RECENT ADVANCES IN MIGRAINE THERAPY

Dr. Abialbon Paul M.D. Pharmacology, Junior Resident

1

Migraine, just a headache

 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.

A 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

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

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
7

Changing paradigms in understanding of migraine pathophysiology

Migraine with aura

Diagnostic criteria: A. At least 2 attacks fullling criteria BD B. Aura consisting of at least one of the following, but no motor weakness:
1. fully reversible visual symptoms including positive features (eg, ickering 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 fullling criteria BD for Migraine without aura begins during the aura or follows aura within 60 minutes E. Not attributed to another disorder.

Migraine without aura

Diagnostic criteria: A. At least 5 attacks fullling criteria BD B. Headache attacks lasting 472 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
10

E. Not attributed to another disorder

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

11

Cortical Spreading Depression

TGVS

Central sensory areas 12

Figure1. Pathogenesis of migraine

Current therapies
Specific migraine treatment Triptans Sumatriptan Rizatriptan Naratriptan Zolmitriptan Eletriptan Almotriptan Frovatriptan Ergot and its derivatives Ergotamine + caffeine Dihydroergotamine

13

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

14

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

16

CGRP receptor antagonists

Calcitonin Gene Related Peptide Alternative splicing of calcitonin gene in ch11 CGRP & CGRP Potent vasodilator & neurotransmitter in nociceptive pathways

17

Why CGRP receptor antagonists?

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.
18

 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 tolerability

19

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??

20

21
Figure 2. Efficacy and adverse effect profile of triptans and telcagepant in different RCTs Dose strengths are plotted along X-axis and %efficacy/ADR events in Y-axis
(8)

Newer drugs in the pipeline

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
22

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

23

 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.
24

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

25

 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
26

 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

27

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 colocalised 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.

28

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
29

 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.

30

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

Table1: Drugs for acute management in clinical trials

32

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

33

 Novel iontophoretic sumatriptan transdermal patch

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

34

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

35

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)
36

Criteria for prophylaxis

37

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

38

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

Grade A evidence: Multiple randomized clinical trials with consistent findings to support efficacy divalproex, 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 support Gabapentin, 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 trials Diltiazem, bupropion, mirtazapine, phenelzine, trazodone, venlafaxine, ibuprofen, cyproheptadine, fluvoxamine, paroxetine, sertraline, doxepin, imipramine, nortriptyline, protriptyline

39

40

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

41

 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

42

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
43

Gap junctions

Figure 4: structure of gap junctions

44

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

46

 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 prophylaxis

47

48

Figure 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

49

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.
50

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

51

52

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

53

References
1. Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the differences between episodic migraine and chronic migraine. Curr Pain Headache Rep. 2012 Feb;16(1):8692. 2. Kalra AA, Elliott D. Acute migraine: Current treatment and emerging therapies. Ther Clin Risk Manag. 2007 Jun;3(3):44959. 3. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Headache Classification Committee of the International Headache Society. Cephalalgia. 1988;8 Suppl 7:196. 4. Mehrotra S, Gupta S, Chan KY, Villaln CM, Centurin D, Saxena PR, et al. Current and prospective pharmacological targets in relation to antimigraine action. Naunyn Schmiedebergs Arch Pharmacol. 2008 Oct;378(4):37194. 5. Gupta VK. Cortical-spreading depression: at the razors edge of scientific logic. J Headache Pain. 2011 Feb;12(1):456. 6. Weir GA, Cader MZ. New directions in migraine. BMC Med. 2011;9:116. 7. Ferrari A, Tiraferri I, Neri L, Sternieri E. Why pharmacokinetic differences among oral triptans have little clinical importance: a comment. J Headache Pain. 2011 Feb;12(1):512. not? J Headache Pain. 2011 Dec;12(6):593601.

54

8. Tfelt-Hansen P. Optimal balance of efficacy and tolerability of oral triptans and telcagepant: a review and a clinical comment. J Headache Pain. 2011 Jun;12(3):27580. 9. Gilmore B, Michael M. Treatment of acute migraine headache. Am Fam Physician. 2011 Feb 1;83(3):27180. 10. Negro A, Martelletti P. Chronic migraine plus medication overuse headache: two entities or not? J Headache Pain. 2011 Dec;12(6):593601. 11. Durham PL, Vause CV. Calcitonin gene-related peptide (CGRP) receptor antagonists in the treatment of migraine. CNS Drugs. 2010 Jul;24(7):53948. 12. Negro A, Lionetto L, Simmaco M, Martelletti P. CGRP receptor antagonists: an expanding drug class for acute migraine? Expert Opin Investig Drugs. 2012 Jun;21(6):80718. 13. Monteith TS, Goadsby PJ. Acute migraine therapy: new drugs and new approaches. Curr Treat Options Neurol. 2011 Feb;13(1):114. 14. Evans MS, Cheng X, Jeffry JA, Disney KE, Premkumar LS. Sumatriptan Inhibits TRPV1 Channels in Trigeminal Neurons. Headache. 2012 May;52(5):77384. 15. Olivia J. Phung P. Orally inhaled dihydroergotamine: A novel ergot delivery method for the treatment of migraine [Internet]. Formulary. 2012 [cited 2012 Jun 20]. Available from: http://formularyjournal.modernmedicine.com/formulary/Modern+Medicine+N ow/Orally-inhaled-dihydroergotamine-A-novel-ergotdel/ArticleStandard/Article/detail/758883

55

16. Tepper SJ, Stillman MJ. What is the best drug-delivery approach for the acute treatment of migraine? Expert Rev Neurother. 2012 Mar;12(3):2535. 17. Mannix LK. Clinical advances in the preventive treatment of migraine. Acta Neurol Taiwan. 2004 Dec;13(4):15869. 18. Modi S, Lowder DM. Medications for migraine prophylaxis. Am Fam Physician. 2006 Jan 1;73(1):728. 19. Loj J, Solomon GD. Migraine prophylaxis: who, why, and how. Cleve Clin J Med. 2006 Sep;73(9):793794, 797, 800801 passim. 20. Krymchantowski AV, da Cunha Jevoux C, Bigal ME. Topiramate plus nortriptyline in the preventive treatment of migraine: a controlled study for nonresponders. J Headache Pain. 2012 Jan;13(1):539. 21. Durham PL, Garrett FG. Neurological mechanisms of migraine: potential of the gap-junction modulator tonabersat in prevention of migraine. Cephalalgia. 2009 Nov;29 Suppl 2:16. 22. Durham PL, Cady R. Insights into the mechanism of onabotulinumtoxinA in chronic migraine. Headache. 2011 Dec;51(10):1573 7. 23. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ. New migraine preventive options: an update with pathophysiological considerations. Rev Hosp Clin Fac Med Sao Paulo. 2002 Dec;57(6):2938. 24. Barbanti P, Aurilia C, Egeo G, Fofi L. Future trends in drugs for migraine prophylaxis. Neurol Sci. 2012 May;33 Suppl 1:13740. 25. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalso J. Harrison's principles of internal medicine. 18th Edition The McGraw-Hill Companies, Inc. 2012.

56

Queries

57

58

Thank You