Headache guidelines

Ozaire Awais MD (

Dr. Awais of Angels Neurological Centers has no relevant financial relationships to disclose.

Michael J Marmura MD (

Dr. Marmura of Thomas Jefferson University Hospital received research support from Teva and honorariums for consulting services from Alder, Amgen, GammaCore, Promius, and Supernus.

Stephen D Silberstein MD, editor. (

Dr. Silberstein, Director of the Jefferson Headache Center at Thomas Jefferson University, receives honorariums from Allergan, Avanir Pharmaceuticals, Curelator, Depomed, Dr. Reddy's Laboratories, eNeura,  INSYS Therapeutics, Lilly USA, Supernus Pharmacerticals,  Thernica and Trigemina for consulting. He is also the  principal investigator for a clinical trials conducted by Alder Biopharmaceuticals, Amgen, electroCore Medical, Lily USA and Teva.

Originally released February 28, 2001; last updated February 4, 2019; expires February 4, 2022

This article updates the results from the 7 evidence-based reviews on the management of patients with migraine and cluster headache: specifically, acute, preventive, and nonpharmacologic treatments for migraine, as well as the role of neuroimaging in patients with headache. There have also been some important updates to treatment of cluster headache, and information from the most recent studies will be presented. The full papers for these treatment guidelines are published elsewhere (Campbell et al 2000; Frishberg et al 2000; Matchar et al 2000; McCrory et al 2000; Ramadan et al 2000; Silberstein and Rosenberg 2000), and only the specific treatment recommendations are summarized below (Holland et al 2012; Silberstein et al 2012; Marmura et al 2015; Robbins et al 2016; Silberstein 2016).

In June 1998, Duke University's Center for Clinical Health Policy Research, in collaboration with the American Academy of Neurology, completed 4 Technical Reviews on migraine sponsored by the Agency for Health Care Policy and Research: self-administered drug treatments for acute migraine (Gray et al 1999a); parenteral drug treatments for acute migraine (Gray et al 1999b); drug treatments for the prevention of migraine (Gray et al 1999c); and behavioral and physical treatments for migraine (Goslin et al 1999). The Education and Research Foundation of the American Academy of Neurology later funded additional reports on diagnostic testing for headache patients, an update on sumatriptan and other 5-HT1 agonists, and a report on butalbital-containing compounds for migraine and tension-type headache, using the same methodology that was used in the original Technical Reviews. A multidisciplinary panel of professional organizations (The US Headache Consortium) produced 4 treatment guidelines, each related to a distinct set of management decisions: diagnostic testing (primarily neuroimaging studies), pharmacological management of acute attacks, migraine-preventive drugs, and behavioral and physical treatments for migraine.

In 2012, the American Academy of Neurology updated and published new preventive treatment guidelines for migraine (Holland et al 2012; Silberstein et al 2012). For pharmacologic therapy, the authors analyzed published studies from June 1999 to May 2009, using a structured review process to classify the evidence relative to the various medications available in the United States for migraine prevention. The author panel reviewed 284 abstracts, which ultimately yielded 30 Class I or Class II articles that are reviewed herein.

The original search identified 179 articles. A supplemental search (2007 to 2009) yielded 105 additional articles. Of the total 284 articles, 30 were pharmacologic and were classified as Class I or Class II and are reviewed herein. In addition, 15 were classified as Class I or Class II and identified as relating to nonsteroidal anti-inflammatory drugs (NSAIDs) and complementary treatments.

Studies were excluded if they included any of the following factors:


• Assessed the efficacy of therapeutic agents for headache other than episodic migraine in adults


• Assessed acute migraine treatment, migraine aura treatment/prevention, or nonpharmacologic treatments (eg, behavioral approaches)


• Used quality of life measures, disability assessment, or nonstandardized outcomes as primary efficacy endpoints


• Tested the efficacy of drugs not available in the United States

Since the guideline publication in 2000, the AAN revised its evidence classification criteria to include study completion rates. Studies with completion rates below 80% were downgraded; thus, several studies in the original guideline have been downgraded.

They found no new Class I or II studies published for acebutolol, atenolol, bisoprolol, carbamazepine, clonazepam, clonidine, clomipramine, fluvoxamine, guanfacine, nabumetone, nadolol, nicardipine, nifedipine, or protriptyline. Recommendations for these agents are based on the evidence reviewed in the original guideline (denoted with an asterisk in Table 1). Currently, no Class I or Class II studies exist for anticoagulants (limited Class III and IV studies were identified; Table 1 includes anticoagulants). Of the total 284 articles, 15 were classified as Class I or Class II and identified as relating to NSAIDs and complementary treatments; they are reviewed herein.

In 2015, a study by Marmura and colleagues provided an updated assessment of the evidence for individual pharmacological therapies for acute migraine treatment (Marmura et al 2015). This assessment is an update to the American Academy Neurology Guidelines that were published in 2000, which summarized the available evidence related to the efficacy of acute migraine medications. The review was conducted by members of the Guidelines Section of the American Headache Society.

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 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 required at least 2 Class I studies, and level B evidence required 1 Class I or 2 Class II studies.

In 2016, the American Headache Society convened an expert panel of authors who defined a search strategy and performed a search of Medline, Embase, the Cochrane database, and clinical trial registries from inception through 2015. The authors provided evidence-based treatment recommendations for adults with acute migraine who require treatment with injectable medication in an emergency department. Identified articles were rated using the American Academy of Neurology s risk of bias tool. They identified 68 unique randomized controlled trials utilizing 28 injectable medications. Of these, 19 were rated Class I (low risk of bias), 21 were rated Class II (higher risk of bias), and 28 were rated Class III (highest risk of bias). Metoclopramide, prochlorperazine, and sumatriptan each had multiple Class I studies supporting acute efficacy, as did dexamethasone for prevention of headache recurrence. All other medications had lower levels of evidence.

In 2016, a systematic review by Robbins and colleagues looked at the available evidence for the acute and prophylactic treatment of cluster headache (Robbins et al 2016). This was updated from the 2010 American Academy of Neurology (AAN) endorsed systematic review.

Since the publication of the 2010 AAN review, there are no new data from randomized, double-blind, controlled trials that contribute to determining the efficacy or safety of the following acute treatments: sumatriptan, zolmitriptan, oxygen, octreotide, dihydroergotamine, prednisone, cocaine/lidocaine, and somatostatin. Thus, the assessment of the data and recommendations regarding these treatments have been carried forward from the 2010 AAN assessment.

Medline, PubMed, and EMBASE databases were searched for double-blind, randomized controlled trials that investigated treatments of cluster headache in adults. To be included, studies must have been double-blind, randomized trials of any treatment versus placebo or sham versus another treatment studying adult participants (at least 18 years of age). Studies of episodic cluster headache, chronic cluster headache, or a combination were included. Studies were excluded if they were not double-blind, if there was no randomization, if a treatment or placebo/sham comparator was not used, and if children were studied. Research published between 1950 and April 15, 2015 was considered for inclusion.

In 2016, Rajapakse and colleagues reviewed Guidelines from the AAN/AHS, Canadian Headache Society, and the European Federation of Neurological Sciences (EFNS), as well as highlighted randomized control trial evidence for use of the following nutraceuticals: riboflavin, coenzyme Q10, magnesium, butterbur, feverfew, and omega-3 polyunsaturated fatty acids (OPFA) (Rajapakse et al 2016). This review will summarize their results.

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