British Journal of Pharmaceutical and Medical Research Vol.04, Issu e 04, Pg .2035 - 2047 , July -August 2019

Available Online at http://www.bjpmr.org

BRITISH JOURNAL OF PHARMACEUTICAL AND MEDICAL RESEARCH

Cross Ref DOI : https://doi.org/10.24942/bjpmr.2019.543 Volume 04, Issue 04 July-August 2019

ISSN:2456-9836 ICV: 60.37 Review Article

“Recent Advances in Drug Therapy of ”

Priyadarsini Baskaran, Venkatraman Karthikeayan and Anusha Natarajan

1Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India. 2Gleneagles Global Hospital, Chennai, Tamil Nadu, India. 3Clinical Investigator, Amaris Clinical (A division of Caplin Point Laboratories), Chennai, India

ARTICLE INFO ABSTRACT

Article History: Migraine is one of the foremost disabling diseases that preponderantly affects the feminine population. The clinical spectrum of migraine encompasses four stages- Received on 08 th July, 2019 the prodrome, aura, the headache phase and also the postdrome. The management Peer Reviewed on 24 th July, 2019 of migraine is directed at aborting and preventing the headache, the associated Revised on 12th August, 2019 th incapacitating symptoms (like photophobia, phonophobia, olfactive Published on 28 August, 2019 hypersensitivity, allodynia, nausea, vomiting, etc.) and also the symptoms of aura (like visual phenomena, sensory phenomena, language aura etc.). The Keywords : pathophysiology of migraine includes the neuronal theory, the activation of the Migraine therapy, New drugs for trigeminovascular system and cortical spreading depression. The present migraine, recent advances in pharmacotherapy is directed against these mechanisms. The drug therapy of migraine therapy migraine includes abortive and prophylactic . Abortive medications presently in use embody nonspecific like NSAIDS and neuroleptics/ antiemetics, and specific medication like triptans, ergot alkaloids and CGRP ( gene related ) receptor antagonists. The newer medication under investigation include 5-HT 1F agonists, nNOS (neuronal nitric oxide synthase) synthase inhibitors, TRPV1 (transient receptor potential vanilloid) receptor modulators, drugs functioning on glutamatergic targets, and benzopyran derivatives. Prophylactic medications are necessary only if the attacks are too frequent or severe. The drugs used are beta blockers, calcium channel blockers, anticonvulsants, antidepressants and onabotulinium toxin A. monoclonal antibodies against CGRP pathway, benzopyran derivatives, dual receptor antagonists, nonspecific phosphodiesterase inhibitors and angiotensin receptor blockers are being investigated as potential new targets for migraine prevention. These treatments should be used suitably and judiciously to forestall complications and to enhance the standard of life in migraine patients.

Br J Phar Med Res Copyright©2019 Priyadarsini Baskaran et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material for any purpose, even commercially, provided the original work is properly cited and states its license.

Corresponding Author: Dr. Anusha. N, Clinical Investigator, Amaris Clinical (A division of Caplin Point Laboratories), Chennai, India

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INTRODUCTION: Migraine comes from the Greek word postdrome. The headache phase has associated “hemikranios” that refers to the unilateral symptoms like photophobia, phonophobia, distribution of pain that 60-75% of individuals olfactory hypersensitivity, cutaneous allodynia, with migraine experience. 1 The migraine attack nausea and emesis. migraine is also classified as consists of four parts- the premonitory phase, the follows: aura phase, the headache phase and also the Table 1-Classification of Migraine 1. Migraine without aura 2. Migraine with aura a. Migraine with typical aura b. Migraine with brainstem aura c. Hemiplegic migraine d. Retinal migraine 3. Chronic migraine 4. Complications of migraine a. Status migrainosus b. Persistent aura without infarction c. Migrainous infarction d. Migraine aura-triggered seizure 5. Probable migraine a. Probable migraine without aura b. Probable migraine with aura 6. Episodic syndromes that maybe associated with migraine a. Recurrent gastrointestinal disturbance b. Benign paroxysmal vertigo c. Benign paroxysmal torticollis Adapted from ICHD -3 beta version 2

The lifetime prevalence of migraine is about thirty certain visual stimuli, , muscle tension, third in girls and thirteen in men. 1Migraine causes physical exertion, and being overheated. substantial pain and incapacity. There’s a genetic Migraine is one amongst the foremost disabling predisposition for developing migraine. Majority medical sicknesses. The socioeconomic burden of of migraine patients have 1-4 attacks per month. treating migraine is incredibly high and also the This is often known as episodic migraine with annual treatment prices accounts for about $17 headaches on fewer than fifteen days per month. billion that is why the illness must be diagnosed Two patients have chronic headache with early and managed suitably. 3 headaches on at least fifteen days per month. Symptoms: About 2.5% of individuals with episodic migraine The prodrome consists of symptoms like fatigue, transform to chronic migraine every year. 1 excessive yawning, excessive thirst, blurred Triggers of a migraine attack include- emotional vision etc. stress, fluctuating female hormones, missed Aura: the most common aura includes visual meals, weather factors, sleep disturbance, odors, phenomena (positive and negative scotomas). The other aura symptoms include sensory phenomena

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(usually unilateral) like paresthesias and headache is prolonged beyond 72 hours a numbness, language aura (e.g. expressive diagnosis of status migrainosus may be made. dysphasias), unilateral motor weakness The migraine postdrome: lasts for 24 hours (Hemiplegic Migraine) or brainstem aura (with following a migraine attack and includes symptoms like diplopia, dysarthria, hypacusis, symptoms like fatigue, excessive thirst, ataxia, etc.). Aura which is not followed by hypersensitivity to visual and auditory stimuli, headache is called as a migraine equivalent or dizziness and neck stiffness, commonly referred acephalgic migraine. to as the migraine hangover. The headache phase consists of moderate to Migraine Genetics: severe throbbing pain that is unilateral in 60-75% Familial Hemiplegic Migraine (FHM) is a type of of patients but bilateral in the rest. 1Nausea, migraine with aura that has an autosomal vomiting and neck pain are frequent dominant pattern of inheritance. In FHM, patients accompaniments. Vomiting can lead to have unilateral motor weakness along with typical dehydration and decreased absorption of orally aura symptoms. The weakness may persist for administered drugs. There is hypersensitivity to several days as opposed to the other aura visual, auditory, cutaneous (cutaneous allodynia) symptoms which disappear in 24 hours. So far 3 and olfactory stimuli during the attack. The genes have been identified for FHM. headache phase lasts from 4-72 hours. If the

Table 2 – Genes associated with familial hemiplegic migraine 1 S.No. Gene Type of Location Function FHM 1. CACNA1A FHM1 Chromosome 19p13 Codes for brain specific voltage gated P/Q type calcium channel 2. ATP1A2 FHM2 Chromosome 1q23 Codes for a major subunit of sodium potassium ATPase pump 3. SCN1A FHM3 Chromosome 2q24 Codes for neuronal voltage gated sodium channel

A meta-analysis of 29 genome wide association Cortical spreading depression: studies identified 12 loci associated with migraine It is considered as the electrophysiological susceptibility. The genes identified were involved substrate of the migraine aura. It starts at the in glutamate regulation, modulation of synaptic occipital pole and spreads forward over the transmission, sensing cold and cold-pain, cerebral hemispheres at a rate of 2-4mm/min. controlling neuronal resting membrane potential This wave causes disruption in ionic gradients and neuronal excitability. 4 and depolarization followed by Pathophysiology: hyperpolarization. This period of brain activation Neuronal factors: followed by brain deactivation corresponds with The migraine attack is due to an alteration in the pattern of positive symptoms (visual normal brain function. Atypical brain function scintillations) followed by negative symptoms during migraine involves widespread areas of the (visual scotoma) typical of the migraine aura. brain. The substantial co-occurrence of symptoms Cortical spreading depression evokes a series of during a migraine attack suggests “parallel cortical, meningeal and brainstem events alteration” in the functional activity of several consistent with the development of headache. But different brain regions/ networks. cortical spreading depression does not occur prior to onset of migraine without aura.

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The trigeminocervical System and Migraine consequence, migraine pain increases and Headache: hypersensitivity develops to environmental and Activation of the trigeminocervical system leads other stimuli. 5 to release of vasoactive (like The Hyperexcitable Migraine Brain: CGRP, substance P, VIP, NO, PACAP) from The migraine brain has greater activation of sensory afferents that innervate the major regions that facilitate stimuli perception as intracranial arteries resulting in vasodilation, compared to the non-migraine brain as seen with plasma protein extravasation, inflammation that functional MRIs. 6 In addition, there is causes the headache of the migraine attack. hypoactivity of pain inhibitory pathways of the Recurrent / prolonged activation of the brainstem during an attack leading to increased trigeminocervical system leads to peripheral and pain. central sensitization. Sensitized neurons have Treatment and Management: lower thresholds for activation and increased The disability caused due to migraine is assessed spontaneous activity. Sensitization increases the with the help of a questionnaire called the pain and discomfort that is experienced during the Migraine Disability Assessment Score (MIDAS). attack and also reduces the effectiveness of Based on the scores the patients are classified into migraine abortive therapies. little or no disability, mild disability, moderate Role of CGRP: disability and severe disability. 7 Goals of Migraine-specific triggers cause primary brain treatment include restoration of function, dysfunction with consequent dilatation of cranial reduction of disability and suffering and reduction blood vessels innervated by sensory fibers of the in disease progression and future expression. trigeminal nerve. The dilatation mechanically Treatment often centers on pharmacotherapy. In activates the perivascular fibers with a pain addition lifestyle modification (reduction of message then conveyed to the brainstem and excessive caffeine intake and alcohol intake, higher brain centers and release of vasoactive cessation of smoking, diet correction, avoidance , such as substance P (SP) and CGRP of irregular sleeping habits) should also be from trigeminal fibers. SP is a potent mediator of practiced. The use of drugs known to cause increased microvascular permeability, and CGRP headaches (reserpine, nifedipine, theophylline is an extremely potent vasodilator. These peptides derivatives, vasodilators including long acting are responsible for neurogenic inflammation with nitrates and alcohol) should be discontinued or increased blood flow, edema formation, and other substitutes should be prescribed. Migraine recruitment of inflammatory cells to the local triggers must also be identified and avoided. area, and with degranulation of mast cells and Pharmacotherapy: release of proinflammatory and inflammatory Pharmacotherapy has two aspects molecules. The process can activate meningeal 1. Symptomatic (acute/ abortive) therapy nociceptors with further increase in the level of 2. Prophylactic therapy activation of the sensory trigeminal fibers, SYMPTOMATIC THERAPY: perpetuating the release of vasoactive peptides, The patient should be made to rest in a quiet dark including CGRP. As migraine progresses, room with an ice pack on the head. Stratified care sensitization occurs in spinal cord and brainstem is the preferred acute management strategy. centers that are the first to receive the nociceptive Treatment should be started as early as possible impulses from the trigeminal afferents. As a since it is very difficult to abort a fully developed

2038 British Journal of Pharmaceutical and Medical Research Vol.04, Issu e 04, Pg .2035 - 2047 , July -August 2019 attack with oral agents. This is because of poor combination with other agents for treatment of gastrointestinal motility and absorption. Acute migraine. NSAIDS may be used in combination treatment should be restricted to 2 to 3 days per with caffeine which may aid absorption, induce week to avoid medication overuse headache. 8 vasoconstriction and reduce the firing of Nonspecific Acute Treatment serotonergic brainstem neurons. NSAIDS may Nonsteroidal anti-inflammatory drugs also be used in combination with antiemetics. (NSAIDS)/acetaminophen (paracetamol): Ketorolac maybe administered IV in the NSAIDS like aspirin, ibuprofen, diclofenac, emergency room if needed. Acetaminophen is indomethacin maybe used alone or in less potent than NSAIDS but well tolerated.

Table 3 – NSAIDS for acute treatment of Migraine 8

Drug Formulation Dosage Aspirin Tablet, oral solution 650 -1000 mg Ibuprofen Tablet, oral suspension, capsule 400-800 mg Maximum initial dose of 1 g Ketorolac (renal toxicity is a concern) Tablet 10 mg Naproxen Tablet, oral suspension 125 -550 mg Naproxen controlled release Tablet 750 mg Maximum initial dose of 825 mg Meclofenamate Capsule 50 mg,100 mg Diclofenac potassium Tablet, powder pack 50 mg Etodolac Tablet, capsule 200 -500 mg Ketoprofen Capsule 50 -75 mg Ketoprofen extended release Capsule 200 mg

Neuroleptics/ antiemetics D2 receptor antagonists may be used alone or in combination with other agents for the treatment of headache and the associated nausea in migraine.

Table 4- Neuroleptics/ antiemetics in the acute treatment of migraine 8

S.No Medication Dose Uses 1. Dopamine Antagonists 5-10 mg Maybe used alone or in combination with NSAIDS or a. Prochlorperazine triptans. Parenteral formulations are more effective. 10 mg Treats the associated gastroparesis allowing better b. absorption of other oral agents. Used in combination with aspirin or paracetamol

c. Chlorpromazine 25 -100 mg Side effects include sedation and orthostatic hypotension 2. Antihistamine - 25-50 mg Treats nausea associated with migraine 3. 5-HT 3 Antagonist – 4 mg Maybe used in combination with other agents where Ondansetron dopamine antagonists are not tolerated.

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Corticosteroids: most most effective when taken early in the Corticosteroids maybe helpful in aborting an attack. acute attack and may be helpful in reducing the Sumatriptan can be administered by oral, risk of headache recurrence. A dose of intranasal or subcutaneous route. 6mg prednisolone 20mg every 6 hours initially subcutaneous injection appears to be more followed by a rapidly tapering dose over the next efficacious. 7 triptans are available in the United 2-3 days will help in aborting an attack of status States, all of which are beneficial in reducing both migrainosus. A single oral dose of pain and associated symptoms (like nausea, dexamethasone may be helpful in preventing photophobia and phonophobia) which improve headache recurrence after a course of NSAIDS or the patient’s ability to return to normal triptans. functioning. Side effects are usually mild to Specific Acute Treatment moderately severe causing local reaction and a Triptans mild tingling or flushing sensation. Heaviness or Impaired 5-HT transmission is a typical migraine pressure like sensation in the neck and chest may trait. Triptans are 5-HT 1B /5-HT 1D receptor occur in a few patients. Sumatriptan has been agonists. 5-HT 1B receptor mediates cranial proved to produce a small reduction in coronary vasoconstriction. 5-HT 1D receptor inhibits release artery diameter and hence caution must be of sensory neuropeptides from the perivascular exercised in patients who have significant risk trigeminal afferents and mediate presynaptic factors for coronary artery disease. Its not safe to dorsal horn stimulation. The 5-HT 1B /5-HT 1D administer triptans within 24 hours of ergot agonists act both at the central and peripheral preparations or other members of triptan class. 5- components of the trigeminal vascular system. HT 1F agonists are under development as Triptans may also enhance descending inhibitory alternatives to triptans. They lack the property of pain pathways and influence the function of 5- vasoconstriction. Naratriptan, almotriptan and HT1 F receptors. The triptans are considered first frovatriptan have favourable side effect profiles. line drugs for treatment of moderate to severe The triptans maybe combined with migraine pain. The triptans start taking effect metoclopramide for improving their oral within 20-60 minutes after an oral dose and may bioavailability. be repeated after 2 hours if necessary. They are

Table 5 – Triptans in the treatment of migraine 1 Drug Route Dose Maximum daily dose Fast acting triptans Almotriptan Oral 6.25, 12.5 mg 25 mg Eletriptan Oral 20, 40 mg 80 mg Rizatriptan Oral 5, 10 mg 30 mg Sumatriptan Oral 25, 50, 100 mg 200 mg Subcutaneous 4, 6 mg 12 mg Intranasal 5, 20 mg 40 mg Zolmitriptan Oral 2.5, 5 mg 10 mg Intranasal 5 mg 10 mg Slower onset triptans Frovatriptan Oral 2.5 mg 7.5 mg Naratriptan Oral 1, 2.5 mg 5 mg

Ergots agonists (less specific than triptans). Pretreatment They can act as vasoconstrictors or vasodilators, with an anti-emetic may be necessary. Oral the action depends upon their dosage and the preparations are less effective than rectal or resting tone of target vessels. They are 5-HT parenteral formulations. 2mg of ergotamine

2040 British Journal of Pharmaceutical and Medical Research Vol.04, Issu e 04, Pg .2035 - 2047 , July -August 2019 tartrate should be taken as soon as an attack of It can cause hypotension so the patient migraine is recognized and the dose maybe must be properly hydrated. repeated after an hour if necessary along with an  Ketorolac 60 mg I.M analgesic-caffeine combination. Rectal  Infusion of 1 gm of magnesium sulphate suppository is far more effective metoclopramide can be taken for nausea. If more than 6mg may be helpful in migraine with aura ergotamine is required per week an alternative  Dexamethasone, in combination with preparation should be used. Ergots are other antimigraine agents, maybe useful in contraindicated in pregnancy and coronary artery the treatment of intractable migraine. disease, hypertension, renal and hepatic failure.  500 mg sodium valproate maybe infused Dihydroergotamine (DHE) can also be used in I.V over 1 hour for the treatment of migraine. It has poor oral bioavailability hence intractable migraine. used as parenteral or intranasal formulation. Treatment of migraine in the emergency  An opioid may be administered, combined department with a drug for nausea if the pain is truly When the migraine attack becomes intolerable the severe. patient comes to the hospital. Treatment options in the emergency department NEWER DRUGS FOR SYMPTOMATIC include: TREATMENT  Sumatriptan 6mg subcutaneously Calcitonin Gene Related Peptide (CGRP)  Metoclopramide 10 mg with 0.5-1mg of Antagonists Calcitonin gene related peptide is a vasodilator DHE I.V that is released both from central and peripheral  Prochlorperazine 10 mg with or without neurons. It is implicated in the transmission of DHE I.V pain signals and is released during severe  Chlorpromazine 0.1 mg/kg body weight migraine attacks. The CGRP receptor antagonists I.V at the rate of 1 mg/mt maybe infused. have no effect on the cerebral or systemic hemodynamics.

Table 6 – CGRP receptor antagonists 9

Drug Name Status of clinical studies Efficacy of treatment

Olcegepant Development terminated because only I.V Better than placebo (BIBN -4096BS) administration was possible

Telcagepant (MK- Development terminated because of Effective in treatment of acute migraine. 0974) increased liver enzymes.

MK-3207 Development terminated because of delayed Better than placebo. Exhibits higher affinity asymptomatic liver test abnormalities. to the CGRP rece ptors than .

Rimegepant (BMS- No further plans to continue development of Better than placebo 927711) the drug

BI 44370 TA Development terminated for unknown Better than placebo reasons

Ubrogepant (MK- Phase 2b trial completed Better than placebo with adverse effects of 1602) 10 nausea and dizziness.

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Serotonin 5-HT 1F Receptor Agonist stimulation. Side effects of I.V administration Activation of 5-HT 1F receptors have no vascular include dizziness, paresthesias and sensation of effects. In preclinical studies, lasmiditan was heaviness in the limbs. The side effects of oral found to inhibit plasma protein extravasation administration include dizziness, vertigo and evoked by stimulation of trigeminal ganglion. fatigue. The drug maybe used in individuals who Lasmiditan also inhibited activation of cells in the have cardiovascular conditions in whom triptans trigeminal nucleus caudalis evoked by trigeminal are contraindicated.

9 Table 7- 5-HT 1F receptor agonists Drug Name Status of clinical studies Effects

Lasmiditan COL -144 Phase 2 proof of concept study Better than placebo

Lasmiditan COL -144 Phase 3 study started in 2015 Better than placebo in phase 2

LY-334370 11 Development terminated due Better than placebo to liver toxicity

Neuronal Nitric Oxide Synthase (nNOS) monoamine transporters. In animal models, Inhibitors ketamine can inhibit cortical spreading CGRP and nNOS are important mediators of depression. In human trials 25mg of intranasal migraine. The NXN-188 is a combined 5-HT 1B/1D ketamine was shown to reduce the duration and agonist and a nNOS inhibitor. The drug has severity of the neurological deficit accompanying completed phase 2 study and showed moderate migraine aura. 9 effect against placebo. It is well tolerated with no Tezampanel (LY293558) is an AMPA serious adverse effects but needs further antagonist. The drug had a better response rate evaluation. A non-selective NOS inhibitor (L- compared to placebo. LY466195 is a selective NG methyl arginine hydrochloride; 546C88 ) competitive antagonist at the iGlur5 (kinate) had shown good results in the treatment of subtype of ionotropic glutamate receptors. It migraine. But further development was stopped showed a good response in the treatment of because of cardiovascular safety concerns and an migraine. Both the drugs were less efficacious unfavorable pharmacokinetic profile. The when compared to sumatriptan, and visual side GW274150, an inducible nitric oxide synthase effects (hazy vision) were severe. BGG492 , an inhibitor was not effective in migraine treatment. AMPA antagonist, was not effective in the 9 treatment of migraine. ADX10059 is a negative Transient Receptor Potential Vanilloid allosteric modulator of mGluR5 subtype of (TRPV1) Receptor Modulators glutamate receptors. mGluR5 receptors are TRPV 1 receptors are involved in peripheral pain implicated in animal pain models. The drug was perception. TRPV1 receptor activation stimulates better than placebo but development was the release of CGRP which activates the terminated owing to increased liver enzymes. 9 trigeminal nucleus. Two drugs were investigated Propofol in this category. SB-705498 showed no benefit Propofol is a sodium channel blocker and also and civamide showed some benefit in the potentiates GABA A receptor activity. Phase 2 treatment of migraine but it wasn't satisfactory. 9 study completed. Phase 2/3 study was started in Drugs acting through Glutamatergic Targets children in 2015. It had a comparable efficacy to Ketamine is a NMDA antagonist. It also sumatriptan but it has addictive potential. modulates the activity of opioid receptors and

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Tonabersat disability, return the patient to normal function, Tonabersat is a benzopyran derivative. It can and improve response to treatment of future acute inhibit cortical spreading depression and attacks. cerebrovascular responses to trigeminal nerve Guidelines for the Preventive Treatment of stimulation in animal pain models. The drug Migraine showed inconsistent results in phase 2 trials and The American academy of neurology and the development was terminated. 9 American headache society have provided 5-HT 1D Agonist guidelines on the drugs that are useful in the 12 PNU-142633 is a selective 5-HT 1D agonist. It was prophylaxis of migraine. not found to be very efficacious but side effects The drugs have been classified into 4 categories like QT prolongation and first degree heart block as follows: were observed. Level A: The following medications are PROPHYLACTIC TREATMENT established as effective and should be offered for A preventive treatment is necessary only when migraine prevention: attacks occur as often as 1 to 2 days a week, when  Antiepileptic drugs (AEDs): divalproex the duration or frequency of attacks seriously sodium, sodium valproate, topiramate impairs the patient’s lifestyle, when there are  β-Blockers: metoprolol, propranolol, severe or prolonged neurological symptoms or timolol lack of response to symptomatic treatment. The most effective prophylactic treatments reduce  Triptans: frovatriptan for short-term headache frequency by 50% in nearly 50% Menstrually associated Migraine (MAMs) patients. The American migraine prevalence and prevention prevention study foumd that only 12% of the Level B: The following medications are probably American subjects with severe migraine were on effective and should be considered for migraine proper preventive management which highlights prevention: the need for early and appropriate prophylactic  Antidepressants: , 8 treatment. venlafaxine The prophylactic drugs are titrated to their  β-Blockers: atenolol, nadolol minimum effective or maximum tolerated dosage.  Triptans: naratriptan, zolmitriptan for This target dosage is maintained for 3 months if beneficial, then continued for 6-12 months to short-term MAMs prevention achieve clinical stabilization. Level C: The following medications are possibly The possible mechanism of action by which effective and may be considered for migraine prophylactic drugs act might include stabilization prevention: of reactive nervous system centers, enhancement  ACE inhibitors: lisinopril of antinociceptive pathways, inhibition of central  Angiotensin receptor blockers: and peripheral sensitization, and inhibition of candesartan cortical spreading depression. Inhibition of  α-Agonists: clonidine, guanfacine cortical excitation and restoration of central  AEDs: carbamazepine nociceptive modulation might also be a possible  β-Blockers: nebivolol, pindolol mechanism. The patient should be monitored to prevent Level U: Evidence is conflicting or inadequate to medication overuse, co morbid conditions should support or refute the use of the following be taken into account, and combination therapy medications for migraine prevention: can be considered in refractory patients. The  AEDs: gabapentin drugs should be tapered once the headache is  Antidepressants controlled. The goals of prevention are to reduce  Selective serotonin reuptake attack frequency and severity, reduce associated inhibitor/selective serotonin-

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norepinephrine reuptake tolerated dose. Amitryptiline can also stabilize inhibitors: fluoxetine, sleep. It's antinociceptive effect has been fluvoxamine attributed to its ability to inhibit serotonin and norepinephrine reuptake. Side effects include  Tricyclics: protriptyline morning drowsiness, dryness of mouth, weight  Antithrombotics: acenocoumarol, gain tachycardia, constipation etc. Serotonin Coumadin, picotamide norepinephrine reuptake inhibitors like  β-Blockers: bisoprolol venlafaxine maybe effective in prophylaxis of  Calcium-channel blockers: nicardipine, migraine. They are of benefit in treating the nifedipine, nimodipine, verapamil associated generalized anxiety disorder or panic  Acetazolamide disorder. Anticonvulsants  Cyclandelate Valproate and topiramate are FDA approved for β Adrenergic Blockers the prophylaxis of Migraine. Timolol and propranolol are FDA approved for Valproate/divalproex sodium is used at doses migraine prophylaxis. Side effects include equal to or lower than that used for epilepsy. It is lethargy, depression, hypotension, bradycardia, contraindicated in pregnant women because of the impotence, nightmares and . It is risk of neural tube defects. Side effects include contraindicated in patients with asthma and nausea, weight gain, tremor and alopecia. Other severe depression and should be used with effects include hepatitis, pancreatitis, caution in people who are taking and agranulocytosis, encephalopathy and elevation of OHAs. Propranolol can be given at doses of 80- liver enzymes. It's use as a prophylactic agent is 240mg per day. Consideration should be given to important in special cases e.g migraine with avoiding beta-blockers in patients with elevated coexisting bipolar disorder. body mass index, diabetes or a family history of Topiramate is used in doses between 100 and diabetes, and migraine with aura since beta 200mg. It may be started at 15 to 25mg and then blockers might cause increased risk of diabetes titrated upward. Patients should be advised to and possible ischemic stroke and prolongation of expect side effects like paraesthesias and altered aura in these patients. taste sensation. Cognitive side effects (like Calcium Channel Blockers delayed word retrieval) may also blunted by this It has been proposed that they work either by slow dose escalation. It may cause oral cleft in the blocking serotonin release or by interfering with foetus id given to pregnant females. neurovascular inflammation or cortical spreading Other antiepileptic drugs that may be used in depression. They also potentiate opioid and migraine prophylaxis include carbamazepine, acetaminophen induced analgesia and inhibit levetiracetam, zomisamide, gabapentin and CGRP release. L-type calcium channel blocker pregabalin. Gabapentin is the most commonly verapamil in doses of 80-160mg three times a day used among these at a dose of around 900mg. It is reduces the incidence of migraine with aura but it well tolerated with somnolence as the most is not very useful in migraine without aura. common side effect. Flunarizine is also useful in migraine prophylaxis. Neurotoxins Limiting side effects may include constipation, Injection of onabotulinium toxin A may help in dizziness, hypotension, and, at higher doses, the treatment of chronic migraine. The clinical cardiac conduction blocks. effect may be delayed or transient after the first Antidepressants set of injections. Repeated injection sets every 3 Amitryptiline and other tricyclic antidepressants months is required for maintenance of benefit. (nortryptiline, imipramine, desipramine) can be used at doses of 10 to 150mg. Dose has to be titrated to minimum effective or maximum

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NEWER DRUGS FOR MIGRAINE Monoclonal antibodies that target the CGRP PROPHYLAXIS pathway

Table 8- Monoclonal antibodies against CGRP 5

Drug Targeted against Status of clinical studies Effects LY2951742 Humanized monoclonal Phase 2 trial completed. Better than placebo. No antibody to CGRP Phase 3 trial is ongoing. serious adverse effects Administered S.C ALD403 Humanized monoclonal Phase 2 study completed. Better than placebo antibody to CGRP Phase 3 trial started in june Administered I.V 2017 (PROMISE 1&2) tr ials AMG334 Human monoclonal Phase 2 study completed. Better than placebo antibody to CGRP 2 phase 3 trials are receptor underway (ARISE & STRIVE) TEV-48125 Humanized monoclonal Phase 2 study completed. Found safe and antibody to CGRP. Phase 3 trial will be started efficacious. Tested in phase 1 studies in october 2017 No serious adverse effects and non -human primates

Blockade of the CGRP pathway is an effective Nonselective phosphodiesterase inhibitor preventive strategy in migraine but none of the Ibudilast inhibits production of pro inflammatory drugs have been tested long enough to exclude cytokines and inhibits glial cell activation. Glial adverse events on long term use. Generation of cells on activation become immunoresponsive autoantibodies to these antibodies is a possible and modulate pain by releasing neuroexcitatory serious complication. The results of the phase 2 signals that can increase neuronal excitability, &3 trials may shed some light on these concerns. activate neighboring glia and produce nociceptive Tonabersat mediators. Ibudilast did not show a better Study results were inconsistent with this response when compared with placebo. 9 benzopyran derivative and development was Angiotensin II receptor antagonist terminated. Candesartan was investigated in a phase 2 trial Dual Antagonists and its efficacy was found to be comparable to The orexinergic system comprises neuropeptides placebo. orexin A&B produced in the hypothalamus. They Anticonvulsant Drugs act via G-protein coupled OX 1 and OX 2 receptors Carisbamate was investigated and found to be and modulate basal and dural evoked nociceptive ineffective. Hence development was terminated. activation in the trigeminocervical complex. The Other treatment modalities: premonitory phase of migraine maybe regulated The other treatment modalities include by the hypothalamus and its orexinergic neurons. neuromodulatory approaches like Filorexant is a dual OX 1 and OX 2 receptor  Occipital nerve stimulation antagonist that was developed for insomnia. It  Sphenopalatine ganglion stimulation was investigated for the prevention of migraine  Single pulse transcranial magnetic but the trial was terminated due to lack of stimulation efficacy. 9  Transcutaneous vagal nerve stimulation

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 Transcutaneous supraorbital nerve practice. Seventh edition. London New York stimulation Oxford Philadelphia St Louis Sydney Toronto: CONCLUSION: Elsevier; 2016. 1695-706 Pharmacotherapy of Migraine is a challenging 2. Headache Classification Committee of the task. Migraine is a subjective phenomenon. International Headache Society (IHS). The Although various scales are available to measure International Classification of Headache the disability the outcomes are largely patient Disorders, 3rd edition (beta version). reported. Therefore the approach to any patient Cephalalgia. 2013;33:629–808. with migraine begins with reassurance and health 3. Bennett PN, Brown MJ, Sharma P. Clinical education. Patients should also be thought to pharmacology. 11th ed. Edinburgh: Elsevier; identify their triggers and avoid them. These 2012.667 p. methods help in minimizing the attack frequency 4. Anttila V, Winsvold BS, Gormley P, Kurth T, and thus the need for prophylactic agents. Bettella F, McMahon G, et al. Genome-wide International headache bodies have not come with meta-analysis identifies new susceptibility loci a clear cut algorithmic approach to a patient with for migraine. Nat Genet. 2013 23;45:912–7. migraine. Therefore the drug therapy of migraine 5. Giamberardino MA, Affaitati G, Curto M, is completely oriented to the response of patient Negro A, Costantini R, Martelletti P. Anti- to a particular drug. The clinician has to decide on CGRP monoclonal antibodies in migraine: choosing a drug based on the patients response to current perspectives. Intern Emerg Med. previous attacks or do a trial of drug after he 2016;11:1045–57. considers the contraindications to be avoided in a 6. Datta R, Aguirre GK, Hu S, Detre JA, particular patient. General principles in Cucchiara B. Interictal cortical pharmacotherapy is using the abortive therapy as hyperresponsiveness in migraine is directly early as possible during an attack of migraine and related to the presence of aura. Cephalalgia Int using drugs to alleviate the clinical symptoms J Headache. 2013;33:365–74. associated with migraine thereby preventing the 7. Stewart WF, Lipton RB, Dowson AJ, Sawyer sensitization of the nervous system to pain. J. Development and testing of the Migraine Prophylactic therapy revolves around the concept Disability Assessment (MIDAS) of preventing or reducing the frequency of Questionnaire to assess headache-related migraine attacks in patients with a high frequency disability. Neurology. 2001;56:S20-8. of migraine episodes. Patients with frequent 8. Rizzoli PB. Acute and preventive treatment of attacks despite prophylaxis should be considered migraine. Contin Lifelong Learn Neurol. on timing of abortive drug therapy, improper 2012;18:764–82. management of triggers, inadequate drug 9. Diener H-C, Charles A, Goadsby PJ, Holle D. titration, drug interactions altering the drug New therapeutic approaches for the prevention kinetics and patient compliance. If the above and treatment of migraine. Lancet Neurol. mechanisms are not operational in the patient 2015;14:1010–22. change of the prophylactic drugs or 10. Voss T, Lipton RB, Dodick DW, Dupre N, Ge neuromodulatory therapies should be planned. JY, Bachman R, et al. A phase IIb randomized, REFERENCES: double-blind, placebo-controlled trial of 1. Daroff RB, Jankovic J, Mazziotta JC, Pomeroy for the acute treatment of migraine. SL, editors. Bradley’s neurology in clinical Cephalalgia Int J Headache. 2016;36:887–98.

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11. Barbanti P, Aurilia C, Egeo G, Fofi L, guideline update: Pharmacologic treatment for Palmirotta R. Serotonin receptor targeted episodic migraine prevention in adults Report therapy for migraine treatment: an overview of of the Quality Standards Subcommittee of the drugs in phase I and II clinical development. American Academy of Neurology and the Expert Opin Investig Drugs. 2017;26:269–77. American Headache Society. Neurology. 12. Silberstein SD, Holland S, Freitag F, Dodick 2012;78:1337–45. DW, Argoff C, Ashman E. Evidence-based

How To Cite This Article: Priyadarsini Baskaran, Venkatraman Karthikeayan and Anusha Natarajan Recent Advances in Drug Therapy of Migraine Br J Pharm Med Res , Vol.04, Issue 04, Pg.2035 - 2047, July - August 2019. ISSN:2456-9836 Cross Ref DOI : https://doi.org/10.24942/bjpmr.2019.543 Source of Support: Nil Conflict of Interest: None declared

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