recent advances in migraine

01/05/2023 Department of Pharmacology & Therapeutics 1

Recent Advances: Migraine

Guide: Dr Raakhi Tripathi

JR-2: Dr Anup Petare


Recent Advances: Migraine

Guide: Dr Raakhi Tripathi

JR-2: Dr Anup Petare


Overview

• Definition• Epidemiology• Types/Classification/Grades• Pathogenesis• Current therapy• Recent advances


Migraine is a chronic neurological disorder characterized by recurrent attacks of headache widely variable in intensity, frequency and duration. Attacks are commonly unilateral and are usually associated with anorexia, nausea and vomiting.

Migraine

- World Federation of Neurology


MigraineDisabling Primary Headache disorder

Ranked 19th by the WHO among all diseases world-wide causing disability

IHS: migraine constitutes 16% of primary headaches

In India, 15-20% of people suffer from migraine with M:F ratio of 1:2

WHO: Severe migraine can be as disabling as quadriplegia


Two major sub-types,

Migraine without aura (common migraine)• Headache with specific features and associated

symptoms

Migraine with aura (classic migraine)• Focal neurological symptoms that usually precede or

sometimes accompany the headache. • Some experience premonitory phase, occurring hours

or days before the headache, and a headache resolution phase


Grades of Migraine Mild migraine: may be one attack per month throbbing but tolerable headache lasting upto 8 hours which does not incapacitate the individual

Moderate migraine: The throbbing headache more intense, lasts for 6-24 hours, nausea/vomiting and other features are more prominent patient is functionally impaired. One or more attacks occur per month.

Severe migraine: 2-3 or more attacks per month of severe throbbing head ache lasting 12-48 hours, often accompanied by vertigo, vomiting and other symptoms; the subject grossly incapacitated during the attack.


Pathogenesis

Vascular theory

Neurogenic

theory

Neurogenic

inflammation

Aura results from intracranial vaso-constriction Headache results from subsequent rebound vasodilatation

Cortical spreading depression of the electrical activity followed by vascular pheno mena

Triggered by Trigeminal sensory system mediated by 5-HT, neurokinin, substance P, calcitonin gene related peptide (CGRP), nitric oxide, etc.


Neurovascular Theory


Signaling cascade

Current therapeutic option..

Acute treatment

Preventive

treatmentBehavioural treatment

To reduce pain and duration of attack

To reduce frequency of attacks and

disability

Identification of triggers Meditation Psychotherapy

Acute/ Abortive therapy

Non-specific treatment: NSAID’sSpecific treatment: Ergot alkaloids 5-HT receptor agonist (Triptans)

Acute therapy: TriptansSelective 5-HT 1B/1D agonist Sumatriptan Almotriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Zolmitriptan

Similar efficacyDiffering

Pharmacokinetic profile

Acute / Abortive therapyFailed analgesics or NSAIDsOral Sumatriptan 50 mg or 100 mg, Rizatriptan 10mg Almotriptan 12.5 mg, Eletriptan 40 mg, Zolmitriptan 2.5 mg

For slower effect or better tolerability: Oral Naratriptan 2.5 mg, Frovatriptan 2.5 mg

Infrequent headache:Ergotamine 1-2 mg oral, Dihydroergotamine nasal spray 2 mg

Headache recurrenceErgotamine 2 mg (perhaps most effective taken rectally, usually with caffeine)Oral Naratriptan 2.5 mg and Eletriptan 80 mg

Early nausea or difficulties taking tabletsSumatriptan 20 mg nasal spray, Zolmitriptan 5 mg nasal spray, Rizatriptan 10 mg dissolvable wafer, zolmitriptan 2.5 mg dispersible tablet ± Anti-emetics

Early vomitingSumatriptan 25 mg suppository, Sumatriptan 6 mg subcutaneous injection ± Anti-emetics

Rapidly developing symptomsSumatriptan 6 mg subcutaneous injection,Dihydroergotamine 1 mg intramuscular injection

Acute / Abortive therapy

Contraindications to Triptans

Coronary artery disease Hypertension Peripheral vascular disease Hemiplegic or Basilar migraine Avoid in those on Ergots, SSRI and TCA Pregnancy and Lactation Should not be used for more than 2 days a week

to decrease the possibility of rebound headache

Preventive therapy

Beta- blockers Propranolol Metoprolol Timolol

Calcium channel blockers Flunarizine Verapamil

Tricyclic antidepressants Amitryptiline Nortryptiline

Anti-epileptics/ Neurostabilizers Topiramate Divalproex sodium Gabapentin

Serotonin antagonists Pizotifen Methysergide

Serotonergic agents Dihydroergotamine

Recent advances

New FDA approvals

New uses of existing drugs

Drugs in pipeline

New devices


Recent Advances: In acute Treatment

Brandes JL, Kudrow D, Stark SR, O'Carroll CP, Adelman JU, O'Donnell FJ, Alexander WJ, Spruill SE, Barrett PS, Lener SE. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA. 2007;297:1443–54. doi: 10.1001/jama.297.13.1443.


Reduction in migraine frequency in patients with chronic migraine with analgesic overuse.

Silvestrini M, Bartolini M, Coccia M, Baruffaldi R, Taffi R, Provinciali L. Topiramate in the treatment of chronic migraine. Cephalalgia. 2003;23:820–4. doi: 10.1046/j.1468 2982.2003.00592.x.Silberstein SD, et L Topiramate Chronic Migraine Study Group Efficacy and safety of topiramate for the treatment of chronic migraline: a randomised, double blind, placebo controlled trial. Headache.2007;47:170–80. doi: 10.1111/j.1526 4610.2006.00684.x. Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ, TOPMAT MIG 201(TOP CHROME) Study Group Topiramate reduces headache days in chronic migraine: a randomised, double blind, placebo controlled study. Cephalalgia. 2007;27:814–23. doi: 10.1111/j.1468 2982.2007.01326.x.


New FDA approvals


TOPAMAX

• March 28, 2014: 1st FDA approval for prophylaxis of migraine headaches in adolescents ages 12 to 17 (100mg)

• ADR: paresthesia, upper respiratory infection, anorexia, abdominal pain


Treximet

• Treximet (Sumatriptan/Naproxen Sodium) Formerly Known as TREXIMA,

• May 2012: Menstrual Migraine in Women With Dysmenorrhea Phase 3 study was completed

https://clinicaltrials.gov/ct2/show/NCT00329459?term=Imitrex+menstrual+migraine&rank=1


Zomig (Zolmitriptan)

• October 2008: USFDA approved Zomig (zolmitriptan) Nasal Spray

• Jan 2015: Treatment of Acute Migraine Headache in Adolescents (TEENZ) Phase 4 study was completed


BOTOX® (OnabotulinumtoxinA)

• 15 Oct 2010 USFDA approved Botox inj : Prevent headaches in adult patients with chronic

migraine. every 12 weeks as multiple injections around the head and neck

• ADR: neck pain and headache.

• Boxed warning: Botulinum toxin may spread from the area of injection to other areas of the body, causing symptoms similar to those of botulism


Transdermal patch: Sumatriptan

January 2013, FDA approved: acute medication sumatriptan delivery by new mechanism (transdermal patch)

ADR: Painful sensation at the patch application site, reddening


• Otopoint-needle implant can effectively relieve headache in migraine patients

• Upregulate plasma 5-HT level.

http://onlinelibrary.wiley.com/o/cochrane/clcentral/articles/654/CN-00778654/frame.html accessed on 3.4.2015.

Acupuncture:

New uses of existing drugs

Dexamethasone addition to standard acute therapy

Proposed to prevent recurrence of migraine through its prevention of neurogenic inflammation

7 Randomized clinical trials (n = 742)

Dexamethasone vs placebo (both + standard therapy): Dexa group was less likely to experience recurrent headache within 24 to 72 hours

Conclusion: Dexamethasone appears to be safe and modestly effective addition to standard migraine abortive therapy for the prevention of migraine recurrenceGiuliano C, Smalligan RD, Mitchon G, Chua M. Role of dexamethasone in the prevention of migraine recurrence in the acute care setting: a review. Postgrad Med. 2012

May;124(3): 110-5

Carvedilol

Additional alpha-1 blocking and antioxidant properties

A very favourable adverse event profile A prospective, open-label trial in 76 patients with

doses titrated from 3.125 mg/day to 6.25 mg twice daily over 2 weeks revealed,

50% reduction in monthly migraine attack frequency at the third month of treatment in 59% patients,

But, 26% patients withdrew due to lack of efficacy or as a result of adverse eventsBigal ME, Krymchantowski AV. Emerging Drugs for Migraine Prophylaxis and Treatment. Medscape General Medicine. 2006;8(2):31.

Tiagabine (TGB) Inhibits the neuronal and glial reuptake of GABA and

therefore enhances GABA-mediated inhibition Open-label study in 41 patients with refractory

migraine using a mean dose of 10 mg/day TGB revealed,

5 patients experienced a remission of their migraine attacks

33 patients had at least a 50% reduction in their attacks

Side effects reported were dizziness, asthenia, tremor and abdominal pain

Safety alert issued in 2005: Risk of new onset seizures and status epilepticus in patients without a history of epilepsy

Levetiracetam Promising drug for the treatment of transformed

migraine Open label trial in 36 transformed migraine patients

with 1000 mg/day of LCT revealed significant reduction in headache frequency at 1 month and 3 months

Efficacy and safety evaluated in 30 patients ( aged 6 – 19 years) with paediatric migraine with 125 – 250 mg BD revealed,

At least 50% reduction in headache frequency and severity in 17 patients with improved quality of life

Used off-label for migraine prophylaxis

Brighina F, Palermo A, Aloisio A, Francolini M, Giglia G, Fierro B. Levetiracetam in the prophylaxis of migraine with aura: a 6-month open-label study. Clin Neuropharmacol. 2006 Nov-Dec;29(6):338-42

Miller GS. Efficacy and safety of levetiracetam in pediatric migraine. Headache. 2004 Mar;44(3):238-43

Zonisamide

Unique combination of pharmacologic actions: Blocks voltage-dependent sodium and T-type

calcium channels Reduces glutamate-mediated excitatory

neurotransmission Inhibits excessive nitric oxide (NO) production,

scavenging hydroxyl and NO radicals Inhibits carbonic anhydraseAll of these mechanisms may play a role in headache and pain modulation possibly via neuronal stabilization

2 open-label trials:

One in 33 patients and second in 34 patients with

refractory migraine with 100 mg/day Zonisamide

showed,

Significant reduction in frequency and severity of

migraine

Side effects reported included paraesthesia,

fatigue, anxiety, and weight lossBermejo PE, Dorado R. Zonisamide for migraine prophylaxis in patients refractory to topiramate. Clin Neuropharmacol. 2009 Mar-Apr;32(2):103-6

Quetiapine

Atypical antipsychotic drug with a high affinity for D4 receptors

Also possesses, High affinity for 5-HT2 receptors Partial agonistic activity at 5-HT1A receptors Blocking activity at alpha1-adrenergic receptors In an open label pilot study in 34 pts with

refractory migraine, 75.9% presented > 50% headache reduction

Potential for migraine prophylaxis

Krymchantowski AV, Jevoux C. Quetiapine for the prevention of migraine refractory to the combination of atenolol + nortriptyline + flunarizine: an open pilot study. Arq Neuropsiquiatr. 2008 Sep;66(3B):615-8.

Tizanidine hydrochloride Alpha-2-adrenergic presynaptic agonist that

inhibits the release of norepinephrine in the brainstem and spinal cord

An open study of 220 patients demonstrated efficacy in chronic migraine

Evidence supports tizanidine as an effective prophylactic adjunct for chronic daily headache

Also, possible importance of an alpha2-adrenergic mechanism underlying the pathophysiology of migraine is suggested

Saper JR, Lake AE 3rd, Cantrell DT, Winner PK, White JR. Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study. Headache. 2002 Jun;42(6):470-82.

Petasites/Butterbur

Extract from the plant Petasites hypridus (butterbur) Inhibits peptide-leukotriene biosynthesis, possibly

through calcium channel regulation efficacy in migraine prevention was studied in 2 trials, A small RCT reported: low dose of petasites, 50 mg

twice daily, significantly reduced the number of migraine attacks per month and the number of migraine days per month

A larger RCT over 5 month by Lipton and colleagues reported:

4-month mean attack count reduced by 48% in patients treated with petasites 75 mg twice daily, by 34% with petasites 50 mg twice daily


Holland PR, Akerman S, Andreou AP, Karsan N, Wemmie JA, Goadsby PJ. Acid-sensing ion channel 1: a novel therapeutic target for migraine with aura. Ann Neurol. 2012 Oct;72(4):559-63. doi: 10.1002/ana.23653. PubMed PMID: 23109150.

Acid-sensing ion channel 1

• Novel therapeutic target for migraine with aura.

• Amiloride: Shown to block cortical spreading depression via this mechanism


Drugs in pipeline


Phase 3: Completed

TARGET:A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Evaluating the Efficacy and Safety of a Single 20 mg Dose of Sumatriptan Powder Delivered Intra-nasally with the Bi-Directional Device in Adults With Acute Migraine With or Without AuraHead-to-Head Comparison Trial: COMPASS: Efficacy and Safety of 20 mg Sumatriptan Powder Delivered Intranasally With the Bi-Directional Device Compared With 100 mg Sumatriptan Tablets in Adults With Acute Migraine With or Without AuraPG Djupesland, P Dočekal, the Czech Migraine Investigators Group Intranasal sumatriptan powder delivered by a novel breath-actuated bi-directional device for the acute treatment of migraine: A randomised, placebo-controlled study Cephalalgia August 2010 vol. 30 no. 8 933-942


NXN-188

• 20 July 2014 trial NXN 188 for the Treatment of Migraine With Aura completed its Phase 2

• Immediate release oral product

• Novel mechanism, selective inhibition of neuronal Nitric Oxide Synthase (nNOS), as well as 5-HT1B/1D activation


Levadex (Dihydroergotamine)

• Multi-center trial, FREEDOM-301, consisted of a randomized, double blind, placebo-controlled

• 16 April 2013 USFDA issued Complete Response Letter on NDA of Levadex raising concern over manufacturing process for the final filled canisters.


• Glutamate receptors antagonist

• In 2007 Phase 2 was completed

https://clinicaltrials.gov/ct2/show/NCT00567086?term=tezampanel&rank=1

Tezampanel(NGX424MIG2001)


Telcagepant (MK-0974)

• In 2010 merck terminated it study with Telcagepant

(0974-049) • Terminated: Identification of two patients with

significant elevations in serum transaminases

• 27 Jan 2015: Phase 3 study of Telcagepant (MK-0974-011) in Participants With Moderate to Severe Acute Migraine With or Without Aura

https://clinicaltrials.gov/ct2/show/NCT00442936?term=telcagepant&rank=1

• Antagonist of the receptor for CGRP


Edvinsson L. CGRP receptor antagonism in migraine treatment. Lancet. 2008;372:2089–90. doi:10.1016/S0140 6736(08)61710 9.

ADX10059


New devices


• 13 December 2013: FDA allows marketing of first device to relieve migraine headache pain (Cerena)

• Device delivers Pulse transcranial magnetic stimulation at the onset of headache or aura

• Disrupts cortical spreading depressionwww.accessdata.fda.gov/cdrh_docs/pdf13/den130022.pdf

Cerena


Cefaly

http://www.accessdata.fda.gov/cdrh_docs/pdf12/k122566.pdf

• 11 March 2014: USFDA approved device for preventing migraine.

• Transcutaneous Electrical Nerve Stimulator to Treat Headache

• Warnings: Indicated for use by adults and should only be used for 20 minutes/day,

• ADR: Tingling or massaging sensation where electrode applied.


Conclusion• <60% migraine patients respond & tolerate preventatives1

• Need for better options for the symptomatic and preventative treatment of migraine

• future seems bright as understanding of the disease improving newer and safer treatment are rising.

1: Pascual J. Recent advances in the pharmacological management of migraine. F1000 Med Rep. 2009 May 8;1. pii: 39. doi: 10.3410/M1-39. PubMed PMID: 20948742; PubMed Central PMCID: PMC2924709.

recent advances in migraine

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