By Davidta Brown, Senior Staff Editor

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The pain, nausea, and light or sound sensitivity that comprise a migraine attack afflict more than 10% of individuals around the world, easily making migraines one of the most globally debilitating diseases of the present day.¹ According to the International Headache Society (IHS), migraines are defined by both pain and frequency. Migraine headache is typically a frontotemporal pain, characterized by unilateral location, pulsating, and associated nausea or vomiting.² Furthermore, each recurrent migraine attack may last from 4 hours to as many as 72 hours if untreated.¹

The IHS classifies migraines as either migraine with aura, or migraine without aura.² Aura is the term given to the series of neurological symptoms that occur before the onset of migraine headache, and may include visual disturbances, “pins and needles” sensations, and motor weakness.² Chronic migraine is another migraine subgroup, distinguished by the occurrence of any headache on fifteen or more days out of a month, and migraine headache on at least eight days out of a month.² Some patients experience a “premonitory phase”, hours or days before the migraine headache, or a resolution phase after the pain has subsided. Premonitory and resolution symptoms may include hyperactivity, hypoactivity, repetitive yawning, or depression.²

Migraine is now known to be a vascular headache, caused by the activation of nerve fibers in the walls of blood vessels supplying the cranial meninges.³ However, since the pathology of this condition is not completely understood, relief consists of either avoiding triggers or treating symptoms. Currently used acute treatments, administered as soon as symptoms occur, include triptans to increase plasma levels of serotonin, which leads to constriction of the blood vessels, and reduction of the pain threshold.³ Ergot derivatives are another option, which create therapeutic effect by binding to serotonin receptors on nerve cells to decrease the transmission of pain signals.³ Patients may also rely on the use of NSAIDs to reduce inflammation and alleviate pain.

The American Academy of Neurology recommends the anti-epileptic drugs divalproex sodium, sodium valproate, and topiramate, as well as β-blockers metoprolol, propranolol, and timolol, as part of their evidence-based guidelines for migraine prophylaxis.⁴ In addition, frovatriptan is suggested for the prevention of menstrual migraine headache.⁴ In terms of comparative effectiveness, topiramate is deemed to be probably as effective as propranolol, sodium valproate, and amitriptyline.⁴ Metoprolol is possibly as effective as aspirin in migraine prevention.⁴

Consistent follow-up evaluation and testing is necessary to treatment with divalproex sodium and sodium valproate, because of the associated risks of liver failure, pancreatitis, and teratogenicity.⁴ Weight changes are another significantly reported adverse effect associated with some of these migraine prophylactics. In one study, 18.8% of patients given topiramate experienced weight loss, and 34.5% of patients treated with sodium valproate showed weight gain.⁴ Among the beta-blockers, metoprolol patients showed no significant adverse events while propranolol patients experienced some drowsiness, fatigue, and weight gain.⁴ Although these drugs can be effective in some people, others do not find relief and some cannot take these medications due to contraindications or the side effect profile of the drug.

For several years, it has been known that a 33-amino acid neuropeptide called calcitonin gene-related peptide (CGRP) has played a role in the causation of migraine pain. While the protein has varied functions throughout the body, it works in the central nervous system to dilate intracranial blood vessels, modulate pain perception, and enhance the release of another pain mediator, substance P.⁵ Plasma levels of CGRP are elevated in individuals suffering from migraine attacks, and intravenous administration of CGRP to patients who are chronic migraine sufferers triggers migraine-like pain.^5,6 This knowledge has made the CGRP molecule a highly favorable target for inhibitory drug therapy.

To this end, several pharmaceutical companies have invested in the research of drugs intended to inhibit CGRP activity at its receptor. Unfortunately, these experimental treatments have shown little long-term clinical success. One study of CGRP-receptor antagonists also revealed that prolonged use leads to elevated plasma transaminase. ^6,7 An investigational antagonist called Telcagepant caused these high levels in patients enrolled in a small phase II study.^8,9 However, since this result has proven to be singular, it is unclear whether the adverse event was a response to the particular compound or to the class as a whole.⁸

Some companies have sought remedy through a different route by targeting the CGRP protein itself and have found greater success. In particular, two therapies that employ monoclonal antibodies to target CGRP have yielded favorable results in clinical trials. One treatment is administered as a single dose by IV, while the other is a biweekly injection, but both are antibody treatments that target CGRP molecules.¹⁰ The IV treatment study followed 163 patients who were randomly given either a single dose of the drug or a single dose of placebo.¹⁰ Before treatment, these patients were suffering 5 to 14 migraines a month.¹⁰After the 5 to 8 week observation period, this number was reduced by a statistically significant average of 5.6 days per month, as opposed to 4.6 fewer migraines per month on the placebo.^{10, 11}

Results from the biweekly injection were similarly positive. Data was collected from 217 patients, randomly given either the placebo or the monoclonal antibodies every other week for 12 weeks.¹⁰ Patients receiving the antibodies experienced 4.2 fewer migraine days per month, compared to 3 fewer days on the placebo.¹⁰ In both the biweekly injection trial and the intravenous trial, a noticeable improvement in patient symptoms was observed with the placebo, but the benefits seen with drug treatment were enough to allow researchers to deem the results clinically relevant. The near absence of adverse effects was another observation that makes these antibodies a serious contender among the other suggested prophylactic treatments. There is still a great deal of research that needs to be done before CGRP-targeting antibodies find a place in the treatment regimen for migraine, and current research is still at an early stage. Nevertheless, in the eyes of the researchers and of millions of migraine-sufferers, targeting CGRP with antibodies is a promising new treatment modality with the potential to alleviate widespread suffering.

 

SOURCES:

1. NINDS Migraine Information Page. NIH National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/disorders/migraine/migraine.htm. Updated April 16, 2014. Accessed June 2, 2014.
2. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalgia. 2013;33(9):629-808. doi: 10.1177/0333102413485658.
3. Headache: Hope Through Resarch. NIH National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/disorders/headache/detail_headache.htm. Accessed August 1, 2014.
4. Silberstein S, Holland S, Freitag F, Dodick D, Argoff C, Ashman E. Evidence-based guideline update: Pharmacologic treatment for episodic migraine prevention in adults Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1337–1345.
5. Arulmani U, MaassenVanDenBrink A, Villalόn C, Saxena P. Calcitonin gene-related peptide and its role in migraine pathophysiology. Eur J Pharmacol 2004; 500(1-3):315-330. doi: 10.1016/j.ejphar.2007.07.035.
6. Bigal ME, Walter S. Monocloncal antibodies for migraine: precenting calcitonin gene-related peptide activity [abstract]. CNS Drugs. 2014; 28(5):389-399. doi: 10.1007/s40263-014-0156-4.
7. Dolgin E. Antibody drugs set to revive flagging migraine target. Nat Rev Drug Discov. 2013;12(4):249-250. doi: 10.1038/nrd3991.
8. Villalόn CM, Olesen J. The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs. Pharmacology & Therapeutics. 2009;124(3):309-323. doi: 10.1016/j.pharmthera.2009.09.2003.
9. Tepper SJ, Cleves C. Telcagepant, a calcitonin gene-related peptide antagonist for the treatment of migraine [Abstract]. Curr Opin Investig Drugs. 2009;10(7):711-20. http://www.ncbi.nlm.nih.gov.jerome.stjohns.edu:81/pubmed/19579177. Accessed August 2, 2014.
10. Norton A. New Drugs May Help Prevent Migraines. HealthDay. http://consumer.healthday.com/head-and-neck-information-17/headaches-health-news-345/new-drug-may-help-prevent-migraines-687057.html. Published April 22, 2014. Accessed June 2, 2014.
11. American Academy of Neurology. New Drugs Offer Hope for Migraine Prevention.; 2014. Available at: https://www.aan.com/PressRoom/Home/GetDigitalAsset/11219. Accessed August 24, 2014.

[pubmed_related keyword1=”migraine” keyword2=”pain” keyword3=”headache”]

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