumatriptan transdermal patch

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Figure 3. Mechanism of drug delivery of a sumatriptan transdermal system

FDA approved formulations

• A needle-free injection of sumatriptan - SUMAVEL®

• An epipen-type needle injection of sumatriptan - ALSUMA

• Rapid-dissolution oral tablets of sumatriptan - IMITREX® RT,

• Soluble oral diclofenac under trade name - CAMBIA™

• Intranasal ketorolac SPRIX®

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Need for prophylactic Rx

• Limitation of dosage allowance per week to prevent toxicity

• The efficacy of these drugs decreases when administered after the onset of the headache

• Physiological changes, non-specific disabling symptoms may occur during the migraine free periods in chronic migraine.

• Long term frequent use of acute abortive treatment may transform the migraine to Medication overuse headache (MOH)

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Criteria for prophylaxis

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Limitations of the current drugs

• Side effects • Limited efficacy• The mechanism of action of most of the prophylactic

drugs is unknown or poorly understood. These drugs are used based on their effectiveness as shown by the various clinical trials

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Table 3. Drugs for migraine prophylaxis. Current levels of evidence

Grade A evidence: Multiple randomized clinical trials with consistent findings to support efficacydivalproex, topiramate, propranolol, timolol, pizotifen (not approved in the United States)amitriptyline

Grade B evidence: Few randomized trials with some evidence supported by recommendation, suboptimal scientific supportGabapentin, atenolol, metoprolol, nadolol, nimodipine, verapamil (cyclandelate and flunarizine not approved in the United States), botulinum toxin type A, aspirin, fenoprofen, flurbiprofen, ketoprofen, mefenamic acid, naproxen, fluoxetine, estradiol, feverfew, magnesium, vitamin B2

Grade C evidence: US Headache Consortium consensus (published in 2000) in the absence of relevant controlled clinical trialsDiltiazem, bupropion, mirtazapine, phenelzine, trazodone, venlafaxine, ibuprofen, cyproheptadine, fluvoxamine, paroxetine, sertraline, doxepin, imipramine, nortriptyline, protriptyline 39

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Topiramate

• Topiramate acts by• Inhibition of voltage-gated sodium channels• Inhibition of high voltage-activity (L-type) calcium

channels• Facilitates neuronal potassium conductance• Augments the inhibitory chloride ion flux caused

by GABA

• Recent evidence favours use of topiramate as the first line choice for migraine prophylaxis

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• A randomised, double-blind, multicentre trial comparing two doses of topiramate (100mg & 200mg) with placebo and propranolol as active control concluded that 100mg of topiramate was effective than the placebo and had similar efficacy of propranolol.

A recent RCT of 38 patients which compared

topiramate monotherapy vs. topiramate + nortriptyline

37% 78.3%

had at least 50% reduction in headache

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Side effects

• Frequent• paraesthesia• fatigue• loss of weight• mild nausea

• Rare side effects • CNS slowing or word finding difficulties• renal stones• secondary angle closure glaucoma

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Gap junctions

Figure 4: structure of gap junctions44

Tonabersat

• Gap junctions connect the protoplasm of two adjacent cells aiding in cellular transfer and communication.

• A gap junction between two cells is formed by the fusion of two hemichannels from adjacent cells.

• Play a role in propagation of calcium waves. • Calcium waves are intracellular increases in the

calcium concentration which spreads to the adjacent cells propagating the hyperactivity of the neurons

• Tonabersat has completed phase II clinical trials 45

OnabotulinumtoxinA

• OnabotulinumtoxinA functions to inhibit the release of excitatory mediators by preventing the fusion of intracellular vesicles

• Injection of onabotulinumtoxinA at the designated therapeutic sites in the head, neck, and shoulders would result in internalization of the neurotoxin into nearby motor or sensory neurons

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• OnabotuliunumtoxinA in motor neurons inhibits the release of acetylcholine, resulting in muscle paralysis.

• Internalization of the neurotoxin in sensory neurons that innervate the skin and muscles could potentially inhibit the release of proinflammatory mediators at several sites within the sensory neuron.

• It also supresses the second order sensory neurons and the glial cells which are involved in sensitization of central nociception

• Approved for chronic migraine prophylaxis47

48Figure 5: Mutations implicated in migraine pathogenesis

Another gene KCNK18 which encodes for TRESK is implicated in migraine with aura.

TRESK is a neuronal potassium channel

Targeting TRESK is a viable pharmacological target for migraine pathogenesis

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Conclusion

• Migraine is a complex multigenic clinically heterogenous neuronal disorder

• The cascade of events is migraine pathogenesis is not well understood.

• The newer neuronal targets promise better acute abortive treatment options.

• It could be well hypothesized that different targets may have varying levels of importance in different patients. There are no studies to show treatment response to newer drugs on older drug non-responders.

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• Further identifying genetic mutations can identify subgroup of patients who would respond better to specific therapeutic targets.

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Future of migraine…

“I began to experience some stiffness in my neck and an ache around my temples. I knew it was an attack of

migraine. I took my inhaler from my bag and took a puff. In 10 minutes I was relieved of the pain. Then I went to the

cinema with my friends and enjoyed the whole day”

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Queries

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Thank You