ISSN 0017-8748 Headache doi: 10.1111/head.12499 © 2015 American Headache Society Published by Wiley Periodicals, Inc. American Headache Society Evidence Assessment The Acute Treatment of Migraine in Adults: The American Headache Society Evidence Assessment of Migraine Pharmacotherapies Michael J. Marmura, MD; Stephen D. Silberstein, MD, FACP; Todd J. Schwedt, MD, MSCI The study aims to provide an updated assessment of the evidence for individual pharmacological therapies for acute migraine treatment. Pharmacological therapy is frequently required for acutely treating migraine attacks. The American Academy of Neurology Guidelines published in 2000 summarized the available evidence relating to the efficacy of acute migraine medications. This review, conducted by the members of the Guidelines Section of the American Headache Society, is an updated assessment of evidence for the migraine acute medications. A standardized literature search was performed to identify articles related to acute migraine treatment that were published between 1998 and 2013. The American Academy of Neurology Guidelines Development procedures were followed. Two authors reviewed each abstract resulting from the search and determined whether the full manuscript qualified for review. Two reviewers studied each qualifying full manuscript for its level of evidence. Level A evidence requires at least 2 Class I studies, and Level B evidence requires 1 Class I or 2 Class II studies. The specific medications – triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan [oral, nasal spray,injectable, transcutaneous patch], zolmitriptan [oral and nasal spray]) and dihydroergotamine (nasal spray,inhaler) are effective (Level A). Ergotamine and other forms of dihydroergotamine are probably effective (Level B). Effective nonspecific medications include acetaminophen, nonsteroidal anti-inflammatory drugs (aspirin, diclofenac, ibuprofen, and naproxen), opioids (butorphanol nasal spray), sumatriptan/naproxen, and the combination of acetaminophen/aspirin/caffeine (Level A). Ketoprofen, intravenous and intra- muscular ketorolac, flurbiprofen, intravenous magnesium (in migraine with aura), and the combination of isometheptene compounds, codeine/acetaminophen and tramadol/acetaminophen are probably effective (Level B). The antiemetics prochlorperazine, droperidol, chlorpromazine, and metoclopramide are probably effective (Level B). There is inadequate evidence for butalbital and butalbital combinations, phenazone, intravenous tramadol, methadone, butorphanol or meperidine injections, intranasal lidocaine, and corticosteroids, including dexamethasone (Level C). Octreotide is probably not effective (Level B). There is inadequate evidence to refute the efficacy of ketorolac nasal spray, intravenous acetaminophen, chlorproma- zine injection, and intravenous granisetron (Level C). There are many acute migraine treatments for which evidence supports efficacy.Clinicians must consider medication efficacy,potential side effects,and potential medication-related adverse events when prescribing acute medications for migraine. Although opioids, such as butorphanol, codeine/acetaminophen, and tramadol/ acetaminophen, are probably effective, they are not recommended for regular use. Key words: migraine, acute treatment, pharmacology, episodic migraine, clinical trial (Headache 2015;55:3-20) Migraine is a highly prevalent disorder character- From the Department of Neurology, Jefferson Headache ized by attacks of moderate to severe throbbing head- Center, Thomas Jefferson University, Philadelphia, PA, USA aches that are often unilateral in location, worsened (M.J. Marmura and S.D. Silberstein); Department of Neurol- by physical activity, and associated with nausea ogy, Mayo Clinic Arizona, Scottsdale, AZ, USA (T.J. Schwedt). and/or vomiting, photophobia, and phonophobia.1,2 Address all correspondence to Michael J. Marmura, 900 Migraine treatment can include preventive therapy Walnut Street Suite 200, Philadelphia, PA 19107, USA. aimed at reducing the frequency and severity of Accepted for publication November 26, 2014. migraine attacks, as well as acute therapy used to 3 4 January 2015 Figure.—Clinical guidelines process. abort a migraine attack. In association with the the following question:Which pharmacological thera- American Headache Society, the American Academy pies are effective in treating acute migraine? of Neurology (AAN) has recently published guide- lines for preventive treatment.3 The last AAN Guide- DESCRIPTION OF THE ANALYTIC lines for acute treatment were published in 2000.4 PROCESS Herein we report the results of an updated sys- The American Headache Society Guidelines tematic review of the published literature addressing Committee performed this project using the AAN the efficacy of medications used for acute treatment protocol for systematic development of clinical guide- of migraine. These studies of acute migraine medica- lines (Figure).6 The author panel comprised headache tions use 1 or more of multiple possible end-points of experts. The members of the guidelines group dis- efficacy, including headache relief (ie, reduction from closed any conflict of interest prior to involvement. severe or moderate intensity to mild or none), head- Persons with a substantial conflict of interest, based ache freedom, decreased disability, the absence of on a portion of their incomes pertinent to the study, nausea or vomiting, and the absence of photophobia were excluded. Although this project began before or phonophobia. Outcomes have been measured at the publication of the new Institute of Medicine varying intervals following medication administra- (IOM) Clinical Practice Guidelines, our methods tion. However, the International Headache Society were largely consistent with the IOM methods, for we Clinical Trial Guidelines published in 2012 suggests attempted to follow these principles of guideline that the percentage of study participants headache- development, rating of evidence, rating strength, and free at 2 hours should usually be used as the primary external review.7 The clinical question was to deter- outcome in acute therapy trials.5 Sustained pain mine which acute treatments are effective for freedom with the absence of other migraine symp- migraine. Migraine was defined using the Interna- toms at 24 or 48 hours is also an important patient- tional Classification of Headache Disorders, 2nd centered outcome and is considered the “ideal” edition diagnostic criteria. We performed formal migraine treatment response.5 Since the last AAN EMBASE and Medline searches up to December Guidelines for acute treatment in 2000, multiple 2013 using predefined search terms to capture all fully large, randomized acute pharmacological migraine published clinical trials relevant to the subject. Search treatment clinical trials have been conducted.4 This terms included “migraine,” “unilateral headache,” updated assessment of the evidence seeks to answer “hemicranias,” or “cephalalgia,” combined with Conflict of Interest: Dr. Marmura has received royalty income from Demos Medical, Cambridge University Press, and MedLink Neurology. Dr. Schwedt has received consulting fees and/or honoraria from Allergan, Inc., Supernus, and Zogenix. He has received royalty income from UpToDate. Dr. Silberstein has received consulting fees and/or honoraria from Allergan, Inc., Amgen, Avanir Pharmaceuticals, Inc., eNeura Inc, ElectroCore Medical LLC, Medscape, LLC, Medtronic, Inc, Mitsubishi Tanabe Pharma America, Inc., Neuralieve, NINDS, Pfizer, Inc, Supernus Pharmaceuticals, Inc., and Teva Pharmaceuticals. His employer, Jefferson University Hospitals, receives research support from Allergan, Inc, Amgen, Cumberland Pharmaceuticals, Inc, ElectroCore Medical, LLC, Labrys Biologics, Eli Lilly and Company, Merz Pharmaceuticals, and Troy Healthcare. Financial Support: Supported by the American Headache Society. Headache 5 “acute” or “immediate” and “drug therapy” or “phar- • Level A: Established as effective (or ineffective) for macotherapy.” We excluded animal studies, non- acute migraine (supported by at least 2 Class I English-language articles, and comments, letters, or studies) editorials, and we removed duplicate articles. We did • Level B: Probably effective (or ineffective) for not consider unpublished data, gray literature, or con- acute migraine (supported by 1 Class I study or 2 ference abstracts for the purpose of this review. The Class II studies) search strategy may be found in Appendix 1. Two • Level C: Possibly effective (or ineffective) for acute study team members reviewed each of the abstracts migraine (supported by 1 Class II study or 2 Class that resulted from the search, and then independently III studies) determined if the study should be excluded from • Level U: Evidence is conflicting or inadequate to further review or if the full manuscript should be support or refute the use of the medication(s) for reviewed. Two reviewers then independently evalu- acute migraine ated each of the studies selected for full-text review and determined whether the study met criteria for TheAAN review published in 2000 did not use the inclusion. In the event of disagreement between the 2 current AAN therapeutic classification. Group 1 con- reviewers, a third study team member reviewed the sisted of medications with at least 2 double-blind, abstract and/or full manuscript to determine inclus- placebo-controlled studies supporting their use, while ion or exclusion. We rated each study based on the group