EDITORIAL

Eager for better migraine therapies Keep your (telcage)PANTs on

Richard B. Lipton, MD Peter S. Sandor, MD

Correspondence to Dr. Lipton: [email protected] Neurology® 2014;83:954–955

Pharmacologic therapies for migraine have traditionally been divided into 2 broad and distinct categories.1–3 Acute treatments are given at the time of a migraine attack to relieve pain and restore function. Preventive treatments are usually taken on a daily basis to reduce the frequency of headaches. Conventional wisdom suggests that the drugs used as acute treatments (i.e., triptans, ergot alkaloids, nonsteroidal antiinflammatory agents) differ from the drugs used as preventive treatments (antiepilepsy drugs, b-blockers, calcium channel blockers, and antidepressants) in mechanism of action, pharmacokinetic profiles, and patterns of use. Some acute treatments, particularly opioids and barbiturates, if used too often, might lead to worsening of headaches in a process variously conceptualized as transformation, chronification, or the development of medication overuse headache.4 In addition, the models used to screen for acute and preventive migraine drugs differ. Acute migraine models often focus on blocking the effects of sagittal sinus or trigeminal nerve stimulation.5,6 Potential migraine preventive medications are assessed for their ability to reduce the frequency of cortical spreading depression in experimental animals.7 Telcagepant and other calcitonin gene-related peptide (CGRP) antagonists have efficacy in animal models for acute treatment and in human beings treated during their migraine attacks.8–10 Given the established efficacy of CGRP blockade in acute treatment, the study of telcagepant as a preventive treatment for migraine in the current issue of Neurology® by Ho and coworkers11 may seem surprising. However, in recent years, the sharp distinction between acute and preventive migraine medications has blurred.11 Triptans and nonsteroidal anti-inflammatory drugs have demonstrated efficacy, not just as acute treatments, but also in migraine prevention.12,13 Propranolol and divalproex sodium, approved by the Food and Drug Administration as migraine preventive treatments, have shown suggestions of efficacy as acute treatments.14,15 The present report provides a strong signal that daily administration of telcagepant is effective as a preventive treatment for migraine. 11 Though the study was

terminated prematurely, over the first month of telcagepant treatment both the 140 mg and 280 mg doses produced reductions in monthly mean headache days and monthly migraine days relative to placebo. The magnitude of the treatment effect at 1 month is comparable to treatment effects seen with topiramate after 3 months.16 Daily telcagepant administration was not associated with the escalation of headaches sometimes seen with the overuse of other acute treatments. However, telcagepant administration was associated with more than threefold elevations of aminotransferases in 13 patients (2.5%) receiving active drug and in none on placebo. As a consequence, the Data Safety Monitoring Committee stopped the study prematurely.11 This work expands the role of CGRP blockade from acute treatment to the realm of preventive therapy. There are currently 4 monoclonal antibodies directed to the CGRP molecule or to its receptor in development for migraine prevention.17 Two recent phase II studies show benefits of CGRP monoclonal antibodies in the preventive treatment of migraine,18 supporting the inferences about mechanism supported by the present study. Despite the great promise of CGRP-targeted treatments, the hepatotoxicity seen with telcagepant is of concern. If it is a consequence of on-target action, CGRP blockade with other small molecules or monoclonal antibodies may lead to liver abnormalities. Fortunately, the monoclonal antibodies have thus far not shown evidence of hepatotoxicity, suggesting that this may well be an off-target toxic effect of the molecule, and not a consequence of CGRP blockade. We have known for many years that CGRP plays a central role in the pathophysiology of migraine.17 Triptans are thought to work, at least in part, by blocking the release of CGRP by the trigeminal nerve.10 The available evidence suggests that therapeutic approaches that target CGRP may be effective both as acute and preventive migraine therapies. Though telcagepant’s hepatotoxicity limits its clinical utility, this seminal study sets a course of great promise for improving the treatment of migraine. We look forward to the day when we can treat our patients with migraine using

See page 958 From the Department of Neurology (R.B.L.), Montefiore Headache Center, Albert Einstein College of Medicine, Bronx, NY; and the Neurology ANNR RehaClinic and University of Zurich (P.S.S.), Cantonal Hospital Baden, Switzerland. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 954

© 2014 American Academy of Neurology

both acute and preventive agents that target CGRP, a class of substances called the “gepants.”

7.

STUDY FUNDING

8.

No targeted funding reported.

DISCLOSURE

9.

The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

REFERENCES 1. Evers S, Afra J, Frese A, et al; European Federation of Neurological Societies. EFNS guideline on the drug treatment of migraine: revised report of an EFNS task force. Eur J Neurol 2009;16:968–981. 2. Worthington I, Pringsheim T, Gawel MJ, et al; Canadian Headache Society Acute Migraine Treatment Guideline Development Group. Canadian Headache Society Guideline: acute drug therapy for migraine headache. Can J Neurol Sci 2013;40(5 suppl 3):S1–S80. 3. Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. 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; 78:1337–1345. 4. Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population based study. Headache 2008;48:1157–1168. 5. Moskowitz MA. Neurogenic inflammation in the pathophysiology and treatment of migraine. Neurology 1993;43 (suppl 3):S16–S20. 6. Knight YE, Edvinsson L, Goadsby PJ. Blockade of calcitonin gene-related peptide release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122, 288. Neuropeptides 1999;33:41–46.

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Eager for better migraine therapies: Keep your (telcage)PANTs on Richard B. Lipton and Peter S. Sandor Neurology 2014;83;954-955 Published Online before print August 8, 2014 DOI 10.1212/WNL.0000000000000782 This information is current as of August 8, 2014 Updated Information & Services

including high resolution figures, can be found at: http://www.neurology.org/content/83/11/954.full.html

References

This article cites 17 articles, 3 of which you can access for free at: http://www.neurology.org/content/83/11/954.full.html##ref-list-1

Subspecialty Collections

This article, along with others on similar topics, appears in the following collection(s): All Headache http://www.neurology.org//cgi/collection/all_headache Migraine http://www.neurology.org//cgi/collection/migraine

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

Eager for better migraine therapies: keep your (telcage)PANTs on.

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