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The World Health Organization considers that severe migraine can be as disabling as quadriplegia Traditionally, headache is given little time in medical teaching, but headache science is advancing rapidly, fuelled by developments in treatment and neuroscience diagnosis and management
Globally, 11-13% of the adult population suffers from active migraine
in the Global Burden of disease study, updated in 2004, migraine on its own was found to account for 1.3 % of all years of life lost to disability worldwide specialists use international headache society diagnostic criteria to support diagnosis in 56 % of countries that responded. usage is lower in africa, the eastern Mediterranean and south-east asia and very low in low- income countries generally. little is done to encourage their use in low-income countries.
(Menken M, Munsat TL, Toole JF. The global burden of disease study—implications for neurology. Arch Neurol 2000;57:418-20). (The World Health Organization considers that severe migraine can be as disabling as quadriplegia)
WHO considers that
Migraine without aura (common migraine) clinical syndrome characterised by headache with specific features and associated symptoms Migraine with aura (classic migraine) characterised by focal neurological symptoms that usually precede or sometimes accompany the headache. Some patients also experience a premonitory phase, occurring hours or days before the headache, and a headache resolution phase.
Premonitory and resolution symptoms include hyperactivity, hypoactivity, depression, craving for particular foods, repetitive yawning and other less typical symptoms reported by some patients.
International classification of headache disorders (ICHD-III)
Even after a century of intense studies, the pathophysiology of migraine is still poorly understood and controversial. Vascular theory emerged from the observation that superficial temporal artery pulsations increased in amplitude with increased throbbing quality of pain.
The Neurovascular theory suggests that… Migraine involves the trigeminal nerve distribution to intracranial arteries. These nerves release peptide neurotransmitters, especially calcitonin gene related peptide, an extremely powerful vasodilator. Substance P and Neurokinnin A may also be involved. Vasodilatation results in extravasation of plasma and plasma proteins into the perivascular space leading to edema. The mechanical stretch then caused by the perivascular edema is the cause of activation of pain nerve endings in the duramater. Also…. It is found that CGRP is the main mediator of trigeminal pain signals. It is released from trigeminal ganglion neurons, both peripherally at the dura and centrally in the spinal trigeminal nucleus and other sites within the CNS. Activation of CGRP receptors on terminals of primary afferent neurons facilitates transmitter release on spinal neurons and increases glutamate activation of AMPA receptors. And.. TRPV1 receptors play an important role in modulating trigeminal sensory processing and for this have been proposed as potential targets for migraine treatment.
Also, now the researchers have identified what they call a “missing link” in the signaling chain from stressed cortical neurons to meningeal pain. That is, the Pannexin 1 mega channels that form large trans membrane pores in the neurons. Opening of the Panx1 mega channels in response to cortical stress, is the spark that ignites the inflammatory cascade and causes and sustains the headache in migraine sufferers. Panx1 channels are opened by the cortical spreading depression, which then leads to caspase 1 activation, a pro-inflammatory signal, which, in turn, causes release of high mobility group box-1 (HMGB1) proteins and activation of nuclear factor kappa B in astrocytes. These stimuli cause sustained production and release of inflammatory mediators from the glia limitans, a membrane covering brain that regulates the movement of small molecules and cells in the parenchymal tissue of the brain. The authors suggest that Panx1 channels may be a new target for migraine prophylaxis and also the downstream inflammatory mediators may also be selectively targeted, or should be considered in mechanisms of action of anti -inflammatory drugs already used in treatment of migraine headache.
Two primary hypothesis have been proposed to explain the action of these drugs… First is… that the vasoconstrictor action of direct 5-HT agonist (Triptans and ergot) will cause vasoconstriction and prevent stretching of the nerve endings Second is .. The Triptans, ergots may activate the 5-HT 1B/1D receptors on the pre-synaptic trigeminal nerve endings to inhibit the release of vasodilating peptides.
Selective 5-HT 1B/1D agonist Sumatriptan and its congeners are currently the first line therapy for acute severe migraine attacks.
Based on the results of meta-analyses of large scale controlled trials and clinical experience, the stratification of acute migraine treatments is as shown in this table…
Naratriptan and Frovtriptan: time to onset of action is 2 -3 hours with a half life up to 5 hours.
Long-term prophylaxis improves quality of life by reducing frequency and severity of attacks and 80% of migraineurs may require prophylaxis. The current therapeutic options for migraine prophylaxis include..
Of all these.. Beta blockers is the present gold standard in migraine prophylaxis..
On 05-06-2013 FDA issued a safety announcement that antiseizure medicaition are contraindicated and should not be taken by pregnant women for the prevention of migraine headaches as it lowers the IQ of children
Each of the two medications as monotherapy is superior to placebo, and note also the numerical advantage of sumatriptan 85 mg versus naproxen 500 mg and the higher efficacy of the combination.
IN a review article by Julio pascal he mentioned about this three trials with topiramate have demonstrated that chronic migraine patients are treatable, even in the presence of analgesic overuse criteria
Topamax was first approved by the FDA in 1996 to prevent seizures. It was approved for migraine prevention in adults in 2004.
Recently Exploring nonoral routes of administration: Intranasal: zolmitriptan 5 mg or sumatriptan 20 mg s.c sumatriptan or i.m./i.v NSAIDs
On Cochrane review a Chinese study mentioned that
Dexamethasone is a corticosteroid that has been proposed to prevent recurrence of migraines through its prevention of neurogenic inflammation.
The use of beta blockers for migraine prevention is not new. But…The use of novel beta blockers, such as Carvedilol, for the prophylactic treatment of migraine is a new concept because it offers additional alpha-1 blocking and antiox idant properties.
Currently the U.S. Headache Consortium recommends Tiagabine for migraine prophylaxis based on expert consensus and clinical experience but the drug is not a standard treatment and does not carry an FDA indication for migraine.
Transformed migraine is very challenging to treat, and there are currently no medications approved by the U.S. FDA for prevention of these headache attacks. Transformed Migraine, also called chronic migraine: Patients usually have a history of episodic migraine in their teens or 20s, with headaches changing over months and years to become more frequent and with less severe associated symptoms. It is diagnosed if patients have headaches at least 15 days per month lasting for at least four hours per attack, with a previous history of migraine.
Thus, Zonisamide is an effective and well tolerated treatment option for prophylaxis in patients with refractory migraine
QTP represents a new hope for migraineurs because it also possesses high affinity for 5-H T2 receptors, partial agonistic activity at 5-H T1A receptors, and a blocking activity at alpha1-adrenergic receptors with a consequent potential for migraine prevention
Petasites is an extract from the plant Petasites hypridus (butterbur), which is a perennial shrub found throughout Europe and parts of Asia and North America. It has been used medicinally for centuries and during the Middle Ages w as used to treat plague and fever.
Thus… Petasites 75 mg twice daily may be an effective alternative preventive treatment for migraine
on 23 feb 2012 usfda made Drug Safety Labeling Changes over the use of ibuprofen in patient complaining of migraine and having Asthma history
Company is hopeful to launch this product.
Based on the results, TorreyPines plans to commence phase III trials in 2008.
Merck believes that the blocking of CGRP receptors ……………….remains an exciting pathway to address the underlying pathophysiology of migraine
The Cerena TMS is manufactured by eNeura Therapeutics
Dr Pierre Rigaux invented cefaly a device as compact like spctacles
Recent Advances in migraine
Guide: Dr Raakhi
JR-2: Dr Anup
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Guide: Dr Raakhi
JR-2: Dr Anup
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• Current therapy
• Recent advances
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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
- World Federation of Neurology
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Disabling Primary Headache disorder
Ranked 19th by the WHO among all diseases world-wide
IHS: migraine constitutes 16% of primary headaches
In India, 15-20% of people suffer from migraine with M:F ratio
WHO: Severe migraine can be as disabling as quadriplegia
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Two major sub-types,
Migraine without aura (common migraine)
• Headache with specific features and associated
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
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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 headache lasting 12-48 hours, often accompanied
by vertigo, vomiting and other symptoms; the subject grossly
incapacitated during the attack.
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Aura results from
depression of the
followed by vascular
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Current therapeutic option..
To reduce pain and
duration of attack
To reduce frequency of
attacks and disability
Identification of triggers
Contraindications to Triptans
Coronary artery disease
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
New FDA approvals
New uses of existing drugs
Drugs in pipeline
Recent Advances: In acute Treatment
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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.
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Reduction in migraine frequency in patients with chronic migraine with
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-
Silberstein SD, et L Topiramate Chronic Migraine Study Group Efficacy and safety of topiramate for the treatment of chronic migraline: a randomised, doubleblind, placebo-
controlled trial. Headache.
2007;47:170–80. doi: 10.1111/j.15264610.2006.00684.x.
Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ, TOPMATMIG201(TOP CHROME) Study Group Topiramate reduces headache days in chronic migrai
a randomised, doubleblind, placebocontrolled study. Cephalalgia. 2007;27:814–23. doi: 10.1111/j.14682982.2007.01326.x.
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New FDA approvals
• March 28, 2014: 1st FDA approval for prophylaxis of
migraine headaches in adolescents ages 12 to 17
• ADR: paresthesia, upper respiratory infection, anorexia,
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• Treximet (Sumatriptan/Naproxen Sodium) Formerly
Known as TREXIMA,
• May 2012: Menstrual Migraine in Women With
Dysmenorrhea Phase 3 study was completed
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• October 2008: USFDA approved Zomig (zolmitriptan)
• Jan 2015: Treatment of Acute Migraine Headache in
Adolescents (TEENZ) Phase 4 study was completed
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• 15 Oct 2010 USFDA approved Botox inj :
Prevent headaches in adult patients with chronic migraine.
every 12 weeks as multiple injections around the head
• 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
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January 2013, FDA approved: acute
medication sumatriptan delivery by new
mechanism (transdermal patch)
ADR: Painful sensation at the patch application site, reddening
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• 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.
Dexamethasone addition to standard
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
Dexamethasone appears to be safe and modestly effective
addition to standard migraine abortive therapy for the
prevention of migraine recurrence
Giuliano 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
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
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 events
Bigal ME, Krymchantowski AV. Emerging Drugs for Migraine Prophylaxis and Treatment. Medscape General Medicine. 2006;8(2):31.
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
Safety alert issued in 2005: Risk of new onset seizures and
status epilepticus in patients without a history of epilepsy
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
Unique combination of pharmacologic actions:
Blocks voltage-dependent sodium and T-type calcium
Reduces glutamate-mediated excitatory neurotransmission
Inhibits excessive nitric oxide (NO) production, scavenging
hydroxyl and NO radicals
Inhibits carbonic anhydrase
All 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 loss
Bermejo PE, Dorado R. Zonisamide for migraine prophylaxis in patients refractory to topiramate. Clin Neuropharmacol. 2009 Mar-Apr;32(2):103-6
Atypical antipsychotic drug with a high affinity for D4
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
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.
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
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
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.
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
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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
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Drugs in pipeline
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Phase 3: Completed
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 Aura
Head-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 Aura
PG 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
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• 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
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• 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.
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• Glutamate receptors antagonist
• In 2007 Phase 2 was completed
• In 2010 merck terminated it study with Telcagepant
• 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
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• Antagonist of the receptor for CGRP
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Edvinsson L. CGRPreceptor antagonism in migraine treatment. Lancet. 2008;372:2089–90. doi:10.1016/S01406736(08)617109.
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• 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 depression
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• 11 March 2014: USFDA approved device for
• Transcutaneous Electrical Nerve Stimulator to Treat
• Warnings: Indicated for use by adults and should only be
used for 20 minutes/day,
• ADR: Tingling or massaging sensation where electrode
• <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.
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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.