American Headache Society EvidenceAssessment

The Acute Treatment of Migraine in Adults: The AmericanHeadache 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 migrainetreatment. Pharmacological therapy is frequently required for acutely treating migraine attacks. The American Academy ofNeurology 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 assessmentof evidence for the migraine acute medications. A standardized literature search was performed to identify articles related toacute migraine treatment that were published between 1998 and 2013. The American Academy of Neurology GuidelinesDevelopment procedures were followed. Two authors reviewed each abstract resulting from the search and determined whetherthe full manuscript qualified for review. Two reviewers studied each qualifying full manuscript for its level of evidence. Level Aevidence 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, transcutaneouspatch], zolmitriptan [oral and nasal spray]) and dihydroergotamine (nasal spray, inhaler) are effective (Level A). Ergotamine andother 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 isometheptenecompounds, codeine/acetaminophen and tramadol/acetaminophen are probably effective (Level B). The antiemeticsprochlorperazine, droperidol, chlorpromazine, and metoclopramide are probably effective (Level B). There is inadequateevidence for butalbital and butalbital combinations, phenazone, intravenous tramadol, methadone, butorphanol or meperidineinjections, 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 supportsefficacy.Clinicians must consider medication efficacy,potential side effects, and potential medication-related adverse events whenprescribing 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-ized by attacks of moderate to severe throbbing head-aches that are often unilateral in location, worsenedby physical activity, and associated with nauseaand/or vomiting, photophobia, and phonophobia.1,2

Migraine treatment can include preventive therapyaimed at reducing the frequency and severity ofmigraine attacks, as well as acute therapy used to

From the Department of Neurology, Jefferson HeadacheCenter, Thomas Jefferson University, Philadelphia, PA, USA(M.J. Marmura and S.D. Silberstein); Department of Neurol-ogy, Mayo Clinic Arizona, Scottsdale, AZ, USA (T.J. Schwedt).

Address all correspondence to Michael J. Marmura, 900Walnut Street Suite 200, Philadelphia, PA 19107, USA.

Accepted for publication November 26, 2014.

ISSN 0017-8748doi: 10.1111/head.12499

Published by Wiley Periodicals, Inc.Headache© 2015 American Headache Society

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abort a migraine attack. In association with theAmerican Headache Society, the American Academyof Neurology (AAN) has recently published guide-lines for preventive treatment.3 The last AAN Guide-lines for acute treatment were published in 2000.4

Herein we report the results of an updated sys-tematic review of the published literature addressingthe efficacy of medications used for acute treatmentof migraine. These studies of acute migraine medica-tions use 1 or more of multiple possible end-points ofefficacy, including headache relief (ie, reduction fromsevere or moderate intensity to mild or none), head-ache freedom, decreased disability, the absence ofnausea or vomiting, and the absence of photophobiaor phonophobia. Outcomes have been measured atvarying intervals following medication administra-tion. However, the International Headache SocietyClinical Trial Guidelines published in 2012 suggeststhat the percentage of study participants headache-free at 2 hours should usually be used as the primaryoutcome in acute therapy trials.5 Sustained painfreedom with the absence of other migraine symp-toms at 24 or 48 hours is also an important patient-centered outcome and is considered the “ideal”migraine treatment response.5 Since the last AANGuidelines for acute treatment in 2000, multiplelarge, randomized acute pharmacological migrainetreatment clinical trials have been conducted.4 Thisupdated assessment of the evidence seeks to answer

the following question:Which pharmacological thera-pies are effective in treating acute migraine?

DESCRIPTION OF THE ANALYTICPROCESS

The American Headache Society GuidelinesCommittee performed this project using the AANprotocol for systematic development of clinical guide-lines (Figure).6 The author panel comprised headacheexperts. The members of the guidelines group dis-closed any conflict of interest prior to involvement.Persons with a substantial conflict of interest, basedon a portion of their incomes pertinent to the study,were excluded. Although this project began beforethe publication of the new Institute of Medicine(IOM) Clinical Practice Guidelines, our methodswere largely consistent with the IOM methods, for weattempted to follow these principles of guidelinedevelopment, rating of evidence, rating strength, andexternal review.7 The clinical question was to deter-mine which acute treatments are effective formigraine. Migraine was defined using the Interna-tional Classification of Headache Disorders, 2ndedition diagnostic criteria. We performed formalEMBASE and Medline searches up to December2013 using predefined search terms to capture all fullypublished clinical trials relevant to the subject. Searchterms included “migraine,” “unilateral headache,”“hemicranias,” or “cephalalgia,” combined with

Conflict of Interest: Dr. Marmura has received royalty income from Demos Medical, Cambridge University Press, and MedLinkNeurology. Dr. Schwedt has received consulting fees and/or honoraria from Allergan, Inc., Supernus, and Zogenix. He has receivedroyalty income from UpToDate. Dr. Silberstein has received consulting fees and/or honoraria from Allergan, Inc., Amgen, AvanirPharmaceuticals, 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 UniversityHospitals, 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.

Figure.—Clinical guidelines process.

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“acute” or “immediate” and “drug therapy” or “phar-macotherapy.” We excluded animal studies, non-English-language articles, and comments, letters, oreditorials, and we removed duplicate articles. We didnot consider unpublished data, gray literature, or con-ference abstracts for the purpose of this review. Thesearch strategy may be found in Appendix 1. Twostudy team members reviewed each of the abstractsthat resulted from the search, and then independentlydetermined if the study should be excluded fromfurther review or if the full manuscript should bereviewed. Two reviewers then independently evalu-ated each of the studies selected for full-text reviewand determined whether the study met criteria forinclusion. In the event of disagreement between the 2reviewers, a third study team member reviewed theabstract and/or full manuscript to determine inclus-ion or exclusion. We rated each study based on thequality of study design, considering the study size andlength of treatment, treatment technique and doses,methods of data collection (prospective or retrospec-tive), presence or absence of placebo, primary andsecondary outcomes, and adverse events. Althoughwe did not exclude open-label or observationalstudies, Class I and II studies required a placebocontrol arm. We considered dropout rates to be lessrelevant in these studies since many investigated asingle migraine attack. Both reviewers completed astandardized data extraction form for each study(Appendix 2). The rating of each study followed rec-ommendations according to the AAN therapeuticclassification of evidence scheme, ranging from ClassI to Class IV. Class I studies, well-designed double-blind, randomized, placebo-controlled trials, wereconsidered best, while Class IV studies were oftenretrospective studies or case reports with unclear out-comes data. For a detailed description of the evidencescheme, see Appendix 3.

When we found no new studies for a particulardrug, ratings were based on previous AAN Guide-lines. In the event of conflicting evidence, meaning atleast 1 negative and 1 positive study for a particularmedication, we considered the Class I studies to bemore important in assigning a level of evidence.

Based on the quality of studies, a level of evi-dence was assigned for each drug, as follows:

• Level A: Established as effective (or ineffective) foracute migraine (supported by at least 2 Class Istudies)

• Level B: Probably effective (or ineffective) foracute migraine (supported by 1 Class I study or 2Class II studies)

• Level C: Possibly effective (or ineffective) for acutemigraine (supported by 1 Class II study or 2 ClassIII studies)

• Level U: Evidence is conflicting or inadequate tosupport or refute the use of the medication(s) foracute migraine

TheAAN review published in 2000 did not use thecurrent AAN therapeutic classification. Group 1 con-sisted of medications with at least 2 double-blind,placebo-controlled studies supporting their use, whilegroup 2 only required 1 study.The concept of Class I orClass II studies was not considered. Because a singleClass II study only supports a Level C recommenda-tion in the new AAN classification, many of the previ-ous group 2 medications are Level C in this review.

ANALYSIS OF EVIDENCEThe original search produced 805 articles, of

which 132 were selected for review. Studies wereexcluded from this report if they met any of the fol-lowing criteria:

• Did not include adult subjects• Did not evaluate medication (ie, were medical

devices or procedures)• Assessed treatment of migraine aura or preventive

treatment (ie, prevention of menstrual migraine)• Evaluated medications that are neither currently

commercially available in the United States norpending approval

• Used nonstandardized primary outcome measures,such as patient satisfaction or disability

• Focused on comparisons between 2 or more medi-cations, rather than placebo

RESULTSWe found no new Class I or II studies published

since the most recent guidelines for butorphanol (intra-

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muscular or nasal spray), combinations of butalbital/aspirin/caffeine or butalbital/aspirin/caffeine/codeine,acetaminophen/codeine, dihydroergotamine (DHE)(nasal spray, intramuscular, or intravenous),flurbiprofen, hydrocortisone, isometheptene, intranasallidocaine, and meperidine.Thus, no new review of previ-ous studies was done, and we assigned levels of evidencefor these agents based on the 2000 AAN Guidelines.4

Currently, no Class I or II studies exist for the use ofintravenous diphenhydramine, intravenous valproate,intravenousverapamil,oral tolfenamicacid,orcelecoxib.Rofecoxib 25 mg and the combination of ergotamine/caffeine/pentobarbital/Bellafoline were included in theprevious version of the guidelines but deleted from thisreview as they are no longer available.

Almotriptan.—In a Class I study, subjects takingalmotriptan 2 mg, 6.25 mg, 12.5 mg, and 25 mg had2-hour headache relief of 30%, 56.3%, 58.5%, and66.5%, respectively, compared with 32.5% withplacebo (P < .05 for 6.25 mg, 12.5 mg, and 25 mg).8

Adverse events were reported by 17.1%, 16.2%,18.3%, and 25.5% of the patients in the almotriptan2 mg, 6.25 mg, 12.5 mg, and 25 mg groups comparedwith 15.0% in the placebo group. Another Class Istudy examined the treatment of 3 migraine attacks.9

Subjects reported headache relief at 2 hours for atleast 2 of 3 attacks in 63.8% and 74.5% of subjectstaking 6.25 mg and 12.5 mg, respectively, in 3 separatemigraine attacks, compared with 35.7% of those usingplacebo (P < .001).

In another 4-arm, randomized, controlled Class Itrial, rates of headache freedom at 2 hours whentreating early (within 1 hour) with 12.5-mgalmotriptan were 53% at 2 hours, and 38% whentreating moderate to severe headache, compared with25% treating early and 17% treating late withplacebo (P = .0004 for early treatment; P = .0002 forlate treatment).10 Adverse events were low (<5%),with no difference between active drug and placebo.In a separate Class I trial, subjects receivedalmotriptan 12.5 mg or placebo within 1 hour of head-ache onset.11 At 2 hours after headache onset,almotriptan-treated patients were more likely to beheadache-free (37.0% vs 23.9% placebo; P = .010)and experience headache relief (72.3% vs 48.4%placebo; P < .001). In a Class I study specifically

looking at sumatriptan nonresponders, subjectsreceiving almotriptan 12.5 mg, compared withplacebo, were more likely to be headache-free at 2hours (47.5% vs 23.2% placebo; P < .05) and experi-ence headache relief at 2 hours (33% vs 14%;P < .05).12

Eletriptan.—Two parallel-group, Class I placebo-controlled trials of 1 migraine attack treated witheletriptan demonstrated superiority against placebofor 20 mg, 40 mg, and 80 mg doses. Subjects in the firststudy who received 20 mg, 40 mg, and 80 mg had2-hour headache relief of 64%, 67%, and 76%,respectively.13 All studied doses were superior to theplacebo response of 51% (P < .05). The second studyrevealed 2-hour headache relief rates of 47%, 62%,and 59% for the 20 mg, 40 mg, and 80 mg doses,respectively, compared with 22% for placebo(P < .01).14 Headache freedom rates at 2 hours were14%, 27%, and 27% for the 20 mg, 40 mg, and 80 mgdoses, which were superior to the 4% rate of head-ache freedom among subjects receiving placebo(P < .01). In a Class I, 3-attack study comparing 40-mgand 80-mg eletriptan against placebo, both eletriptandoses were superior to placebo for headache relief at2 hours and headache freedom at 2 hours (40 mg:62% headache relief, 32% headache freedom; 80 mg:65% headache relief, 34% headache freedom;placebo: 19% headache relief, 3% headache freedom;P < .001).15

A Class I study of early treatment with eletriptan20 mg, eletriptan 40 mg, or placebo for 1 migraineattack found headache-free rates at 2 hours of 22%for placebo, 35% for 20 mg (P < .01 compared withplacebo), and 47% for 40 mg (P < .001 comparedwith placebo).16 Although subjects were encouragedto treat migraine early, early treatment was notrequired. In those who were treated when headachewas mild, the 40-mg 2-hour headache-free rate was68%, compared with 25% for placebo (P < .001).

Another double-blind, parallel-group, placebo-controlled Class I study specifically studied eletriptanin subjects with poor response or tolerability tosumatriptan.17 Subjects with up to 3 attacks weretreated with either eletriptan 40 mg, eletriptan 80 mg,or placebo. Both eletriptan 40 mg and eletriptan80 mg demonstrated consistency of response that was

6 January 2015

superior to placebo; headache relief rates at 2 hourson at least 2 of 3 attacks in subjects taking eletriptan40 mg (66%), 80 mg (72%), or placebo (15%;P < .001).

A Class I study that asked subjects to treatmigraine with 80-mg eletriptan during the aura phasebefore headache onset failed to demonstrate superi-ority against placebo. Sixty-one percent of subjectswho treated with eletriptan developed moderate-to-severe headache within 6 hours, vs 46% subjects whotreated with placebo (P = ns).18

Frovatriptan.—Two Class I combined paralleldose-titration studies reported that frovatriptan2.5 mg was more effective than placebo at 2 hours forheadache relief (40% vs 23%; P < .001).19 Doseshigher than 2.5 mg were no more effective at 4 hours(P = ns).

A Class I dose-titration study comparingfrovatriptan 0.5 mg, 1 mg, 2.5 mg, and 5 mg vs placebofound that 2.5 mg was more effective than placebo at2 hours for headache relief (38% vs 25%; P < .05),while the other doses of frovatriptan were not supe-rior to placebo.20 All doses of frovatriptan were supe-rior to placebo at 4 hours for headache relief (48% for0.5 mg, 68% for 2.5 mg vs 33% for placebo; P < .02).

In a Class II crossover study of 2 migraine attacks,1 with frovatriptan 2.5 mg, followed by placebo in 2hours if headache increased to moderate or severe,and the other with placebo, followed by frovatriptan2.5 mg in 2 hours for moderate or severe headache,sustained headache freedom at 24 hours was morecommon in subjects taking frovatriptan early (40%)compared with those taking it late (31%; P < .05).21

Naratriptan.—The 2000 AAN Guidelines con-cluded that naratriptan was effective for acutemigraine. Since that guideline, a Class I study evalu-ated naratriptan 2.5 mg vs placebo for the treatmentof menstrually related migraine.22 Subjects takingnaratriptan were more likely to be headache-free at 4hours (58% vs 30%; P = .004).

Rizatriptan.—Rizatriptan was established as effec-tive for the treatment of acute migraine in the 2000AAN Guidelines. Since that guideline, a Class I trialcompared rizatriptan oral dissolvable tablets, 5 mgand 10 mg, vs placebo for the treatment of 1 attack.23

Headache relief at 2 hours was 74%, 59%, and 28% in

the 10 mg, 5 mg, and placebo groups, respectively(P < .01). The 10 mg dose was more effective than5 mg (P < .05). Headache-free rates at 2 hours were42%, 35%, and 10% (P < .01).

Two other Class I studies evaluated rizatriptan10 mg vs placebo for the treatment of migraine ofmild intensity treated within 1 hour of onset.24 Sub-jects using rizatriptan were more likely to achieveheadache freedom at 2 hours (57.3% and 58.9% vs31.1% and 31.1%; P < .001) and had 24-hour sus-tained headache freedom (42.6% and 48.0% vs23.2% and 24.6%; P < .001).

Two Class I studies compared rizatriptan 10 mgand placebo (randomized 2:1) for the treatment of1 menstrually related migraine attack.25 Rizatriptanwas significantly more effective in terms of both2-hour headache relief (70% and 73% vs 53% and50% for placebo; P < .001) and 24-hour sustainedheadache freedom (46% and 46% vs 33% and 33%;P = .016 study 1; P = .024 study 2).

A Class I study compared rizatriptan oral dissolv-able tablets 10 mg with placebo in patients takingtopiramate for migraine prophylaxis.26 Subjects with 3attacks were treated in this randomized, placebo-controlled, double-blind, multiple-attack study: 2 withrizatriptan and 1 with placebo. Rizatriptan was supe-rior to placebo in terms of 2-hour headache relief(55.0% vs 17.4%; P < .001), sustained headache relieffrom 2 to 24 hours (32.6% vs 11.1%; P < .001), and2-hour headache freedom (36.0% vs 6.5%; P < .001).

In a Class II study of sumatriptan nonresponders,rizatriptan 10 mg orally disintegrating tablet wascompared with placebo for the treatment of a singlemigraine attack.27 To be included in the study, subjectshad to fail treatment with open-label genericsumatriptan 100 mg in the baseline phase. Subjectswith 3 attacks were treated: 2 with rizatriptan and 1with placebo in random order. In this population,rizatriptan was superior for 2-hour headache freedom(22% vs 12%; P = .013), 2-hour headache relief (51%vs 20%; P < .001), and sustained headache freedomfrom 2 to 24 hours (20% vs 11%; P = .036).

Sumatriptan.—The 2000 AAN Guidelines estab-lished sumatriptan tablets 25 mg, 50 mg, and 100 mg,sumatriptan nasal spray, and sumatriptan injection4 mg and 6 mg as effective.

Headache 7

In a Class I study of sumatriptan 50 mg and100 mg for 1 migraine attack compared with placebo,51.1% and 66.2% of subjects were headache-free at 2hours in the 50 mg and 100 mg groups, compared with19.6% of subjects treating with placebo (P < .001).28

Two large Class I pooled studies that comprised2696 patients found sumatriptan was superior toplacebo as early as 20 minutes with the 100 mg dosefor headache relief (6% vs 4% placebo; P ≤ .05) andat 30 minutes with the 50 mg dose (19% vs 14%placebo; P ≤ .05).29 Two-hour headache-free rates,considered a secondary outcome measure in thisstudy, were 40% with 50 mg, 47% with 100 mg, and15% with placebo (P < .01). Similar results wereobserved for the individual studies. In study 1,sumatriptan tablets were significantly more effectivethan placebo at 25 minutes with the 100 mg dose andat 50 minutes with the 50 mg dose. In study 2,sumatriptan tablets were significantly more effectivethan placebo at 17 minutes for the 100 mg dose and at30 minutes for the 50 mg dose (P ≤ .05). In the pooleddata, the cumulative percentages of patients with painrelief by 2 hours after dosing were 72% for the100 mg dose and 67% for the 50 mg dose, comparedwith 42% for placebo (P ≤ .001; both sumatriptandoses vs placebo). The cumulative percentages ofpatients with a pain-free response by 2 hours were47% for the 100 mg dose, 40% for the 50 mg dose, and15% for placebo (P ≤ .001; both sumatriptan doses vsplacebo). In the individual studies, significantly morepatients receiving either sumatriptan dose weremigraine-free 2 hours after dosing, and had sustainedpain relief and a sustained pain-free response over 24hours, compared with placebo (P ≤ .001; bothsumatriptan doses vs placebo). The only drug-relatedadverse events reported in less than 2% of patients inany treatment group in either study were nausea(both studies: 3% sumatriptan 100 mg, 2% suma-triptan 50 mg, 1% placebo) and paresthesia (study 1:<1% sumatriptan 100 mg, <1% sumatriptan 50 mg,0% placebo; study 2: 3% sumatriptan 100 mg, 1%sumatriptan 50 mg, <1% placebo).

A Class I study of sumatriptan injection 4 mgreported 2-hour headache relief in 70% ofsumatriptan-treated subjects and 22% of thosereceiving placebo (P < .001).30 Sumatriptan injections

first showed superiority over placebo at 10 minutesfor headache relief (11% vs 6%; P = .039).

A Class I study compared a new iontophoreticpatch formulation of sumatriptan (6.5 mg transder-mal with delivery over 4 hours) with placebo for acutemigraine treatment.31 Sumatriptan patch was superiorto placebo patch for the primary end-point of head-ache freedom at 2 hours (18% vs 9%; P = .0092). Forsecondary measures, active drug was superior at 2hours for freedom from photophobia (51% vs 36%;P = .0028), freedom from phonophobia (55% vs 39%;P = .00021), freedom from nausea (84% vs 63%; P =.0001), and headache relief (53% vs 29%; P = .0001).

A Class I randomized, double-blind, parallel-group, placebo-controlled study compared the effec-tiveness of intranasal sumatriptan 10 mg, intranasalsumatriptan 20 mg, with placebo for a single migraineattack.32 Patients were instructed to use a new bidi-rectional powder delivery device for a moderate tosevere attack. Intranasal sumatriptan 10 mg (54% vs25%; P < .05) and 20 mg (57% vs 25%; P < .05) wereboth superior to placebo for headache freedom andheadache relief at 2 hours (10 mg 84% vs 44%,P < .001; 20 mg 80% vs 44%, P < .01).

Sumatriptan/Naproxen Sodium.—Two largestudies compared a fixed combination of sumatriptan85 mg and naproxen sodium 500 mg againstsumatriptan 85 mg alone, naproxen sodium 500 mgalone, and against placebo.33 In study 1, 2-hourheadache-free rates were 34% for the sumatriptan85 mg/naproxen sodium 500 mg combination,compared with 25% for sumatriptan 100 mg, 15%for naproxen 500 mg, and 9% for placebo. Thesumatriptan/naproxen sodium combination was supe-rior to sumatriptan alone (P = .009), naproxen, andplacebo (P < .001). The incidence of headacherelief 2 hours after dosing was 65%, 55%, 44%, and28% with sumatriptan/naproxen sodium, sumatriptanmonotherapy, naproxen sodium monotherapy, andplacebo, respectively, in study 1 (P < .001 forsumatriptan/naproxen sodium, sumatriptan, andnaproxen sodium vs placebo). In study 2, 2-hourheadache-free rates were 30% for the sumatriptan85 mg/naproxen sodium 500 mg combination, com-pared with 23% for sumatriptan 100 mg, 16% fornaproxen sodium 500 mg, and 10% for placebo. The

8 January 2015

sumatriptan/naproxen sodium combination was supe-rior to sumatriptan alone (P = .02), naproxen, andplacebo (P < .001). The headache relief percentagesin study 2 were 57%, 50%, 43%, and 29% (P < .001for sumatriptan/naproxen sodium, sumatriptan, andnaproxen sodium vs placebo; P = .03 for sumatriptan/naproxen sodium vs sumatriptan).

In a Class I 2-attack, crossover study ofsumatriptan 85 mg/naproxen sodium 500 mg againstplacebo in persons with poor response to short-acting triptans (almotriptan, eletriptan, rizatriptan,sumatriptan, or zolmitriptan), sumatriptan/naproxensodium treatment was superior to placebo for 2- to24-hour sustained headache-free response (study 1:26% vs 8%; study 2: 31% vs 8%; P < .001 for bothcomparisons).34 Headache-free rates at 2 hours werealso superior in the sumatriptan/naproxen sodiumgroup (study 1: 40% vs 17%; study 2: 44% vs 14%;P < .001).

Zolmitriptan.—Oral zolmitriptan was rated aseffective for acute migraine treatment in the 2000AAN Guidelines.

In a Class I study of zolmitriptan 2.5 mg oraldissolvable tablets against placebo for 2 migraineattacks, 2-hour headache-free rates were higher inthose taking zolmitriptan (40% vs 20%; P < .001).35

Headache-free rates were also higher at 1 hour(13% vs 8%, P = .004) and 1.5 hours (25% vs 15%;P < .001).

Zolmitriptan 5 mg oral dissolvable tablets werecompared against placebo in a Class I study for thetreatment of 1 migraine attack.36 For the primary end-point, headache relief at 30 minutes, zolmitriptan wassuperior to placebo (16.5% vs 12.5%; P = .048). Sus-tained headache freedom for 24 hours withzolmitriptan 5 mg was also superior to placebo(42.5% vs 16.4%; P < .0001).

Two Class I studies compared zolmitriptan nasalspray 5 mg against placebo. In the first study, subjectswith 1 or 2 attacks were treated with eitherzolmitriptan nasal spray or placebo.37 Headache reliefat 2 hours was greater in the zolmitriptan nasal spraygroup compared with placebo (66.2% vs 35.0%;P < .001), with rates of headache relief fromzolmitriptan being superior to placebo as early as 15minutes. Actual headache relief rates for zolmitriptan

nasal spray and placebo groups, respectively, were18.3% and 11.4% at 15 minutes, 39.2% and 24.1% at30 minutes, and 56.9% and 34.2% at 1 hour (P < .001).

The second study compared zolmitriptan nasalspray 5 mg with placebo for the treatment of 1 attackand used a primary outcome of total symptomfreedom (freedom from headache, nausea, photopho-bia, and phonophobia) at 1 hour.38 Zolmitriptan nasalspray was superior to placebo for total symptomfreedom (14.5% vs 5.1%; P < .0001) at 1 hour. Sec-ondary outcomes showed zolmitriptan to be superiorto placebo for headache relief as early as 10 minutes(15.1% vs 9.1%; P = .0079) and for headache freedomas early as 30 minutes (7.7% vs 3.2%; P = .0039). Theheadache relief rate at 2 hours post-dose was 66.2%for the zolmitriptan group, compared with 35.0% forthe placebo group (P < .001). Zolmitriptan nasalspray also produced significantly higher headacherelief rates than placebo at all earlier time pointsassessed, starting as early as 15 minutes post-dose(P < .001). Similar results were obtained for theanalysis of the first attack. Significantly higher pain-free rates were obtained with zolmitriptan nasalspray, compared with placebo, from 15 minutes post-dose onward (P < .005).

DHE.—A Class I double-blind, placebo-controlled, proof-of-concept efficacy trial analyzedDHE administration with a breath-synchronizedinhaler for the treatment of acute migraine.39 Treat-ment was randomized to 0.5 mg, 1.0 mg, and placeboin a 2:2:1 ratio. Rates of headache relief at 2 hourswere higher in those subjects receiving 0.5 mg (72%)compared with placebo (33%; P = .019), but not inthose subjects receiving 1.0 mg (65%; P = .071). Sub-jects receiving 0.5 mg (44%) and 1.0 mg (35%) weremore likely to be headache-free at 2 hours comparedwith placebo (7%; P = .015 and .050, respectively).

A larger Class I phase 3, double-blind, placebo-controlled, parallel-group, single-attack study com-pared inhaled DHE 1.0 mg with placebo for thetreatment of acute migraine, with the primary end-points of headache relief, and absence of photopho-bia, phonophobia, and nausea at 2 hours.40 Patientswere treated with DHE at the time of moderate orsevere headache. Subjects treating with DHE weremore likely to experience headache relief at 2 hours

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(59% vs 35%; P < .0001), and freedom from phono-phobia (53% vs 34%; P < .0001), photophobia (47%vs 27%; P < .0001), and nausea or vomiting (67% vs59%; P = .0210). DHE was also significantly moreeffective for headache freedom at 2 hours (28% vs10%; P < .001) and for 2- to 24-hour sustained head-ache freedom (23% vs 7%; P < .001).

Acetaminophen.—Based on the 2000 AAN Guide-lines, oral acetaminophen was considered probablyeffective for acute migraine based on available evi-dence (Level B).41,42 Since that guideline, a Class Istudy comparing oral acetaminophen 1000 mg withplacebo for non-incapacitating migraine, ie, vomitingless than 20% attacks and no need for bed rest, found2-hour headache relief in 57.8% of those taking acet-aminophen vs 38.7% taking placebo (P = .002).43

Acetaminophen was superior in terms of 2-hourheadache relief in those with severe headache (50.9%vs 27% placebo; P = .008). There was not a signifi-cantly better response to acetaminophen in the sub-group of subjects with moderate headache (62% vs48.1% placebo; P = .07). Two-hour headache-freerates were higher in subjects taking acetaminophen(22.4%) than in those treating with placebo (11.3%;P = .01).

A Class II study of intravenous acetaminophen1000 mg for the treatment of 1 acute migraine attack,with 30 clinic patients in each group, failed to demon-strate significant differences between acetaminophenand placebo in terms of headache freedom at 2 hours(10% vs placebo 13%; P = ns), headache relief at 2hours (30% vs 20% placebo; P = ns), and headachefreedom after 24 hours (31% vs 33% placebo;P = ns).44

Chlorpromazine.—A Class I study compared intra-venous chlorpromazine 0.1 mg/kilogram vs placebo inthe acute treatment of migraine with or without aurain the emergency department.45 Compared withplacebo, chlorpromazine-treated subjects had higherrates of headache relief at 30 minutes (46% vs 7%;P < .05) and at 60 minutes (82% vs 15%; P < .05).Rates of headache freedom at 1 hour were greateramong chlorpromazine-treated subjects (65% vs 8%;P < .05). Benefits were similar in subjects who hadmigraine with aura and in those who had migrainewithout aura.

Droperidol.—In a Class I study, droperidol pro-vided superior rates of 2-hour headache relief com-pared with placebo.46 Subjects in this study wererandomized to receive injections of 0.1 mg, 2.75 mg,5.5 mg, and 8.25 mg or matching placebo for treat-ment of moderate to severe migraine.Two-hour head-ache relief rates were superior for subjects receiving2.75 mg (87%), 5.5 mg (81%), and 8.25 mg (85%)compared with placebo (57%; P < .002). Headacherelief from droperidol was superior to placebo asearly as 1 hour for the 2.75 mg dose (P < .01), 90minutes for the 5.5 mg dose (P < .001), and 30minutes for the 8.25 mg dose (P < .001).

Phenazone.—A Class II study of oral phenazone1000 mg vs placebo for 1 migraine attack treatedwithin 4 hours of migraine onset determined that sub-jects receiving phenazone were more likely to have2-hour headache relief compared with placebo(48.6% vs 27.2% placebo; P = .002).47 Phenazone wassuperior to placebo for those subjects with moderateintensity headache (53.6% vs 32.4% placebo;P = .016) and for those subjects with severe headache(38.9% vs 17.1% placebo; P = .042). Two-hourheadache-free rates were also higher in the phena-zone group vs placebo (27.6% vs 13.6%; P = .016).

Aspirin.—The 2000 AAN Guidelines establishedoral aspirin as effective for the acute treatment ofmigraine. In a Class I crossover study of 2 migraineattacks, using aspirin mouth-dispersible formulation900 mg vs placebo, 2-hour headache relief wasachieved in 48% of the aspirin group compared with19% of the placebo group (P < .0005).48 Aspirinbegan to show superiority over placebo at 30 minutesin terms of headache intensity and at 3 hours forheadache freedom.

In a separate double-blind, placebo-controlledClass I study of 1 migraine attack, aspirin 1000 mgwas compared with placebo.49 Aspirin was superior interms of headache relief at 2 hours (52% vs 34%;P < .001), and 20% of patients receiving aspirin wereheadache-free from 1 to 6 hours after treatment, com-pared with 6% of those receiving placebo (P < .05).

Diclofenac.—In the 2000 AAN Guidelines,diclofenac was considered probably effective for theacute treatment of migraine.50,51 Since that guideline,a Class I study compared treatment with diclofenac

10 January 2015

100 mg, diclofenac 50 mg, sumatriptan 100 mg, andplacebo.52 Subjects were asked to treat 4 separatemigraine attacks, and they received a different treat-ment for each attack (1 of each). One hundred forty-four patients received at least 1 treatment, and 115patients (80%) completed the study. The primaryoutcome was 2-hour headache intensity using a visualanalog scale where 100 mm was maximal headache.Both diclofenac 50 mg and 100 mg were superior toplacebo (22 mm average with 100 mg, 26 mm with50 mg, and 46 mm with placebo; P < .001).

In another Class I trial, subjects treated 4migraine attacks, 2 with diclofenac 65 mg, and 2 withplacebo, in random order.53 Subjects with migrainewith aura were excluded. Subjects treating migrainewith diclofenac were more likely to be headache-freeat 2 hours (45.8% vs 25.1%; P < .0001).

Another Class I study evaluated the use of 50-mgdiclofenac potassium sachets and diclofenac 50 mgtablets in comparison to placebo in a crossover trial.54

Patients using sachets were more likely to beheadache-free at 2 hours than those using placebo(24.7% vs 11.7%; P < .0001) and those using 50 mgtablets (24.7% vs 18.5%; P = .0035). Subjects usingtablets were more often headache-free at 2 hoursthan those using placebo (18.5% vs 11.7%; P = .0040).For 2-hour headache relief, both sachets (46.0% vs24.1%; P < .0001) and tablets (41.6% vs 24.1%;P < .0001) outperformed placebo.

Another Class I study compared 50-mgdiclofenac potassium oral solution with placebo in adouble-blind, randomized, placebo-controlled, single-attack trial.55 Diclofenac was superior for 2-hourheadache freedom (25% vs 10%; P < .001), freedomfrom nausea (65% vs 53%; P = .002), freedom fromphotophobia (41% vs 27%; P < .001), and phonopho-bia (44% vs 27%; P < .001) compared with placebo.

Ibuprofen.—The 2000 AAN Guidelines estab-lished ibuprofen as effective for acute migraine treat-ment. Since that guideline, a Class II study comparedibuprofen 200 mg and ibuprofen 400 mg withplacebo.56 Subjects were excluded if they experiencedeither incapacitating migraines requiring bed restmore than 50% of the time or vomiting more than20% of the time. For mild to moderate intensity head-aches, 2-hour headache relief occurred in 41.7% of

those taking ibuprofen 200 mg, in 40.8% of thosetaking ibuprofen 400 mg, and in 28.1% of the placebogroup (P = .004 for 200 mg; P = .006 for 400 mg). Inthose with severe migraine, 400 mg was superior toplacebo (36.9% vs 21.6% placebo; P = .048), but therewas no significant difference for the 200 mg group.

Ketorolac.—A Class II study evaluated an intrana-sal formulation of ketorolac tromethamine, contain-ing 6% lidocaine for the acute treatment of migrainewith and without aura, treated within the first 4 hoursof a migraine attack.57 There was no significant differ-ence for headache freedom at 2 hours in the ketorolacgroup compared with placebo (18% vs 10%; P = .17).Ketorolac was superior to placebo for several second-ary outcome measures, including lack of disability at 2hours (24% vs 10%; P = .009) and 2-hour headacherelief (51.5% vs 31.9%; P = .02).

Tramadol/Acetaminophen.—A Class I study com-pared tramadol 75 mg/acetaminophen 650 mg (givenas 2 tablets) with 2 placebo tablets for the treatmentof a single migraine attack.58 Headache relief at 2hours was superior for subjects taking tramadol/acetaminophen (55.8 vs 33.8% placebo; P < .001.)Headache freedom at 2 hours was also superior inthose taking tramadol/acetaminophen (22.1% vs9.3% placebo; P < .001). Tramadol/acetaminophenwas superior to placebo for photophobia at 2 hours(34.6% vs 52.2%; P = .003) and phonophobia (34.3%vs 44.9%; P = .008), but not for migraine-relatednausea (38.5% vs 29.4% placebo; P = .681).

Tramadol.—Intravenous tramadol 100 mg wascompared with placebo for acute emergency treat-ment of a single attack in a single-blind Class IIstudy.59 Tramadol was superior for the primary end-point of 50% headache relief at 1 hour (76% vs35.6%; P = .04), but not for the secondary end-pointof headache freedom (29% vs 11% placebo; P = ns).

Octreotide.—In a Class I placebo-controlled cross-over study, patients treated acute migraine with atleast moderate intensity with either 100-μg subcuta-neous octreotide or placebo. Octreotide was not supe-rior for headache relief at 2 hours (14% vs 20%placebo; P = ns) or for pain freedom at 2 hours (2%vs 7% placebo; P = ns).60

Magnesium.—In a Class II placebo-controlledtrial of intravenous magnesium sulfate (1 g for the

Headache 11

treatment of 1 migraine attack), magnesium providedbenefit superior to placebo at 60 minutes for thetreatment of migraine with aura attacks in regard toheadache relief (50% vs 13%; P < .05) and headachefreedom (37% vs 7%; P < .05).61 In subjects withoutaura, there was no significant difference betweenmagnesium and placebo (headache relief: 33% vs17%; headache freedom: 23% vs 10%; P = ns for bothcomparisons).

Another Class II study of intravenous magne-sium compared treatment with 2-g magnesium sulfatewith 10-mg metoclopramide and placebo in a 1:1:1ratio for the treatment of 1 migraine attack in theemergency department.62 The primary end-point washeadache intensity on a visual analog scale at 30minutes. Average headache intensity at 30 minuteswas 3.9 mm in those receiving magnesium, 3.7 mmafter metoclopramide, and 4.8 after placebo. Therewere no significant differences between treatmentarms, but there was a benefit from magnesium com-pared with placebo in the subgroup experiencingmigraine with aura compared with placebo (P = .04)and metoclopramide (P = .03).

Intravenous Valproate.—In a Class IV open-labelstudy, patients with various primary headache disor-ders received 1 treatment of intravenous valproatefor headache of moderate or severe intensity usingdoses ranging from 300 mg to 1200 mg. The majorityof patients (63.1%) reported improvement, althoughthose with episodic headache were more likely to doso.63 Another Class IV study reported the use of intra-venous valproate 500 mg via slow intravenous bolusinjection for acute migraine. In this observationalstudy, 32 of 36 patients, including those with orwithout ongoing valproate prophylaxis, reportedimprovement after treatment (Table).64

DISCUSSIONThis systematic assessment of the literature is a

comprehensive evaluation of the evidence for efficacyof individual migraine acute medications. Thestrength of the evidence for each medication has beengraded. Thus, this American Headache Society evi-dence assessment can be used as a guide for knowingwhich medications have been shown to be superior toplacebo for the acute therapy of migraine and for

knowing the strength of the evidence supportingthat superiority. According to this evidence assess-ment, specific medications within the followingclasses are deemed effective for migraine acutetherapy: triptans, ergotamine derivatives, nonsteroi-dal anti-inflammatory drugs (NSAIDs), opioids, andcombination medications. Several other medicationsare “probably effective” or “possibly effective” aslisted above.

This systematic assessment of the literature doesnot provide guidance regarding which medicationsshould be used for the acute therapy of migraine for aspecific patient. Although a clinician would want toprescribe an acute migraine medication that hasstrong evidence in support of its efficacy, potentialside-effects, potential adverse events, patient-specificcontraindications to certain medications, and drug–drug interactions all need to be considered whenchoosing a migraine acute medication. In clinicalpractice, acute treatment can be associated withserious adverse events, such as tolerance and depen-dence with barbiturates or opioids, peptic ulcer orrenal disease with NSAIDs, or worsening migrainefrom medication-overuse headache. Thus, categoriza-tion of a medication as having Level A evidence ofbenefit does not necessarily mean that the medicationshould be considered a first-line drug for the acutetreatment of migraine. For example, althoughbutorphanol nasal spray has strong evidence for itssuperiority over placebo, this medication is com-monly avoided due to concerns about dependence,addiction, and development of medication-overuseheadache.

This review also does not address acute migrainetreatment in children or the elderly. There is limitedevidence for the treatment of acute migraine in chil-dren, and both high placebo responses and theshorter attack length in pediatric migraine influenceclinical trial design.2,65,66 Clinical trials usually excludepatients aged 65 and over, meaning there is little evi-dence for the acute treatment of migraine in elderlypatients.

This systematic assessment of the literaturecannot be used to compare the efficacy of individualmigraine acute therapies. This assessment reportsthe strength of evidence supporting superiority of

12 January 2015

Table.—Strength of the Evidence

Level A Level B Level C Level U Others

AnalgesicAcetaminophen 1000 mg

(for non-incapacitatingattacks)

Antiemetics*Chlorpromazine IV

12.5 mgDroperidol IV 2.75 mg*Metoclopramide IV 10 mg*Prochlorperazine IV/IM

10 mg; PR 25 mg

AntiepilepticValproate IV 400-1000 mg

NSAIDsCelecoxib

400 mg

Level B negativeOtherOctreotide SC 100

μg

ErgotsDHE*Nasal spray 2 mgPulmonary inhaler 1 mg

ErgotsDHE * IV, IM, SC 1 mg*Ergotamine/caffeine

1/100 mg

Ergot*Ergotamine 1-2 mg

Others*Lidocaine IV*Hydrocortisone

IV 50 mg

Level C negativeAntiemetics

*ChlorpromazineIM 1 mg/kg

*Granisetron IV40-80 μg/kg

NSAIDs*Aspirin 500 mgDiclofenac 50, 100 mgIbuprofen 200, 400 mg*Naproxen 500, 550 mg

NSAIDs*Flurbiprofen 100 mgKetoprofen 100 mgKetorolac IV/IM 30-60 mg

NSAIDsPhenazone 1000 mg

NSAIDsKetorolac

tromethaminenasal spray

Opioids*Butorphanol nasal spray

1 mg

Opioid*Butorphanol IM 2 mg*Codeine 30 mg PO*Meperidine IM 75 mg*Methadone IM 10 mg*Tramadol IV 100 mg

AnalgesicAcetaminophen

IV 1000 mg

TriptansAlmotriptan 12.5 mgEletriptan 20, 40, 80 mgFrovatriptan 2.5 mg*Naratriptan 1, 2.5 mg*Rizatriptan 5, 10 mg

Sumatriptan*Oral 25, 50, 100 mg*Nasal spray 10, 20 mg

Patch 6.5 mg*SC 4, 6 mg

Zolmitriptan nasal spray2.5, 5 mg*Oral 2.5, 5 mg

OthersMgSO4 IV (migraine with

aura) 1-2 g*Isometheptene 65 mg

SteroidDexamethasone IV 4-16 mg

Combinations*Acetaminophen/aspirin/

caffeine 500/500/130 mgSumatriptan/naproxen

85/500 mg

Combinations*Codeine/acetaminophen

25/400 mgTramadol/acetaminophen

75/650 mg

Others*Butalbital 50 mg*Lidocaine intranasal

Combinations*Butalbital/acetaminophen/

caffeine/codeine 50/325/40/30 mg

*Butalbital/acetaminophen/caffeine 50/325/40 mg

*Based on 2000 American Academy of Neurology evidence review.Level A: Medications are established as effective for acute migraine treatment based on available evidence.Level B: Medications are probably effective for acute migraine treatment based on available evidence.Level C: Medications are possibly effective for acute migraine treatment based on available evidence.Level U: Evidence is conflicting or inadequate to support or refute the efficacy of the following medications for acute migraine.Level B negative: Medication is probably ineffective for acute migraine.Level C negative: Medication is possibly ineffective for acute migraine.

Headache 13

individual drugs relative to placebo, but it does notcompare the relative efficacy of migraine acute medi-cations to one another. Such comparisons are bestmade through well-conducted, head-to-head studiesor carefully conducted network meta-analyses. Fur-thermore, there is substantial variability in the designof the studies included in this assessment with regardto subject inclusion and exclusion criteria (eg,migraine phenotype, frequency, and severity; exclu-sion of patients with specific medical conditions;allowance for use of migraine prophylactic therapy;inclusion of patients who had failed prior migraineacute therapies), number of attacks treated, timingfor administering the acute therapy (eg, treat whenmild vs treat when moderate to severe; early afteronset of migraine vs later after onset of migraine),and outcome measures. Primary outcome measuresvaried, but the most common were 2-hour headacherelief, followed by 2-hour headache freedom. Otherprimary outcomes included change in headacheintensity before and after treatment based on visualanalog scales; time to headache freedom, 24-hour sus-tained relief; and 4-hour headache relief. Secondarymeasures also differed, but usually included relief ofnausea, photophobia, phonophobia, and disability, aswell as measures of headache relief. Headachefreedom and sustained headache relief are harder toachieve than 2-hour headache relief, so studies thatuse headache relief instead of headache freedom as aprimary outcome are more likely to have a higherpercentage of responders.

The studies included in this assessment of theliterature evaluated the efficacy of migraine acutemedications in adults with episodic migraine with orwithout aura. However, they did not evaluate the effi-cacy of these medications for the treatment of statusmigraine, in patients with chronic migraine, or for thetreatment of menstrual migraine. Furthermore, insome studies, subjects with especially severe migrainewere excluded. Thus, the specific characteristics of anindividual patient and the migraine attack that is tobe treated must be considered before applying thefindings of this evidence assessment. Some of the evi-dence assessments in this analysis rely on work donefor the original 2000 AAN Guidelines. It is possiblethat errors or misclassifications that occurred during

that process might not have been identified. Thisproject was undertaken before the US Institute ofMedicine published its recommendations for guide-lines processes. Thus, these guidelines do not conformentirely to those recommendations. For example, wedid not formally incorporate assessments of sideeffects and harms into our assessment process.

CONCLUSIONSAccording to this systematic review of the litera-

ture and structured grading of the evidence strength,specific medications within the following classes areconsidered “effective” for the acute therapy ofmigraine: triptans, ergotamine derivatives, NSAIDs,opioids, and combination medications. Several othermedications are considered “probably effective” or“possibly effective.” This evidence base for medica-tion efficacy should be considered along with poten-tial medication side effects, potential adverse events,patient-specific contraindications to use of a particu-lar medication, and drug-to-drug interactions whendeciding which medication to prescribe for acutetherapy of a migraine attack.

Acknowledgments: Dr. Christina Szperka (Division

of Neurology, Children’s Hospital of Philadelphia), Dr.

Eric Hastriter (Department of Neurology, Mayo Clinic

Scottsdale), Dr. Laura McGowan (Buffalo Medical

Group), and Dr. Shatabdi Patel (Department of Neurol-

ogy, Thomas Jefferson University) all reviewed articles

for this study. The authors wish to thank the American

Headache Society and Linda McGillicuddy for their

assistance in organizing this study.

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54. Diener HC, Montagna P, Gacs G, et al. Efficacy andtolerability of diclofenac potassium sachets inmigraine: A randomized, double-blind, cross-overstudy in comparison with diclofenac potassiumtablets and placebo. Cephalalgia. 2006;26:537-547.

55. Lipton RB, Grosberg B, Singer RP, et al. Efficacyand tolerability of a new powdered formulation ofdiclofenac potassium for oral solution for the acutetreatment of migraine: Results from the Interna-tional Migraine Pain Assessment Clinical Trial(IMPACT). Cephalalgia. 2010;30:1336-1345.

56. Codispoti JR, Prior MJ, Fu M, Harte CM, NelsonEB. Efficacy of nonprescription doses of ibuprofenfor treating migraine headache. A randomized con-trolled trial. Headache. 2001;41:665-679.

57. Pfaffenrath V, Fenzl E, Bregman D, Farkkila M.Intranasal ketorolac tromethamine (SPRIX(R))containing 6% of lidocaine (ROX-828) for acute

treatment of migraine: Safety and efficacy data froma phase II clinical trial. Cephalalgia. 2012;32:766-777.

58. Silberstein SD, Freitag FG, Rozen TD, et al.Tramadol/acetaminophen for the treatment of acutemigraine pain: Findings of a randomized, placebo-controlled trial. Headache. 2005;45:1317-1327.

59. Alemdar M, Pekdemir M, Selekler HM. Single-doseintravenous tramadol for acute migraine pain inadults: A single-blind, prospective, randomized,placebo-controlled clinical trial. Clin Ther. 2007;29:1441-1447.

60. Levy MJ, Matharu MS, Bhola R, Meeran K,Goadsby PJ. Octreotide is not effective in the acutetreatment of migraine. Cephalalgia. 2005;25:48-55.

61. Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intra-venous magnesium sulphate in the acute treatmentof migraine without aura and migraine with aura. Arandomized, double-blind, placebo-controlled study.Cephalalgia. 2002;22:345-353.

62. Cete Y, Dora B, Ertan C, Ozdemir C, Oktay C. Arandomized prospective placebo-controlled studyof intravenous magnesium sulphate vs meto-clopramide in the management of acute migraineattacks in the emergency department. Cephalalgia.2005;25:199-204.

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Headache 17

APPENDIX 1: ADVANCED SEARCH STRATEGY FOR RELEVANT ARTICLES

Searches Results

Migraine and related terms component1 Migraine Disorders2 migraine*.mp.3 (unilateral adj2 headach*).mp.4 cephalalgi*.mp.5 hemicrania?.mp.6 or/1-5

Acute component7 acute*.mp.8 immediate.mp.9 or/7-8

Drug therapy and related terms component10 exp Drug Therapy/11 (drug adj2 therap*).mp.12 pharmacotherap*.mp.13 ae.fs.14 ad.fs.15 dt.fs.16 pd.fs.17 th.fs.18 tu.fs.19 or/10-18

Combined results, limited to human, English, 2004-current, and excluded comments, editorial, and letter20 6 and 9 and 1921 limit 20 to (comment or editorial or letter)22 20 not 2123 exp animals/ not (exp animals/ and exp humans/)24 22 not 2325 limit 24 to (English language and yr = “2004 -Current”)26 remove duplicates from 25

18 January 2015

APPENDIX 2: DATA EXTRACTION FORM

Headache 19

APPENDIX 3: STUDY CLASSIFICATIONFOR THERAPEUTIC INTERVENTIONSFROM THE AMERICAN ACADEMY OFNEUROLOGY

Class I– Randomized, controlled clinical trial in a represen-

tative population– Masked or objective outcome assessment– Relevant baseline characteristics are presented and

substantially equivalent between treatment groups,or there is appropriate statistical adjustment fordifferences

– Also required:a. Concealed allocationb. Primary outcome(s) clearly definedc. Exclusion/inclusion criteria clearly definedd. Adequate accounting for dropouts (with at least

80% of enrolled subjects completing the study)and crossovers with numbers sufficiently low tohave minimal potential for bias

e. For non-inferiority or equivalence trials claim-ing to prove efficacy for 1 or both drugs, thefollowing are also required*:1. The authors explicitly state the clinically

meaningful difference to be excluded bydefining the threshold for equivalence ornon-inferiority.

2. The standard treatment used in the study issubstantially similar to that used in previousstudies establishing efficacy of the standardtreatment (eg, for a drug, the mode ofadministration, dose, and dosage adjust-ments are similar to those previously shownto be effective).

3. The inclusion and exclusion criteria forpatient selection and the outcomes of

patients on the standard treatment are com-parable to those of previous studies estab-lishing efficacy of the standard treatment.

4. The interpretation of the study results isbased on a per-protocol analysis thataccounts for dropouts or crossovers.

Class II– Cohort study meeting criteria a–e (see Class I) or a

randomized, controlled clinical trial that lacks 1 or2 criteria b–e (see Class I)

– All relevant baseline characteristics are presentedand substantially equivalent among treatmentgroups or there is appropriate statistical adjust-ment for differences

– Masked or objective outcome assessment

Class III– Controlled studies (including well-defined natural

history controls or patients serving as their owncontrols)

– A description of major confounding differencesbetween treatment groups that could affectoutcome**

– Outcome assessment masked, objective, or per-formed by someone who is not a member of thetreatment team

Class IV– Did not include patients with the disease– Did not include patients receiving different inter-

ventions– Undefined or unaccepted interventions or outcome

measures– No measures of effectiveness or statistical precision

presented or calculable

20 January 2015