This is the current release of the guideline.

This guideline updates a previous version: Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000 Sep 26;55(6):754-62.

Migraine headache

Adults with migraine headaches

Computerized searches of the MEDLINE, PsycINFO, and CINAHL databases identified new studies. The search strategy used the MeSH term "headache" (exploded) and a published search strategy for identifying randomized controlled trials in adults that were published in English between June 1999 and May 2007. Additional MEDLINE searches revealed studies published through May 2009, which were reviewed and are included as supplemental articles.

Studies of nonsteroidal anti-inflammatory drugs (NSAIDs) and complementary treatments available in the United States were included in the analysis if they randomized patients with migraine to the agent under study or a comparator treatment (including placebo) and utilized masked (blinded) outcome assessment.

Clinical studies reviewed were limited to those assessing efficacy of NSAIDs and complementary treatments for prevention of episodic migraine in adults (e.g., <15 days/month). Studies were excluded if they assessed the efficacy of therapeutic agents for prevention or treatment of chronic migraine, intractable migraine, tension-type headache, or headache in adolescents or children. Also excluded were studies that assessed acute migraine treatment, migraine aura treatment or prevention, or nonpharmacologic treatments. Studies using quality of life measures, disability assessment, or nonstandardized outcomes as primary efficacy endpoints were not included. NSAIDs and complementary treatments not commonly or readily available in the United States are not reviewed in this guideline.

The original search identified 179 articles and included pharmacologic and complementary treatments and nonsteroidal anti-inflammatory drugs (NSAIDs). The supplemental search from 2007 to 2009 yielded an additional 105 articles. 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 in this guideline.

Classification of Evidence for the Rating of a Therapeutic Study

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or non-inferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II or III criteria including consensus or expert opinion.

* Note that numbers 1–3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

At least 2 panelists independently reviewed each selected study and rated it using the American Academy of Neurology (AAN) therapeutic classification of evidence scheme (see the "Rating Scheme for the Strength of the Evidence" field). Differences in ratings were resolved by author panel discussion.

Since the 2000 guideline publication, the AAN revised its evidence classification criteria to include study completion rates. Studies whose completion rates are below 80% were downgraded.

The American Academy of Neurology and the American Headache Society participated in the development process. An author panel of headache and methodologic experts was assembled to review the evidence.

Conclusion and recommendations were linked to the strength of the evidence (see the "Rating Scheme for the Strength of the Recommendations" field).

Classification of Recommendations

A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome > 5 and the lower limit of the confidence interval is > 2.

A formal cost analysis was not performed and published cost analyses were not reviewed.

Drafts of the guidelines have been reviewed by at least three American Academy of Neurology (AAN) and American Headache Society (AHS) committees, a network of neurologists, Neurology peer reviewers, and representatives from related fields. This guideline was approved by the Quality Standards Subcommittee on February 19, 2011; by the Practice Committee on June 19, 2011; by the AHS Board of Directors on March 29, 2012; and by the AAN Board of Directors on November 7, 2011.

Definitions of the levels of the recommendations (A, B, C, U) and classification of the evidence (Class I-IV) are provided at the end of the "Major Recommendations" field.

Conclusions

• Petasites is established as effective for migraine prevention (2 Class I studies).
• Riboflavin is probably effective for migraine prevention (1 Class I trial and 1 imprecise Class II study).
• Co-Q10 is possibly effective for migraine prevention (1 Class II study).
• A combination of soy isoflavones (60 mg), dong quai (100 mg), and black cohosh (50 mg) is possibly effective for migraine prevention (1 Class II study). Percutaneous estradiol is possibly effective for migraine prevention (1 Class II study); however, there is an increased risk of migraine recurring after estradiol patch discontinuation.
• Magnesium is probably effective for migraine prevention (multiple Class II trials). MIG-99 (feverfew) is probably effective for migraine prevention (1 Class I study, 1 positive Class II study, and 1 underpowered negative Class II study).
• The efficacy of hyperbaric oxygen (HBO) for migraine prevention is unclear (1 imprecise negative Class II study).
• The efficacy of omega-3 for migraine prevention is unclear (1 imprecise Class I study).

Clinical Context

In a previous epidemiologic study, 38.7% of study participants had ever used a migraine preventive treatment, of which only 12.4% were current users and 17.2% were coincident users (taking a migraine preventive treatment for other reasons). The proportion of those who use nonsteroidal anti-inflammatory drugs (NSAIDs) or individual complementary treatments specifically for migraine prevention is unclear at this time, and is a topic which warrants further study. Additionally, the treatments reviewed herein are those available in the United States. In other countries, treatments may not be available commercially or may be available in other dosages or in other preparations or combinations. Therefore, the results from this and other guidelines are limited to those treatments available in the United States.

Additionally, studies assessing the efficacy of NSAIDs and complementary treatments for migraine prevention are limited and should be considered relative to other available pharmacologic therapies reviewed in a separate guideline. Silberstein and colleagues report divalproex sodium, sodium valproate, topiramate, metoprolol, propranolol, and timolol are effective for migraine prevention and should be offered to patients with migraine to reduce migraine attack frequency and severity (Level A).

Additionally, the clinical evidence for NSAIDs and complementary treatments for migraine prevention should be reviewed with caution because there are clear discrepancies in how patients were selected for study inclusion; how severe, frequent, or disabling their attacks were; and how severity was assessed. Also, these treatments are unregulated. There are few or no studies on how these medications should be taken—specifically relative to dosing strategies and coadministration with other prescription pharmacologic treatments. When patients are instructed or choose to take NSAIDs or complementary treatments for migraine prevention, it is important that they be followed over the course of treatment so dosing and titration modifications and adverse effect (AE) risk can be monitored. Prospective long-term safety of many of these agents is not well studied specifically regarding their use as preventive migraine treatments.

It is reasonable also for clinicians to inquire about the doses being used and frequency of use of NSAIDs and complementary treatments. Frequent medication use or high dose levels may increase the risk of headache progression or medication overuse, which may lead to other secondary health complications (e.g., gastrointestinal upset/bleeding with aspirin or NSAIDs or headache rebound with discontinuation of feverfew). Complete review and disclosure of coexisting conditions are warranted, as complementary or pharmacologic therapies taken for coexisting conditions (e.g., depression) may exacerbate headache. Because migraine is frequent in women of childbearing age, the potential for adverse fetal effects related to migraine prevention strategies is of particular concern. Little has been done to establish the long-term safety and efficacy of these agents during pregnancy or breastfeeding.

Additionally, when patients have unlimited access to over-the-counter medications, they may be unaware of the continued need for routine physician follow-up for a chronic illness such as migraine, as illness severity may progress or improve, often warranting medication changes (see table e-1 of the data supplement [see the "Availability of Companion Documents" field]). It also is important for patients to understand the magnitude of benefit that can be expected from preventive migraine therapies; moreover, patient education about migraine and appropriate management is important in successful patient care. For some patients, a 35% reduction in headache frequency or intensity may be deemed an insufficient level of improvement, thus leading them to risk dose escalation. Additionally, patients with migraine may need to be educated about appropriate use and risks of these agents.

Finally, recent studies suggest that some medications used for migraine may offer long-term protection against headache progression whereas other agents may elevate progression risk. Specifically, one epidemiologic study assessing medication use in the general migraine population reports that aspirin or ibuprofen use may protect against progression from episodic to chronic headache conditions. In contrast, opioid use was positively associated with chronic headache conditions. Although conclusions are preliminary regarding the benefits and risks of selected agents for long-term use, studies suggest that these agents may play a significant role in headache progression and patterns, lending further emphasis to the importance of following patients closely, including regular assessment of NSAIDs, and other complementary treatments for migraine prevention.

Recommendations

Level A. The following therapy is established as effective and should be offered for migraine prevention:

• Petasites (butterbur)

Level B. The following therapies are probably effective and should be considered for migraine prevention:

• NSAIDs: fenoprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium
• Herbal therapies, vitamins, and minerals: riboflavin, magnesium, MIG-99 (feverfew)
• Histamines: histamine subcutaneous (SC)

Level C. The following therapies are possibly effective and may be considered for migraine prevention:

• NSAIDs: flurbiprofen, mefenamic acid
• Herbal therapies, vitamins, and minerals: Co-Q10, estrogen
• Antihistamines: cyproheptadine

Level U. Evidence is inadequate or conflicting to support or refute the use of the following therapies for migraine prevention:

• NSAIDs: aspirin, indomethacin
• Herbal therapies, vitamins, and minerals: omega-3
• Other: HBO

Level B negative. The following therapy is probably ineffective and should not be considered for migraine prevention:

• Leukotriene receptor antagonists: montelukast

Definitions:

Classification of Recommendations

A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.)*

B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven.

Classification of Evidence for the Rating of a Therapeutic Study

Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

The following are also required:

1. Concealed allocation
2. Primary outcome(s) clearly defined
3. Exclusion/inclusion criteria clearly defined
4. Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias.
5. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*:
   1. The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or non-inferiority.
   2. The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective).
   3. The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment.
   4. The interpretation of the results of the study is based upon a per protocol analysis that takes into account dropouts or crossovers.

Class II: A randomized controlled clinical trial of the intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria a–e above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets b–e above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.**

Class IV: Studies not meeting Class I, II or III criteria including consensus or expert opinion.

* Note that numbers 1–3 in Class Ie are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III.

**Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

None provided

The type of supporting evidence is identified and graded for each recommendation (see the "Major Recommendations" field).

No additional Class I or Class II studies were published since the original guideline for fenoprofen, ibuprofen, ketoprofen, naproxen, naproxen sodium, or indomethacin. Recommendations regarding these treatments are based on the evidence reviewed in the original guideline (denoted in table 1 in the updated guideline document).

Migraine prevention: reduction in migraine attack frequency, intensity, duration, and disability

An implementation strategy was not provided.

Not applicable: Guideline was not adapted from another source.

This guideline was developed with financial support from the American Academy of Neurology and the American Headache Society. None of the authors received reimbursement, honoraria, or stipends for their participation in the development of this guideline.

Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society

Guideline Authors: S. Holland, PhD; S.D. Silberstein, MD, FACP; F. Freitag, DO; D.W. Dodick, MD; C. Argoff, MD; E. Ashman, MD

Quality Standards Subcommittee Members 2009–2011: Jacqueline French, MD, FAAN (Co-Chair); John D. England, MD, FAAN (Co-Chair); Eric Ashman, MD; Stephen Ashwal, MD, FAAN (Ex-Officio); Misha-Miroslav Backonja, MD; Richard L. Barbano, MD, PhD, FAAN; Michael G. Benatar, MBChB, DPhil; John J. Halperin, MD, FAAN; Deborah Hirtz, MD, FAAN (Ex-Officio); Jonathan Hosey, MD, FAAN (Ex-Officio); Andres M. Kanner, MD; Steven R. Messé, MD; Leslie A. Morrison, MD; Pushpa Narayanaswami, MD, MBBS; Dean M. Wingerchuk, MD, MSc, FRCP(C); Theresa A. Zesiewicz, MD, FAAN.

Conflict of Interest

The American Academy of Neurology (AAN) and the American Headache Society (AHS) are committed to producing independent, critical and truthful clinical practice guidelines (CPGs). Significant efforts are made to minimize the potential for conflicts of interest to influence the recommendations of this CPG. To the extent possible, the AAN and AHS keep separate those who have a financial stake in the success or failure of the products appraised in the CPGs and the developers of the guidelines. Conflict of interest forms were obtained from all authors and reviewed by an oversight committee prior to project initiation. AAN and AHS limit the participation of authors with substantial conflicts of interest. The AAN and AHS forbid commercial participation in, or funding of, guideline projects. Drafts of the guidelines have been reviewed by at least three AAN and AHS committees, a network of neurologists, Neurology peer reviewers, and representatives from related fields. The AAN Guideline Author Conflict of Interest Policy can be viewed at the American Academy of Neurology website .

Disclosure

Dr. Holland (formerly Dr. Pearlman) receives consulting income from Map Pharmaceuticals and the American Headache Society and research support from Albert Einstein College of Medicine. Dr. Silberstein is on the advisory panel of and receives honoraria from AGA, Allergan, Amgen, Capnia, Coherex, Colucid, Cydex, GlaxoSmithKline, Lilly, MAP, Medtronic, Merck, Minster, Neuralieve, NINDS, NuPathe, Pfizer, St. Jude Medical, and Valeant. He is on the speakers' bureau of and receives honoraria from Endo Pharmaceuticals, GlaxoSmithKline, and Merck. He serves as a consultant for and receives honoraria from Amgen and Novartis. His employer receives research support from AGA, Allergan, Boston Scientific, Capnia, Coherex, Endo Pharmaceuticals, GlaxoSmithKline, Lilly, MAP, Medtronic, Merck, NINDS, NuPathe, St. Jude Medical, and Valeant Pharmaceuticals. Dr. Freitag has served on the scientific advisory boards of Zogenix Pharmaceuticals, Allergan Pharmaceuticals, Nautilus, MAP Pharmaceuticals, and Nupathe; has received travel expenses and or honoraria from GlaxoSmithKline, Zogenix, Merck, Nautilus, Allergan, Diamond Headache Clinic Research and Educational Foundation (not for profit), and the American Headache Society (travel). Dr. Freitag is a member of the Board of Directors of the National Headache Foundation. Dr. Dodick, within the past 3 years, serves on advisory boards and has consulted for Allergan, Alder, Pfizer, Merck, Coherex, Ferring, Neurocore, Neuralieve, Neuraxon, NuPathe Inc., MAP, SmithKlineBeecham, Boston Scientific, Medtronic, Inc., Nautilus, Eli Lilly & Company, Novartis, Colucid, GlaxoSmithKline, Autonomic Technologies, MAP Pharmaceuticals, Inc., Zogenix, Inc., Impax Laboratories, Inc., Bristol Myers Squibb, Nevro Corporation, Atlas, Arteaus, and Alder Pharmaceuticals. Within the past 3 years, Dr. Dodick has received funding for travel, speaking, or editorial activities from CogniMed, Scientiae, Intramed, SAGE Publishing, Lippincott Williams & Wilkins, Oxford University Press, Cambridge University Press, Miller Medical, Annenberg for Health Sciences; he serves as Editor-in-Chief and on the editorial boards of The Neurologist, Lancet Neurology, and Postgraduate Medicine; and has served as Editor-in-Chief of Headache Currents and as an Associate Editor of Headache; he receives publishing royalties for Wolff's Headache, 8th edition (Oxford University Press, 2009) and Handbook of Headache (Cambridge University Press, 2010). Within the past 3 years, Dr. Dodick has received research grant support from Advanced Neurostimulation Systems, Boston Scientific, St Jude Medical, Inc., Medtronic, NINDS/NIH, Mayo Clinic. Dr. Argoff has served on a scientific advisory board for the Department of Defense and DSMB for the NIH; has received funding for travel and/or speaking and/or has served on a speakers' bureau for Pfizer (King), Janssen (Pricara), Millennium Laboratories, Neurogesx, Forest Laboratories, Eli Lilly, Covidien, and Endo Pharmaceuticals; has received research support from Endo Pharmaceuticals, Forest Laboratories, Eli Lilly, Neurogesx, Pfizer, and SBRT funded by the NIH; and has received stock/stock options from Pfizer. Dr. Ashman is the Level of Evidence editor for Neurology and serves on the AAN Guideline Development Subcommittee. He reports no other disclosures. Full disclosures were provided at the time of Board approval. Go to Neurology.org  for full disclosures.

This is the current release of the guideline.

This guideline updates a previous version: Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000 Sep 26;55(6):754-62.

Electronic copies: A list of American Academy of Neurology (AAN) guidelines, along with a link to a Portable Document Format (PDF) file for this guideline, is available at the AAN Web site .

Print copies: Available from the AAN Member Services Center, (800) 879-1960, or from AAN, 1080 Montreal Avenue, St. Paul, MN 55116.

The following are available:

• Update: Pharmacologic treatment for episodic migraine prevention in adults. AAN summary of evidence-based guideline for clinicians. St. Paul (MN): American Academy of Neurology. 2012. 2 p. Available in Portable Document Format (PDF) from the American Academy of Neurology (AAN) Web site .
• Pharmacologic treatment of episodic migraine prevention in adults. Case presentation. St. Paul (MN): American Academy of Neurology. 2012. 6 p. Available in PDF from the AAN Web site .
• Evidence-based guidelines update: Pharmacologic treatments and NSAIDs and other complementary treatments for episodic migraine prevention in adults. Slide presentation. St. Paul (MN): American Academy of Neurology. 2012. Available from the AAN Web site .
• Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache. CME course. Available online to subscribers of Neurology at the Neurology Web site .
• Evidence-based guidelines update: Pharmacologic treatments and NSAIDs and other complementary treatments for episodic migraine prevention in adults. Podcast. St. Paul (MN): American Academy of Neurology. 2012. Available from the AAN Web site .
• 2012 AAN press conference: New guidelines on preventing migraine headache. Video. Available from the AAN Web site .
• Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache. Data supplement (e-appendices, e-tables). Available from the AAN Web site .
• AAN guideline development process [online]. St. Paul (MN): American Academy of Neurology. Available from the AAN Web site .

The following is available:

• NSAIDS and complementary treatments for migraine prevention in adults. AAN summary of evidence-based guideline for patients and their families. St. Paul (MN): American Academy of Neurology. 2012. 2 p. Electronic copies: Available in English  and Spanish  in Portable Document Format (PDF) from the American Academy of Neurology (AAN) Web site.

Please note: This patient information is intended to provide health professionals with information to share with their patients to help them better understand their health and their diagnosed disorders. By providing access to this patient information, it is not the intention of NGC to provide specific medical advice for particular patients. Rather we urge patients and their representatives to review this material and then to consult with a licensed health professional for evaluation of treatment options suitable for them as well as for diagnosis and answers to their personal medical questions. This patient information has been derived and prepared from a guideline for health care professionals included on NGC by the authors or publishers of that original guideline. The patient information is not reviewed by NGC to establish whether or not it accurately reflects the original guideline's content.

This NGC summary was completed by ECRI on February 12, 2002. The information was verified by the guideline developer on September 5, 2003. This summary was updated by ECRI on January 12, 2005 following the release of a public health advisory from the U.S. Food and Drug Administration regarding the use of some non-steroidal anti-inflammatory drug products. This summary was updated on April 15, 2005 following the withdrawal of Bextra (valdecoxib) from the market and the release of heightened warnings for Celebrex (celecoxib) and other nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). This summary was updated by ECRI on June 16, 2005, following the U.S. Food and Drug Administration advisory on COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). This summary was updated by ECRI on October 3, 2005, following the U.S. Food and Drug Administration advisory on Paxil (paroxetine). This summary was updated by ECRI on December 12, 2005, following the U.S. Food and Drug Administration advisory on Paroxetine HCL - Paxil and generic paroxetine. This NGC summary was updated by ECRI Institute on June 28, 2012.

This NGC summary is based on the original guideline, which is copyrighted by the American Academy of Neurology.