AMBASSADOR PROGRAM GUIDELINE FOR MANAGEMENT OF PRIMARY HEADACHE IN ADULTS

BACKGROUND DOCUMENT

(SUPPORTING DOCUMENTS AND PROCESS DESCRIPTION)

AUGUST 2013

August, 2013

ABBREVIATIONS

CPG clinical practice guideline

CS case series study

EO expert opinion

G guideline

G1 to G6 seed guidelines

GDG Guideline Development Group

HTA health technology assessment

IHE Institute of Health Economics

IHS International Headache Society

MA meta-analysis

NA not applicable

NR narrative review

NRCS non-randomized comparative study

NRT non-randomized trial

NSAID non-steroidal anti-inflammatory drug

qSR quasi-systematic review

RCT randomized controlled trial

SC Steering Committee

SR systematic review

TOP Toward Optimized Practice

Ambassador Program. Guideline for Management of Primary Headache in Adults. Background Document i August, 2013

TABLE OF CONTENTS Abbreviations ...... i Scope of this Document ...... 1 About the Alberta Headache Guideline ...... 2 Purpose ...... 2 Objectives ...... 2 Target Users ...... 2 Multidisciplinary Participation ...... 2 Guideline Documents ...... 3 For clinicians ...... 3 For patients ...... 4 Conflict of Interest ...... 4 Funding and Editorial Independence ...... 4 Legal Aspects ...... 4 Terms of Use ...... 4

Stage I – Set-Up: Background and Planning ...... 6 Overview of the Alberta Ambassador Guideline Adaptation Program ...... 6 Set-up and Planning of the Alberta Headache Guideline Development Process ...... 7 About Headache ...... 8 Summary of the epidemiology and disease burden of common headache disorders ...... 8 Knowledge gaps in the primary care treatment of headache disorders ...... 10 References ...... 12

Stage II – Adaptation: Identifying, Selecting, and Appraising the Seed Guidelines ...... 15 Rationale ...... 15 Identifying Seed Guidelines ...... 16 Inclusion criteria ...... 16 Exclusion criteria ...... 17 Literature search strategies ...... 17 Selecting the Seed Guidelines ...... 23 Critically Appraising the Seed Guidelines ...... 24

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Extracting Data ...... 25 References ...... 26

Stage II – Adaptation: Guideline Development Process ...... 28 General Process ...... 28 Rationale and Process for Developing Recommendations ...... 32 Classification of Recommendations ...... 33 Limitations of the Guideline Development Process ...... 34 References ...... 35

Stage III – Finalization: Reviewing, Evaluating, and Endorsing the Guideline ...... 36 Reviewing the Alberta CPG ...... 36 GDG and their colleagues ...... 36 Primary care practitioners ...... 37 Advisory committee ...... 37 Patients and lay people ...... 37 Endorsement ...... 38 Evaluation Strategy ...... 38 Key review criteria ...... 38 References ...... 40

Stage III – Finalization: Disseminating, Implementing, and Updating the Guideline ...... 41 Potential Barriers to Guideline Uptake and Implementation ...... 41 Key actors ...... 42 Dissemination and Implementation Plan...... 44 Update Process ...... 44 References ...... 48

Applicability of the Guideline – Economic/Cost Implications ...... 49 General Aspects ...... 49 Economic Information Reported in the Seed Guidelines ...... 50 Resource Implications of the Alberta CPG ...... 50 References ...... 50

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Appendix A: Participants in the Alberta CPG Development Process ...... 52 Appendix B: The Guideline Development Process—Participants and Roles ...... 59 Appendix C: Excluded Guidelines ...... 63 Appendix D: Modifications Made to the AGREE Tool ...... 69 References ...... 69 Appendix E: Included Seed Guidelines ...... 70 References ...... 71 Appendix F: Critical Appraisal Results (modified AGREE tool) ...... 73 Appendix G: Inventory of Guideline Recommendations ...... 77 Appendix H: Summary of Parking Lot Items...... 217 References ...... 243 Appendix I: Sample of the Additional Information Provided to the GDG and Subcommittees .... 254 Appendix J: Sample of the Document Used to Track GDG Deliberations ...... 262 Appendix K: Process Used to Formulate Recommendations ...... 263 Appendix L: Recommendation Categories ...... 264 Appendix M: Feedback on Guideline Documents ...... 266 Appendix N: Declaration of Competing Interest Form ...... 278

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SCOPE OF THIS DOCUMENT This background document outlines the methods used to develop the Alberta Clinical Practice Guideline (CPG) for Management of Primary Headache in Adults, which was produced as part of the Alberta Ambassador Guideline Adaptation Program.

This document should be cited as: Institute of Health Economics (IHE). Ambassador Program guideline for management of primary headache in adults: background document. Edmonton (AB): Institute of Health Economics; 2013. Available from: http://www.ihe.ca/research/--the-alberta-ambassador-program/--headache- guideline/headache-methods/

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ABOUT THE ALBERTA HEADACHE GUIDELINE

This section contains the following information on the Alberta CPG for Management of Primary Headache in Adults: √ the purpose, objectives, and target audience √ the multidisciplinary committees involved in its production √ the type and location of documents available to clinicians and patients √ conflict of interest and editorial independence of the Guideline Development Group √ terms of use

Purpose The purpose of the Alberta Clinical Practice Guideline (CPG) for Management of Primary Headache in Adults is to help Alberta clinicians make evidence-informed decisions about the care of adult patients (aged 18 years or older) with headache. The guideline was written to provide healthcare professionals in community practice and patients in Alberta with guidance about the prevention, diagnosis, evaluation, management, and treatment of headache. It is expected that providing relevant, up-to-date information to assist primary care practitioners in the prevention, diagnosis, evaluation, management, and treatment of headache will allow more patients to be competently managed in the primary care setting and decrease unnecessary referrals to increasingly overburdened specialists. Objectives The primary objectives are to: • increase the use of evidence-informed approaches to the prevention, assessment, diagnosis, and treatment of headache for patients in primary care • promote appropriate specialist referrals and use of diagnostic tests in patients with headache • encourage patients to engage in appropriate self-care Target Users The guideline is intended to be used by any primary healthcare provider (for example, family physician, physical therapist, occupational therapist, nurse, nurse practitioner, pharmacist, psychologist, or chiropractor) in a primary care setting who is responsible for the care of patients with headache. Multidisciplinary Participation Three multidisciplinary committees were involved in the development of the Alberta CPG for Management of Primary Headache in Adults.

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• The Steering Committee (SC) guided the collection and collation of research material, provided operational oversight, and acted as a secretariat to the Guideline Development Group and Advisory Committee. • The Advisory Committee (AC) advised the SC on strategic matters. • The Guideline Development Group (GDG) prepared the CPG. A Research Team of health technology assessment (HTA) researchers with methodological expertise from the Institute of Health Economics (IHE) assisted the SC and GDG in the development of the Alberta CPG. See Appendix A for the profile of each committee participant. See Appendix B for a flow diagram of the Alberta CPG development process and an outline of the roles and activities of each of the committees. Guideline Documents The Alberta CPG for Management of Primary Headache in Adults and its companion documents are hosted by Toward Optimized Practice (TOP), the program responsible for provincial CPGs, through its website at www.topalbertadoctors.org/cpgs.php?sid=65&cpg_cats=88. The Alberta CPG was posted on the TOP website on 27 September 2012. For clinicians 1. Guidelines a. Summary Guideline for Management of Primary Headache in Adults (8-page summary document) b. Guideline for Primary Care Management of Headache in Adults (full guideline) c. Quick Reference (2-page algorithm and medication tables) d. Guideline (mobile version/personal digital assistant (PDA)—forthcoming) 2. Practice tools a. Headache History Guide (forthcoming) b. Headache Diary Sheet c. Headache disability measurement tools (external tools): • Headache Impact Test [HIT-6] • Migraine Disability Assessment Scale [MIDAS] 3. Canadian Guideline for Safe and Effective Use of Opioids for Chronic Non-Cancer Pain endorsed by the College of Physicians and Surgeons of Alberta (external tool) 4. Instructional video: Temporomandibular and Neck Exam (external tool) 5. Guideline for Primary Care Management of Headache in Adults: Background Document (supporting documents and process description)

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For patients 1. Patient information sheets (forthcoming) a. What You Should Know About Headache b. What You Should Know About Migraine Headache c. What You Should Know About Migraine Preventive Medications d. What You Should Know About Tension-Type Headache e. What You Should Know About Medication-Overuse Headache f. What You Should Know About Headache Self-Management 2. Commonly Reported Food Triggers for Migraine Attacks (forthcoming) 3. Food Triggers, Caffeine and Migraine Attacks—forthcoming) Conflict of Interest All GDG, SC, and Research Team members completed a declaration of competing interest using a standard form (see Appendix N). Competing interest was defined as being financial or nonfinancial interest, either direct or indirect, that could affect the recommendations contained in the Alberta CPG. Four members of the GDG declared competing interests (see Appendix N). However, the collaborative nature of the CPG development process, which involved a large (n=21), multidisciplinary GDG led by two co-chairs, ensured that these interests had no influence on the design, data analysis, formulation, or content of the guideline. Funding and Editorial Independence Alberta’s HTA program was established under the Health Research Collaboration Agreement between the IHE and the Alberta Health Ministry. Funding for this initiative was provided by Alberta Health. Alberta Health Services, Calgary Zone provided (clinical leadership and) an in-kind contribution. The abovementioned funders had no influence on the recommendations contained in the final Alberta CPG. Legal Aspects Toward Optimized Practice, the program responsible for provincial guidelines, hosts the Alberta CPG and possesses the associated legal and intellectual property rights. The Alberta CPG was posted on the Toward Optimized Practice (TOP) website on 27 September 2012 (www.topalbertadoctors.org/cpgs.php?sid=65&cpg_cats=88). Terms of Use Users are free to share (copy, distribute, and transmit) and remix (adapt) the work under the following conditions.

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• Attribution: The work must be attributed in the manner specified by the author or licensor (but not in any way that suggests the author or licensor endorse you or your use of the work). • Non-commercial: The work may not be used for commercial purposes. • Share alike: If the work is altered, transformed, or built upon, the resulting work may be distributed under the same licence as or a similar licence to this one. For any reuse or distribution, the user must make clear to others the licence terms of this work. Any of the above conditions can be waived if the user gets permission from the copyright holder. The author’s moral rights are retained in this licence.

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STAGE I – SET-UP Stage 1 – Set-up

BACKGROUND AND PLANNING Formulate research question

Stage II – Adaptation This section contains information on: Search for and screen seed CPGs √ the Ambassador Program – its genesis and establishment Assess and select seed CPGs √ the set up of the guidance development phase of the program Extract data into evidence tables √ headache – the epidemiology and economic burden, as well as the knowledge gaps identified Draft guideline document among primary care practitioners regarding its management Stage III – Finalization

Review and refine draft guideline

Finalize and endorse guideline

Disseminate guideline and plan update

Overview of the Alberta Ambassador Guideline Adaptation Program The Alberta Ambassador Program is a knowledge translation strategy that was trialled in Alberta Canada in 2004–05. The first phase of the Program (the Ambassador Pilot Project), which was completed in 2005, used clinical opinion leaders to present evidence to healthcare providers about various treatments for chronic pain. Information about the first phase of the program is available from the Ambassador Program website (www.ihe.ca/research/--the-alberta-ambassador-program/) and a series of peer-reviewed publications.1-3 Funding for the Ambassador Pilot Project was provided by a capacity-building grant from the Canadian Agency for Drugs and Technologies in Health (formerly known as the Canadian Coordinating Office for Health Technology Assessment). The success of the initial Ambassador Program led to additional funding from Alberta Health to expand the scope of the project. The second phase of the program started in 2006 and focused on developing evidence-based, Alberta-specific CPGs for the management of two conditions: low back pain (from 2006 to 2009; updated in 2011) and headache (from 2010 to 2012). This second iteration of the HTA Ambassador Program built on the Ambassador Pilot Project, with the aims of: • collaborating with local champions to develop locally adapted CPGs for low back pain and headache in order to guide clinicians through a sequential process of determining the clinically appropriate treatment options available in their region

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• supporting local networks in disseminating the CPGs to clinicians in Alberta • updating and maintaining the HTA Ambassador website as a resource for clinicians and patients • designing and implementing an appropriate approach for evaluating the impact of the CPGs • exploring strategies for engaging the public in HTA research transfer on the topics of low back pain and headache management Set-up and Planning of the Alberta Headache Guideline Development Process Several activities occurred in preparation for the second phase of the Ambassador Program. • On 27 February 2006 an ad hoc planning meeting was held involving experts in the field of CPG dissemination to develop an action plan for the second phase of the program. The recommendation was to conduct a small-scale needs analysis and to ensure that appropriate partnerships were established. • During May and June 2006 a survey was conducted of those who participated in the Ambassador Pilot Project.4 The aim was to gauge the need among these individuals for care pathways in the areas of low back pain and headache, as well as to assess their interest in participating in a videoconference to initiate the second phase of the Ambassador Program. • On 8 September 2006 a meeting was held of the Advisory Committee for the Alberta HTA Ambassador Program, with the aim of gathering more advice on the development of guidelines and clinical pathways for primary care clinicians regarding low back pain and headache. The meeting included a presentation of the results from the survey of Ambassador Pilot Project participants. The AC decided that a more extensive knowledge assessment should be conducted, ideally with a focus on increasing physicians’ response rates. • On 30 November 2006 a videoconference meeting was held of health professionals interested in participating in the guideline development process. The group comprised primary care practitioners, administrators, and physicians with expertise and interest in low back pain, from the across the province of Alberta. The participants discussed the best process for conducting a survey of the extant knowledge gaps among primary care practitioners in Alberta regarding the management of low back pain and headache, and shared ideas about a process for developing point-of-care tools in chronic pain management. • During February and March 2007 a knowledge assessment survey of low back pain and headache management was conducted among primary care practitioners in Alberta. At a meeting on 11 April 2007 findings from this survey were presented to the AC for the development of the low back pain guideline. The committee recommended that the Ambassador Program continue to pursue the development of low back pain and headache CPGs. • In June 2007, members of the GDG responsible for the Alberta CPG on low back pain and a convenience sample of Alberta clinicians were given a list of 19 pharmacological and non-

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pharmacological treatments for headache and asked to indicate those that were of the greatest interest to community practitioners in Alberta, and to add additional treatments. • In March 2009 the Alberta CPG for the Evidence-Informed Primary Care Management of Low Back Pain was published.5 An evaluation was conducted that: o identified the successful strategies and major challenges associated with the process used to develop the CPG o benchmarked the process with the ADAPTE framework o detailed opportunities for improving the process in preparation for its use in developing a headache guideline6,7 • In October 2009 a survey was conducted of physicians attending Continuing Medical Education (CME) sessions. The survey collected information on the need for an evidence- informed guideline on headache and on factors that prevented the clinicians from using guidelines and providing the best care possible to patients with headache. The survey also served as a means of recruiting clinicians with an interest in headache to participate in the development of the Alberta headache guideline. • In October 2009 a draft project Charter was created8 and during November and December 2009 the SC actively recruited GDG and AC members. Twelve members of the GDG that was responsible for developing the Alberta CPG for the Evidence-Informed Primary Care Management of Low Back Pain,5 including the GDG Chair, agreed to reprise their roles for the headache guideline. • The AC for the headache guideline first met on 23 February 2010; the GDG began work on the headache guideline on 22 March 2010. About Headache Summary of the epidemiology and disease burden of common headache disorders Headache disorders are usually classified as primary or secondary. Primary headache disorders have no identifiable cause, whereas secondary headache disorders are associated with an identified pathological cause, such as an infection, a brain tumour, or a stroke.9 Although headache disorders are prevalent worldwide,10 the intermittent nature of some of these disorders makes it difficult to estimate their incidence and prevalence.11,12 Globally, 46% of the adult population has an active headache disorder, 42% has tension-type headache, and 3% has chronic daily headache.10 The estimated prevalence of migraine is between 5% and 17%.10,13,14 Among people with tension-type headache, the majority experience pain on one day a month or less, which is classified as infrequent episodic tension-type headache. However, 18% to 37% of sufferers have tension-type headache several times a month and 10% to 25% have it weekly. Among tension-type sufferers, 2% to 3% have chronic tension-type headache usually lasting for the greater part of a lifetime.15 Approximately 3% to 5% of individuals with episodic headache progress to chronic daily headache.14,16 Medication overuse headache, a potentially treatable and preventable disorder, is common among individuals with chronic daily headache and occurs in about 1% of the adult population.10 In the general population, the lifetime prevalence is 66% for headache, 14% to 16% for migraine, 46% to 78% for tension-type headache, and 0.06% to 0.3% for cluster headache.9,10,14

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Studies conducted in Canada, France, Germany, and the United States show that migraine prevalence is affected by age, gender, and socioeconomic factors. Migraine is most prevalent in individuals aged between 25 and 55 years, with the highest prevalence occurring during the peak productive years (30 to 49 years of age).9,12,13,17-19 Women are more likely to experience migraine than men, particularly between the ages of 40 and 45 years, when the female-to-male ratio reaches its zenith at 3.3:1.12,14,19 In the United States, Caucasians are more likely to suffer migraines than African-Americans or Asians,9,12-14,17-19 as are individuals with the lowest relative household incomes.9,12,13,17-19 In 1994 the prevalence of migraine among Canadians was 7.8% for men and 24.9% for women;20,21 thus, at least 2.6 million adult women and 0.8 million adult men in Canada had migraine.20 In 2005, the prevalence of migraine was 26% among 1219 Canadian women who responded to a national telephone survey. This prevalence is slightly higher than for women in England, France, Germany, and the United States.20 Because of its chronic nature, migraine is associated with high levels of emotional distress and disability, as well as with impaired quality of life for the affected individuals, their families, and society as a whole.9,12,14,18,21-24 A report published by the World Health Organization in 2001 ranks migraine among the 20 leading causes of years of life lived with disability: • in all ages for both genders (rank 19) • for women aged between 15 and 44 years (rank 14)25 Emerging evidence indicates that, in some patients, migraine may be a chronic progressive disorder characterized by an escalating frequency of headache attacks.16,19 Approximately 60% of migraineurs have one or more headache attacks per month.13,21 Moderate or severe pain is experienced by approximately 90% of migraineurs, with 75% reporting impaired function and 33% requiring bed rest during their attacks.13 Similar rates of significant debilitation are reflected in Canadian data.19,21 More than 70% of Canadian migraine sufferers experience impairments in interpersonal relationships,19 and 97% of women from a 2005 Canadian survey reported at least one psychosocial impact resulting from migraines (such as lack of control over their lives, missed days at work, missed family activities, or lack of understanding or cynicism from those around them).20 In general, headache accounts for about 20% of work absences due to sickness,11 with migraine being a major cause of absenteeism and decreased work productivity.9,22-24 A 1992 Canadian study estimated that seven million work days are lost per year as a direct result of migraine headaches.20,21 A 2005 survey found that, on average, Canadian women experienced at least partial incapacitation on almost 21 days a year due to migraine.20 It is estimated that migraine costs the United Kingdom almost £2 billion a year in direct and indirect costs, with over 100,000 people absent from work or school every working day because of migraine.26 In the United States, the estimated annual cost of migraine headache is between $13 billion and $17 billion.27 Approximately one tenth of this cost is attributed to medication, with triptans accounting for the bulk of this amount (approximately $1.2 billion).27 Tension-type headache is also a costly disorder to society because of its high prevalence.15 In one United States survey, conducted between 1993 and 1994, 8.3% of people with episodic tension-type headache reported lost work days (8.9 work days per person per year, on average) due to their headaches and 43.6% reported reduced-effectiveness days (5.0 days per person per year, on average). Among individuals with chronic tension-type headache, 11.8% reported lost work days (27.4 work

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days per person per year, on average) and 46.5% reported reduced-effectiveness days (20.4 work days per person per year, on average).28 Despite its evident clinical, economic, and social burden, migraine has historically been under- diagnosed and undertreated.9,13,17-19,21,22,29 Many migraineurs, even those with disabling headaches, have never consulted a physician for their problem.9 Vast quantities of over-the-counter medications are taken for headache disorders9 and treatment is often suboptimal and characterised by low adherence.29 More than one in four migraineurs are candidates for preventive therapy. However, although most migraine sufferers use acute treatment to relieve their headaches, a substantial number of people who might benefit from prophylactic therapy do not receive it.12,13 Prompt diagnosis and effective treatment, in conjunction with better information and education for patients and health professionals, are essential for improving the primary care management of headache and migraine.21 Knowledge gaps in the primary care treatment of headache disorders Survey results Following a recommendation by the Ambassador Program Advisory Committee, a detailed knowledge assessment was conducted in April 2007 before work commenced on developing the Alberta low back pain and headache guidelines. The purpose of the assessment was to determine the level of knowledge among specific healthcare providers (physicians, nurses, physical therapists, occupational therapists) regarding the diagnosis and treatment of low back pain and headache, and to solicit their views on the barriers to the effective management of chronic pain. Fifty knowledge questions were developed using a true/false response format. The questions were designed to ascertain the respondent’s knowledge of specific aspects of care, as acquired from published CPGs related to low back pain and headache. A total of 147 primary care practitioners in Alberta responded to the online survey, with 105 respondents completing the entire survey.30 The average score for the headache section of the assessment was 58%. Generally, questions about diagnosis were more likely to be answered correctly than questions about pharmacological treatments. Physicians had an average knowledge score of 66% for the headache section, whereas non-physicians had an average score of 55%, suggesting that a greater knowledge gap exists among non-physicians. This knowledge assessment had a number of important methodological limitations that may have implications for its generalizability to the Alberta health-provider population as a whole. A convenience sample was used to recruit health professionals, although the response rate was very low. Survey questions were derived from published clinical guidelines. As a result, they may have been more focused on the practice issues of physicians rather than on those of non-physicians and may not have adequately addressed the knowledge base of non-physicians. Nonetheless, the survey suggested that community-based healthcare providers in Alberta have significant knowledge gaps relating to the diagnosis and treatment of headache. Respondents indicated that lack of access to CPGs was one of the major barriers to effective chronic pain management. The conclusion was that the development and effective dissemination of an Alberta- specific CPG on low back pain and headache would be an appropriate strategy by which to address these knowledge gaps.

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In June 2007, members of the GDG responsible for the Alberta CPG on low back pain and a convenience sample of Alberta clinicians were given a list of 19 pharmacological and non- pharmacological treatments for headache and asked to select the seven most important treatments in Alberta community practice, and to add additional treatments. The following responses were received from six physicians, eight nurses, one occupational therapist, one pharmacist, one psychologist, and one physical therapist. • Pharmacological treatments: non-opiate analgesics, opiate combination analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), ergotamines, triptans, beta blockers, calcium channel blockers, tricyclic antidepressants, serotonin antagonists, anticonvulsants, and botulinum toxin. • Non-pharmacological treatments: avoidance of possible triggers, relaxation techniques, stress management training, cognitive behavioural therapy, acupuncture, neck spinal manipulation, neck physiotherapy, and management of medication-overuse headache. • Additional comments: how to prevent further headaches, including cluster headache, by avoiding the cause; how to include multidisciplinary team approaches or chiropractic interventions. A survey conducted in October 2009 among 28 family physicians in Calgary and Red Deer indicated that half of the participants were frequently (n=10) or occasionally (n=5) using guidelines for the management of headache in their patients. Only five participants indicated that these guidelines were “very useful”, while 17 considered them “somewhat useful.” The vast majority (n=22) of the 26 participants who answered the question stated that focused, evidence-based headache guidelines would be helpful for making correct headache diagnoses in the office. The participants indicated that guidelines would be helpful for the following treatments and conditions: • medication-overuse headache (n=25) • migraine prophylaxis (n=24) • migraine treatment (n=22) • tension-type headache treatment and prophylaxis (n=20) • cluster headache (n=23) • headache related to cervical spine disorders (n=21) • behavioural treatments, such as relaxation, stress management, etc. (n=21) • physical treatments, such as acupuncture, physiotherapy, etc. (n=20) • herbal and non-prescription treatments (n=18) Conclusion of the Advisory Committee The results of the survey conducted among primary care practitioners in Alberta in October 2009 were presented to the Advisory Committee at a meeting on 23 February 2010. The Advisory Committee felt that the information supported the decision to proceed with the development of an Alberta CPG on headache.

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References 1. Rashiq S, Barton P, Harstall C, Schopflocher D, Taenzer P. The Alberta Ambassador Program: delivering Health Technology Assessment results to rural practitioners. BMC Medical Education 2006;6:21. 2. Scott NA, Moga C, Barton P, Rashiq S, Schopflocher D, Taenzer P, et al. Creating clinically relevant knowledge from systematic reviews: the challenges of knowledge translation. Journal of Evaluation in Clinical Practice 2007;13(4):681-8. 3. Taenzer P, Schopflocher D, Rashiq S, Harstall C. The Alberta Chronic Pain Ambassador Program. In: Rashiq S, Schopflocher D, Taenzer P, Jonsson E, editors. Chronic pain: a health policy perspective. Weinheim (Germany): Wiley Blackwell; 2008:255-72. 4. Thornley R, Schuller T. Ambassador Program pre-videoconference survey results summary. Edmonton (AB): Alberta Heritage Foundation for Medical Research; 2006. Available from: www.ihe.ca/documents/pre-videoconference-survey-result.pdf (accessed 14 March 2013). 5. Institute of Health Economics (IHE). Ambassador Program guideline for the evidence-informed primary care management of low back pain. Edmonton (AB): Institute of Health Economics; 2009, Revised 2011. Available from: www.topalbertadoctors.org/cpgs.php?sid=65&cpg_cats=90 (accessed 14 March 2013). 6. Sumera Management Consulting for the Institute of Health Economics. Ambassador Program: process evaluation. Edmonton (AB): Institute Of Health Economics; 2009. Available from: www.ihe.ca/documents/Evaluation%20Report%20Sumera %20Management%20Consulting.pdf (accessed 14 March 2013). 7. Harstall C, Taenzer P, Zuck N, Angus DK, Moga C, Scott A. Adapting low back pain guidelines within a multidisciplinary context: a process evaluation. Journal of Evaluation in Clinical Practice. 2012; doi:10.1111/j.1365-2753.2012.01848.x. 8. Institute of Health Economics (IHE). Primary care headache assessment and management guideline: Project charter. Edmonton (AB): Institute of Health Economics; 2009, Revised 2011. Available from: www.ihe.ca/documents/Headache%20Guideline%20Project%20Charter_1.pdf (accessed 14 March 2013). 9. Bigal ME, Lipton RB, Stewart WF. The epidemiology and impact of migraine. Headache 2004;4(2):98-104. 10. Stovner LJ, Hagen K, Jensen R, Katsarava Z, Lipton RB, Scher AI, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27(3):193-210. 11. Latinovic R, Gulliford M, Ridsdale L. Headache and migraine in primary care: consultation, prescription, and referral rates in a large population. Journal of Neurology, Neurosurgery and Psychiatry 2006;77(3):385-7. 12. Hazard E, Munakata J, Bigal ME, Rupnow MFT, Lipton RB. The burden of migraine in the United States: current and emerging perspectives on disease management and economic analysis. Value in Health 2009;12(1):55-64.

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13. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007;68:343-9. 14. Robbins MS, Lipton RB. The epidemiology of primary headache disorders. Seminars in Neurology 2010;30(2):107-19. 15. Bendtsen L, Jensen R. Tension-type headache: the most common, but also the most neglected, headache disorder. Current Opinion in Neurology 2006;19(3):305-9. 16. Munakata J, Hazard E, Serrano D, Klingman D, Rupnow MFT, Tierce J, et al. Economic burden of transformed migraine: results from the American Migraine Prevalence and Prevention (AMPP) Study. Headache 2009;49(4):498-508. 17. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 2001;41(7):646-57. 18. National Institute of Neurological Disorders and Stroke. 21st century prevention and management of migraine headaches. Clinician 2001;19(11):1-32. 19. Lipton RB, Bigal ME. Migraine: epidemiology, impact, and risk factors for progression. Headache 2005;45(Suppl 1):S3-S13. 20. Cooke LJ, Becker WJ. Migraine prevalence, treatment and impact: the Canadian women and migraine study. Canadian Journal of Neurological Science 2010;37(5):580-7. 21. Becker WJ, Gladstone JP, Aube M. Migraine prevalence, diagnosis, and disability. Canadian Journal of Neurological Science 2007;34(Suppl 4):S3-S9. 22. Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WF. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 2001;41(7):638-45. 23. Radat F, Lanteri-Minet M, Nachit-Ouinekh F, Massiou H, Lucas C, Pradalier A, et al. The GRIM2005 study of migraine consultation in France. III: Psychological features of subjects with migraine. Cephalalgia 2008;29:338-50. 24. Burton WN, Landy SH, Downs KE, Runken MC. The impact of migraine and the effect of migraine treatment on workplace productivity in the United States and suggestions for future research. Mayo Clinical Proceedings 2009;84(5):436-45. 25. World Health Organization. The world health report 2001—Mental health: New understanding, new hope. Chapter 2; 2001. Available from: www.who.int/whr/2001/en/index.html (accessed 14 March 2013). 26. Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of headache in adults. A national clinical guideline. SIGN Publication No. 107. Edinburgh: SIGN; 2008. Available from: www.sign.ac.uk/guidelines/fulltext/107/index.html (accessed 14 March 2013). 27. Goldberg LD. The cost of migraine and its treatment. The American Journal of Managed Care 2005;11(2 Suppl):S62-7. 28. Schwartz BS, Steward WF, Simon D, Lipton RB. Epidemiology of tension-type headache. JAMA 1998;279(5):381-3.

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29. Bigal M, Krymchantowski AV, Lipton RB. Barriers to satisfactory migraine outcomes. What have we learned, where do we stand? Headache 2009;49(7):1028-41. 30. Lopatka H. Alberta primary care practitioner knowledge assessment for low back pain and headache management: summary report. Edmonton (AB): LopAlta Consulting; 2007. Available from: www.ihe.ca/documents/Knowledge-Assessment-Survey.pdf (accessed 14 March 2013).

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STAGE II – ADAPTATION Stage I – Set-Up IDENTIFYING, SELECTING, AND APPRAISING Formulate research question THE SEED GUIDELINES Stage II – Adaptation

This section contains information on: Search for and screen seed CPGs

√ the rationale for choosing an adaptation approach over Assess and select seed CPGs de novo guideline production Extract data into evidence tables √ the search strategy used to identify the seed guidelines Draft guideline document √ the criteria used to select the seed guidelines √ the method and results of the critical appraisal of the Stage III – Finalization selected guidelines Review and refine draft guideline

Finalize and endorse guideline

Disseminate guideline and plan update Rationale CPGs are systematically developed statements that assist practitioners and patients in choosing appropriate interventions for specific clinical situations.1 The creation of CPGs can take different approaches that range from de novo development to adopting or adapting existing guidelines. The development and adaptation of CPGs are processes that necessitate extensive resources and expertise to ensure high quality outcomes.2 The CPG adaptation process encompasses a variety of options, from accepting the entire guideline and its recommendations to partial acceptance of some of the guideline recommendations or its companion documents, with or without modification. For example, the Guidelines Advisory Committee3 in Ontario, Canada, endorses guidelines based primarily on the methodological rigour of their development process, the quality of the linkage between evidence and recommendations for best clinical practice, and their applicability to the local context. In contrast, the COMPUS4 program within the Canadian Agency for Drugs and Technology in Health unbundles existing guidelines, reviews and updates the pertinent evidence, and constructs a new guideline with input from a panel of experts. The adaptation process takes advantage of existing high quality CPGs while also allowing guideline developers to modify the guideline to meet the needs, priorities, legislation, policies, and resources of a targeted setting.2 Adapting pre-existing guidelines offers the advantages of reduced duplication, decreased resource commitment, increased efficiency, and enhanced local uptake. Adaptation may include only one guideline or multiple guidelines. Preliminary literature searches and consultation with clinical experts in Alberta have revealed the existence of an important body of CPGs on headache disorders that could be adapted to meet local needs, thereby avoiding the unnecessary duplication of effort in developing a guideline from scratch.

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In addition, it was thought that the adaptation approach would capitalize on the heightened interest and receptivity of local users generated by the Ambassador Pilot Project, thereby allowing the production of a CPG that was more tailored and relevant to the Alberta context. Thus, the second phase of the Ambassador Program aimed to adapt and contextualize good quality international and national guidelines on the management of headache disorders in the primary care setting to the provincial healthcare system. Identifying Seed Guidelines Inclusion criteria Guidelines Guidelines (“seed” guidelines) were included if they focused on the diagnosis, conservative nonsurgical treatment, or prevention of primary headache and were designed for use in primary healthcare settings by physicians, physical therapists, chiropractors, occupational therapists, nurses, community-based nurses, pharmacists, mental health professionals, and other healthcare providers who treat patients with headache. Only CPGs formulated in countries with developed market economies were included since the health status, cultural norms, access to health care, and disease burden of individuals from countries with transitional or developing economies were likely to be too different from those in Canada to be clinically relevant. Countries deemed to have developed economies, as defined by the United Nations, were Australia, Canada, Japan, New Zealand, the United States of America, and European countries (except for those with transition economies).5 Patient group Patients included individuals aged 18 years or older. Guidelines that referred to adult patients or focused on headache in pregnant women without providing a specific age range were also included on the basis that the majority of the populations in these guidelines were likely to be at least 18 years of age. Condition For guidelines on treatment and diagnosis, only those that used the diagnostic criteria developed by the International Headache Society6 were included. Guidelines were included if they dealt with the prevention, diagnosis and investigation, and treatment of primary headache that is not related to or caused by another disorder. These headache types include migraine, tension-type, and cluster headache as well as other primary headaches (thunderclap headache, hemicranias continua, new daily-persistent headache). Other trigeminal autonomic cephalalgias, such as chronic paroxysmal hemicranias and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA), were excluded because of their low incidence. Guidelines on medication-overuse headache (secondary headache) were also included because this headache type is typically present in a subgroup of patients with primary headache who have over- medicated. Cervicogenic headaches (secondary headache) were also included because a significant number of patients present to primary care physicians with this malady. Headache related with temporomandibular disorder is briefly discussed. However, other secondary headaches related to a causative disorder, such as trauma or infection, were excluded.

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Exclusion criteria Guidelines were excluded that focused on diagnostic techniques, interventions, or treatments applied in the emergency department or inpatient setting (for example, surgical treatments). Also excluded were guidelines focused on children or adolescents, or patients with specific causes for headache, such as head or neck trauma (except for cervicogenic headache), cranial or cervical vascular disorders, non-vascular intracranial disorders (for example, neoplasm or idiopathic intracranial hypertension), use of a substance or its withdrawal (except for secondary medication- overuse headache), temporomandibular joint disorder, infection, disorders of homeostasis, psychiatric disorders, or disorders or lesions of the cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures. Literature search strategies A preliminary systematic literature search was conducted to identify relevant guidelines published in English between January 2000 and April 2006. The search was further refined and updates were conducted in April 2009, October 2009, August 2010, and May 2011 (see Table 1). The date restriction was applied to ensure the guidelines collected were current and clinically relevant. Medical Subject Headings (MeSH) relevant to this topic are: headache; Headache disorders. Table 1: Search strategy used to identify relevant headache seed guidelines (May 2011 update)

Database Search Date Search Terms* PubMed 11 May 2011 ("Headache"[MeSH] OR "Headache Disorders"[MeSH] Limits: www.pubmed.gov Entrez Date from 2009/04/01, Practice Guideline, Guideline) OR ((Headache* OR migraine*) AND (in process[sb] OR publisher[sb]) AND (guideline* OR "clinical decision" OR "clinical pathway")) EMBASE 11 May 2011 1. (headache$ OR migraine$ OR hemicrania$ OR cephalgia$ OR cephalalgia$ OR sunct).ti. 2. *"headache AND facial pain"/ OR *chronic paroxysmal hemicrania/ OR *cluster headache/ OR *drug induced headache/ OR *headache/ OR *hypnic headache/ OR *primary headache/ OR *postdural puncture headache/ OR *sinus headache/ OR *sunct syndrome/ OR *vascular headache/ OR exp *chronic daily headache/ OR exp *migrane/ OR exp *tension headache/ OR exp *trigeminal autonomic cephalalgia/ 3. 1 OR 2 4. practice guideline/ AND (guideline$ OR recommendation$).ti,ab. 5. (consensus statement OR practice parameter).ti. 6. (guideline$ OR recommendation$).ti. 7. OR/4-6 8. 3 AND 7 9. limit 8 to yr="1996 -Current" 10. limit 9 to English language

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PsycINFO 11 May 2011 1. exp headache/ 2. (headache$ OR migraine$ OR hemicrania$ OR cephalgia$ OR cephalalgia$ OR sunct).ti. 3. 1 OR 2 4. treatment guidelines/ 5. (guideline$ OR recommendation$ OR consensus statement OR practice parameter).ti. 6. 4 OR 5 7. 3 AND 6 8. limit 7 to (English language AND yr="1996 -Current") AMA Clinical Practice 11 May 2011 Browsed list of guidelines Guidelines www.topalbertadoctors. org/cpg.html CMA Infobase 11 May 2011 Headache; headaches; migraine; migraines; cephalgia head pain www.cma.ca/clinicalreso urces/practiceguidelines National Guidelines 11 May 2011 Disease/condition: headache Clearinghouse Sort order: publication date www.ngc.org UK National Library for 11 May 2011 Headache* OR migraine* Health Guidelines Finder www.library.nhs.uk/ guidelinesFinder New Zealand Guidelines 11 May 2011 Headache OR migraine OR headaches OR migraines Group www.nzgg.org.nz Scottish Intercollegiate 11 May 2011 Browsed list of guidelines Guidelines Network www.sign.ac.uk Guidelines Advisory 11 May 2011 Topic search: Migraine management Committee www.gacguidelines.ca/ index.cfm Institute for Clinical 11 May 2011 Browsed health care guidelines by topic Systems Improvement www.icsi.org/guidelines _and_more/ NICE 11 May 2011 Browsed list of published clinical guidelines www.nice.org.uk/guidan ce/index.jsp?status=3&d -16544- p=1&action=byType&t ype=2

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Google 11 May 2011 "practice guideline" OR "clinical guidelines" headache OR migraine www.google.ca limited to English pages

Websites National Headache 11 May 2011 Guideline; guidelines Foundation www.headaches.org/ American Academy of 11 May 2011 Guideline search by topic: headache Neurology www.aan.com/go/ practice/guidelines Canadian Headache 11 May 2011 Guideline; guidelines Society www.headachenetwork. ca/ American Headache 16 May 2011 Browsed list of links to practice parameters, guidelines, and Society classification www.americanheadaches ociety.org/professionalr esources/ProfessionalRe sourcesHeadacheInform ationforClinicians.asp International Headache 16 May 2011 Reviewed lists of guidelines Society www.i-h- s.org/frame_non_memb ers.asp American Academy of 16 May 2011 Headache AND guideline Family Physicians www.aafp.org/online/ en/home.html American College of 16 May 2011 Browsed list of current guidelines Physicians www.acponline.org/clini cal_information/guideli nes/current/ American Academy of 16 May 2011 Browsed clinical guidelines section. Pain Medicine www.painmed.org/clinic al_info/guidelines.html American Pain Society 16 May 2011 Browsed list of guidelines www.ampainsoc.org/ pub/cp_guidelines.htm

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Registered Nurses’ 16 May 2011 Browsed list of guidelines and factsheets Association of Ontario www.rnao.org/Page.asp? PageID=1212&SiteNod eID=155&BL_ExpandI D *A total of 480 grey literature records and 245 citations from bibliographic databases were obtained from the searches. Notes: Publication date limit: From January 2000 onward. * and $ are truncation characters that retrieve possible suffix variations of the root word; for example, surg* retrieves surgery, surgical, surgeon, etc. Semicolons are used to indicate terms that were searched separately. In some cases, GDG members requested additional research evidence to finalize some of the Alberta CPG recommendations, so primary studies cited in the seed guidelines in support of their recommendations were retrieved for closer examination. For some of these recommendations, a database of systematic reviews on headache disorders (known as the IHE database), which was created for the Ambassador Project in 2006, was searched for systematic reviews published in English between January 2000 and October 2010. The IHE database was updated in January 2007, May 2007, March 2009, November 2009, March 2010, and October 2010. The search strategy for the systematic reviews in this database is outlined in Table 2. Table 2: Search strategy used to identify relevant systematic reviews for the IHE database (October 2010 update)

Database Search Date Search Terms* The Cochrane Library 19 October headache* OR migraine* OR hemicrania* OR cephalgia* OR www.thecochranelibrary. 2010 cephalalgia* OR sunct in Record Title or Keywords, from 2010 com PubMed 20 October 1. "Headache Disorders"[MeSH] OR “Headache”[MeSH] www.pubmed.gov 2010 Limits: English, Publication date from 30 March 2010 - 31 October 2010 2. (headache OR headaches OR migraine OR migraines OR cephalgia* OR cephalalgia* OR hemicrania* OR SUNCT) AND (inprocess[sb] OR publisher[sb] OR pubmed NOT medline[sb]) Limits: English, Publication Date from 30 March – 31 October 2010 3. headache[ti] OR headaches[ti] OR migraine[ti] OR migranes[ti] OR cephalgia*[ti] OR cephalalgia*[ti] OR hemicrania*[ti] OR SUNCT[ti] OR head pain*[ti] Limits: English, Publication date from 30 March 2010 – 31 October 2010 4. search[tiab] OR meta-analysis[Publication Type] OR MEDLINE[tiab] OR (systematic[tiab] AND review[tiab]) 5. (#1 OR #2 OR #3) AND #4 6. #5 Limits: All Child: 0-18 years 7. #6 Limits: All Adult: 19+ years 8. #5 NOT (#6 NOT #7) 9. (child*[ti] OR pediatric*[ti] OR paediatric*[ti] OR adolescen*[ti]

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OR school*[ti] OR teen*[ti] OR juvenile*[ti]) NOT adult*[ti] 10. #8 NOT #9 CRD Databases 19 October 1. MeSH Headache EXPLODE 1 2 3 (HTA, DARE, NHS 2010 2. MeSH Headache Disorders EXPLODE 1 EED) 3. headache*:ti OR migraine*:ti OR cephalgia*:ti OR cephalagia*:ti www.york.ac.uk/inst/ OR hemicrania*:ti OR SUNCT:ti crd/crddatabases.htm 4. #1 OR # 2 OR #3 RESTRICT YR 2010 EMBASE 19 October 1. (headache$ OR migraine$ OR hemicrania$ OR cephalgia$ OR 2010 cephalalgia$ OR sunct).ti. 2. *"headache AND facial pain"/ OR *chronic paraxysmal hemicrania/ OR *cluster headache/ OR *drug induced headache/ OR *headache/ OR *hypnic headache/OR *primary headache/ OR *postdural puncture headache/ OR *sinus headache/ OR *sunct syndrome/ OR *vascular headache/ OR exp *chronic daily headache/ OR exp *migraine/ OR exp *tension headache/ OR exp *trigeminal autonomic cephalalgia/ 3. meta-analys$.mp OR search$.tw. OR review.pt. 4. (1 OR 2) AND 3 5. ((child$ OR pediatric$ OR paediatric$ OR adolescent$ OR school$ OR teen$ OR juvenile$) NOT adult$).jw,ti. 6. (4 NOT 5) 7. ("200946" OR "200947" OR "200948" OR "200949" OR 20095$ OR 2010$).em. 8. 6 AND 7 9. limit 8 to English language Note: The * before the subject headings in this search limits the search to records where the subject heading is considered by the indexer to be one of the foci of the article. Web of Science 19 October #1. TI=(headache* OR migraine* OR cephalgia* OR cephalalgia* 2010 OR hemicrania* OR SUNCT) AND TS=(“systematic review” OR metaanalys* OR "systematically reviewed" OR meta-analys*) #2. TS=(child* OR pediatric* OR paediatric* OR juvenile* OR teen* OR adolescen* OR school*) NOT TS=adult* #3. #1 NOT #2 DocType=All document types; Language=English; Databases=SCI- EXPANDED, SSCI, A&HCI Timespan=2010 CINAHL 19 October S1. (MH Headache+ AND (TI meta analy* OR AB meta analy* OR 2010 MH meta analysis OR TX metaanalys* OR MH systematic review OR PT review OR PT systematic review)) S2. (TI (migraine* OR headache* OR cephalgia* OR cephalalgia* OR hemicrania* OR SUNCT) AND TX meta analy* OR metaanalys* OR systematic review)) S3. S1 OR S2 S4. Limit S3 to Age Groups: Fetus, Conception to Birth, Infant, Newborn 0-1 month, Infant, 1-23 months, Child, Preschool 2-5 years, Child, 6-12 years, Adolescence, 13-18 years

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S5. S4 NOT (S4 AND MW Adult) S6. (S3) NOT (S5) Limits: Publication Year –2010; Language – English Library Catalogues NEOS (Central Alberta 1 November Subject (headache$ OR migraine$) AND Any field (review OR meta Library Consortium) 2010 OR meta analysis) www.library.ualberta.ca/ catalogue AMICUS 1 November aw(headache OR headaches OR migraine OR migraines) AND www.nlc-bnc.ca/amicus 2010 aw(review OR meta) AND dat >2005 LocatorPLUS (National 1 November (headache headaches migraine migraines)[in Subject] AND (review Library Medicine US) 2010 meta metaanalysis meta-analysis ) [in Keyword Anywhere] locatorplus.gov/ Theses Canada Portal 1 November Title Keyword: Headache OR headaches OR migraine OR migraines www.collectionscanada.g 2010 Subject Keyword: Headache OR headaches OR migraine OR c.ca/thesescanada/index migraines -e.html Proquest Dissertations 1 November TITLE(headache* OR migraine*) OR IT(headache* OR migraine*) and Theses Full Text 2010 AND (review OR meta analy* OR meta-analys* OR metaanalys*) Published in last 2 years Government Alberta Health and 2 November Headache OR migraine systematic-review OR meta-analysis Wellness 2010 www.health.gov.ab.ca Health Canada 2 November "systematic review" | "meta analysis" migraine OR headache site:hc- www.hc-sc.gc.ca/index- 2010 sc.gc.ca eng.php Date: past year HTA Agencies/Coverage Agencies AETMIS 2 November Browsed list of publications, 2009 www.aetmis.gouv.qc.ca 2010 CADTH 2 November Headache; headaches; migraine; migraines www.cadth.ca/index.ph 2010 p/en/hta/reports- publications/search ICES 2 November Headache; headaches; migraine; migraines www.ices.on.ca/ 2010 HTA at McGill 2 November Browsed list of publications, 2010 www.mcgill.ca/tau/ 2010 Medical Advisory 2 November Browsed list of publications, 2010 Secretariat 2010 www.health.gov.on.ca/ english/providers/progr am/mas/mas_mn.html

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CCE 2 November Browsed list of current evidence reviews www.med.monash.edu. 2010 au/healthservices/cce/ MHRA (UK) 2 November Headache; headaches; migraine; migraines www.mhra.gov.uk 2010 Search in titles only NICE (UK) 2 November Headache; headaches; migraine; migraines www.nice.org.uk/ 2010 NZHTA 2 November Headache OR migraine OR headaches OR migraines nzhta.chmeds.ac.nz 2010

NCCHTA 2 November Browsed list of publications, 2009 www.ncchta.org/ 2010 Blue Cross Blue Shield 2 November Browsed list of TEC assessments Technology 2010 Assessments www.bcbs.com/bluereso urces/tec/vols/ Aetna Clinical Policy 2 November Headache; migraine Bulletins 2010 www.aetna.com/about/ cov_det_policies.html Internet Search Engine Google 2 November headache OR migraine systematic-review OR meta-analysis - www.google.ca 2010 pubmed -bmj *A total of 378 grey literature records and 3705 citations from bibliographic databases were obtained from the searches. Notes: Publication date limit: From January 2000 onward. * and $ are truncation characters that retrieve possible suffix variations of the root word; for example, surg* retrieves surgery, surgical, surgeon, etc. Semicolons are used to indicate terms that were searched separately. New interventions and recommendations The IHE database was searched to identify recently published systematic reviews of new interventions that were considered important by the GDG, but that were not covered in the seed guidelines. These included duloxetine and desvenlafaxine for migraine prophylaxis. Occasionally, new recommendations were generated when the GDG members requested and reviewed additional research evidence. In some cases, the IHE database was searched for systematic reviews on these particular interventions, which included normobaric oxygen for migraine and exercise for migraine, tension-type, and cervicogenic headache (see Appendix H). Selecting the Seed Guidelines The initial selection of guidelines was made by one reviewer and double-checked by a second reviewer. Guidelines were excluded that, on the basis of their abstract, clearly did not meet the inclusion criteria. Copies of the full text of potentially eligible guidelines were retrieved. In some cases, closer examination of the full text revealed that the guideline did not meet the inclusion criteria. Consequently, these papers were excluded (see Appendix C). When a single guideline

Ambassador Program. Guideline for Management of Primary Headache in Adults. Background Document 23 August, 2013 development group had published more than one guideline, only the most recent version was used. From the 64 relevant guidelines identified by the search strategy, the IHE Research Team, in consultation with one GDG co-chair, compiled a final shortlist of 18 potential seed guidelines. Critically Appraising the Seed Guidelines The included guidelines were assessed with respect to various aspects of methodology and reporting using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument.7,8 Although a new edition of the tool, AGREE tool (II), was published in May 2009,9,10 to maintain consistency and continuity in the guideline appraisal process, the Research Team decided to continue using the original AGREE tool7,8 that had been used in the first and second editions of the Alberta CPG on low back pain.11,12 The AGREE instrument is an internationally developed, generic tool that is validated, transparent, and widely accepted, with satisfactory reliability for most domains. The instrument has 23 key items organized into six domains. 1. Scope and purpose (items 1–3) reflects the overall aim/objective of CPG, specific clinical question(s), and target population. 2. Stakeholder involvement (items 4–7) contains representation of views of intended users. 3. Rigour of development (items 8–14) is the process used to gather and synthesize the evidence, and the methods used to formulate and update the recommendations. 4. Clarity of presentation (items 15–18) assesses the language and format of the CPG. 5. Applicability (items 19–21) refers to the organizational and cost implications of applying the guideline. 6. Editorial independence (items 22–23) indicates the independence of the recommendations and acknowledgement of possible conflict of interest within the GDG. The tool is accompanied by a detailed User Guide that explains how to score the 23 items.13 Each guideline is assessed by at least two (ideally four) appraisers using a four-point scale (ranging from 4 = “strongly agree” to 1 = “strongly disagree”) to rate each of the 23 items. These scores are then combined for each of the six domains and converted into standardized domain scores as per the following formula: Standardized domain score (%) = obtained score – minimum possible score × 100 maximum possible score – minimum possible score The six domain scores are independent and cannot be combined into a single score. Instead, appraisers can provide an overall assessment of the guideline according to the following categories: • strongly recommended • recommended (with provisos or alterations) • would not be recommended • unsure

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The Research Team modified the AGREE tool to reduce the ambiguity and subjectivity associated with item scoring, and to enable the differentiation of good quality guidelines from poor quality guidelines. Three modifications were made.14 1. A detailed set of instructions, or dictionary, based on the AGREE User Guide, was constructed using logical operators (AND, OR, NOT) to quantify what constitutes a score of 4, 3, 2, or 1 for each of the 23 items (see Appendix D). 2. Seven “essential” criteria were identified for categorizing guidelines as good, moderate, or poor quality.15 Item 8: Systematic search conducted Item 10: Methods used to formulate recommendations described Item 12: Link between recommendations and evidence Item 13: External review by experts Item 15: Specific, unambiguous recommendations Item 22: Editorially independent from funder Item 23: Conflicts of interest reported The average quality score (maximum possible of 28 [7 × 4]) was then rated as: Good 22 to 28 points Average 15 to 21 points Poor 0 to 14 points Two reviewers undertook seed guideline quality assessments independently, and discussed the dictionary with respect to the interpretation of questions prior to assessing the guidelines. Reviewers discussed any items where the scores differed by at least two points, to minimise coding bias. At a meeting on 9 February 2010 the SC discussed and approved the AGREE tool modifications and the results obtained after applying the tool to the included seed guidelines. The methods were subsequently presented to the GDG on 22 March 2010. Extracting Data Two reviewers extracted guideline information into standardized evidence inventory tables that were developed a priori. However, duplicate data extraction and cross-checking were not performed. The evidence inventory tables included: • guideline profile information (title, country, intervention category: for example, diagnosis, prophylaxis, pharmaceutical and non-pharmaceutical treatment) • a synopsis of the recommendations • a list of the number and types of studies referenced by the guideline to support its recommendations Discordant recommendations among guidelines were highlighted within the table. After consultation with the SC, the strength of the recommendations, as stated by the seed guidelines, was added to the

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evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Additional research evidence and information was required, particularly when recommendations were overlapping, discordant, or absent. These supplementary requests by the GDG, named “parking lot” items, necessitated examination of the individual studies cited by the seed guideline(s) or examination of other research evidence, that is, systematic reviews on headache identified by a supplementary search of literature published between January 2000 and October 2010 (see Table 2). An article was deemed to be a systematic review if it met all of the following criteria as defined by Cook et al. (1997):16 • focused clinical question • explicit search strategy • use of explicit, reproducible, and uniformly applied criteria for article selection • critical appraisal of the included studies • qualitative or quantitative data synthesis. Only systematic reviews that focused on the diagnosis, nonsurgical treatment, or prevention of primary headache among adults in the primary care setting were considered. When no systematic review was available for a specific intervention, information was considered from the most recent quasi-systematic review (defined as a review that did not critically appraise the included studies) or narrative review listed in the systematic review database. References 1. Institute of Medicine Committee to Advise the Public Health Service on Clinical Practice Guidelines. Clinical practice guidelines: directions for a new program. Washington (DC): National Academy Press; 1990. 2. Davis D, Goldman J, Palda VA. Handbook on clinical practice guidelines. Ottawa (ON): Canadian Medical Association; 2007. Available from: www.cma.ca//multimedia/CMA/Content_Images/CMAInfobase/EN/handbook.pdf (accessed May 8, 2009). 3. Guidelines Advisory Committee. Advancing the use of evidence-based clinical practice guidelines. Available from: www.gacguidelines.ca/index.cfm?PID=16666&PIDList=16666 (accessed May 8, 2009). 4. Canadian Agency for Drugs and Technologies in Health. COMPUS [website]. Available from: www.cadth.ca/index.php/en/compus/about (accessed May 8, 2009). 5. United Nations. List of country groupings and sub-groupings for the analytical studies of the United Nations World Economic Survey and other UN reports. Geneva: United Nations; 2009. Available from: http://unpan1.un.org/intradoc/groups/public/ documents/un/unpan008092.pdf (accessed May 8, 2009). 6. Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders: abbreviated pocket version. Oxford (UK): Blackwell Publishing; 2007.

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7. The AGREE Collaboration. Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project. Quality & Safety in Health Care 2003;12(1):18–23. 8. The AGREE Collaboration. AGREE instrument. London (UK): The AGREE Collaboration; 2001. Available from: www.agreetrust.org/resource-centre/the-original-agree-instrument/the- original-agree-instrument-translations/ (accessed 14 March 2013). 9. The AGREE Next Steps Consortium. Appraisal of Guidelines for Research & Evaluation II. 2009. Available from: www.agreetrust.org/ (accessed 14 March 2013). 10. Brouwers M, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, et al. for the AGREE Next Steps Consortium. AGREE II: Advancing guideline development, reporting and evaluation in healthcare. Canadian Medical Association Journal 2010;182:E839–842; doi: 10.1503/090449. 11. Institute of Health Economics (IHE). Ambassador Program guideline for the evidence-informed primary care management of low back pain. Edmonton (AB): Institute of Health Economics; 2009, Revised 2011. Available from: www.topalbertadoctors.org/cpgs.php?sid=65&cpg_cats=90 (accessed 14 March 2013). 12. Institute of Health Economics (IHE). Ambassador Program guideline for the evidence-informed primary care management of low back pain, 2nd edition: background document. Edmonton (AB): Institute of Health Economics; 2011. Available from: www.ihe.ca/research/ambassador-program/--low- back-pain/low-back-pain-guideline/guideline-documents/ (accessed 14 March 2013). 13. The AGREE Collaboration. AGREE instrument training manual. London (UK): The AGREE Collaboration; 2003. 14. Scott NA, Moga C, Harstall C. Making the AGREE tool more user friendly: the feasibility of a user guide based on Boolean operators. Journal of Evaluation in Clinical Practice 2009;15(6):1061- 73. 15. Hayward RSA, Wilson MC, Tunis SR, Bass EB, Guyatt G, for the Evidence-Based Medicine Working Group. Users’ guides to the medical literature, VIII: how to use clinical practice guidelines, A – are the recommendations valid? JAMA 1995;274(7):570-4. 16. Cook DJ, Mulrow CD, Haynes RB. Systematic reviews: synthesis of best evidence for clinical decisions. Annals of Internal Medicine 1997;126(5):376-80.

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STAGE II – ADAPTATION Stage I – Set-Up GUIDELINE DEVELOPMENT PROCESS Formulate research question

Stage II – Adaptation

Search for and screen seed CPGs This section contains information on: Assess and select seed CPGs √ the multidisciplinary process used to adapt the seed guidelines Extract data into evidence tables

√ the rationale for classifying the recommendations as “do,” Draft guideline document “do not do” (not recommended), and “do not know” Stage III – Finalization √ the limitations of the guideline development process

Review and refine draft guideline

Finalize and endorse guideline

Disseminate guideline and plan update General Process Appendix B, Figure B.2, shows a flow diagram of the guideline development process. The initial literature search identified 14 potential seed guidelines that met the inclusion criteria. An update search, conducted in August 2010, identified three additional guidelines, and a further search in May 2011 identified a fourth potential seed guideline. The modified AGREE tool was used to appraise all potentially eligible seed guidelines. Results were reviewed by the SC at three meetings, held on 9 February 2010 and 4 September 2010, and on 11 July 2011. Twelve guidelines were excluded due to their poor or average quality rating (see Appendices C and F). These decisions, as well as the references and quality appraisal results for all potentially eligible seed guidelines, were presented to the GDG on 22 March 2010 (five seed guidelines) and mentioned on 29 November 2010 (one seed guideline). Thus, six of the 18 guidelines that were scored as good quality were selected as seed guidelines. One guideline covered various headache types (migraine, tension-type headache, cluster headache, and others), three focused on migraine, one focused on tension-type headache, and one focused on cluster headache (see Appendix E). See Appendix F for the AGREE critical appraisal results (standardized domain scores and average quality scores based on the seven essential criteria) for the included seed guidelines. One of the included guidelines, G3, met all of the inclusion criteria but the main guideline document was published in French. However, an extensive English language translation was available that contained all the recommendations. Both English and French language documents were reviewed when the guideline was assessed with the AGREE tool. Evidence inventory tables for all six seed guidelines were produced for the GDG (see Appendix G). The GDG reviewed all the documents for the seed guidelines (the guidelines plus their companion documents, evidence inventory tables, and AGREE scores) and engaged in deliberations during 13 half-day meetings (one face-to-face and 12 web conferences) over a 23-month period. The web

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conferencing software, WebEx (Cisco Systems Inc., San Jose (CA), USA), allowed all participants to view documents simultaneously and to register their preferences via an online voting system. The agenda and all documents were provided in advance and participants had the option of joining in via telephone if an Internet connection was not available. Two experienced co-chairs guided all the meetings. Roundtables were conducted during each meeting to ensure that all participants had a voice in the proceedings and that process reviews were instigated at strategic points throughout. Each of the topic areas (diagnosis and investigation, interventions for migraine, tension-type headache, cluster headache, and medication-overuse headache) were addressed in a sequential fashion to ensure there were separate discussions on the formulation of recommendations for each. In many cases, one co-chair (a neurologist with expertise in headache management) created “straw dog” recommendations, based on the seed guideline recommendations, prior to the GDG discussions. These, along with the relevant evidence inventory tables, were then reviewed at the GDG meeting. After GDG meetings, the same co-chair refined or reworded recommendations based on the feedback received from participants. This additional work by the co-chair served to focus discussion and promote consensus on recommendation wording. The red flags and referral recommendations were reviewed by two external experts, one with expertise in emergency medicine and the other with an expertise in ophthalmology. Input on the recommendations for diagnosis and neuroimaging was also obtained from two external radiology experts. All final decisions were made by consensus. In many cases, additional evidence was required when uncertainties or disagreements arose regarding interpretation of the evidence from the seed guidelines or when new interventions were considered that had not been included in the seed guidelines. These requests by the GDG, named “parking lot” items, encompassed the examination of individual research studies cited by the seed guidelines as well as additional systematic reviews on headache disorders identified by a supplementary search of literature published between January 2000 and October 2010 (see Table 2). The parking lot items were referred for further analysis to ad hoc GDG subcommittees comprising one or both GDG co- chairs, one HTA researcher, and at least one volunteer from the GDG with expertise in the relevant area (see Figure 1). Consensus-based decisions made by the subcommittees were then presented to the GDG for final approval. Occasionally, new recommendations were generated from parking lot item discussions. These included: • examination for temporomandibular disorders • lifestyle migraine triggers • normobaric oxygen for migraine • exercise for migraine, tension-type, and cervicogenic headache • referral for cervicogenic headache and headache secondary to temporomandibular disorders See Appendix H for information about the parking lot items and other miscellaneous requests made by the GDG, the deliberations of the subcommittees, and the dates when the actions and final approval of the recommendations took place.

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Figure 1: GDG subcommittees

The GDG identified 55 parking lot items from a total of 187 recommendations (see Figure 2). After they had reviewed the additional evidence and subcommittee deliberations, redundant recommendations were subsequently incorporated into other recommendations or removed (see Appendix H). Figure 2: Process of formulating recommendations and resolving parking lot items

See Appendix I for a sample of a parking lot item document prepared by the Research Team for discussion in a subcommittee meeting. Other parking lot item documents are available upon request.

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To keep track of the deliberations relating to the formulation of the Alberta CPG recommendations, the SC and the Research Team developed an internal document that included: • the original wording of each recommendation from the seed guidelines • discussions undertaken and decisions made by the subcommittees • revisions of each draft recommendation • the evidence source for each recommendation This document was provided to the GDG at each meeting and continuously updated throughout the guideline development process. See Appendix J for a sample of this document. The SC and Research Team added harm statements to some recommendations, where appropriate; these were sourced from the original seed guideline recommendations or from elsewhere in the seed guidelines. Harm statements were added to the following recommendations. • Management of migraine headache: o acute pharmacological therapy: non-steroidal anti-inflammatory drugs and acetaminophen, triptans, antiemetics, and ergotamine

o pharmacological prophylactic therapy: beta-blockers, antidepressants, antiepileptics, pizotifen, and flunarizine • Management of tension-type headache: o acute pharmacological therapy: non-steroidal anti-inflammatory drugs and acetaminophen

o pharmacological prophylactic therapy: amitriptyline, mirtazapine, and venlafaxine • Management of cluster headache: o acute pharmacological prophylactic therapy: verapamil, lithium, and topiramate • Other headache disorders (hemicrania continua): o pharmacological therapy: indomethacin The medication tables provided with the Alberta CPG for acute (symptomatic) and prophylactic treatment of migraine were adapted from two seed guidelines (G1 and G6) and other various sources2-5 by two pharmacists from the GDG and one co-chair (a neurologist with expertise in headache management). The GDG reviewed the medication tables. Definitions of various terms and other general clarifications required for the interventions covered by and included in the seed guidelines were provided to the GDG (see Appendix G, Tables G.9 and G.10, for a glossary of this information). The SC developed separate algorithms for headache diagnosis, prophylactic and acute medications for migraine, pharmacological therapy for tension-type headache (episodic and chronic), medication- overuse headache, and cluster headache. The algorithms were reviewed by the GDG and a group of family physicians from the South Calgary Primary Care Network who participated in a focus group on 9 April 2012. In response to the feedback received, the SC developed a single algorithm with help from TOP (see Appendix M for details on the focus group feedback).

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The SC, in collaboration with the GDG, also developed companion documents and practice tools for clinicians (an eight-page summary document and a headache history guide) and for patients (a headache diary sheet, a list of commonly reported food triggers for migraine attacks, six patient information sheets, and information about caffeine and migraine attacks, including the caffeine content of common drinks and foods). GDG members reviewed the patient information sheets in November 2012. In addition, two focus groups were conducted with members of the IHE Lay Committee (October 2012) and with headache patients (14 May 2013). Rationale and Process for Developing Recommendations Each recommendation from the Alberta CPG was sourced from one or multiple seed guidelines and was accepted, supplemented, or changed as follows: • accepted or accepted with minor modification (for example, wording) • accepted but supplemented with expert opinion • additional information retrieved/considered, specifically: o original recommendation accepted/changed based only on studies included in seed guidelines o original recommendation accepted/changed based on additional evidence from systematic review literature search o additional evidence supplemented with expert opinion After GDG meetings, one co-chair (a neurologist with expertise in headache management) refined or reworded recommendations based on feedback received from participants. These revised recommendations were then submitted for review by the GDG at subsequent meetings. Over a series of teleconferences and email correspondences held between May 2011 and February 2012, the SC appraised and, where necessary, refined the final wording of each recommendation according to the principles of the GLIA tool,6,7 which is designed for appraising the implementability of CPGs. It explores different dimensions of individual recommendations, such as decidability, executability, effect on process of care, presentation and formatting, measurable outcomes, apparent validity, novelty/innovation, flexibility, and computability. The final version of the recommendations was presented to and approved by the GDG on 27 February 2012. In the Alberta CPG, the type of evidence (evidence source) referenced by the seed guideline(s) in support of the original recommendation was represented in several possible ways. (Note: Some evidence types are not listed because not all study designs were cited by the seed guidelines.) • Systematic review (SR): as cited by the seed guideline(s) or identified by the search for supplementary literature (IHE database), published between January 2000 and October 2010, that was required by the GDG to resolve parking lot items. • Quasi-systematic review (qSR): a review with a systematic search strategy that does not include a critical appraisal of the included studies. • Randomized controlled trial (RCT): as cited by the seed guideline(s).

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• Non-randomized comparative study (NRCS): non-randomized trial with concurrent or historical controls, case-control study, or a study of the sensitivity and specificity of a diagnostic test as cited by the seed guideline(s). • Case series (CS): cross-sectional study, case series study, or case report as cited by the seed guideline(s). • Guideline (G): as cited by the seed guideline(s). • Narrative review (NR): narrative review, or consensus statement or report, as cited by the seed guideline(s). • Expert opinion (EO) as cited by the seed guideline(s): when no evidence was provided by the seed guideline in support of the recommendation. • EO (GDG): after examining other references nominated by the GDG members (SRs, NRs, RCTs, Gs) or when no evidence from SRs was found on an intervention, a new recommendation was drafted based on the collective EO of the Ambassador GDG. For evidence cited by the seed guideline(s), only the highest level of evidence was listed. For example, when the evidence cited by a seed guideline(s) was from SRs and studies of other design (qSR, RCT, NRCS, CS, G, or NR) only SR is listed as the source. When no SR was referenced in the seed guideline, the evidence source was indicated in the following order: qSR, RCT, NRCS, CS, G, NR, EO. The same classification for the evidence source was applied when multiple seed guidelines were used to inform one recommendation. Each recommendation in the Alberta guideline came from one or more seed guideline(s), was based on evidence from SRs or qSRs (IHE database), or was created by the GDG, based on their collective professional opinion and an analysis of relevant evidence. The background statements in the Alberta guideline were derived from the seed guidelines or were created by the GDG, based on their collective professional opinion and an analysis of relevant SRs or other published evidence provided by the GDG that was not captured in the IHE database. The GDG considered the balance of benefits and harms for the inteventions listed in the Alberta Guideline. Italicized statements relating to harm are included in the recommendations, where appropriate. These statements were sourced from the original seed guideline recommendations or from elsewhere in the seed guidelines, or were created by the GDG based on their collective professional opinion. Classification of Recommendations Although six good quality guidelines were found (see Appendix E), the AGREE tool could not verify the validity of the guideline recommendations and the underlying evidence, or reconcile differences in evidence rating scales. In addition, the seed guidelines were inconsistent in how they rated the quality of the evidence and the strength of the recommendations. Also, because of time constraints, the Ambassador Program guideline adaptation process could not unbundle the seed guidelines to review the research evidence cited by the guidelines to support their recommendations. Therefore, a process was developed to ensure a standardized definition of the final guideline recommendations made by the GDG (what constituted a “do” “do not do”, or “do not know” recommendation), to systematically meld the seed guidelines’ recommendations into consistently

Ambassador Program. Guideline for Management of Primary Headache in Adults. Background Document 33 August, 2013 worded recommendations, and to display the source (for example, seed guideline(s), expert opinion) of the final recommendations in a transparent and systematic way (see Appendix K). In the Alberta CPG, the recommendations are categorized into three groups (see Table 3): • do • do not do (not recommended) • do not know See Appendix L for more details on the available recommendation categories. Table 3: Definitions for recommendation categories

Recommendation Category Description

Do The GDG accepted the original recommendation, which provided a prescriptive direction to perform the action or used the term “effective” to describe it.  The GDG supplemented a recommendation or created a new one, based on their collective professional opinion and/or systematic reviews which supported the action.

Do not do The GDG accepted the original recommendation, which provided a prescriptive direction to (not recommended) “not” perform the action, used the term “ineffective” to describe it or stated that the evidence does “not support” it.  The GDG supplemented a recommendation or created a new one, based on their collective professional opinion and/or systematic reviews, which did not support the action.

Do not know The GDG accepted the original recommendation, which did not recommend either for or against the action or stated that there was “no evidence,” “insufficient or conflicting ? evidence,” or “no good evidence” to support its use. The GDG supplemented a recommendation or created a new one, based on their collective professional opinion and/or systematic reviews, which was equivocal with respect to supporting the action.

Limitations of the Guideline Development Process Using seed guidelines minimized resource commitment and the expedited development process ensured the continued engagement of clinical experts. Stakeholder buy-in was also fostered by the contextualization process. However, several challenges were identified. • The AGREE tool identified well-developed and reported guidelines but could not verify the validity of the recommendations and the underlying evidence, nor could it reconcile differences in evidence rating scales. • Clinical judgement was needed for overlapping, discordant, or absent recommendations. • The strength and quality of the underlying empirical evidence was not formally assessed and could not be defined by terms such as good, fair, poor, insufficient, or conflicting, which made categorizing the strength and type of recommendations problematic. • Faith in the process can be undermined by the fear of using inferior seed guidelines.

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• Recently published evidence is not necessarily incorporated. • Not all recommended treatment options are available in all communities, nor are all treatment options necessarily covered by CPGs. References 1. Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders: abbreviated pocket version. Oxford (UK): Blackwell Publishing; 2007 2. Repchinsky C (Editor-in-Chief). Compendium of Pharmaceuticals and Specialties. Ottawa (ON): Canadian Pharmacists Association; 2013. 3. Sol P, Pelet B, Guignard JP, Debontridder O. Extrapyramidal reactions due to domperidone. Lancet 1980;2(8198):802. 4. Albibi R, McCallum RW. Metoclopramide: pharmacology and clinical application. Annals of Internal Medicine 1983;98(1):86-95. 5. Nakhai-Pour HR, Broy P, Sheehy O, Bérard A. Use of nonaspirin nonsteroidal anti- inflammatory drugs during pregnancy and the risks of spontaneous abortion. CMAJ 2011;183(15):1713-20. 6. Shiffman RN, Dixon J, Brandt C, Essaihi A, Hsiao A, Michel G, et al. The GuideLine Implementability Appraisal (GLIA): development of an instrument to identify obstacles to guideline implementation. BMC Medical Informatics and Decision Making 2005;5:23. 7. Yale University. GuideLine Implementability Appraisal (GLIA). New Haven (CT): Yale University; 2005. Available from: http://nutmeg.med.yale.edu/glia/login.htm;jsessionid%20=DFE8740FF9FF152296DD79BF BAA723B6 (accessed 14 March 2013).

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STAGE III – FINALIZATION Stage I – Set-Up REVIEWING, EVALUATING, AND ENDORSING THE GUIDELINE Formulate research question

Stage II – Adaptation

This section contains information on: Search for and screen seed CPGs

√ the process used to review the Alberta CPG for Assess and select seed CPGs Management of Primary Headache in Adults Extract data into evidence tables √ the endorsement of the Alberta CPG Draft guideline document √ the evaluation of the Alberta CPG √ key review criteria for assessing the CPG’s impact Stage III – Finalization

Review and refine draft guideline

Finalize and endorse guideline

Disseminate guideline and plan update Reviewing the Alberta CPG The Alberta Guideline for Management of Primary Headache in Adults (quick reference algorithm and medication tables, main guideline, and companion documents) was reviewed by various stakeholders: • family physicians with experience and interest in headache management and members of the GDG reviewed the quick reference algorithm and medication tables, main guideline, and companion documents • lay people and patients with headache conditions reviewed the patient information sheets The SC and Research Team collated all feedback and incorporated it, where possible, into the Alberta CPG. All changes were subsequently presented to the GDG. GDG and their colleagues In March 2012, GDG members were asked, via an online survey, to review 10 key messages developed for the guideline with respect to their importance, relevance, and relative precedence. They were also asked to comment on any amendments required or other key messages that should be added. Ten respondents provided feedback that helped inform the final version of the key messages and practice points included in the summary guideline document (see Appendix M, Table M.1). Another online survey was conducted among GDG members in November 2012 in which they were asked to review the six patient information sheets developed for the headache guideline. See Appendix M (Table M.2a) for a summary of the feedback received from the eight respondents.

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Primary care practitioners Four family physicians from the South Calgary Primary Care Network who had from 2 to 15 years of clinical practice experience participated in a focus group led by a member (neurologist) of the GDG on 9 April 2012. One Research Team member and one representative from TOP also attended the meeting. The aim of the focus group was for primary care physicians (the target audience for the guideline) to review the guideline documents (main guideline, quick reference algorithm, and medication tables) with respect to their relevance and usability. In addition, participants were asked about their intention to use the guideline, potential facilitators or barriers to implementing the recommendations, and suggestions for additional practice tools that could be developed to enhance guideline uptake and buy-in. See Appendix M (Table M.3) for a summary of the responses. Participants were also asked to comment on a selection of seven of the 10 key guideline messages and to rank their relative importance (see Appendix M, Table M.1). Ad hoc feedback was provided on the two-page algorithm and medication table summary by primary care practitioners within Alberta who were in attendance at the following professional meetings: • The 57th Annual Scientific Assembly of the Alberta College of Family Physicians: Banff, Alberta; 23 to 25 February 2012 • The 6th Pain Society of Alberta Annual Conference: Canmore, Alberta; 28 to 29 September 2012 • The Calgary Pain Conference: Trends and Treatments: Calgary, Alberta; 7 December 2013 • The 58th Annual Scientific Assembly of the Alberta College of Family Physicians: Banff, Alberta; 28 February 2013 to 2 March 2013 Advisory committee On 13 December 2011 the Alberta CPG guideline and algorithms for the management of headache were presented to AC members for their review and comment. See Appendix M, Table M.4, for a sample of their feedback. Patients and lay people The six patient information sheets were reviewed by two focus groups of lay people (5 October 2012) and patients from the Calgary Headache Assessment & Management Program (14 May 2013). The purpose of the focus groups was to evaluate the patient information sheets and to canvass ideas on how to make the information more relevant and useful to patients and lay people. Participants were asked about the content, readability, format, and presentation of each information sheet. Overall, feedback from both focus groups was positive (see Appendix M, Tables M.2b and M.2c). The IHE lay committee participants indicated that if the patient sheets were handed to them by their physicians they would trust the information. However, simply handing out the documents without any explanation might not work. Participants also had some concerns about the length of some of the sheets and their accessibility, particularly the electronic format, which may be difficult for people to access during an episode of severe headache. Feedback received from the IHE lay committee in October 2012 and from the GDG members in November 2012 was incorporated into the patient information sheets before they were presented to

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the focus group of headache patients in May 2013. The patients considered the information credible, but had the same concerns as the lay committee about accessibility and readability, especially for someone experiencing a headache episode. Endorsement The Alberta Guideline for Management of Primary Headache in Adults has been endorsed by the TOP program, which is funded under the Master Agreement between the Alberta Medical Association (AMA), Alberta Health Services, and Alberta Health. TOP is administered by the AMA. Evaluation Strategy Key review criteria A draft dissemination and implementation plan1 for the Alberta Guideline for Management of Primary Headache in Adults was presented to the Advisory Committee at a meeting, which also involved key stakeholders and researchers, on 13 December 2011. This document included a section on evaluating the impact of the CPG. The key evaluation question is: Did the dissemination and implementation (KT) strategy work? The objective of the KT strategy was “to positively inform and influence the treatment of headache pain: that is, encourage and support adherence to the CPG.” The Canadian Academy of Health Sciences (CAHS)2 notes the following five broad types of long-term impacts of research: • advancing knowledge • capacity-building • informing decision-making • health impacts • broad economic and social impacts The indicators and metrics used to measure effect should be appropriate (valid, relevant, transparent), feasible (cost, timelines), and well matched to the specific project under evaluation. Potential evaluation questions and metrics for evaluating the impact of the Alberta Guideline for Management of Primary Headache in Adults are listed below. Advancing Knowledge This refers to measures of research quality, activity, outreach, and structure. Question: Have we influenced the science around guideline development? Indicators/Metrics: Presentations and publications • Number of presentations given by SC or GDG members; particularly on the process of developing the guidelines, such as the use of the AGREE tool and the ADAPTE framework • Publication counts in highly cited publications

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Capacity-Building This refers to personnel, additional research activity funding, and infrastructure. Typically this encompasses the number of research students engaged in projects and, for organizations, the level of additional research funding. It can also include aspirational indicators such as receptor capacity. Questions: Did we receive any other research funding? Did we improve receptor and absorptive capacity? Indicators/Metrics: • Number of collaborations (informed through the process evaluation) • Other research dollars leveraged Informed Decision-Making This refers to health-related decision-making, research-related decision-making, health products/industry decision-making, and general public decision-making. Questions: Were we successful at making our key audiences aware of the guidelines? Are people using the guideline to inform their decision-making? Indicators/Metrics: • Bibliometrics o Publication in key audience publications o Publication counts in highly cited publications • Website diagnostics o Hits on website o Average time spent on website o Number of pages viewed on website o Downloaded material (patient information sheet) and relative download rate compared with discipline benchmark o Downloads to PDAs • Mentions in patient organization communication vehicles o Recommended/referred to by related public campaigns o Links posted on other national and international guideline sites o Cited in public policy documents (for example, the Primary Care Network newsletter)

o Surveys of sample groups of primary care providers (separate research project—see below)

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Health Impacts This refers to health status, determinants of health, and system changes. Question: Where primary providers and patients adhere to the guidelines, is there a positive impact on health status and health system indicators? Indicators/Metrics: • Desirable changes in physician behaviour include: o Assessment of red flags o Increased provision of appropriate education and reassurance to patients o Reduction of inappropriate recommendations regarding neuroimaging, electroencephalography, or sinus and cervical spine X-rays

o Increase in appropriate prescribing for behavioural therapies o Reduction of inappropriate prescribing of pharmacological therapies o Increase in appropriate prescribing of patient self-management programs • Evaluation of social media tools Broad Economic and Social Impacts This refers to activity, commercialization, health benefit, well-being, and social benefit indicators. Question: Have the guidelines generated any spin-off activity or products? Indicators/Metrics: • To be determined

References 1. Institute of Health Economics. Dissemination and implementation of evidence-informed primary care management of headache guideline. The Alberta HTA Ambassador Program. Draft document presented at the Advisory Committee meeting, 13 December 2011. Edmonton (AB); Institute of Health Economics; Last updated November 2011. 2. Panel on Return on Investment in Health Research. Making an impact: A preferred framework and indicators to measure returns on investment in health research. Ottawa (ON): Canadian Academy of Health Sciences; 2009. Available from: www.cahs-acss.ca/wp- content/uploads/2011/09/ROI_FullReport.pdf (accessed 19 March 2013).

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STAGE III – FINALIZATION Stage I – Set-Up

DISSEMINATING, IMPLEMENTING, AND Formulate research question

UPDATING THE GUIDELINE Stage II – Adaptation

Search for and screen seed CPGs This section contains information on: Assess and select seed CPGs √ the potential organizational barriers to implementing the Alberta CPG; Extract data into evidence tables

√ the plan for disseminating and implementing the Draft guideline document CPG within Alberta; Stage III – Finalization √ the process for updating the Alberta CPG.

Review and refine draft guideline

Finalize and endorse guideline

Disseminate guideline and plan update

Potential Barriers to Guideline Uptake and Implementation Information about barriers to appropriately managing chronic pain and to the uptake of practice guidelines was obtained from surveys conducted in 2006, 2007, 2009, and 2012 as part of the Ambassador Program. See Table 4 for details on participant responses. Ambassador Program Pre-Videoconference Survey, 29 May 2006.1 A survey was sent to 141 individuals who participated in the Ambassador Program Pilot Project workshops conducted in the fall of 2004. Sixty-one individuals completed the survey (21 nurses, 15 rehabilitation occupational therapists and physical therapists, nine physicians, five administrators, four pharmacists, four psychologists, two social workers, and one other), which translated into a 46% response rate. The survey included questions about potential barriers to using care pathways. Alberta HTA Ambassador Program knowledge gaps and needs assessment, 24 July 2007.2 A total of 147 professionals responded to an online survey, with 105 respondents completing the entire survey (33 pharmacists, 27 family physicians, 23 nurses, 15 physical therapists, five occupational therapists, two specialist physicians, and three others). The survey included a question about the barriers to managing chronic pain. Physician survey, October 2009. Twenty-eight family physicians attending Continuing Medical Education sessions in Calgary and Red Deer were asked about the need for an evidence- informed guideline on headache and about perceived barriers to using guidelines and providing the best care possible to patients with headache. See Figure 3 for a summary of the responses. Feedback on the draft of the Alberta CPG for Management of Primary Headache in Adults, April 2012. Four family physicians from the South Calgary Primary Care Network participated in a focus group to review the guideline documents (main guideline, quick reference algorithm, and

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medication tables) and to comment on potential facilitators or barriers to implementing the recommendations.

Figure 3: Perceived barriers to providing the best care possible to patients with

headache (n=23)

16 14 14 12 12 12 10 10 9 9 9

8 7 7 6 6 6 6 no. responses 5 5 4 4 4 3 3 2 2 2 1 1 1 0 0 0 0 0 0 0 0 Agree Agree Agree Agree Agree Agree Disagree Disagree Disagree Disagree Disagree Disagree Strongly agree Strongly agree Strongly agree Strongly agree Strongly agree Strongly agree Strongly disagree Strongly disagree Strongly disagree Strongly disagree Strongly disagree Strongly disagree Neutral (Neither agree or disagree) Neutral (Neither agree or disagree) Neutral (Neither agree or disagree) Neutral (Neither agree or disagree) Neutral (Neither agree or disagree) Neutral (Neither agree or disagree)

Lack of knowledge of Not enough time to do a Lack of knowledge of evidence Lack of access to resources Patient unwillingness to take Concerns about addiction comprehensive headache complete assessment based treatments such as specialists, imaging, prescribed medications assessment self-management training programs, physio

Key actors A dissemination and implementation plan3 for the Alberta CPG was developed and shared with the AC at a face-to-face meeting on 13 December 2011. Two ex officio GDG members with expertise in knowledge translation, systematic reviews, evidence-based research and guideline development also reviewed the plan, which included information on: • audience (target audience and their state of practice and knowledge; barriers and facilitators to change) • content (internal to the guideline and key messages customized for each audience) • strategies and tactics (including timing and responsibilities) • evaluation process and outcomes (short- and long-term impact) The plan also identified the following key actors in the dissemination and implementation process. Physicians and other healthcare providers Literature on physician compliance with CPGs4 suggests that guideline adherence is affected by a complex interplay of factors that influence practitioner knowledge, attitudes, and behaviours. Many determinants, such as regulatory decisions, allocation of resources, and availability of treatment options, are out of the practitioner’s control.

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Patients Patient preferences can be a significant barrier to guideline adherence. Patients often present to practitioners with preconceived notions about the management of their condition and outdated knowledge about treatments. Consequently, they often look for a specific cause for their pain and expect rapid resolution of the problem. From a physician’s perspective, agreement with guideline recommendations is a basic but not sufficient precondition for guideline implementation. Physicians may agree with the guideline content but believe that guideline stipulations are not congruent with patient wishes.2 Public The public is an audience for the Alberta CPG, but the public can also be seen as a strategy to support dissemination and implementation with other decision-makers in the healthcare system. The general public can understand scientific material, but needs assistance in extracting meaning and relevance, and an explanation of the significance of limitations is required. Therefore, any effective strategy for communicating with the general public requires a sustained effort and is likely to be very costly. It is useful to gauge public reaction to population-based campaigns through focus groups before developing materials. In large media campaigns, it is difficult to tailor media messages for particular subgroups that are at different stages of readiness. Therefore, key messages should be built on a social marketing-based knowledge translation strategy. Government Government representation and involvement has been part of the Ambassador Program from its inception. These representatives are in the best position to inform the dissemination and implementation of the Alberta CPG within government and in the primary care networks. Professional associations and colleges Professional associations and colleges are an important means of facilitating communication with allied health professionals. They are also an audience in their own right, as the Alberta CPG might or might not align with their profession-specific guidelines. Health regions and provincial authorities Clinicians from Alberta Health Services (AHS) have participated in the development of the Alberta CPG and senior AHS administrators are members of the AC. This linkage will capitalize on the considerable experience and multiple communication channels available within AHS, enabling the dissemination and implementation of the Alberta CPG throughout AHS and to community based clinicians and the public. Insurers and others The interest in the Alberta CPG within this audience group will vary according to their specific involvement with the guideline. The intensity of the dissemination and implementation with these groups will vary accordingly.

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Dissemination and Implementation Plan The Alberta CPG for Primary Care Management of Headache in Adults dissemination plan includes five main strategies to manage barriers. 1. Develop patient support materials (information sheets, website). 2. Involve partners: (a) TOP to launch guideline (b) GDG to champion the CPG in their regions/zones (c) Advisory Committee members to champion through their organizations 3. Facilitate access to the Alberta CPG on the TOP website from provincial, national, and international associations and organizations. 4. Contact and connect with important stakeholders such as Alberta Health, Alberta Health Services, and the primary care networks. 5. Promote the CPG to professionals through different channels such as workshops, teaching support for continuing medical education (CME) in faculties of medicine (Calgary and Edmonton), rural CME sessions, videoconferences, webinars, participation at conferences and other professional meetings, and publication in professional newsletters and peer- reviewed Canadian and international journals. A repository document was created for logging the knowledge translation activities conducted before and after the launch of the Alberta CPG. The document, which is continuously updated, includes information on the type of activity (what, who, when, where), its objective, the intended audience, and any evaluation or feedback received. Update Process The Alberta CPG for Primary Care Management of Headache in Adults will be assessed annually and will be updated when new evidence is found that changes the recommendations. An Update Committee will be established that will be responsible for the ongoing review and maintenance of the Alberta CPG. The committee will include former members of the GDG with expertise in the field. HTA researchers from the IHE will provide technical support. The task of the committee is to ensure that the currency of the guideline is maintained over time. Toward Optimized Practice, the program responsible for provincial guidelines, and HTA researchers from the IHE will co-lead the updating of the scientific content of the Alberta CPG.

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Table 4: Potential barriers and challenges to chronic pain management, the use of care pathways, and implementing the Alberta CPGs recommendations

Potential Barriers to Implementing the Potential Barriers to the Use of Care Potential Barriers to Chronic Pain and Headache Alberta CPG Recommendations Pathways1 (Survey, 2006) Management2 (Surveys, 2007 and 2009) (Focus Group, 2012) Guideline/Pathway factors Not available in form and format needed Access to guidelines Not practical, too rigid Not practical, too rigid Access to a simple algorithm to sort through different Too lengthy to use on a regular basis—more like a Lack of satisfaction with the initial guideline or chronic pain models reference document pathway Lack of a tabular summary of treatment options Multiple contradictory pathways No obvious benefit to patients Unsure of its quality Developed with little input from physicians Variation in interpretation across clinicians and cases Practice environment/Organizational barriers No institutional support Accessibility to resources, such as pain management Lack of time to use the CPG in the clinical setting Lack of time to use care pathways in the clinical specialists, diagnostic imaging, self-management training setting programs, and physiotherapy programs Challenges to allocating time to inform staff of Accessibility to alternative and effective non-drug treatment new materials modalities such as mind/body work like yoga, tai chi, exercise programs, and nutrition considerations (especially Lack of staff availability for migraine) Lack of communication, e.g., between Poor understanding of, and support for, a holistic mind– departments body view of chronic pain and appropriate alternative Lack of networking treatment approaches (e.g., craniosacral therapy, visceral The service model in the region does not release therapy, myofascial release therapy, acupuncture) in support the use of care pathways conjunction with emotional/psychological support Lack of communication mechanism between various disciplines managing the patient Lack of time to do a complete assessment

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Table 4: Potential barriers to chronic pain management and the use of care pathways, and implementing the Alberta CPGs recommendations (cont’d)

Potential Barriers to Implementing the Potential Barriers to the Use of Care Potential Barriers to Chronic Pain and Headache Alberta CPG Recommendations Pathways1 (Survey, 2006) Management2 (Surveys, 2007 and 2009) (Focus Group, 2012) Educational environment/Knowledge barriers Lack of awareness about relevant pathways Poor understanding of and support for a holistic mind– Pathways not compatible with practitioner body view of chronic pain and appropriate alternative values/experience treatment approaches Inconsistent interpretation and use of care Lack of knowledge of evidence-based treatments pathways across clinicians and cases Healthcare environment Lack of resources (infrastructure/information Limited resources (staff, funding for rehabilitation Lack of infrastructure and information technology technology to support use of care pathways, programs) to support the use of CPG funding, staff) Cumbersome approval process for pathways Practitioner factors Lack of time and/or other resources (electronic Concern about patient drug-taking behaviour (e.g., abuse, Information overload records, information technology resources) addiction) Resistance of clinicians to trying new Physician prescribing practices: family physicians frequently approaches and lack of physician buy-in are not following current professional medical standards Lack of interest in education (they under-medicate, overmedicate, or medicate in a substandard fashion) Lack of awareness Accurate diagnosis and subsequent appropriate treatment Lack of competency Lack of information and cohesiveness among health No obvious benefit to practice professionals when managing a patient with chronic pain Pain management is directed by a doctor, not by Poor understanding of, and support for, a holistic mind– a pathway body view of chronic pain and appropriate alternative Information overload treatment approaches Lack of knowledge of comprehensive headache assessment

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Table 4: Potential barriers to chronic pain management and the use of care pathways, and implementing the Alberta CPGs recommendations (cont’d)

Potential Barriers to Implementing the Potential Barriers to the Use of Care Potential Barriers to Chronic Pain and Headache Alberta CPG Recommendations Pathways1 (Survey, 2006) Management2 (Surveys, 2007 and 2009) (Focus Group, 2012) Patient factors Difficulties in reconciling patient preferences Patient willingness to accept recommendations for with pathway recommendations management instead of focusing on cure Patient complexity, multiple concerns Patient engagement and compliance with learning self- management techniques Patient noncompliance with self-care as advised Patient unwillingness to take prescribed medications Ability to override physician opinion if current treatment does not seem to work Self-diagnosis, self-treatment, and use of non-prescription medications General misinformation among patients about chronic pain, especially back pain Patients with special conditions (dementia)

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References 1. Thornley R, Schuller T. Ambassador Program pre-videoconference survey results summary. Edmonton (AB): The Alberta Heritage Foundation for Medical Research; 2006. Available from: www.ihe.ca/documents/pre-videoconference-survey-result.pdf (accessed 21 December 2012). 2. Lopatka H. Alberta primary care practitioner knowledge assessment for low back pain and headache management: summary report. Edmonton (AB): LopAlta Consulting; September 2007. Available from: www.ihe.ca/documents/Knowledge-Assessment-Survey.pdf (accessed 21 December 2012). 3. Institute of Health Economics. Dissemination and implementation of evidence-informed primary care management of headache guideline. The Alberta HTA Ambassador Program. Draft document presented at the Advisory Committee meeting, 13 December 2011. Edmonton (AB); Institute of Health Economics; Last updated February 2013. 4. Scott NA, Moga C, Harstall C. Managing low back pain in the primary care setting: the know– do gap. Pain Research & Management 2010;15(6):392-400.

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APPLICABILITY OF THE GUIDELINE – ECONOMIC/COST IMPLICATIONS This section contains information on: √ the economic burden of headache pain √ the economic information reported in the seed guidelines √ potential resource implications of the Alberta CPG for Management of Primary Headache in Adults

General Aspects Migraine is associated with high levels of emotional distress and disability, as well as with impaired quality of life for the affected individuals, their families, and society as a whole.1 The economic impact of migraine can be assessed in terms of direct medical costs and indirect (productivity loss) costs. Direct costs include medical care costs associated with inpatient and outpatient visits, prescription drug claims, laboratory and diagnostic services, management of side effects, and family costs.1 Migraine is often associated with comorbid conditions such as psychiatric disorders (anxiety and depression), asthma, and epilepsy. Consequently, estimates of the economic burden of migraine often include the costs of managing these comorbid conditions.1 However, the direct medical costs represent only a fraction of the overall cost of the disease to society. Indirect costs attempt to capture these other economic effects, which include the cost of missed work days and impaired work performance, unemployment or underemployment because of migraine, short-term disability, the burden experienced between migraine attacks, and time lost due to caring for family members with migraine.1 In general, headache accounts for about 20% of absences due to sickness,2 with migraine being a major cause of absenteeism and decreased work productivity.1,3-6 A 1992 Canadian study estimated that seven million work days are lost per year as a direct result of migraine headaches.7-9 A 2005 survey found that, on average, Canadian women experienced at least partial incapacitation on almost 21 days a year due to migraine.8 Emerging evidence indicates that migraine may be a chronic progressive disorder characterized by escalating frequency of headache attacks (transformed migraine).10 In the United States, the average annual total costs (including direct and indirect costs) for patients with transformed migraine were at least four times higher than for individuals whose migraine frequency remained unchanged, owing to increased health care utilization, more visits to primary care physicians, neurologist or headache specialists, pain clinics, and emergency rooms, as well as more time missed at work.10 Tension-type headache is also a costly disorder to society because of its high prevalence.11 A general belief exists that medical care is based on scientific evidence and that clinical decisions about the assessment, diagnosis, treatment, and management of a particular condition should also be evidence based. However, professionals often have their own specific clinical opinions that affect the use of medical services and also their costs. Despite its evident clinical, economic, and social burden, migraine has historically been under-diagnosed and undertreated, and treatment is often suboptimal and characterised by low compliance.12 Adherence to CPGs may assist practitioner and patient decisions on appropriate health care and may also improve practice and reduce costs.

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Economic Information Reported in the Seed Guidelines Formal economic evaluations or cost analyses were not included in any of the seed guidelines, nor did they discuss the economic implications of their recommendations. The following general statements on economic aspects were made by the seed guidelines (see Appendix E for seed guideline references). • Management decisions on the use of preventive therapies should be guided by considerations of the recurrence and frequency of headaches, the contraindications and adverse events associated with treatment, the patient’s preferences, the presence of uncommon migraine conditions, and the cost of both acute and preventive therapies (G1). • One of the goals of acute migraine treatment is to be cost-effective for overall management. Consideration of patient preference (formulations, cost, dosing schedules, and tolerability) was also listed among the general consensus-based principles of care (G1). • Patient reassurance. Patients with high scores on the hospital anxiety and depression scale who did not receive a scan had significantly higher health service costs overall due to a greater use of headache resources such as psychiatric and psychology services than did comparable patients who received a scan (one publication, cited in G4). Resource Implications of the Alberta CPG Because of time and resource constraints, a formal cost analysis or economic evaluation of the impact of the Alberta CPG was not conducted. Nevertheless, information derived from such analyses (cost of implementation of multidisciplinary treatment programs, cost of unnecessary imaging tests, etc.) is important and useful for the decision-making process. Studies to address the resource implications of the Alberta CPG are planned for the future. References 1. Hazard E, Munakata J, Bigal ME, Rupnow MFT, Lipton RB. The burden of migraine in the United States: current and emerging perspectives on disease management and economic analysis. Value in Health 2009;12(1):55-64. 2. Latinovic R, Gulliford M, Ridsdale L. Headache and migraine in primary care: consultation, prescription, and referral rates in a large population. Journal of Neurology, Neosurgery and Psychiatry 2006;77(3):385-7. 3. Bigal ME, Lipton RB, Stewart WF. The epidemiology and impact of migraine. Headache 2004;4(2):98-104. 4. Lipton RB, Diamond S, Reed M, Diamond ML, Stewart WF. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache 2001;41(7):638-45. 5. Radat F, Lanteri-Minet M, Nachit-Ouinekh F, Massiou H, Lucas C, Pradalier A, et al. The GRIM2005 study of migraine consultation in France. III: Psychological features of subjects with migraine. Cephalalgia 2008;29:338-50. 6. Burton WN, Landy SH, Downs KE, Runken MC. The impact of migraine and the effect of migraine treatment on workplace productivity in the United States and suggestions for future research. Mayo Clinical Proceedings 2009;84(5):436-45.

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7. Pryse-Phillips W, Findlay H, Tugwell P, Edmeads J, Murray TJ, Nelson RF. A Canadian population survey on the clinical, epidemiologic and societal impact of migraine and tension- type headache. Canadian Journal of Neurological Science 1992;19(3):333-9. 8. Cooke LJ, Becker WJ. Migraine prevalence, treatment and impact: the Canadian women and migrane study. Canadian Journal of Neurological Science 2010;37(5):580-7. 9. Becker WJ, Gladstone JP, Aube M. Migraine prevalence, diagnosis, and disability. Canadian Journal of Neurological Science 2007;34(Suppl 4):S3-S9. 10. Munakata J, Hazard E, Serrano D, Klingman D, Rupnow MFT, Tierce J, et al. Economic burden of transformed migraine: results from the American Migraine Prevalence and Prevention (AMPP) Study. Headache 2009;49(4):498-508. 11. Bendtsen L, Jensen R. Tension-type headache: the most common, but also the most neglected, headache disorder. Current Opinion in Neurology 2006;19(3):305-9. 12. Bigal M, Krymchantowski AV, Lipton RB. Barriers to satisfactory migraine outcomes. What have we learned, where do we stand? Headache 2009;49(7):1028-41.

Note: See Appendix E for references for the seed guidelines (G1 and G4).

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APPENDIX A: PARTICIPANTS IN THE ALBERTA CPG DEVELOPMENT PROCESS Guideline Development Group (GDG)—Active Members

Zone City/Site Affiliation, Discipline, Area of Expertise Calgary Calgary Werner Becker MD, BSc, FRCP(C) (co-chair) Professor, Department of Clinical Neurosciences University of Calgary Neurology Calgary Paul Taenzer BSc, PhD, RPsych (co-chair) Adjunct Clinical Assistant Professor, Faculty of Medicine University of Calgary Psychology, pain management Calgary MD, CCFP, FCFP Associate Professor Emeritus, Department of Family Medicine University of Calgary Primary care Calgary MD, CCFP Private community physician Primary care Calgary MD, FRCPC (Neurology), DABPN Clinical Assistant Professor, Division of Neurology Department of Clinical Neurosciences, University of Calgary Neurology Calgary MD, DO, CCFP, Consultant Chronic Pain Centre, Alberta Health Services Musculoskeletal chronic pain management Calgary BSc PT, BPE Chronic Pain Centre, Alberta Health Services College of Physical Therapists of Alberta, Canadian Physiotherapy Association Manual therapy, acupuncture, intramuscular stimulation, therapeutic exercise Calgary MD, CCFP, FCFP, Consultant Chronic Pain Centre, Alberta Health Services Family medicine Calgary PhD Alberta Health Services Psychology, chronic pain, chronic headaches Calgary MD, CCFP Medical Director, Chronic Pain Centre, Alberta Health Services Family medicine, chronic pain management Calgary Registered Nurse Clinic Coordinator Calgary Headache Assessment & Management Program (CHAMP) Alberta Health Services Pain management, headache

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Zone City/Site Affiliation, Discipline, Area of Expertise Central Sylvan Lake BSc, MSc, MD, CCFP, FCFP Director of Rural and Regional Health, University of Alberta Physician, Sylvan Family Health Centre Family medicine, medical education Wainwright MD, BSc Physician Family medicine Edmonton Edmonton BScPharm Clinical Pharmacist, Alberta Health Services Pharmacy, pain management Edmonton BScMLS, MHSA Director Health Technology Assessment (HTA) Institute of Health Economics Health technology assessment, systematic reviews Edmonton BSc, DC, MSc, PhD Associate Professor, Canada Research Chair in Spinal Function University of Alberta Spinal biomechanics Edmonton BA (Hons), MD Associate Dean, Community Engagement Professor, Department of Family Medicine University of Alberta Family medicine Edmonton BSc, BScOT Clinic Director, LifeMark Health Institute, LifeMark Health, Inc. Chronic pain Edmonton MD, MSc, CCFP Undergraduate Program Director Assistant Professor, University of Alberta Family medicine South Lethbridge MD, FCFP Family physician, Chinook Regional Hospital Practice limited to chronic pain management Medicine Hat BScPT Physical Therapist, Medicine Hat Regional Hospital Alberta Health Services Chronic pain, physiotherapy

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Resigned Members The following individuals have withdrawn from the GDG because of time constraints and/or workload issues.

Zone City/Site Affiliation, Discipline, Area of Expertise Calgary Calgary BSP, MBA Chronic Pain Centre, Alberta Health Services Clinical Pharmacy

GDG Ex-officio Members

Zone City/Site Affiliation, Discipline, Area of Expertise Calgary Calgary MSc Director, Clinical Epidemiology Health Technology Assessment & Innovation, Alberta Health Services Systematic reviews, evidence-based research, guideline development Edmonton Edmonton MSc Director Knowledge Transfer Initiatives Alberta Innovates – Health Solutions Knowledge transfer Edmonton MD, MSc Research Associate HTA, Institute of Health Economics Health technology assessment, methodologist Edmonton BSc (Hons), PhD Research Associate HTA, Institute of Health Economics Health technology assessment, methodologist Edmonton Staff from Charis Management Consulting, Inc. and the Institute of Health Economics Project coordinator

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Steering Committee (SC) and Research Team Members

Zone City/Site Name Affiliation, Discipline, Area of expertise Calgary Calgary Paul Taenzer*‡ BSc, PhD, RPsych Co-chair of the GDG Adjunct Clinical Assistant Professor, Faculty of and the AC Medicine University of Calgary Psychology, pain management Project manager Calgary Werner Becker*‡ MD, BSc, FRCP(C) Co-chair of the GDG Professor, Department of Clinical Neurosciences and the SC University of Calgary Neurology Edmonton Edmonton Christa Harstall*†‡ BScMLS, MHSA Co-chair of the SC and Director Health Technology Assessment (HTA) the AC Institute of Health Economics Health technology assessment, systematic reviews Project manager Edmonton Carmen Moga†‡ MD, MSc Research Associate HTA, Institute of Health Economics Health technology assessment, methodologist Edmonton Ann Scott†‡ BSc (Hons), PhD Research Associate HTA, Institute of Health Economics Health technology assessment, methodologist Edmonton Various# Staff from Charis Management Consulting, Inc. and the Institute of Health Economics Project coordinator Other Members of the Research Team Edmonton Edmonton Dagmara Chojecki MLIS Institute of Health Economics Information specialist *SC members;†Research Team members; ‡Members who participated at the GDG videoconference meetings; #Owing to staffing issues, six different people filled this role over the course of the project, including a member of the Research Team

Advisory Committee (AC) Members

Name Affiliation, Discipline Christa Harstall (Chair) Institute of Health Economics Director, Health Technology Assessment Paul Taenzer (Chair) Adjunct Clinical Assistant Professor, Faculty of Medicine, University of Calgary Michael Aherne Director of Initiative Development Pallium Project Donna Angus Director, Knowledge Transfer Initiatives Alberta Innovates – Health Solutions JoAnne Beckie Alberta Health Services

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Name Affiliation, Discipline Werner Becker Professor, Department of Clinical Neurosciences, University of Calgary Alberta Health Services, Calgary Joan Berezanski Executive Director Clinical Advisory and Research Branch Alberta Health Robyn Blackadar Executive Director, Knowledge Management Quality Practice and Partnerships Alberta Health Angela Estey Executive Director Chronic Disease Specialty Linkages (Children & Adults) Alberta Health Services Sharon Habermann Alberta Health Services Rob Hauptman Pain Society of Alberta Sheila Kelly Manager, Regional Pain Program Alberta Health Services Gordon Mackie Canadian Headache Society Blair MacKinnon Dissemination Coordinator, Primary Care Unit Alberta Health June Norris Manager, Allied Health Operations Public Health, Primary Care and Chronic Disease Management Alberta Health Services John Parboosingh Professor Emeritus, University of Calgary Consultant, Community Learning, PEAK Project Douglas Perry Senior Provincial Clinical Advisor Clinical Advisory & Research Branch Alberta Health Saifee Rashiq Associate Professor, Director Division of Pain Medicine, Department of Anesthesiology and Pain Medicine University of Alberta Don Schopflocher Associate Professor & Research Statistician, Faculty of Nursing University of Alberta Chris Spanswick Pain Medicine/Medical Leader, Alberta Health Services Assistant Professor, Department of Anaesthesia, University of Calgary Doug Stich Program Director, Toward Optimized Practice Susan Ulan Senior Medical Advisor College of Physicians & Surgeons of Alberta Barry Ulmer Executive Director Chronic Pain Association of Canada Richard Ward President Alberta College of Family Physicians Susan Williams Assistant Deputy Minister Health Policy and Service Standards Divisions Alberta Health

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Name Affiliation, Discipline Paul Woods Alberta College of Family Physicians Michele Zielinski Executive Director Clinical Practice Improvement: Quality Performance Improvement Alberta Health Services

Advisory Committee Ex-officio Members

Name Affiliation, Discipline

Egon Jonsson Professor, School of Public Health, University of Alberta Community Health Sciences, University of Calgary Executive Director & CEO, Institute of Health Economics Various Staff from Charis Management Consulting, Inc. and the Institute of Health Economics Project coordinator

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Figure A.1: Multidisciplinary GDG participation from the Alberta Health Services zones (active members)

North Zone

Edmonton

Zone Central

Zone

Calgary

Zone

South Zone

Source: www.albertahealthservices.ca/ahs-map-ahs-zones.pdf

Edmonton Zone: family physicians (2), occupational therapist/director (1), pharmacist (1), chiropractor (1), HTA researcher (1) Central Zone: family physicians (2) Calgary Zone: family physicians (4), osteopathic physician (1), specialist physicians (neurologists) (2), psychologists (2), registered nurse (1), knowledge management specialist (1) South Zone: physician (1), physical therapist (1)

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APPENDIX B: THE GUIDELINE DEVELOPMENT PROCESS— PARTICIPANTS AND ROLES Stakeholder buy-in is essential for implementing and disseminating guidelines, particularly for those adapted from pre-existing guidelines. A unique collaborative process was established to ensure that all stakeholders had a voice in the guideline adaptation process, which involved multiple committees and partnerships (see Figure B.1). Figure B.1: Relationships among the committees in the guideline development process

Advisory Steering Research Committee Committee Team

Project Team

Guideline Development Group

Ad hoc Subcommittees

Ambassador Program Directors The Ambassador Program Directors were accountable to the IHE and were responsible for the fiscal management, reporting, and goal attainment of the project. They also were responsible for monitoring and directing the work of the Project Coordinator, who was responsible for the day-to- day management of the project. Project Team The Project Team comprised the combined membership of the SC and the Research Team. The Project Team provided project oversight, identified areas for methodological development, and implemented efficient tracking tools. The Project Team was also responsible for the final editing of the guideline recommendations and the development and implementation of the dissemination strategy. Steering Committee (SC) Role • Provided operational leadership and fiscal oversight. • Provided research information and guided the Research Team. • Acted as a secretariat to the GDG and AC.

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• Provided progress reports to the AC. • Wrote or revised guideline recommendations, based on GDG deliberations, for subsequent reassessment by the GDG. • Responsible for final decisions regarding the wording of the guideline recommendations. Membership • Clinical ambassadors, health technology assessment expert, and project coordinator. The committee met by telephone monthly, or more often as required. It also met face-to-face several times to refine the guideline recommendations. As part of the Project Team, members of the Research Team attended the majority of the SC meetings. Advisory Committee Role • Provided general project oversight and advised on the strategic direction for the guideline. • Advised the SC on the development, implementation, and evaluation of the guideline Membership • Representatives from the sponsoring agency, the Ministry of Health, the provincial health research funder, the Alberta Health Services zones, Alberta Innovates–Health Solutions, the provincial Primary Care Network Program, physician regulatory agencies, the provincial medical guideline group, established provincial knowledge translation programs, and a patient advocacy group. This committee met face-to-face twice over 2 years. Guideline Development Group (GDG) Role • Developed the provincial template for the Alberta CPG and point-of-care tools and supported their adaptation to the local health system. • Reviewed and contextualized each recommendation from the selected seed guidelines and requested review of research evidence. • Worked in ad hoc subcommittees to analyze supplementary research evidence provided by the Research Team. Membership • This was a multidisciplinary group from across the province (four out of five zones) consisting of primary care practitioners (for example neurologists, nurses, pharmacists, physicians, physical therapists, psychologists, chiropractors, and occupational therapists), physician education leaders, SC members, and Research Team members. • The group was representative for the geographical region and was led by two chairpersons who attended the videoconference meetings as well as the subcommittee meetings.

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The GDG met twelve times over 2 years (May 2010 to February 2012) via web conference to assess and formulate the recommendations, by telephone for subcommittee meetings, and in one face-to- face meeting at the beginning of the guideline development process. Some discussions were also conducted by email. Research Team Role The Research Team, guided by the SC and the AC, played multiple roles and served various functions in the guideline development and implementation process, including: • selection and critical appraisal of published guidelines • preparation of background documents and development of a system for tracking decision points • methodological advancement and translation of research evidence • active leadership and participation on all committees (AC, SC, GDG) • presentation of relevant research information to the GDG • co-chairing of subcommittee discussions on selected interventions • preparation and condensation of all the materials to expedite the review by the GDG • active participation in developing the provincial template for the Alberta CPG and point-of- care tools • participation in the process of writing the guideline documents • active engagement in the dissemination plan • provision of support to the committee responsible for updating the guideline at two-year intervals Other Collaborations and Partnerships The Toward Optimized Practice (TOP) program is responsible for provincial CPGs and was one of the major partners in the Alberta CPG initiative. See Figure B.2 for an outline of the other collaborations formed throughout the development of the Alberta CPG.

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Figure B.2: The Alberta CPG development process

Knowledge assessment survey for headache management conducted among Alberta primary care practitioners

Formation of a multidisciplinary Advisory Committee (AC) to provide project oversight

Knowledge gap identified; research question formulated (prevention, diagnosis, and treatment of headache); target audience delineated

Comprehensive literature search conducted to identify seed Input from research librarians guidelines

64 possible clinical practice guidelines (CPGs) identified; 18 seed CPGs selected based on clinical relevance

Input from HTA researchers and methodologists

AGREE tool used to select 6 good quality ‘seed’ CPGs

Input from two multidisciplinary committees Evidence inventory tables with seed CPG recommendations (Steering Committee, GDG) developed

Guideline Development Group (GDG) deliberations via web conferences Input from external clinical experts

Guideline documents written

Input from external clinical experts, lay committee, Guideline reviewed and refined and patients

Collaboration with program responsible for Guideline endorsed provincial guidelines (Toward Optimized Practice)

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APPENDIX C: EXCLUDED GUIDELINES Table C.1: Summary of excluded guidelines

Publication Reason for exclusion Armon C, Evans RW. Addendum to assessment: Prevention of post-lumbar Guideline focused on specific puncture headaches current guideline. Report of the Therapeutics and Technology cause of headache Assessment Subcommittee of the American Academy of Neurology. Neurology 2005;65(4);510-2. Best Practice Statement: Management of chronic pain in adults. NHS Quality Improvement Not a guideline Scotland; February 2006. Available from: www.nhshealthquality.org/nhsqis/files/BPSManage_chronic_pain%20_adults%20( Feb06).pdf (accessed 29 October 2009). Bigal ME, Lipton RB. Acute treatment of migraine headache. Current Treatment Not a guideline (narrative Options in Neurology 2003;5(6):423-30. review) British Association of Audiovestibular Physicians. Migraine related vertigo: classification Target population (adult) not and diagnostic criteria. November 2008. Available from: stated www.baap.org.uk/docs/2008%20BAAP%20MRV%20classification%20and%20dia gnosis.pdf (accessed 29 October 2009). Bunn WB, Garber H. Disease management in migraine: A managed care migraine Did not use International consensus statement. Managed Care Interface 2007;20(SUPPL. A):16-24. Headache Society (IHS) diagnostic criteria Target population (adult) not stated Burgunder JM, Finsterer J, Szolnoki Z, Fontaine B, Baets J, Van Broeckhoven C, et Guideline; did not meet al. EFNS guidelines on the molecular diagnosis of channelopathies, epilepsies, Ambassador inclusion criteria migraine, stroke, and dementias. European Journal of Neurology. 2010;17(5):641-8. Cassina M, Di Gianantonio E, Toldo I, Battistella PA, Clementi M. Migraine Not a guideline (narrative therapy during pregnancy and lactation. Expert Opinion on Drug Safety. 2010;9(6):1-12. review) Derby hospitals NHS Foundation Trust. Guidelines for the management of migraine. 2005. Guidelines for inpatient care Available from: www.derbyshirecountypct.nhs.uk/content/files/Clinical%20Guidelines/Migraine% 20version%201.5.pdf (accessed 28 October 2009). Dodick D, Lipton RB, Martin V, Papademetriou V, Rosamond W, Target population (adult) not MaassenVanDenBrink A, et al. Consensus statement: cardiovascular safety profile stated of triptans (5-HT agonists) in the acute treatment of migraine. Headache 2004;44(5):414-25. Dowson AJ, Lipscombe S, Sender J, Rees T, Watson D on behalf of the MIPCA Target population (adult) not Migraine Guidelines Development Group. New guidelines for the management of stated migraine in primary care. Current Medical Research and Opinion 2002;18(7):414-39. Dowson AJ, Sender J, Lipscombe S, Cady RK, Tepper SJ, Smith R, et al. Target population (adult) not Establishing principles for migraine management in primary care. International Journal stated of Clinical Practice 2003;57(6):493-507. Edlow JA, Panagos PD, Godwin SA, Thomas TL, Decker WW. American College Guideline focused on patients of Emergency Physicians. Clinical policy: critical issues in the evaluation and with headache presenting to the management of adult patients presenting to the emergency department with acute emergency department headache. Annals of Emergency Medicine 2008;52(4):407-36.

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Evans RW, Armon C, Frohman EM, Goodin DS. Assessment: prevention of post– Guideline focused on specific lumbar puncture headaches: report of the Therapeutics and Technology Assessment cause of headache Subcommittee of the American Academy of Neurology. Neurology 2000;55(7):909- 14. Evans RW, Tepper SJ, Shapiro RE, Sun-Edelstein C, Tietjen GE. The FDA alert on Not a guideline (position paper) serotonin syndrome with use of triptans combined with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors: American Headache Society position paper. Headache 2010;50(6):1089-99. Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, et al. EFNS guideline on the Target population (adult) not drug treatment of migraine—report of an EFNS task force. European Journal of stated, but has a special section Neurology 2006;13(6):560-72. on children and adolescents Included a revised report (guideline) published in 2009. Evers S. Treatment of migraine with prophylactic drugs. Expert Opinion on Target population (adult) not Pharmacotherapy 2008; 9(15):2565-73. stated Single author Freeman MC. Migraine-preventive medications: Guidelines for success. Headache and Target population (adult) not Pain: Diagnostic Challenges, Current Therapy 2006;17(2):83-9. stated Single author Fumal A, Schoenen J. Current migraine management—patient acceptability and Not a guideline future approaches. Journal of Neuropsychiatric Disease and Treatment 2008;4(6):1043-57. Garza I, Swanson JW. Prophylaxis of migraine. Journal of Neuropsychiatric Disease and Not a guideline Treatment 2006;2(3):281-91. Glover C. Guidelines for community pharmacists on the management of headache. Target population (adult) not Pharmaceutical Journal 2008;280(7493):311-18. stated Gronseth G, Cruccu J, Alksne C, Argoff M, Brainin K, Burchiel T, et al. Report of Target population (adult) not the Quality Standards Subcommittee of the American Academy of Neurology and stated the European Federation of Neurological Studies. Practice Parameter: The diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review). Neurology 2008;71(15);1183-90. Haag G, Diener HC, May A, Meyer C, Morck H, Straube A, et al. Self-medication Guideline; treatment of of migraine and tension-type headache: summary of the evidence-based headaches initiated by the recommendations of the Deutsche Migraine und Kopfschmerzgesellschaft patients themselves without any (DMKG), the Deutsche Gesellschaft fur Neurologie (DGN), the Osterreichische consultation with their physician Kopfschmerzgesellschaft (OKSG) and the Schweizerische Kopfwehgesellschaft Target population (adult) not (SKG). The Journal of Headache and Pain 2011;12(2):201-17. stated Holroyd KA, Drew JB. Behavioral approaches to the treatment of migraine. Did not use IHS diagnostic Seminars in Neurology 2006; 26(2):199-207. criteria Institute for Clinical Systems Improvement (ICSI). Diagnosis and treatment of headache. Target population included Bloomington (MN): ICSI; March 2009. Available from: patients 12 years of age and www.icsi.org/headache/headache__diagnosis_and_treatment_of_2609.html older (accessed 22 October 2009). January 2011 update: Institute for Clinical Systems Improvement (ICSI). Diagnosis and treatment of headache. Bloomington (MN): ICSI; 2011. Available from: www.icsi.org/headache/headache__diagnosis_and_treatment_of_2609.html (accessed 17 June 2011).

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Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, Silberstein S, et al. Practice Guideline; did not focus on adult parameter: pharmacological treatment of migraine headache in children and population adolescents: report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society Neurology 2004;63(12);2215-24. Lewis DW, Ashwal S, Dahl G, Dorbad D, Hirtz D, Prensky A, et al. Practice Guideline; did not focus on adult parameter: evaluation of children and adolescents with recurrent headaches: report population of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society Neurology 2002;59(4);490-8. Lipscombe S, Rees T, Dowson AJ. Tailoring Migraine Management in Primary Care Target population (adult) not to the Needs of the Individual Patient. Headache Care 2004;1(2);147-57. stated Mannix LK. Comorbidities of migraine. 2004. Available from: Monograph www.headaches.org/pdf/CME_Mono02.pdf (accessed 28 October 2009). Marcus DA. Manual for headache management. Headache Quarterly 2002;13(2):97- Target population (adult) not 103. stated Single author National Headache Foundation. 2006. Monographs NHF Migraine Prevention Summit Proceedings Issue 1: Overview of Migraine Issue 2: The Importance of Communicating With Patients Issue 3: Impact of Migraine: Evaluating Patient Disability Issue 4: Advances in Preventive Therapies for Migraine Available from: www.headaches.org/ (accessed 28 October 2009). National Health Service (NHS). Institute for Innovation and Improvement Clinical Target population included Knowledge Summaries: Headache tension type. Last revised August 2009. Available from: patients 6 years and older www.cks.nhs.uk/headache_tension_type#-386639 (accessed 29 October 2009). National Health Service (NHS). Institute for Innovation and Improvement. Clinical Target population included Knowledge Summaries: Headache assessment. July 2005. Available from: patients 6 years and older www.cks.nhs.uk/headache_assessment#-362886 (accessed 29 October 2009). National Health Service (NHS). Institute for Innovation and Improvement. Clinical Target population included Knowledge Summaries: Headache medication overuse. Last revised August 2009. Available patients 12 years and older from: www.cks.nhs.uk/headache_medication_overuse#386525001 (accessed 29 (adolescents and adults) October 2009). National Institute for Health and Clinical Excellence (NICE). Stereotactic radiosurgery Not a primary care intervention for trigeminal neuralgia using the gamma knife. August 2004. Available from: www.nice.org.uk/nicemedia/pdf/ip/IPG085guidance.pdf (accessed 29 October 2009). National Institute for Health and Clinical Excellence (NICE). Trigeminal neuralgia— Clinical expert considered Management. November 2008. Available from: trigeminal neuralgia to be within www.cks.nhs.uk/trigeminal_neuralgia#-339540 (accessed 19 November 2009). the purview of specialists only and not appropriate for a primary care guideline

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Naumann M, So Y, Argoff CE, Childers MK, Dykstra DD, Gronseth GS, et al. Target population (adult) not Therapeutics and Technology Assessment Subcommittee of the American Academy stated of Neurology. Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008;70(19):1707-14. Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, et al. New Not a guideline appendix criteria open for a broader concept of chronic migraine. Cephalalgia 2006;26(6):742-6. Saper JR, Lake AE 3rd, Bain PA, Stillman MJ, Rothrock JF, Mathew NT, et al. A Based on Saper and Lake (2008) practice guide for continuous opioid therapy for refractory daily headache: patient Did not use the IHS diagnostic selection, physician requirements, and treatment monitoring. Headache. criteria 2010;50(7):1175-93. Saper JR, Lake AE. Continuous opioid therapy (COT) is rarely advisable for Did not use the IHS diagnostic refractory chronic daily headache: Limited efficacy, risks, and proposed guidelines. criteria Headache 2008;48(6):838-49. Saper JR, Lake AE. Sustained opioid therapy should rarely be administered to Did not use the IHS diagnostic headache patients: Clinical observations, literature review, and proposed guidelines. criteria Headache Currents 2006;3(3):67-70. Schroeder BM. AAFP/ACP-ASIM release guidelines on the management and Target population (adult) not prevention of migraines. American Family Physician 2003;67(6):1392-7. stated Same as Snow et al. (2002) (see Table C.2). Silberstein SD. Treatment recommendations for migraine. Nature Clinical Practice Target population (adult) not Neurology 2008; 4(9):482-9. stated Single author Taylor FR, Kaniecki RG. Symptomatic treatment of migraine: when to use Not a clinical practice guideline NSAIDs, triptans, or opiates. Current Treatment Options in Neurology 2011;13(1):15-27. (narrative review) Torelli P, Campana V, Cervellin G, Manzoni GC. Management of primary Proposal of recommendations headaches in adult emergency departments: A literature review, the Parma ED for headaches in adults in experience and a therapy flow chart proposal. Neurological Sciences 2010;31(5):545-53. emergency departments University of Warwick. Headache. University of Warwick, Joint Royal Colleges Guidelines for emergency Ambulance Liaison Committee; 2007. Available from: ambulance crews www2.warwick.ac.uk/fac/med/research/hsri/emergencycare/prehospitalcare/jrcal cstakeholderwebsite/guidelines/headache_2006.pdf (accessed 29 October 2009). Van Kleef M, Lataster A, Narouze S, Mekhail N, Geurts JW, Van Zundert J. Guideline; does not provide any Evidence-based interventional pain medicine according to clinical Diagnoses. 2. recommendations on treatments Cluster headache. Pain Practice 2009; 9(6):435-42. used in primary care Wenzel RG, Sarvis CA, Krause ML. Over-the-counter drugs for acute migraine Clinical expert considered the attacks: literature review and recommendations. Pharmacotherapy 2003;23(4):494-505. guideline too pharmacy-focused Wheeler SD. phenotype-driven preventive strategies for migraine and other Not a guideline (narrative headaches. Neurologist 2009; 15(2):59-70. review, secondary and tertiary care) VA/DoD clinical practice guideline for the management of opioid therapy for chronic pain. Did not use IHS diagnostic Guideline summary. Washington (DC): Department of Veterans Affairs (U.S.); 2010. criteria Available from: www.healthquality.va.gov/COT_312_Full-er.pdf (accessed 20 May 2011).

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Chen YY, Chen HM, Chen WH, Chen WT, Fuh JL, Juang KD, et al. Neuroimaging Chinese language guidelines in nonacute headaches: Treatment guideline subcommittee of the Taiwan headache society. Acta Neurologica Taiwanica 2010;19(2):137-44. Pearlman SH, Dodick DW. Therapeutic guidelines for headache. Handbook of Clinical Review of other guidelines’ Neurology 2010; 97:183-194. recommendations; includes additional published research evidence Sances G, Catarci T. Management of headache patients. Handbook of Clinical Review of available clinical Neurology 2010; 97:127-35. practice guidelines

Table C.2: Guidelines excluded after review by the Steering Committee

Publication Reason for exclusion E1 Low score on AGREE tool National Health Service (NHS) Institute for Innovation and Improvement. Clinical (average quality) Knowledge Summaries: Headache—cluster. London, UK: NHS; 2009. Available from: www.cks.nhs.uk/headache_cluster (accessed 24 November 2009). E2 Target population (adult) not Jordan JE, Seidenwurm DJ, Davis PC, Brunberg JA, De La Paz RL, Dormont PD, stated et al. Expert Panel on Neurologic Imaging. Headache. Reston (VA): American Did not use International College of Radiology; 2006. Available from: www.acr.org/ac (accessed 22 October Headache Society (IHS) 2009). diagnostic criteria Low score on AGREE tool (average quality) E3 Included children and adults, Steiner TJ, Paemeleire K, Jensen R, Valade D, Savi L, Lainez MJ, et al. European although not clearly stated in principles of management of common headache disorders in primary care. Journal introduction (some separate of Headache Pain 2007;8 Suppl 1:S3-47. information on adults and children) Low score on AGREE tool (average quality) E4 Target population (adult) not Sandrini G, Friberg L, Janig W, Jensen R, Russell D, Sanchez del Rio M, et al. stated Neurophysiological tests and neuroimaging procedures in non-acute headache: Recommendations mention guidelines and recommendations. European Journal of Neurology 2004;11(4):217-24. paediatric patients 2011 update: Sandrini G, Friberg L, Coppola G, Janig W, Jensen R, Kruit M, et al. Low score on AGREE tool Neurophysiological tests and neuroimaging procedures in non-acute headache (average quality) (2nd edition). European Journal of Neurology 2011;18(3): 373-81. E5 Target population (adult) not Snow V, Weiss K, Wall EM, Mottur-Pilson C, for the American Academy of stated Family Physicians and the American College of Physicians–American Society of Low score on AGREE tool Internal Medicine. Pharmacologic management of acute attacks of migraine and (average quality) prevention of migraine headache. Annals of Internal Medicine 2002;137(10):840-9. E6 Target population (adult) not Migraine in Primary Care Advisors (MIPCA). Guidelines for the management of migraine stated in primary care. Second edition. Number 8; January 2004. Available from: Low score on AGREE tool www.mipca.org.uk/pdf/newsletters/NL8_Guidelines_2ndEd.pdf (accessed 29 (average quality) October 2009).

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E7 Target population (adult) not Inland Empire Health Plan. Clinical practice guideline for the diagnosis and management of stated migraine. February 2007. Available from: Low score on AGREE tool http://ww2.iehp.org/NR/rdonlyres/1F37DF38-6D3C-4761-AFA7- (average quality) 81939F4B3478/0/Migraine.pdf; http://216.25.88.43/upload/NS_BASH/Shared_care_prescribing_guidelines.pdf (accessed 28 October 2009). November 2010 update: Available from: http://ww2.iehp.org/NR/rdonlyres/1F37DF38-6D3C-4761-AFA7- 81939F4B3478/0/Migraine.pdf (accessed 20 May 2011). E8 Some information on children as British Association for the Study of Headache. Guidelines for all healthcare professionals well adults. Delineation is not in the diagnosis and management of migraine, tension-type, cluster and medication-overuse consistent throughout the headache. January 2007. Available from: document. http://216.25.88.43/upload/NS_BASH/BASH_guidelines_2007.pdf; Low score on AGREE tool (poor http://216.25.88.43/upload/NS_BASH/Shared_care_prescribing_guidelines.pdf quality) (accessed 28 October 2009). 2010 update: Available from: http://217.174.249.183/upload/NS_BASH/2010_BASH_Guidelines.pdf (accessed 20 May 2011). E9 Target population (adult) not National Headache Foundation. Standards of care for headache diagnosis and treatment. stated; has a separate chapter on 5th Edition. Chicago (IL): National Headache Foundation; 2008. pediatric migraine Low score on AGREE tool (poor quality) E10 Did not use IHS diagnostic Macintyre PE, Schug SA, Scott DA, Visser EJ, Walker SM; APM:SE Working criteria Group of the Australian and New Zealand College of Anaesthetists and Faculty of Low score on AGREE tool Pain Medicine. Acute Pain Management: Scientific Evidence. 3rd edition. Melbourne, (average quality) Australia: ANZCA and FPM; 2010. Available from: Note: Could be used as a background www.anzca.edu.au/resources/books-and-publications/acutepain.pdf (accessed 8 reference for the recommendations on September 2010). drugs in pregnancy E11 Did not use IHS diagnostic Finnish Medical Society Duodecim. Systemic diseases in pregnancy. In: EBM criteria Guidelines. Evidence-Based Medicine [Internet]. Helsinki, Finland: Wiley Low score on AGREE tool (poor Interscience, John Wiley & Sons; 2007. Available from: quality) www.guideline.gov/content.aspx?id=11046 (accessed 8 September 2010). E12 Low score on AGREE tool Francis GJ, Becker WJ, Pringsheim TM. Acute and preventive pharmacologic (average quality) treatment of cluster headache. Neurology 2011;75:463-73.

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1 APPENDIX D: MODIFICATIONS MADE TO THE AGREE TOOL Examples of the detailed instructions constructed using logical operators (AND, OR, NOT) for the AGREE tool items are listed below. Item 7 – Piloted among target users 4 – Guideline piloted among target users and methods reported. 3 – Guideline piloted among target users but methods not reported. 2 – Unclear. 1 – Guideline not piloted among target users. Item 8 – Systematic methods used to search for evidence Information about the search terms used, sources consulted, and date limits of the literature searches should be provided. 4 – All three elements (search terms, sources, date limits) reported. 3 – Two elements reported. 2 – Unclear or only one element reported. 1 – Information is not provided about the methods used to search for evidence. Item 16 – Different management options presented 4 – Different management options were considered to be adequately presented if the comparators for each intervention were stated in the guideline (for example, sumatriptan is more effective than naratriptan in patients with migraine). 3 – The comparators were stated for only some of the interventions. 2 – Unclear. 1 – The comparators for the interventions were not stated. Item 19 – Organizational barriers discussed 4 – Not applicable or organizational barriers discussed and required changes outlined. 3 – Organizational barriers mentioned but required changes not outlined. 2 – Unclear. 1 – Organizational barriers not discussed. References 1. Scott NA, Moga C, Harstall C. Making the AGREE tool more user friendly: the feasibility of a user guide based on Boolean operators. Journal of Evaluation in Clinical Practice 2009;15(6):1061- 73.

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APPENDIX E: INCLUDED SEED GUIDELINES* Table E.1: Summary of included seed guidelines

Type of Headache, Definition; Target Population; Source Database Guideline, Country Intended Users; Setting; Focus Clinical Algorithms G1 Type of headache: Migraine Source: Google USA Target population: Adults Clinical algorithm: 469 references Setting: Primary care setting Available Intended users: Not stated Focus: Diagnostic testing (primarily neuroimaging studies), pharmacological management of acute attacks, migraine-preventive drugs, and behavioural and physical treatments G2 Type of headache: Migraine Source: PubMed Europe Target population: Age not stated (has a separate section that briefly Clinical algorithm: 193 references discusses children and adolescents) Not available (excluded references for Setting: Not stated pregnant women and Intended users: Not stated children) Focus: Drug treatment G3 Type of headache: Migraine Source: PubMed France Target population: Adults (aged 18 to 65 years) and children (aged 5 Clinical algorithm: 51 references on adults to 17 years) presented separately Not available (total references 59) Setting: Not stated Note: Article publication Intended users: General practitioners, specialists, pharmacists summarizes the Focus: Diagnosis and management guideline; entire guideline is available in French G4 Type of headache: Migraine, tension-type headache, trigeminal Source: United United Kingdom autonomic cephalalgias, medication-overuse headache Kingdom National 275 references Target population: Adults Library for Health Setting: Primary and secondary care Guidelines Intended users: General practitioners, community pharmacists, Clinical algorithm: patients with headache, opticians, dental practitioners Not available Focus: Diagnosis and management G5 Type of headache: Cluster headache and the other trigeminal Source: PubMed Europe autonomic cephalalgias Clinical algorithm: 143 references Target population: Age not stated Not available Setting: Not stated Intended users: Physicians Focus: Prevention, management, and treatment G6 Type of headache: Tension-type headache Source: PubMed Europe Target population: Adults (update search, August 129 references Setting: Not stated 2010) Intended users: Clinical neurologists, other health care professionals Clinical algorithm: and healthcare providers Not available Focus: Drug treatment * Guidelines are not presented in any specific order. The identifiers (G1, G2, etc.) have been randomly assigned for the purpose of organization only.

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References for Included Seed Guidelines G1 US Headache Consortium. Evidence-based guidelines for migraine headache. US Headache Consortium Guidelines. St USA Paul (MN): US Headache Consortium; 2000. Available from: https://www.americanheadachesociety.org/professionalresources/USHeadacheConsortiumGuidelines.a sp (accessed 24 November 2009). Companion documents: Program description and methods: Available from: www.aan.com/professionals/practice/pdfs/gl0086.pdf (accessed 31 January 2012). Frishberg BM, Rosenberg JH, Matchar DB, McCrory DC, Pietrzak MP, Rozen TD, et al. Evidence based guidelines in the primary care setting: neuroimaging in patients with non-acute headache. Available from: www.aan.com/professionals/practice/pdfs/gl0088.pdf (accessed 31 January 2012). Matchar DB, Young WB, Rosenberg JH, Pietrzak MP, Silberstein SD, Lipton RB, et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management of acute attacks. Available from: www.aan.com/professionals/practice/pdfs/gl0087.pdf (accessed 31 January 2012). Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. Available from: www.aan.com/professionals/practice/pdfs/gl0090.pdf (accessed 31 January 2012). Campbell JK, Penzien DB, Wall EM. Evidence-based guidelines for migraine headache: behavioral and physical treatments. Available from: www.aan.com/professionals/practice/pdfs/gl0089.pdf (accessed 31 January 2012). Patient summary: Available from: www.aan.com/professionals/practice/guidelines/migraine/Migraine_Guide_Patients.pdf (accessed 31 January 2012). Summary guideline: Available from: https://www.aan.com/practice/guideline/uploads/120.pdf (accessed 31 January 2012). Summary report: Available from: www.neurology.org/cgi/reprint/55/6/754.pdf (accessed 31 January 2012). AAN Encounter Kit—Headache: Available from: www.aan.com/go/practice/quality/headache (accessed 31 January 2012). Algorithm for imaging: Available from: www.aan.com/go/practice/quality/headache (accessed 31 January 2012). G2 Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, et al. EFNS guideline on the drug treatment of Europe migraine--revised report of an EFNS task force. European Journal of Neurology 2009;16(9):968-81. Available from: www.efns.org/fileadmin/user_upload/CME_articles/CME_article_2009_September.pdf; www.efns.org/fileadmin/user_upload/guidline_papers/EFNS_guideline_2009_drug_treatment_of_migr aine.pdf (accessed 31 January 2012). Companion documents: Information about the Task Force and methods: Available from: www.efns.org/EFNS-Guideline- Papers.270.0.html; www.efns.org/fileadmin/user_upload/guidline_papers/EFNS_guideline_2004_neurological_manageme nt_guidelines.pdf (accessed 31 January 2012). Complete summary by the National Guideline Clearinghouse (NGC): Available from: http://guideline.gov/content.aspx?f=rss&id=24517 (accessed 31 January 2012). G3 Géraud G, Lantéri-Minet M, Lucas C, Valade D; French Society for the Study of Migraine Headache France (SFEMC). French guidelines for the diagnosis and management of migraine in adults and children. Clinical Therapeutics 2004;26(8):1305-18. Companion documents (French language): Available from: www.has-sante.fr/portail/jcms/c_272212/prise-en-charge-diagnostique-et- therapeutique-de-la-migraine-chez-ladulte-et-chez-lenfant-aspects-cliniques-et-economiques (accessed 10 December 2009).

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G4 Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of headache in adults. United Edinburgh, Scotland: SIGN; 2008. Available from: www.sign.ac.uk/guidelines/fulltext/107/index.html; Kingdom www.sign.ac.uk/pdf/sign107.pdf (accessed 24 November 2009). Quick reference guide: Available from: www.sign.ac.uk/pdf/qrg107.pdf (accessed 30 October 2009). Summary: Available from: www.bmj.com/cgi/section_pdf/337/nov20_1/a2329.pdf?ijkey=TPs6QosisH0tqqF&keytype=ref (accessed 30 October 2009). Methods: Available from: www.sign.ac.uk/pdf/sign50.pdf (accessed 31 January 2012). G5 May A, Leone M, Afra J, Linde M, Sandor PS, Evers S, et al. EFNS guidelines on the treatment of cluster Europe headache and other trigeminal-autonomic cephalalgias. European Journal of Neurology 2006;13(10):1066-77. Available from: www.efns.org/fileadmin/user_upload/guidline_papers/EFNS_guideline_2006_cluster_headache_and_o ther_trigeminal_autonomic.pdf (accessed 29 October 2009). Companion documents: Complete summary by the National Guideline Clearinghouse (NGC): Available from: www.guideline.gov/summary/pdf.aspx?doc_id=10471&stat=1&string (accessed 29 October 2009). Information about the Task Force and methods: Available from: www.efns.org/EFNS-Guideline- Papers.270.0.html; www.efns.org/fileadmin/user_upload/guidline_papers/EFNS_guideline_2004_neurological_manageme nt_guidelines.pdf (accessed 31 January 2012). G6 Bendtsen L, Evers S, Linde M, Mitsikostas DD, Sandrini G, Schoenen J. EFNS guideline on the Europe treatment of tension-type headache—Report of an EFNS task force. European Journal of Neurology 2010;17(11)1318-25. Available from: www.efns.org/fileadmin/user_upload/CME_articles/CME_article_2010_November.pdf (accessed 29 October 2009). Companion documents: Information about the Task Force and methods: Available from: www.efns.org/EFNS-Guideline- Papers.270.0.html; www.efns.org/fileadmin/user_upload/guidline_papers/EFNS_guideline_2004_neurological_manageme nt_guidelines.pdf (accessed 31 January 2012).

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APPENDIX F: CRITICAL APPRAISAL RESULTS (MODIFIED AGREE TOOL) Table F.1: Standardized domain scores, AGREE (%)—included seed guidelines G1† (USA) G2 (Europe) G3 (France) G4 (UK) G5 (Europe) G6 (Europe) M M M M, TT, C, O C TT AGREE domain* (D/Ma/T/P) (Ma/T) (D/Ma/T/P) (D/E/Ma/T/P) (Ma/T/P) (T/P)

Scope and purpose 94 78 100 100 78 83

Stakeholder involvement 29 38 42 75 38 50

Rigor of development 76 83 81 76 83 79

Clarity and presentation 100 75 96 100 71 75

Applicability 22 33 67 67 6 0

Editorial independence 50 100 67 92 100 100

AGREE – Appraisal of Guidelines for Research and Evaluation Type of headache: C – cluster headache; M – Migraine; O – other primary headaches; TT – tension-type headache Focus: D – diagnosis; E – evaluation; Ma – management; T – treatment; P – prophylaxis

* Two reviewers undertook the quality assessments independently † See Appendix E for seed guideline references

Note: Guidelines are not presented in any specific order. The identifiers (G1, G2, etc.) have been randomly assigned for the purpose of organization only.

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Table F.2: Standardized domain scores, AGREE (%)—guidelines excluded by the Steering Committee

E8 E9 E1† E6 E7 (UK) (USA) E10 E11 (UK) E2 E3 E4 E5 (UK) (USA) 2007 2008 (ANZ) (Finland) E12 (Canada) C (USA) (Europe) (Europe) (USA) M 2007 M, TT, M, TT, 2010 2007 AGREE (D/Ma H H H M (D/Ma/ M C, O C, O M, TT, C M C domain* ) (D) (D/T) (D) (Ma/P) T) (D/Ma) (D/Ma) (D/T/P) (Ma/T) (Ma/T) (T/P)

Scope and 89 78 83 78 72 78 44 50 78 67 61 94 purpose

Stakeholder 50 42 67 33 42 50 13 33 21 63 33 21 involvement

Rigor of 71 52 48 52 31 38 36 40 24 79 29 57 development

Clarity and 96 96 67 67 92 88 50 79 54 96 46 75 presentation

Applicability 61 50 61 22 0 0 56 61 33 0 0 0

Editorial 50 42 100 42 50 33 17 8 17 33 25 67 independence

AGREE – Appraisal of Guidelines for Research and Evaluation; ANZ – Australia/New Zealand Type of headache: C – cluster headache; H – headache; M – Migraine; O – other primary headaches; TT – tension-type headache Focus: D – diagnosis; E – evaluation; Ma – management; T - treatment; P – prophylaxis

* Two reviewers undertook the quality assessments independently † See Appendix C, Table C.2 for excluded guidelines references Note: Guidelines are not presented in any specific order. The identifiers (G1, G2, etc.) have been randomly assigned for the purpose of organization only.

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Table F.3: Average quality score based on seven designated quality criteria—included seed guidelines

G1* (USA) G2 (Europe) G3 (France) G4 (UK) G5 (Europe) G6 (Europe) M M M M, TT, C, O C TT AGREE domain (D/Ma/T/P) (Ma/T) (D/Ma/T/P) (D/E/Ma/T/P) (Ma/T/P) (T/P)

Main score 23 26.5 24.5 25.5 26 25.5

Quality rating† Good Good Good Good Good Good

AGREE – Appraisal of Guidelines for Research and Evaluation Type of headache: C – cluster headache; M – Migraine; O – other primary headaches; TT – tension-type headache Focus: D – diagnosis; E – evaluation; Ma – management; T – treatment; P – prophylaxis

* See Appendix E for seed guidelines references. † Two reviewers rated guidelines independently with respect to the following essential quality criteria: how well their methods excluded bias by examining the search strategy used; how the recommendations were formulated and presented; whether the recommendations were directly linked to the evidence; the external review process; and whether conflicts of interest and funding sources were reported. The guidelines were rated as follows: Good 22 to 28 points Average 15 to 21 points Poor 0 to 14 points Note: Guidelines are not presented in any specific order. The identifiers (G1, G2, etc.) have been randomly assigned for the purpose of organization only.

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Table F.4: Average quality score based on seven designated quality criteria—guidelines excluded by the Steering Committee

E8 E9 E3 E4 E6 E7 (UK) (USA) E10 E11 E1* E2 (Europe (Europe E5 (UK) (USA) 2007 2008 (ANZ) (Finland) E12 (Canada) (UK) (USA) ) ) (USA) M 2007 M, TT, M, TT, 2010 2007 AGREE C H H H M (D/Ma/ M C, O C, O M, TT, C M C domain* (D/Ma) (D) (D/T) (D) (Ma/P) T) (D/Ma) (D/Ma) (D/T/P) (Ma/T) (Ma/T) (T/P)

Main score 21 18.5 18.5 17.5 16.5 16.5 15 13.5 12.5 21.0 13.0 20.5

Average Average Average Average Average Average Average Poor Poor Average Poor Average Quality rating†

AGREE – Appraisal of Guidelines for Research and Evaluation; ANZ – Australia/New Zealand Type of headache: C – cluster headache; H – headache; M – Migraine; O – other primary headaches; TT – tension-type headache Focus: D – diagnosis; E – evaluation; Ma – management; T – treatment; P – prophylaxis

* See Appendix C, Table C.2 for excluded guidelines references. † Two reviewers rated guidelines independently with respect to the following essential quality criteria: how well their methods excluded bias by examining the search strategy used; how the recommendations were formulated and presented; whether the recommendations were directly linked to the evidence; the external review process; and whether conflicts of interest and funding sources were reported. The guidelines were rated as follows: Good 22 to 28 points Average 15 to 21 points Poor 0 to 14 points Note: Guidelines are not presented in any specific order. The identifiers (G1, G2, etc.) have been randomly assigned for the purpose of organization only.

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APPENDIX G: INVENTORY OF GUIDELINE RECOMMENDATIONS* In navigating the tables, please note the following. 1. The recommendations are grouped as follows: • Diagnosis and investigation: primary headache (Table G.1a), secondary headache (Table G.1b), assessment tools (Table G.1c), clinical investigations (Table G.1d) • Acute migraine—pharmacological interventions: acute migraine (Table G2.a), menstrual migraine (Table G.2b), migraine in pregnancy (Table G.2c) • Migraine—non-pharmacological interventions: (Table G3.a) • Migraine prophylaxis: migraine—pharmacological interventions (Table G4.a), menstrual migraine (Table G.4b), migraine in pregnancy (Table G.4c) • Tension-type headache (TTH): patient education (Table G.5a), pharmacological prophylaxis (Table G.5b), acute pharmacological treatment (Table G.5c), non-pharmacological treatment (Table G.5d), treatment of TTH in pregnancy (Table G.5e) • Medication-overuse headache: general statements, definitions, and assessment (Table G.6a), pharmacological prophylaxis (Table G.6b), treatment (Table G.6c) • Cluster headache: trigeminal autonomic cephalalgias—diagnosis (Table G.7a), cluster headache—acute treatment (Table G.7b), cluster headache—pharmacological prophylaxis (Table G.7c), paroxysmal hemicrania, hemicrania continua, and SUNCT—acute treatment (Table G.7d) 2. The Rating of Recommendation column (only in tables for tension-type, cluster, and medication-overuse headache) denotes the strength of the recommendation as stated by the seed guideline (see Table G.8 for explanation of ratings). 3. In cases where recommendations are discordant, the leftmost column (headed Item) has been shaded grey and a brief description of the disagreement is written in italics under the relevant item name. 4. The bolded integers in the columns under the Supporting Evidence (rightmost) section of the table represent the total number of discrete studies of that type cited by the guideline to support its recommendation. Thus, when there are multiple publications for a single study, the integers are less than the number of references listed below them. * See Appendix E for seed guidelines references.

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August, 2013 Inventory of Guideline Recommendations for Diagnosis and Investigation Table G.1a: Diagnosis - symptoms and signs of primary headaches Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Migraine G1 (USA) (Summary guideline for clinicians) Not provided The International Headache Society (IHS) criteria are the basis for migraine diagnosis. G3 (France) (Summary [English] p. 1307; Main guideline [French] p. 16-29) Professional consensus It is recommended to use the IHS diagnostic criteria (for migraine without aura and for typical aura with migraine headache) in routine clinical practice (see Table G.9 for IHS adapted diagnostic criteria). The diagnosis of migraine is based on a clinical triad: Professional consensus • recurrent attacks separated by totally pain-free intervals; • characteristic migraine symptoms; • unremarkable clinical examination. Critical analysis of the diagnostic criteria for migraine demonstrates an acceptable 2 1 level of interobserver variability and good specificity, but unsatisfactory sensitivity. 1,2 3 Therefore, the criteria are restrictive and cannot provide the diagnosis in all patients with migraine. To avoid this problem in routine practice, and thus avoid depriving certain patients of appropriate management, it is recommended to use ICHD-II Code 1.6.1 (probable migraine without aura, fulfilling all diagnostic criteria except one) (see Table G.9 for ICHD-II Code 1.6.1). G4 (UK) (p. 6-7) 2 1 3 3 7 Patients who present with a pattern of recurrent episodes of severe disabling 4,5 6 7-9 10-12 13-19 headache associated with nausea and sensitivity to light, and who have a normal neurological examination, should be considered to have migraine (see Table G.9 for ICHD-II diagnostic criteria). Tension-type G4 (UK) (p.7) 1 2 1 headache A diagnosis of tension-type headache should be considered in a patient presenting 20 7,8 13 with bilateral headache that is non-disabling where there is a normal neurological examination. Differential G3 (France) (Summary [English] p. 1307; Main guideline [French] p.21) 2 diagnosis migraine Migraine must be distinguished from tension headache, a more diffuse headache that 13,21 – tension-type is non-pulsating, non-aggravated by exercise, and less intense (mild or moderate headache pain) than migraine, with no accompanying gastrointestinal symptoms but sometimes with phonosensitivity and/or photosensitivity. Migraine and tension headache are often associated or intertwined in the same patient.

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Table G.1a: Diagnosis - primary headaches (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Trigeminal G4 (UK) (Main guideline p. 7-8; BMJ Summary p. 1231) 2 1 1 autonomic When a patient presents with frequent, brief, unilateral headaches with autonomic 4,22 23 13 cephalalgias features a trigeminal autonomic cephalalgia should be considered. (cluster headache, These headaches are rare but excruciatingly severe and have specific treatments. other) Patients with a new suspected trigeminal autonomic cephalalgia should be referred for specialist assessment. Hemicrania G4 (UK) (p. 9) 1 1 continua When a patient presents with chronic daily headache which is strictly unilateral, 22 13 hemicrania continua should be considered. Patients with new suspected hemicrania continua should be referred for specialist assessment. New daily G4 (UK) (p. 9) Based on clinical experience of guideline development group persistent In patients with new daily persistent headache, referral for specialist assessment (Background studies cited: NR24, Other 13) headache should be considered.

CS – case series study; G – guideline; ICHD - International Classification of Headache Disorders; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.1b: Diagnosis - symptoms and signs of secondary headaches

Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Clinical and G4 (UK) (p. 10) 1 1 3 neurological Patients presenting with headache for the first time or with headache that differs 4 25 11,12,26 examination from their usual headache should have a clinical examination, a neurological examination including fundoscopy, and blood pressure measurement. Neurological examination in patients first presenting with headache should include: Based on clinical experience of the guideline development group • fundoscopy; • cranial nerve assessment, especially pupils, visual fields, eye movements, facial power and sensation and bulbar function (soft palate, tongue movement); • assessment of tone, power, reflexes and coordination in all four limbs; • plantar responses; • assessment of gait, including heel-toe walking. There should be more detailed assessment if prompted by the history. The examination should be tailored to include any focal neurological symptoms. Neck examination for cervicogenic headache (p. 11) 1 1 2 Neck examination should be carried out in all patients presenting with headache 27 12 13,28 including assessment of: • neck posture; • range of movement; • muscle tone; • muscle tenderness.

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Table G.1b: Diagnosis - secondary headaches (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Red flags and G4 (UK) (Main guideline p. 9-10; BMJ summary p. 1231-1232) referral Patients who present with headache and red flag features of potential secondary headache should be referred to an appropriate specialist for further assessment. Red flag features: • New onset or change in headache in patients who are aged over 50 years 3 1 25,29,30 11 • Thunderclap: rapid time to peak headache intensity (seconds to 5 minutes) 5 1 25,29,31-33 26 • Focal neurological symptoms (e.g. limb weakness, aura <5 minutes or >1 hour) 2 4 5,34 9,30,31,35

• 1 1 Non-focal neurological symptoms (e.g. cognitive disturbance) 34 26

• Change in headache frequency, characteristics, or associated symptoms 1 1 2 5 30 11,26 • Abnormal neurological examination 2 2 25,35 11,26 • Headache that changes with posture 1 1 36 37 • Headache that awakens the patient (N.B. migraine is the most frequent cause of 1 1 36 11 morning headache)

• Headache precipitated by physical exertion or valsalva manoeuvre (e.g. 1 1 coughing, laughing, straining, sneezing, bending, heavy lifting) 36 11

• Patients with risk factors for cerebral venous sinus thrombosis 1 2 34 38,39

• Jaw claudication or visual disturbance 2 4,40 • Neck stiffness 2 29,41 • Fever 1 41

• New onset headache in a patient with a history of human immunodeficiency 1 virus (HIV) infection 26 (continued over page) • New onset headache in a patient with a history of cancer 1 12

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Table G.1b: Diagnosis - secondary headaches (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Red flags and G4 (UK) referral Thunderclap headache (Main guideline p. 10, BMJ summary p. 1232) 1 3 1 1 (cont’d) Patients with a first presentation of thunderclap headache should be referred 42 25,29,33 26 13 immediately to hospital for same day specialist assessment for exclusion of subarachnoid haemorrhage, meningitis, or cerebral venous sinus thrombosis by computerized tomography (CT) brain scan, and lumbar puncture if CT brain scan is normal.

Raised intracranial pressure (Main guideline p. 11-12; BMJ summary p. 1232) 1 1 4

Patients with headache and features suggestive of raised intracranial pressure, such as 36 43 11,12,26,44 worse lying flat, valsalva headache, focal or non-focal symptoms or signs, or papillo- oedema, should be referred urgently for specialist assessment.

Patients with headache and features suggestive of central nervous system infection, 2 1 such as fever and rash, should be referred immediately to hospital for same day 29,41 26 specialist assessment. Intracranial hypotension (spontaneous or iatrogenic) (p. 12) 1 Intracranial hypotension should be considered in all patients with headache 37 developing or worsening after assuming an upright posture. Based on clinical experience of the guideline development group (Main guideline p. 17; BMJ summary p. 1232) (Background studies cited: CS45-48) All patients with suspected low pressure headache should be referred to a specialist (neurologist or headache clinic) for consideration of the most appropriate investigation. Giant cell (temporal) arteritis (GCA) (Main guideline p. 12; BMJ summary p.1232) 1 GCA should be considered in any patient over the age of 50 years presenting with a 40 new headache or change in headache. Check erythrocyte sedimentation rate and C- reactive protein levels. Patients with symptoms suggestive of GCA should be referred urgently for specialist Based on clinical experience of the guideline development group assessment. Angle closure glaucoma (p. 12) 1 1 Angle closure glaucoma should be considered in a patient with headache associated 49 30 with a red eye, halos, or unilateral visual symptoms. (continued over page) Acute angle closure glaucoma is an ophthalmological emergency. Based on clinical experience of the guideline development group

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Table G.1b: Diagnosis - secondary headaches (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Red flags and G4 (UK) referral Medication overuse headache (p. 10 & 35) 3 (cont’d) Medication overuse headache must be excluded in all patients with chronic daily 13,16,50 headache (headache ≥15 days per month for >3 months). Clinicians should be aware that patients using any acute or symptomatic headache 1 5 3 treatment are at risk of medication overuse headache. Patients with migraine, 51 23,52-55 50,56,57 frequent headache and those using opioid-containing medications or overusing triptans are at most risk. When diagnosing medication overuse headache, psychiatric comorbidity and 1 dependence behaviour should be considered. 58 Patients with medication overuse headache who have psychiatric comorbidity or dependence behaviour should have these conditions treated independently. Referral to a psychiatrist or a clinical psychologist should be considered. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.1c: Diagnosis - assessment tools

Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other History taking G3 (France) (Summary [English] p. 1308, Main guideline [French] p. 38) 1 3 1 59 60-62 63 Anxiety and/or depressive disorders concurrent with migraine further aggravate disability. Careful history taking is recommended to look for signs of depression or anxiety, and to focus therapy not only on the pain, but also on any associated depression and anxiety. Headache diaries G3 (France) (Summary [English] p. 1308; Main guideline [French] p. 38) Professional consensus 64-66 and questionnaires To achieve optimal management of migraine, it is recommended to advise (Background studies cited: Other ) patients to keep a diary. Patients should note the date, duration, intensity, and triggering factors of the attack, as well as any medications used to treat it. This diary can be used by the physician to better determine the severity of the migraine, to take into account the impact of the disease on activities of daily living, and to assist in the choice of treatment and type of follow-up measures required. (Summary [English] p. 1308, Main guideline [French] p. 38-42) 1 4 67 68-71 Several scales have been developed to measure the quality of life and productivity of migraineurs (SF-36, Short-Form Headache Impact Test [HIT/HIT-6] and Migraine Disability Assessment Scale [MIDAS] are referenced; translated in French). Among the migraine population, it would be important to identify those patients who require regular medical care. Further research should be performed in this area. G4 (UK) (p. 13-14) 1 2 3 1 13 72 73,74 7,8,75 12 17,76-87 Practitioners should consider using headache diaries and appropriate assessment questionnaires (e.g. HIT/HIT-6, MIDAS, ID Migraine) to support the diagnosis and management of headache. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SF-36 -Short Form (36) Health Survey; SR/MA – systematic review/meta-analysis

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Table G.1d: Diagnosis - clinical investigations Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Neuroimaging G1 (USA) (Summary guideline for clinicians) Not provided There is insufficient evidence to recommend any diagnostic testing other than neuroimaging. (Main guideline p. 15) 3 7 1 Neuroimaging is not usually warranted for patients with migraine and normal 88-90 91-97 98 neurological examination. (Main guideline p. 16) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs Data were insufficient to make an evidence-based recommendation regarding the (Background studies cited: NRCS89, CS97 use of neuroimaging for tension-type headache. (Main guideline p. 14) 5 Neuroimaging should be considered in patients with non-acute headache and an 92,99-102 unexplained abnormal finding on the neurological examination. (Main guideline p. 15-16) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs For patients with atypical headache features or patients who do not fulfill the strict definition of migraine (or have some additional risk factor), a lower threshold for neuroimaging may be applied. (Main guideline p. 14-15) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs Evidence is insufficient to make specific recommendations regarding neuroimaging (Background studies cited: CS100,102) in the presence or absence of neurological symptoms. G4 (UK) (p. 15-17) 3 1 Neuroimaging is not indicated in patients with a clear history of migraine, without 103-105 11 red flag features for potentially secondary headache, and a normal neurological examination. (p. 17) Based on clinical experience of the guideline development group Further investigation should be considered in patients with headaches which are (Background studies cited: NR106, CS29,33, Other 13) precipitated, rather than aggravated, by exercise.

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Table G.1d: Diagnosis - clinical investigations (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Computed G3 (France) (Summary [English] p. 1308, Main guideline [French] p. 29-32) Professional consensus tomography (CT) There is no indication for cerebral CT or MRI in patients with migraine defined by (Background studies cited: NRCS89,107, CS108,109) and magnetic International Headache Society (IHS) diagnostic criteria for migraine with or without resonance imaging aura or to differentiate migraine from tension headache. (MRI) In patients with known migraine, cerebral CT scanning or MRI is recommended in cases of sudden-onset headache (so-called “thunderclap” headache) and recent (past 3 months) headache different from the usual migraine. In cases of acute, severe, intense headache that develops in <1 minute and lasts >1 hour, emergency non-contrast cerebral CT scanning or MRI is recommended.

G4 (UK) (p. 15-17) 1 2 Clinicians requesting neuroimaging should be aware that both MRI and CT can 110 111,112 identify incidental neurological abnormalities which may result in patient anxiety as well as practical and ethical dilemmas with regard to management.

Effectiveness of CT versus MRI Consensus achieved by the US Headache Consortium in the absence of relevant RCTs G1 (USA) (p. 16) (Background studies cited: NRCS89, CS95,113) Data were insufficient to make any evidence-based recommendations regarding the relative sensitivity of MRI compared with CT in the evaluation of migraine or other non-acute headache. CT G4 (UK) (p. 15-17) 2 Brain CT should be performed in patients with headache who have unexplained 11,114 abnormal neurological signs, unless the clinical history suggests MRI is indicated. Thunderclap headache (p. 16) 2 1 1 1 In patients with thunderclap headache, unenhanced CT of the brain should be 42,106 29 26 13 performed as soon as possible and preferably within 12 hours of onset.

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Table G.1d: Diagnosis - clinical investigations (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other MRI G4 (UK) (p. 16) 1 2 Brain MRI should be considered in patients with cluster headache, paroxysmal 22 23,115 hemicranias, or Short-lasting, Unilateral, Neuralgiform headache attacks with Conjunctival injection and Tearing (SUNCT). Brain MRI should be carried out in patients presenting with headache that is 1 1 1 precipitated, rather than aggravated, by cough. 106 116 13 Electroenceph- G1 (USA) (Summary for clinicians) Not provided alography (EEG) EEG is not indicated in the routine evaluation of headache. G3 (France) (Summary [English] p. 1308) Professional consensus EEG is not indicated in patients with migraine as defined by the IHS diagnostic (Background study cited: NR117) criteria. EEG is not recommended to rule out secondary headaches; CT scanning and MRI are indicated for this. Sinus and cervical G3 (France) (Summary [English] p. 1308, Main guideline [French] p.32) Professional consensus spine radiography, There is no indication for radiography of the sinuses or the cervical spine, ophthalmic and ophthalmic examination, orthoptic examination, or abdominal sonography for the orthoptic diagnosis of migraine. examination, abdominal sonography Lumbar puncture G4 (UK) (p. 17-18) 1 1 2 1 Patients with thunderclap headache and a normal CT should have a lumbar 118 42,119 29,120 121 puncture. In patients who require a lumbar puncture for thunderclap headache, oxyhemoglobin and bilirubin should be included in cerebrospinal fluid analysis. Opening pressure should be measured when lumbar puncture is indicated in patients Based on clinical experience of the guideline development group with headache. Subarachnoid haemorrhage (p. 17-18) Based on clinical experience of the guideline development group In patients with suspected subarachnoid haemorrhage, neuroimaging should be performed prior to lumbar puncture. Lumbar puncture in CT negative patients with suspected subarachnoid haemorrhage should be carried out as soon as possible after 12 hours has elapsed from the onset of symptoms. In delayed presentations, lumbar puncture can be performed up to two weeks from onset of symptoms.

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Table G.1d: Diagnosis - clinical investigations (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Erythrocyte G4 (UK) (p. 18) 1 1 sedimentation rate ESR and CRP (but preferably a combination of these diagnostic tests to maximise 40 122 (ESR), C-reactive sensitivity and specificity) should be measured in patients with suspected giant cell protein (CRP) and arteritis. plasma viscosity Other G4 (UK) (p. 18) Not provided investigations No evidence was identified on the benefits of routine full blood count assessment or the use of X-ray of the cervical spine in the diagnosis of patients with headache. [N.B. This is not a recommendation in the guideline.] CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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15. Lipton RB, Stewart WF, Celentano DD, Reed ML. Undiagnosed migraine headaches. A comparison of symptom-based and reported physician diagnosis. Archives of Internal Medicine 1992;152(6):1273-8. [Study type: survey] 16. Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 2006;26(6):742-6. [Study type: operational diagnostic criteria] 17. Lipton RB, Dodick D, Sadovsky R, Kolodner K, Endicott J, Hettiarachchi J, et al. A self- administered screener for migraine in primary care: The ID Migraine validation study. Neurology 2003;61(3):375-82. [Study type: methodological paper] 18. Maizels M, Burchette R. Rapid and sensitive paradigm for screening patients with headache in primary care settings. Headache 2003;43(5):441-50. [Study type: evaluation diagnostic test] 19. Mulleners WM, Aurora SK, Chronicle EP, Stewart R, Gopal S, Koehler PJ. Self-reported photophobic symptoms in migraineurs and controls are reliable and predict diagnostic category accurately. Headache 2001;41(1):31-9. [Study type: survey] 20. Stovner L, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, et al. The global burden of headache: a documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27(3):193-210. 21. Rasmussen BK, Jensen R, Schroll M, Olesen J. Interrelations between migraine and tension- type headache in the general population. Archives of Neurology 1992;49(9):914-8. [Study type: survey] 22. Matharu MS, Boes CJ, Goadsby PJ. Management of trigeminal autonomic cephalalgias and hemicrania continua. Drugs 2003;63(16):1637-77. 23. Cohen AS, Matharu MS, Goadsby PJ. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA)—a prospective clinical study of SUNCT and SUNA. Brain 2006;129(Pt 10):2746-60. 24. Goadsby PJ, Boes C. New daily persistent headache. Journal of Neurology, Neurosurgery, and Psychiatry 2002;72 Suppl 2:ii6-ii9. 25. Locker TE, Thompson C, Rylance J, Mason SM. The utility of clinical features in patients presenting with nontraumatic headache: an investigation of adult patients attending an emergency department. Headache 2006;46(6):954-61. 26. American College of Emergency Physicians (ACEP). Critical issues in the evaluation and management of patients presenting to the emergency department with acute headache. Annals of Emergency Medicine 2002;39(1):108-22. 27. Zito G, Jull G, Story I. Clinical tests of musculoskeletal dysfunction in the diagnosis of cervicogenic headache. Manual Therapy 2006;11(2):118-29. 28. Sjaastad O, Fredriksen TA, Pfaffenrath V. Cervicogenic headache: diagnostic criteria. The Cervicogenic Headache International Study Group. Headache 1998;38(6):442-5. [Unable to identify study type from the abstract.] 29. Landtblom AM, Fridriksson S, Boivie J, Hillman J, Johansson G, Johansson I. Sudden onset headache: a prospective study of features, incidence and causes. Cephalalgia 2002;22(5):354-60.

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30. Maggioni F, Dainese F, Mainardi F, Lisotto C, Zanchin G. Intermittent angle-closure glaucoma in the presence of a white eye, posing as retinal migraine. Cephalalgia 2005;25(8):622- 6. 31. Aygun D, Bildik F. Clinical warning criteria in evaluation by computed tomography the secondary neurological headaches in adults. European Journal of Neurology 2003;10(4):437-42. 32. Shibata T, Kubo M, Kuwayama N, Hirashima Y, Endo S. Warning headache of subarachnoid hemorrhage and infarction due to vertebrobasilar artery dissection. Clinical Journal of Pain 2006;22(2):193-6. 33. Linn FH, Rinkel GJ, Algra A, Van Gijn, J. Headache characteristics in subarachnoid haemorrhage and benign thunderclap headache. Journal of Neurology, Neurosurgery, and Psychiatry 1998;65(5):791-3. 34. Agostoni E. Headache in cerebral venous thrombosis. Neurological Sciences 2004;25 Suppl 3:S206-S210. 35. Joseph R, Cook GE, Steiner TJ, Clifford RF. Intracranial space-occupying lesions in patients attending a migraine clinic. Practitioner 1985;229(1403):477-81. 36. Skau M, Brennum J, Gjerris F, Jensen R. What is new about idiopathic intracranial hypertension? An updated review of mechanism and treatment. Cephalalgia 2006;26(4):384-99. 37. Schievink WI. Misdiagnosis of spontaneous intracranial hypotension. Archives of Neurology 2003;60(12):1713-8. 38. Cumurciuc R, Crassard I, Sarov M, Valade D, Bousser MG. Headache as the only neurological sign of cerebral venous thrombosis: a series of 17 cases. Journal of Neurology, Neurosurgery, and Psychiatry 2005;76(8):1084-7. 39. Iurlaro S, Beghi E, Massetto N, Guccione A, Autunno M, Colombo B, et al. Does headache represent a clinical marker in early diagnosis of cerebral venous thrombosis? A prospective multicentric study. Neurological Sciences 2004;25 Suppl 3:S298-9. 40. Smetana GW, Shmerling RH. Does this patient have temporal arteritis? JAMA 2002;287(1):92-101. 41. Van de Beek, D, de Gans, J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. New England Journal of Medicine 2004;351(18):1849-59. 42. Al-Shahi R, White PM, Davenport RJ, Lindsay KW. Subarachnoid haemorrhage. BMJ 2006;333(7561):235-40. 43. Hamilton W, Kernick D. Clinical features of primary brain tumours: a case-control study using electronic primary care records. The British Journal of General Practice 2007;57(542):695-9. 44. Grant R. Overview: Brain tumour diagnosis and management/Royal College of Physicians guidelines. Journal of Neurology, Neurosurgery, and Psychiatry 2004;75 Suppl 2:ii18-ii23. [Unable to identify study type from the abstract.] 45. Yousry I, Forderreuther S, Moriggl B, Holtmannspotter M, Naidich TP, Straube A, et al. Cervical MR imaging in postural headache: MR signs and pathophysiological implications. AJNR. American Journal of Neuroradiology 2001;22(7):1239-50.

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46. Moayeri NN, Henson JW, Schaefer PW, Zervas NT. Spinal dural enhancement on magnetic resonance imaging associated with spontaneous intracranial hypotension. Report of three cases and review of the literature. Journal of Neurosurgery 1998;88(5):912-8. 47. Pannullo SC, Reich JB, Krol G, Deck MD, Posner JB. MRI changes in intracranial hypotension. Neurology 1993;43(5):919-26. 48. Rabin BM, Roychowdhury S, Meyer JR, Cohen BA, LaPat KD, Russell EJ. Spontaneous intracranial hypotension: spinal MR findings. AJNR. American Journal of Neuroradiology 1998;19(6):1034-9. 49. Coleman AL. Glaucoma. Lancet 1999;354(9192):1803-10. 50. Silberstein SD, Olesen J, Bousser MG, Diener HC, Dodick D, First M, et al. The International Classification of Headache Disorders, 2nd Edition (ICHD-II)—revision of criteria for 8.2 Medication-overuse headache. Cephalalgia 2005;25(6):460-5. [Study type: operational diagnostic criteria] 51. Paemeleire K, Crevits L, Goadsby PJ, Kaube H. Practical management of medication-overuse headache. Acta Neurologica Belgica 2006;106(2):43-51. 52. Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC. Features of medication overuse headache following overuse of different acute headache drugs. Neurology 2002;59(7):1011-4. 53. Paemeleire K, Bahra A, Evers S, Matharu MS, Goadsby PJ. Medication-overuse headache in patients with cluster headache. Neurology 2006;67(1):109-13. 54. Katsarava Z, Schneeweiss S, Kurth T, Kroener U, Fritsche G, Eikermann A, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004;62(5):788-90. 55. Zwart JA, Dyb G, Hagen K, Svebak S, Holmen J. Analgesic use: a predictor of chronic pain and medication overuse headache: the Head-HUNT Study. Neurology 2003;61(2):160-4. 56. Bahra A, Walsh M, Menon S, Goadsby PJ. Does chronic daily headache arise de novo in association with regular use of analgesics? Headache 2003;43(3):179-90. [Study type: survey] 57. Williams D, Cahill T, Dowson A, Fearon H, Lipscombe S, O'Sullivan E, et al. Usage of triptans among migraine patients: an audit in nine GP practices. Current Medical Research and Opinion 2002;18(1):1-9. [Study type: survey, audit] 58. Atasoy HT, Atasoy N, Unal AE, Emre U, Sumer M. Psychiatric comorbidity in medication overuse headache patients with pre-existing headache type of episodic tension-type headache. European Journal of Pain 2005;9(3):285-91. 59. Breslau N, Rasmussen BK. The impact of migraine. Epidemiology, risk factors, and comorbidities. Neurology 2001;56(6 Suppl 1):S4-S12. 60. Merikangas KR, Angst J, Isler H. Migraine and psychopathology. Results of the Zurich cohort study of young adults. Archives of General Psychiatry 1990;47(9):849-53. 61. Swartz KL, Pratt LA, Armenian HK, Lee LC, Eaton WW. Mental disorders and the incidence of migraine headaches in a community sample. Results from the Baltimore Epidemiologic Catchment Area follow-up study. Archives of General Psychiatry 2000;57(10):945-50.

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62. Breslau N, Davis GC. Migraine, physical health and psychiatric disorder: a prospective epidemiologic study in young adults. Journal of Psychiatric Research 1993;27(2):211-21. 63. Breslau N, Schultz LR, Stewart WF, Lipton RB, Lucia VC, Welch KMA. Headache and major depression. Is the association specific to migraine? Neurology 2000;54(2):308-13. 64. Lanteri-Minet M, Lucas C, Leroy L. Framing 99. Lettre Neurol 2000;4(Suppl 5):5-19. [Study type: letter] 65. Henry P, Auray JP, Gaudin AF, Dartigues JF, Duru G, Lantéri-Minet M, et al. Prevalence and clinical characteristics of migraine in France. Neurology 2002;59(2):232-7. 66. Henry P, Michel P, Brochet B, Dartigues JF, Tison S, Salamon R. A nationwide survey of migraine in France: prevalence and clinical features in adults. Cephalalgia 1992;12(4):229-37. [Study type: survey] 67. Michel P, Dartigues JF, Lindoulsi A, Henry P. Loss of productivity and quality of life in migraine sufferers among French workers: results from the GAZEL cohort. Headache 1997;37(2):71-8. 68. Leplège A, Ecosse E, Verdier A, Perneger TV. The French SF-36 health survey: translation, cultural adaptation and preliminary psychometric evaluation. Journal of Clinical Epidemiology 1998;51(11):1013-23. [Study type: survey, methodological paper] 69. Richard A, Henry P, Chazot G, Massiou H, Tison S, Marconnet R, et al. Qualité de vie et migraine. Validation du questionnaire QVM en consultation hospitalière et en médecine générale. Thérapie 1993;48(2):89-96. [Unable to identify study type from the abstract.] 70. Lantéri-Minet M, Auray JP, El Hasnaoui A, Dartigues JF, Duru G, Henry P, et al. Prevalence and description of chronic daily headache in the general population in France. Pain 2003;102(1-2):143-9. [Study type: survey] 71. Gandek B, Alacoque J, Uzun V, Andrew-Hobbs M, Davis K. Translating the Short-Form Headache Impact Test (HIT-6) in 27 countries: methodological and conceptual issues. Quality of Life Research 2003;12(8):975-9. [Study type: survey, methodological paper] 72. Dowson AJ. Assessing the impact of migraine. Current Medical Research and Opinion 2001;17(4):298-309. 73. Stewart W, Lipton R. Need for care and perceptions of MIDAS among headache sufferers study. CNS Drugs 2002;16 Suppl 1:5-11. 74. Bigal ME, Rapoport AM, Lipton RB, Tepper SJ, Sheftell FD. Assessment of migraine disability using the migraine disability assessment (MIDAS) questionnaire: a comparison of chronic migraine with episodic migraine. Headache 2003;43(4):336-42. 75. Coeytaux RR, Kaufman JS, Chao R, Mann JD, Devellis RF. Four methods of estimating the minimal important difference score were compared to establish a clinically significant change in Headache Impact Test. Journal of Clinical Epidemiology 2006;59(4):374-80. 76. Holmes WF, MacGregor EA, Sawyer JP, Lipton RB. Information about migraine disability influences physicians' perceptions of illness severity and treatment needs. Headache 2001;41(4):343-50. [Study type: survey]

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77. Kosinski M, Bayliss MS, Bjorner JB, Ware JE Jr, Garber WH, Batenhorst A, et al. A six-item short-form survey for measuring headache impact: the HIT-6. Quality of Life Research 2003;12(8):963-74. [Study type: survey, methodological paper] 78. Bayliss MS, Dewey JE, Dunlap I, Batenhorst AS, Cady R, Diamond ML, et al. A study of the feasibility of Internet administration of a computerized health survey: the headache impact test (HIT). Quality of Life Research 2003;12(8):953-61. [Study type: survey, methodological paper] 79. De Diego EV, Lanteri-Minet M. Recognition and management of migraine in primary care: influence of functional impact measured by the headache impact test (HIT). Cephalalgia 2005;25(3):184-90. [Study type: survey] 80. Bjorner JB, Kosinski M, Ware JE Jr. Calibration of an item pool for assessing the burden of headaches: an application of item response theory to the headache impact test (HIT). Quality of Life Research 2003;12(8):913-33. [Study type: survey, methodological paper] 81. Ware JE Jr, Kosinski M, Bjorner JB, Bayliss MS, Batenhorst A, Dahlof CG, et al. Applications of computerized adaptive testing (CAT) to the assessment of headache impact. Quality of Life Research 2003;12(8):935-52. [Study type: survey] 82. Lipton RB, Stewart WF, Sawyer J, Edmeads JG. Clinical utility of an instrument assessing migraine disability: the Migraine Disability Assessment (MIDAS) questionnaire. Headache 2001;41(9):854-61. [Study type: survey, research support] 83. Stewart WF, Lipton RB, Kolodner K, Liberman J, Sawyer J. Reliability of the migraine disability assessment score in a population-based sample of headache sufferers. Cephalalgia 1999;19(2):107-14. [Study type: survey tests' performance] 84. Stewart WF, Lipton RB, Whyte J, Dowson A, Kolodner K, Liberman JN, et al. An international study to assess reliability of the Migraine Disability Assessment (MIDAS) score. Neurology 1999;53(5):988-94. [Study type: survey tests' performance] 85. Stewart WF, Lipton RB, Kolodner K. Migraine disability assessment (MIDAS) score: relation to headache frequency, pain intensity, and headache symptoms. Headache 2003;43(3):258-65. [Study type: survey tests' performance] 86. Kilminster SG, Dowson A, Bundy M. The Headache Impact Test 1 and the Short Pain Inventory: Outcome measures compared. International Journal of Pharmaceutical Medicine 2003;17(1):23-32. [Study type: survey tests' performance] 87. Lipton RB, Goadsby PJ, Sawyer JPC, Blakeborough P, Stewart WF. Migraine: diagnosis and assessment of disability. Reviews in Contemporary Pharmacotherapy 2000;11(2):63-73. [Unable to identify study type from the abstract.] 88. Igarashi H, Sakai F, Kan S, Okada J, Tazaki Y. Magnetic resonance imaging of the brain in patients with migraine. Cephalalgia 1991;11(2):69-74. 89. De Benedittis G, Lorenzetti A, Sina C, Bernasconi,V. Magnetic resonance imaging in migraine and tension-type headache. Headache 1995;35(5):264-8. 90. Robbins L, Friedman H. MRI in migraineurs. Headache 1992;32(10):507-8. 91. Sargent JD, Solbach P. Medical evaluation of migraineurs: review of the value of laboratory and radiologic tests. Headache 1983;23(2):62-5.

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92. Cala LA, Mastaglia FL. Computerized axial tomography findings in a group of patients with migrainous headaches. Proceedings of the Australian Association of Neurologists 1976;13:35-41. 93. Cull RE. Investigation of late-onset migraine. Scottish Medical Journal 1995;40(2):50-2. 94. Hungerford GD, du Boulay GH, Zilkha KJ. Computerised axial tomography in patients with severe migraine: a preliminary report. Journal of Neurology, Neurosurgery, and Psychiatry 1976;39(10):990-4. 95. Kuhn MJ, Shekar PC. A comparative study of magnetic resonance imaging and computed tomography in the evaluation of migraine. Computerized Medical Imaging and Graphics 1990;14(2):149-52. 96. Osborn RE, Alder DC, Mitchell CS. MR imaging of the brain in patients with migraine headaches. AJNR. American Journal of Neuroradiology 1991;12(3):521-4. 97. Sargent JD, Lawson RC, Solbach P, Coyne L. Use of CT scans in an out-patient headache population: an evaluation. Headache 1979;19(7):388-90. 98. Cuetter AC, Aita JF. CT scanning in classic migraine. Headache 1983;23(4):195. [Study type: letter] 99. Carrera GF, Gerson DE, Schnur J, McNeil BJ. Computed tomography of the brain in patients with headache or temporal lobe epilepsy: findings and cost-effectiveness. Journal of Computer Assisted Tomography 1977;1(2):200-3. 100. Duarte J, Sempere AP, Delgado JA, Naranjo G, Sevillano MD, Claveria LE. Headache of recent onset in adults: a prospective population-based study. Acta Neurologica Scandinavica 1996;94(1):67-70. 101. Larson EB, Omenn GS, Lewis H. Diagnostic evaluation of headache. Impact of computerized tomography and cost-effectiveness. JAMA 1980;243(4):359-62. 102. Mitchell CS, Osborn RE, Grosskreutz SR. Computed tomography in the headache patient: is routine evaluation really necessary? Headache 1993;33(2):82-6. 103. Sempere AP, Porta-Etessam J, Medrano V, Garcia-Morales I, Concepcion L, Ramos A, et al. Neuroimaging in the evaluation of patients with non-acute headache. Cephalalgia 2005;25(1):30- 5. 104. Wang HZ, Simonson TM, Greco WR, Yuh WT. Brain MR imaging in the evaluation of chronic headache in patients without other neurologic symptoms. Academic Radiology 2001;8(5):405-8. 105. Tsushima Y, Endo K. MR imaging in the evaluation of chronic or recurrent headache. Radiology 2005;235(2):575-9. 106. Cutrer FM, Boes CJ. Cough, exertional, and sex headaches. Neurologic Clinics 2004;22(1):133-49. 107. Kruit MC, Van Buchem MA, Hofman PA, Bakkers JT, Ferrari MD, Launer LJ. Posterior circulation lesions in migraine. A population-based, case-control MR imaging study, the camera-project. Neurology 2002;58(Suppl 3:A127).

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108. Linn FHH, Wijdicks EFM, Van der Graaf Y, Weerdesteyn-Van Vliet FAC, Bartelds AIM, Van Gijn J. Prospective study of sentinel headache in aneurysmal subarachnoid haemorrhage. Lancet 1994;344(8922):590-3. 109. Cooney BS, Grossman RI, Farber RE, Goin JE, Galetta SL. Frequency of magnetic resonance imaging abnormalities in patients with migraine. Headache 1996;36(10):616-21. 110. Howard L, Wessely S, Leese M, Page L, McCrone P, Husain K, et al. Are investigations anxiolytic or anxiogenic? A randomised controlled trial of neuroimaging to provide reassurance in chronic daily headache. Journal of Neurology, Neurosurgery, and Psychiatry 2005;76(11):1558-64. 111. Vernooij MW, Ikram MA, Tanghe HL, Vincent AJ, Hofman A, Krestin GP, et al. Incidental findings on brain MRI in the general population. New England Journal of Medicine 2007;357(18):1821-8. [Study type: survey] 112. Weber F, Knopf H. Incidental findings in magnetic resonance imaging of the brains of healthy young men. Journal of the Neurological Sciences 2006;240(1-2):81-4. [Study type: survey] 113. Demaerel P, Boelaert I, Wilms G, Baert AL. The role of cranial computed tomography in the diagnostic work-up of headache. Headache 1996;36(6):347-8. 114. Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, et al. EFNS guideline on the drug treatment of migraine—report of an EFNS task force. European Journal of Neurology 2006;13(6):560-72. 115. Favier I, Van Vliet JA, Roon KI, Witteveen RJ, Verschuuren JJ, Ferrari MD, et al. Trigeminal autonomic cephalgias due to structural lesions: a review of 31 cases. Archives of Neurology 2007;64(1):25-31. 116. Pascual J, Iglesias F, Oterino A, Vazquez-Barquero A, Berciano J. Cough, exertional, and sexual headaches: an analysis of 72 benign and symptomatic cases. Neurology 1996;46(6):1520-4. 117. Gronseth GS, Greenberg MK. The utility of the electroencephalogram in the evaluation of patients presenting with headache: a review of the literature. Neurology 1995;45(7):1263-7. 118. Detsky ME, McDonald DR, Baerlocher MO, Tomlinson GA, McCrory DC, Booth CM. Does this patient with headache have a migraine or need neuroimaging? JAMA 2006;296(10):1274- 83. 119. Davenport R. Sudden headache in the emergency department. Practical Neurology 2005;5(3):132- 43. 120. O'Neill J, McLaggan S, Gibson R. Acute headache and subarachnoid haemorrhage: a retrospective review of CT and lumbar puncture findings. Scottish Medical Journal 2005;50(4):151-3. 121. Webb S, Bone I, Lindsay K. The investigation of acute severe headache suggestive of probable subarachnoid haemorrhage: a hospital-based study. British Journal of Neurosurgery 2003;17(6):580- 4. [Study type: survey] 122. Hayreh SS, Podhajsky PA, Raman R, Zimmerman B. Giant cell arteritis: validity and reliability of various diagnostic criteria. American Journal of Ophthalmology 1997;123(3):285-96.

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Inventory of Guideline Recommendations for Acute Migraine - Pharmacological Interventions Table G.2a: Acute migraine - pharmacological interventions Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Acute treatment G1 (USA) (p. 46) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs (general No recommendations can be made regarding dosing regimens. Dose ranges are statements) presented for reference purposes only. No dosing information is provided for treatments lacking relevant RCTs. (p.31) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs Use migraine-specific agents (triptans, dihydroergotamine, ergotamine) in patients with more severe migraine and in those whose headaches respond poorly to non- steroidal anti-inflammatory drugs (NSAIDs) or combination analgesics, such as acetylsalicylic acid plus acetaminophen plus caffeine. (Summary guideline for clinicians) Not provided Acute care should be individualized on the basis of patient’s symptoms and level of disability. Goals for acute treatment: • Treat attacks effectively, rapidly, and consistently to minimize adverse events. • Restore the patient’s ability to function. • Minimize the need for backup and rescue medications (see Glossary in Table G.10). • Optimize self-care and reduce subsequent use of resources. Guide to acute treatment: • Act promptly. Failure to use an effective treatment promptly may increase pain, disability, and the impact of the headache. • Use triptans (naratriptan, rizatriptan, sumatriptan, and zolmitriptan) and dihydroergotamine in patients who have moderate or severe migraine, or whose mild-to-moderate headaches respond poorly to NSAIDs or

combinations, such as acetylsalicylic acid plus acetaminophen plus caffeine, or other agents, such as ergotamine. • NSAIDs (oral), combination analgesics containing caffeine, and isometheptene combinations are options for mild-to-moderate migraine attacks or severe attacks that have been responsive in the past to similar agents. • Select a non-oral route of administration for patients with migraine (continued over page) associated with severe nausea or vomiting. • Do not restrict antiemetics just to patients who are vomiting or likely to vomit.

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Acute treatment • Use a self-administered rescue medication for patients whose severe Not provided (general migraine does not respond to (or fails) other treatments. statements) • Limit and carefully monitor opiate- and butalbital-containing analgesics. (cont’d) • Guard against medication-overuse headache (“rebound headache”). Attempt to limit acute therapy to 2 days per week.

G2 (Europe) (p. 968) Based on clinical experience of guideline development group

The acute treatment of migraine attacks should follow the concept of stratified treatment.

G3 (France) (Summary [English] p. 1309) Professional consensus

During a patient’s initial consultation, it is recommended to ask the patient about his

or her usual migraine medication practices and the relief obtained with it, using the following questions: • Do you have significant relief ≤ 2 hours after taking the medication?

• Is the medication well tolerated?

• Do you take only 1 dose?

• Can you resume normal occupational, social, and family activities 2 hours after taking the medication?

If the patient says yes to all four questions, his or her treatment regimen should not be changed. If the patient says no to at least one of these questions, the physician should prescribe an NSAID and a triptan together. The patient should be instructed to start with the NSAID and use the triptan only if relief is not obtained 2 hours after receiving the NSAID. If the NSAID is ineffective or poorly tolerated, a triptan should be prescribed as the first-line drug. (Summary [English] p. 1309-1310) Professional consensus 1 If an ergot derivative or triptan is being used, the patient should wait until a (Background study cited: Other ) headache develops before treating an attack preceded by aura. For all patients with migraine, the total number of doses taken per month should be counted, using a diary, to identify excessive use of medication (≥10 days/month for

> 3 months). Excessive use occurs frequently in patients with migraine and can lead to the development of chronic daily headache related to medication overuse. This is true for all of (continued over page) the migraine medications.

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Acute treatment G4 (UK) (Main guideline p. 19; BMJ summary p. 1232) Based on clinical experience of guideline development group (general Practitioners should recognise that a patient’s standard therapy may not give a (Background studies cited: G2) statements) consistent response across all attacks. A strategy for managing resistant attacks (cont’d) should be planned with patients. Adopt a stepped approach tailored to the patient’s symptoms. When initiating acute treatment for migraine the risks of medication overuse Based on clinical experience of guideline development group headache should be discussed with the patient. Patients using any acute or symptomatic headache treatment are at risk of medication overuse headache; those with migraine and frequent headache and those using opioids or triptans are at most risk. NSAIDs, G1 (USA) (p. 10-12, p. 29) 1 combination Acetaminophen is not a specific treatment option for migraine. (Doses tested: 650 to 3 analgesics, and 4000 mg.) non-opiate analgesics NSAIDs (oral) and combination analgesics 11 10 1 4-14 3,15-19,20-23 24 Their favourable tolerability makes these agents a reasonable first-line treatment choice for mild-to-moderate migraine attacks or severe attacks that have been Some difference (G1 responsive in the past to similar NSAIDs or non-opiate analgesics. versus G2, G3, G4) with respect to the use (Doses tested: acetylsalicylic acid – 500 mg to 1000 mg; diclofenac K - 50 mg to 100 of acetaminophen mg; flurbiprofen – 100 mg to 300 mg; ibuprofen - 400 mg to 2400 mg; naproxen - 750 mg to 1250 mg; naproxen sodium – 750 mg to 1750 mg; piroxicam [sublingual] -

40 mg; pirprofen - 400 mg; tolfenamic acid - 200 mg to 400 mg; acetaminophen plus acetylsalicylic acid plus caffeine - 500 mg plus 500 mg plus 130 mg [2 tablets].) The following, while not a recommendation, was mentioned in G1 regarding potential harm. Common adverse events: gastric irritation, discomfort, nausea, and vomiting. NSAIDs should not be used in patients with ulcer or renal disease. For combination analgesics also include insomnia. Ketorolac (intramuscular) is an option that may be used in a physician-supervised Consensus achieved by the US Headache Consortium in the absence of relevant RCTs setting, although conclusions regarding clinical efficacy cannot be made at this time. (Background studies cited: RCT25-27; NRCS28) (Doses tested: 30 mg to 60 mg.)

The following, while not a recommendation, was mentioned in G1 regarding potential harm. Common adverse events: drowsiness and nausea. Should not be used in patients with renal or (continued over page) gastrointestinal diseases.

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other NSAIDs, G2 (Europe) (p. 968-969) 1 18 1 combination Analgesics are the first choice for mild or moderate migraine attacks. In order to 29 6,9,10,30-44 17 analgesics, and prevent drug overuse headache, the intake of simple analgesics should be restricted non-opiate to 15 days per month and the intake of combined analgesics to 10 days per month. analgesics The following analgesics have efficacy in acute migraine treatment. (cont’d) • Acetylsalicylic acid (1000 mg oral) – gastrointestinal side effects

• Acetylsalicylic acid (1000 mg intravenous) – risk of bleeding

• Ibuprofen (200 mg to 800 mg) – side effects as for acetylsalicylic acid

• Naproxen (500 mg to 1000 mg) – side effects as for acetylsalicylic acid

• Diclofenac (50 mg to100 mg), including diclofenac-K • Acetaminophen (1000 mg oral; 1000 mg suppository) – caution in liver and kidney failure • Acetylsalicylic acid (250 mg oral) + acetaminophen (200 mg to 250 mg) + caffeine (50 mg) – side effects as for acetylsalicylic acid and

acetaminophen

• Metamizol (1000 mg oral) – risk of agranulocytosis

• Metamizol (1000 mg intravenous) – risk of hypotension

• Phenazon (1000 mg oral) – side effects as for acetaminophen • Tolfenamic acid (200 mg oral) – side effects as for acetylsalicylic acid In very severe attacks, intravenous acetylsalicylic acid is recommended. G3 (France) (Summary [English] p. 1309 & 1310; Main guideline [French] p. 8 3 30-37) 6,8,14,33,35,4 17,18,31 Recommended nonspecific agents include NSAIDs: naproxen sodium, ibuprofen, 5-47 ketoprofen or diclofenac K; acetylsalicylic acid monotherapy or in combination

with metoclopramide; and acetaminophen monotherapy. (continued over page) (Dose tested: naproxen sodium - 750 mg to 825 mg; ibuprofen - 200 mg and 800 mg; ketoprofen - 75 mg and 150 mg; diclofenac - 50 mg and 100 mg; acetylsalicylic acid [effervescent] - 1000 mg; acetaminophen - 1000 mg.)

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other NSAIDs, G3 (France) (cont’d) Professional consensus combination Combining metoclopramide hydrochloride with acetylsalicylic acid reduces the risk (Background studies cited: RCT48,49) analgesics, and for gastrointestinal symptoms but does not potentiate the analgesic effect of non-opiate acetylsalicylic acid. analgesics (Dose tested: carbaspirin calcium plus metoclopramide HCl - aspirin 900 mg and (cont’d) metoclopramide 10 mg given at attack onset.) (Lysine acetylsalicylate plus metoclopramide: dose tested - 900 mg given at attack onset.) The following, while not a recommendation, was mentioned in G3 regarding potential harm. Metoclopramide: Adverse effects: neuropsychiatric disorders, tardive dyskinesia, extrapyramidal symptoms, endocrine disorders. Contraindications: pheochromocytoma, gastrointestinal bleeding, stenosis or perforation of the gastrointestinal tract, history of drug-induced tardive dyskinesia. Salicylate: Adverse effects: gastrointestinal disturbances, hemorrhagic syndrome, hypersensitivity reactions, Reye’s syndrome. Contraindications: active gastroduodenal ulcer, hypersensitivity to salicylates, risk for haemorrhage. No clinical evidence shows that combining caffeine with acetaminophen or Professional consensus acetylsalicylic acid potentiates the effect of these drugs. Adjunctive use of caffeine (Background studies cited: RCT10) cannot be recommended because it may induce drug abuse or dependence/addiction. (Dose tested: acetaminophen plus acetylsalicylic acid plus caffeine - 250 mg plus 250 mg plus 65 mg.) G4 (UK) (p. 19) 6 1 Acetylsalicylic acid (900 mg) or ibuprofen (400 mg) is recommended for acute 30,45,50-53 54 treatment in patients with all severities of migraine. Acetylsalicylic acid should be avoided in patients with asthma or peptic ulceration. Other NSAIDs (tolfenamic acid, diclofenac, naproxen, and flurbiprofen) can be Based on clinical experience of guideline development group used in the treatment of acute migraine attacks. (Background studies cited: Other55) Acetaminophen (1000 mg) is recommended as acute treatment for mild to moderate 1 1 migraine. 33 54

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Opiate analgesics G1 (USA) (p. 12-14, p 30-31) 2 1 1 Butorphanol nasal spray 56,57 58 59 Some difference (G1 Clinical experience and expert consensus concur that butorphanol represents a versus G2, G3, G4) treatment option for some patients with migraine. (Doses tested: 1 to 2 mg; dose with respect to the use approved: 1 mg.) of opiate analgesics The following, while not a recommendation, was mentioned in G1 regarding potential harm. Adverse events include dizziness, drowsiness, nausea and/or vomiting, vertigo, blurred vision, nervousness, and taste perversion. Specifically, butorphanol may be considered when other medications cannot be used Consensus achieved by the US Headache Consortium in the absence of relevant RCTs or as a rescue medication when significant sedation would not jeopardize the patient. Clinical concerns regarding the use of butorphanol lie in the fact that it is widely

used despite the established risk of overuse and dependence. In special patients for whom use might be indicated, special attention should be given to these clinical concerns. Oral opiate combinations may be considered for use in acute migraine when 3 7 sedation side effects will not put the patient at risk and/or the risk for abuse has 5,13,60 22,23,61-65 been addressed. (Doses tested: Acetaminophen plus codeine - 400 to 650 mg plus 16 to 25 mg; Migraleve® - 2 to 8 tablets.) Parenteral opiates may be considered for rescue therapy in a supervised setting for 5 2 acute migraine when sedation side effects will not put the patient at risk and when 26,66-69 58,70 the risk abuse has been addressed.

(Doses tested: butorphanol [intramuscular] – 1 mg to 3 mg, meperidine

[intramuscular] – 75 mg to 100 mg, meperidine [intravenous] - 0.4 mg/kg up to 3 doses; methadone - 10 mg.) The following, while not a recommendation, was mentioned in G1 regarding potential harm. (continued over page) Common adverse events: sedation, nausea and dizziness. Although opiates provide significant pain relief, physicians must evaluate the risk-benefit ratio. Dependency may be a concern in some patients. Limit use due to increased risk of headache rebound and dependency.

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Opiate analgesics G2 (Europe) (p.971) 3 1 (cont’d) Opioids and tranquilizers should not be used in the acute treatment of migraine. 71-73 74 G3 (France) (Summary [English] p. 1309) Professional consensus Opiate analgesics (e.g. codeine sulphate, propoxyphene hydrochloride, tramadol (Background study cited: Other75) hydrochloride, morphine sulphate) should not be used alone or in combination for migraine because of the risk of abuse or dependence/addiction. G4 (UK) (p. 24) 1 Opioid analgesics should not be routinely used for the treatment of patients with acute 76 migraine due to the potential for development of medication overuse headache. Ergot alkaloids G1 (USA) (p. 8-10, p. 27-28) 9 5 5 Ergotamine (oral or suppository) (and caffeine combination) 4,56,77-83 15,21-23,84 85-89 Some difference (G1, In the treatment of selected patients with moderate to severe migraine, ergot G2, G3 versus G4) derivates may be considered.

with respect to the use (Ergotamine: dose tested - 1 mg to 5 mg; dose approved - 2 mg.) of ergotamine (Ergotamine plus caffeine: doses tested - 2 mg to 6 mg ergotamine and 200 mg to 600 mg caffeine; doses approved - 2 mg ergotamine plus 200 mg caffeine.) (Ergostine plus caffeine: doses tested - 2 mg plus 200 mg.)

Dihydroergotamine (subcutaneous/intravenous/intramuscular) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs

Because of their inability to tolerate or take oral medication, patients with nausea and vomiting may be given dihydroergotamine (subcutaneous/intravenous/intramuscular). Initial treatment with dihydroergotamine (subcutaneous/intramuscular) is a reasonable choice when: • the headache is moderate to severe, or • an adequate trial of NSAIDs or other non-opiate analgesics (including (continued over page) combination analgesics such as acetaminophen plus acetylsalicylic acid plus caffeine) has failed to provide adequate relief in the past.

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Ergot alkaloids The following, while not a recommendation, was mentioned in G1 regarding Consensus achieved by the US Headache Consortium in the absence of relevant RCTs (cont’d) potential harm. The most common adverse events with dihydroergotamine include nausea, vomiting, dysphoria, flushing, restlessness, and anxiety. Should not be used in patients at risk for ischemic heart disease. Treatment associated with low recurrence rates. Dihydroergotamine (subcutaneous/intramuscular) have less adverse events than when delivered intravenously. Contraindications: (Source: American Academy of Neurology, Encounter Kit) Dihydroergotamine should not be given within 24 hours of administration of triptans (sumatriptan, rizatriptan, zolmitriptan, naratriptan, almotriptan, frovatriptan, eletriptan); uncontrolled hypertension (blood pressure > 165/95); history of ischemic heart disease; history of angina; history of Prinzmetal’s angina (atypical angina); history of peripheral vascular disease; pregnancy. If the patient has chest pain or severe anxiety following the first dose of dihydroergotamine, do not repeat.

The use of dihydroergotamine (subcutaneous/intramuscular) may be considered in 2 patients with moderate to severe migraine. 89,90

(Dose tested: intramuscular - 1 mg; subcutaneous - 1 mg, dose approved - 1 mg;

intravenous – 1 mg to 2 mg.)

Dihydroergotamine (intravenous) plus antiemetics is an appropriate treatment choice 3 1 1 for patients with severe migraine. 68,69,91 70 92

(Doses tested: 0.5 mg to 1 mg.)

Dihydroergotamine nasal spray 1 3 2 5 93 94-96 97,98 99-103 The use of dihydroergotamine nasal spray is an appropriate treatment choice and should be considered for use in patients with moderate to severe migraine.

(Doses tested: 0.5 mg to 4 mg; dose approved - 2 mg.)

The following, while not a recommendation, was mentioned in G1 regarding potential harm. Common adverse events include nasal congestion, nausea and vomiting. Should not be used in patients with risk of ischemic heart disease. Associated with low incidence of recurrence.

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Ergot alkaloids G1 (USA) (cont’d) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs (cont’d) Because of their inability to tolerate or take oral medications, patients with nausea and vomiting may be given intranasal dihydroergotamine. Initial treatment with dihydroergotamine nasal spray is a reasonable choice when: • the headache is moderate-to-severe, or • an adequate trial of NSAIDs or other non-opiate analgesics (including combination analgesics such as acetaminophen plus acetylsalicylic acid plus caffeine) has failed to provide adequate relief in the past. G2 (Europe) (p. 969-70) 4 1 1 83,104-106 107 108 Ergot alkaloids should be restricted to patients with very long migraine attacks or with regular recurrence. The only compounds with sufficient evidence of efficacy are ergotamine tartrate (oral) and dihydroergotamine 2 mg (suppository). Ergot alkaloids

can induce drug overuse headache very fast and in very low doses, therefore their use must be limited to 10 days per month. The following, while not a recommendation, was mentioned in G2 regarding potential harm. Major side effects are nausea, vomiting, paresthesia, and ergotism. Contraindications are cardiovascular and cerebrovascular diseases, Raynaud’s disease, arterial hypertension, renal failure, pregnancy, and lactation.

G3 (France) (Summary [English] p. 1309 & 1310; Main guideline [French] p. 40-41) 1 2 108 94,109 Ergotamine tartrate and dihydroergotamine mesylate nasal spray or injection is recommended. Licensed in France: • Ergotamine tartrate - 2 mg/day; maximum 6 mg/day and 10 mg/week; • Dihydroergotamine mesylate: o intranasal solution - one spray in each nostril at attack onset; o injectable solution - 1 ampoule, may be repeated once 30 (continued over page) minutes to 60 minutes later; maximum 2 mg/day and 8 mg/week.

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Ergot alkaloids The following, while not a recommendation, was mentioned in G3 regarding 1 2 (cont’d) potential harm. 108 94,109 Adverse effects: Ergotamine tartrate: ergotism, nausea, vomiting. Dihydroergotamine mesylate intranasal solution: transient local reactions, nasal obstruction, rhinorrhea; Dihydroergotamine mesylate injectable solution: ergotism, precordial pain. Contraindications: Ergot derivates: hypersensitivity to ergot derivatives, peripheral vascular disease, coronary artery disease, shock, hypertension, severe infection, severe liver failure. (Summary [English] p. 1309) Professional consensus If a patient treats with ergotamine tartrate, his or her treatment regimen should not (Background study cited: NR108) be changed if he or she has effective migraine relief (no pain or mild pain) 2 hours after receiving ergotamine, has no contraindications to its use, and is not requiring increasingly higher doses. G4 (UK) (p. 24) 1 1 1 Ergotamine is not recommended for patients with acute migraine. 110 104 54 The following, while not a recommendation, was mentioned in G4 regarding potential harm. Ergotamine can cause side effects such as nausea, vomiting, abdominal pain, and muscular cramps. It should not be used in patients who have cerebrovascular or cardiovascular disease. Triptans (serotonin G1 (USA) (p. 14-18, p. 31) 41 9 7 [5-HT1B/1D] The triptans are an appropriate treatment choice and may be considered for use in 14,31,34,83,96, 146-154 155-161 agonists) patients with moderate to severe migraine who have no contraindications for its use. 109,111-145 (Sumatriptan nasal spray: doses tested - 1 mg to 40 mg; doses approved - 5 mg, 10 mg, 20 mg.) (Naratriptan [oral]: doses tested - 1 mg to 2.5 mg; doses approved - 1mg, 2.5 mg.) (Rizatriptan [oral]: doses tested - 5 mg to 40 mg; doses approved - 5 mg, 10 mg.) (Sumatriptan [oral]: doses tested - 25 mg to 100 mg; doses approved - 25 mg, 50 mg.) (Zolmitriptan [oral]: doses tested - 1 mg to 25 mg; doses approved - 2.5 mg, 5 mg.) (continued over page)

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Triptans The following, while not a recommendation, was mentioned in G1 regarding 41 9 7 (cont’d) potential harm. 14,31,34,83,96, 146-154 155-161 Nasal spray adverse effects include unpleasant taste and flushing. Chest symptoms are common, but 109,111-145 true ischemic events are rare. Contraindicated in patients with risk of heart disease, basilar or hemiplegic migraine, or uncontrolled hypertension. Based on post-marketing information, rare incidences of myocardial infarction and stroke have been reported. Naratriptan is associated with a slower onset of action and lower recurrence rate. Sumatriptan [subcutaneous] is associated with a very rapid onset of action.

Because of their inability to take oral medications, patients with nausea and vomiting Consensus achieved by the US Headache Consortium in the absence of relevant RCTs may be given intranasal or subcutaneous sumatriptan.

G2 (Europe) (p. 968, 970-71) 3 4 22 6 4 4

Triptans are recommended for the acute treatment of migraine attacks. The 162-164 165-168 14,31,112, 107,185-189 190-193 194-197 following triptans have efficacy in acute migraine treatment. 136,143,145,16 9-184 • Sumatriptan 25 mg, 50 mg, 100 mg (oral including rapid-release); 25 mg (suppository); 10 mg, 20 mg (nasal spray); 6 mg (subcutaneous) – 100 mg sumatriptan is reference to all triptans • Zolmitriptan 2.5 mg, 5 mg (oral including disintegrating form); 2.5 mg, 5 mg (nasal spray) • Naratriptan 2.5 mg (oral) – lesser but longer efficacy than sumatriptan • Rizatriptan 10 mg (oral including 5 mg when taking propranolol wafer form) • Almotriptan 12.5 mg (oral) – probably less side effects than sumatriptan • Eletriptan 20 mg, 40 mg (oral) – 80 mg allowed if 40 mg not effective

• Frovatriptan 2.5 mg (oral) – lesser but longer efficacy than sumatriptan

In very severe attacks, subcutaneous sumatriptan is recommended.

General side effects for all triptans: chest symptoms, nausea, distal paresthesia, fatigue.

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Triptans G2 (Europe) (cont’d) 3 4 22 6 4 4 (cont’d) General contraindications: untreated arterial hypertension, coronary heart disease, cerebrovascular 162-164 165-168 14,31,112, 107,185-189 190-193 194-197 disease, Raynaud’s disease, pregnancy and lactation, age less than 18 years (except sumatriptan 136,143,145,16 9-184 nasal spray) and age over 65 years, severe liver or kidney failure. G3 (France) (Summary [English] p. 1309 & 1311; Main guideline [French] p. 42-46; 1 162 Summary recommendations [French] p. 9) Triptans are effective for migraine headache, associated gastrointestinal symptoms, and phonosensitivity or photosensitivity.

(Doses tested: sumatriptan - 25 mg, 50 mg, 100 mg; zolmitriptan - 2.5 mg, 5 mg; naratriptan - 2.5 mg; rizatriptan - 5 mg, 10 mg; eletriptan - 20 mg, 40 mg, 80 mg; frovatriptan - 2.5 mg; almotriptan - 12.5 mg.) The following, while not a recommendation, was mentioned in G3 regarding potential harm. Adverse effects: vascular flushing, vertigo, weakness, asthenia, somnolence, nausea, vomiting, coronary spasm (<1% of attacks), moderate or severe hypertension, paresthesia, sensation of weakness, tingling, heat, pressure, or tightness.

Contraindication: hypersensitivity to selective serotonin receptor agonists, history of myocardial infarction or ischemic heart disease, vasospasm (Prinzmetal’s angina), peripheral vascular disease, stroke or transitory ischemic attack, severe liver failure, moderate or severe hypertension or uncontrolled mild hypertension, combination with monoamine oxidase inhibitor. (Summary [English] p. 1309) 1 1 Each triptan has efficacy and tolerability profiles different from the others, but these 162 180 differences are minimal. A patient who does not respond to one triptan may respond to another. A patient who does not respond to a particular triptan during an initial migraine attack may respond to it in subsequent attacks.

Before concluding that a particular triptan is ineffective in a patient, it should be Professional consensus tried for ≥ 3 attacks, unless it is poorly tolerated. Irrespective of the type of treatment, the patient should take the medication as early 1 1 as possible after the onset of migraine headache. Delaying administration of an oral 198 199 triptan after the onset of a migraine headache might reduce the likelihood of complete relief, increase the risk for headache recurrence and adverse effects, and prolong suffering.

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Triptans G4 (UK) (Main guideline p. 20-22; BMJ summary p. 1232) 5 2 2 1 (cont’d) Oral triptans are recommended for acute treatment in patients with all severities of 110,200-203 204,205 30,104 54 migraine if previous attacks have not been controlled using simple analgesics. Almotriptan 12.5 mg, eletriptan 40-80 mg, or rizatriptan 10 mg are the preferred oral triptans for acute migraine. Triptans are contraindicated in patients with ischemic heart disease, previous myocardial infarction, coronary vasospasm, or uncontrolled or severe hypertension. Triptans should be used with caution in hemiplegic migraine. If a patient does not respond to one triptan an alternative triptan should be offered. 1 206 Triptans should be taken at, or soon after, the onset of the headache phase of a 1 migraine attack. 2 Triptan nasal sprays/subcutaneous injections Based on clinical experience of guideline development group Nasal zolmitriptan or subcutaneous sumatriptan should be considered in severe (Background studies cited: G2) migraine or where vomiting precludes oral route or where oral triptans have been ineffective. Triptan and NSAID combinations 1 For recurrent or prolonged attacks or attacks recurring regularly after successful 174 treatment with a triptan, consider a combination of sumatriptan 50-100 mg and naproxen sodium 500 mg. Antiemetics G1 (USA) (p. 6-7; p. 25-26) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs Oral antiemetics may be used as an adjunct in the treatment of nausea associated (Background studies cited: RCT162,207) with migraine. (Domperidone: doses tested - 30 mg to 120 mg.) The following, while not a recommendation, was mentioned in G1 regarding potential harm. No adverse events were reported with domperidone administered during the prodrome. (continued over page)

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Antiemetics (cont’d) G1 (USA) (cont’d) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs Intramuscular metoclopramide may be considered as an adjunct to control nausea in (Background studies cited: RCT208,209, NRCS210) the treatment of migraine. (Dose tested: 10 mg) The following, while not a recommendation, was mentioned in G1 regarding potential harm. Extrapyramidal adverse events (e.g. dystonia) and sedation are associated with metoclopramide, but were rarely reported in the clinical trials reviewed. In some patients with migraine sedation may be useful.

Intravenous metoclopramide may be an appropriate choice as an adjunct therapy for Consensus achieved by the US Headache Consortium in the absence of relevant RCTs the treatment of headache pain or nausea for migraine in the appropriate setting.

Metoclopramide intravenous may be considered as monotherapy for migraine pain 3 relief. (Doses tested: 0.1 mg/kg for 1-3 doses to 10 mg) 211-213

Prochlorperazine (intravenous/intramuscular/suppository) may be a therapeutic 3 choice for migraine in the appropriate setting. (Doses tested: intravenous - 10 mg; 208,211,214 intramuscular - 10 mg; suppository - 25 mg.) Prochlorperazine suppository may be considered as an adjunct in the treatment of Consensus achieved by the US Headache Consortium in the absence of relevant RCTs acute migraine with nausea and vomiting. The following, while not a recommendation, was mentioned in G1 regarding potential harm. Metoclopramide and prochlorperazine share the common adverse event of drowsiness and sedation. Evidence is insufficient at this time to establish, or refute, a role for serotonin receptor 5-HT antagonists (granisetron and zatosetron) as monotherapy in the 2 3 215,216 management of acute attacks. However, 5-HT antagonists may be considered as an adjunct therapy to control 3 Consensus achieved by the US Headache Consortium in the absence of relevant RCTs nausea in selected patients with migraine attacks. (Summary guideline for clinicians) Not provided (continued over page) Do not restrict antiemetics just to patients who are vomiting or likely to vomit.

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Antiemetics (cont’d) G2 (Europe) (p. 969) 5 The use of antiemetics in acute migraine attacks is recommended to treat nausea and 212,217-220 potential emesis and because it is assumed that these drugs improve the resorption of analgesics. The following antiemetics are recommended for use in migraine attacks. • Metoclopramide (10 mg to 20 mg oral; 20 mg suppository; 10 mg intramuscular, intravenous, subcutaneous) is recommended for adults and adolescents. Side effects: dyskinesia; contraindicated in childhood and in pregnancy; also analgesic efficacy. • Domperidone (20 mg to 30 mg oral) – side effects less severe than for metoclopramide. G4 (UK) (p. 23) 1 Oral and rectal antiemetics can be used in patients with acute migraine attacks to 2 reduce symptoms of nausea and vomiting and to promote gastric emptying. A combination of acetylsalicylic acid and metoclopramide can be used for the 1 treatment of patients with acute migraine attacks. 221 Fixed analgesic/antiemetic combinations can be used for the treatment of patients 1 1 with acute migraine attacks. 110 222 Intravenous metoclopramide can be used in the acute management of patients with 1 1 migraine. 223 224 Other drugs G1 (USA) (p. 7-8, p. 26-27) 1 1 Butalbital plus acetylsalicylic acid plus caffeine plus codeine 56 85 Based on concerns of overuse, medication-overuse headache, and withdrawal, the use of barbital-containing analgesics should be limited and carefully monitored. (Doses tested: 50 mg plus 325 mg plus 40 mg plus 30 mg.) The following, while not a recommendation, was mentioned in G1 regarding (continued over page) potential harm. Sedation is a common adverse event.

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Table G.2a: Acute migraine - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Other drugs (cont’d) G1 (USA) (cont’d) 2 3 (p. 18-19, p. 31-32) 3,225 89,226,227 Isometheptene and isometheptene-combination agents Based on clinical evidence and favourable tolerability, isometheptene-containing compounds may be a reasonable choice for patients with mild to moderate headache. (Doses tested: isometheptene - 130 mg to 780 mg; isometheptene mucate plus acetaminophen plus dichloralphenazone - 2 to 6 capsules or 2 to 5 capsules.) The following, while not a recommendation, was mentioned in G1 regarding potential harm. Adverse events: drowsiness, dizziness and nausea. (p. 19, p. 32) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs Dexamethasone or hydrocortisone (Background studies cited: Other92,228) Corticosteroids may be considered as a treatment choice for rescue therapy for patients with status migrainosus. (Dose tested: 6 mg) The following, while not a recommendation, was mentioned in G1 regarding potential harm. Consider limiting treatment to once per week. (p. 19, p. 32) 1 1 Intranasal lidocaine 229 230 Evidence is insufficient at this time to establish a defined role for intranasal lidocaine in the management of acute migraine headache. (Dose tested: 4% solution, 1 to 4 drops.) The following, while not a recommendation, was mentioned in G1 regarding potential harm. Adverse events: intranasal sensation/irritation common, short duration of action, and possible headache recurrence. (p. 19, p. 32) 2 Intravenous lidocaine 231,232

Evidence is insufficient to support the role for intravenous lidocaine in the management of acute migraine. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis Note: Statements in italics relate to harm. These statements were sourced from the recommendations or from elsewhere in the seed guidelines.

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16. Tfelt-Hansen P, Olesen J. Effervescent metoclopramide and aspirin (Migravess) versus effervescent aspirin or placebo for migraine attacks: a double-blind study. Cephalalgia 1984;4(2):107-11. 17. Havanka-Kanniainen H. Treatment of acute migraine attack: ibuprofen and placebo compared. Headache 1989;29(8):507-9. 18. Andersson PG, Hinge HH, Johansen O, Andersen CU, Lademann A, Gotzsche PC. Double- blind study of naproxen vs placebo in the treatment of acute migraine attacks. Cephalalgia 1989;9(1):29-32. 19. Nappi G, Micieli G, Tassorelli C, Viotti E, Altavilla T. Effectiveness of a piroxicam fast dissolving formulation sublingually administered in the symptomatic treatment of migraine without aura. Headache 1993;33(6):296-300. 20. Pearce I, Frank GJ, Pearce JM. Ibuprofen compared with paracetamol in migraine. Practitioner 1983;227(1377):465-7. 21. Hakkarainen H, Gustafsson B, Stockman O. A comparative trail of ergotamine tartrate, acetyl salicylic acid and a dextropropoxyphene compound in acute migraine attacks. Headache 1978;18(1):35-9. 22. Hakkarainen H, Quiding H, Stockman O. Mild analgesics as an alternative to ergotamine in migraine. A comparative trial with acetylsalicylic acid, ergotamine tartrate, and a dextropropoxyphene compound. Journal of Clinical Pharmacology 1980;20(10):590-5. 23. Treves TA, Streiffler M, Korczyn AD. Naproxen sodium versus ergotamine tartrate in the treatment of acute migraine attacks. Headache 1992;32(6):280-2. 24. Awidi AS. Efficacy of flurbiprofen in the treatment of acute migraine attacks: a double-blind cross-over study. Current Therapeutic Research 1982;32(3):492-7. [Unable to identify study type— abstract not available.] 25. Shrestha M, Singh R, Moreden J, Hayes JE. Ketorolac vs chlorpromazine in the treatment of acute migraine without aura. A prospective, randomized, double-blind trial. Archives of Internal Medicine 1996 12;156(15):1725-8. 26. Larkin GL, Prescott JE. A randomized, double-blind, comparative study of the efficacy of ketorolac tromethamine versus meperidine in the treatment of severe migraine. Annals of Emergency Medicine 1992;21(8):919-24. 27. Duarte C, Dunaway F, Turner L, Aldag J, Frederick R. Ketorolac versus meperidine and hydroxyzine in the treatment of acute migraine headache: a randomized, prospective, double- blind trial. Annals of Emergency Medicine 1992;21(9):1116-21. 28. Davis CP, Torre PR, Williams C, Gray C, Barrett K, Krucke G, et al. Ketorolac versus meperidine-plus-promethazine treatment of migraine headache: evaluations by patients. American Journal of Emergency Medicine 1995;13(2):146-50. 29. Lampl C, Voelker M, Diener HC. Efficacy and safety of 1,000 mg effervescent aspirin: individual patient data meta-analysis of three trials in migraine headache and migraine accompanying symptoms. Journal of Neurology 2007;254(6):705-12.

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30. Diener HC, Bussone G, de Liano H, Eikermann A, Englert R, Floeter T, et al. Placebo- controlled comparison of effervescent acetylsalicylic acid, sumatriptan and ibuprofen in the treatment of migraine attacks. Cephalalgia 2004;24(11):947-54. 31. Tfelt-Hansen P, Henry P, Mulder LJ, Scheldewaert RG, Schoenen J, Chazot G. The effectiveness of combined oral lysine acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine. Lancet 1995;346(8980):923-6. 32. Karachalios GN, Fotiadou A, Chrisikos N, Karabetsos A, Kehagioglou K. Treatment of acute migraine attack with diclofenac sodium: a double-blind study. Headache 1992;32(2):98-100. 33. Lipton RB, Baggish JS, Stewart WF, Codispoti JR, Fu M. Efficacy and safety of acetaminophen in the treatment of migraine: results of a randomized, double-blind, placebo- controlled, population-based study. Archives of Internal Medicine 2000;160(22):3486-92. 34. Myllyla VV, Havanka H, Herrala L, Kangasniemi P, Rautakorpi I, Turkka J, et al. Tolfenamic acid rapid release versus sumatriptan in the acute treatment of migraine: comparable effect in a double-blind, randomized, controlled, parallel-group study. Headache 1998;38(3):201-7. 35. The Diclofenac-K/Sumatriptan Migraine Study Group. Acute treatment of migraine attacks: efficacy and safety of a nonsteroidal anti-inflammatory drug, diclofenac-potassium, in comparison to oral sumatriptan and placebo. Cephalalgia 1999;19(4):232-40. 36. Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous dipyrone in the acute treatment of migraine without aura and migraine with aura: a randomized, double blind, placebo controlled study. Headache 2002;42(9):862-71. 37. Chabriat H, Joire JE, Danchot J, Grippon P, Bousser MG. Combined oral lysine acetylsalicylate and metoclopramide in the acute treatment of migraine: a multicentre double- blind placebo-controlled study. Cephalalgia 1994;14(4):297-300. 38. Diener HC, Eikermann A, Gessner U, Gobel H, Haag G, Lange R, et al. Efficacy of 1,000 mg effervescent acetylsalicylic acid and sumatriptan in treating associated migraine symptoms. European Neurology 2004;52(1):50-6. 39. Diener HC, Pfaffenrath V, Pageler L, Peil H, Aicher B. The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single- dose, placebo-controlled parallel group study. Cephalalgia 2005;25(10):776-87. 40. Gobel H, Heinze A, Niederberger U, Witt T, Zumbroich V. Efficacy of phenazone in the treatment of acute migraine attacks: a double-blind, placebo-controlled, randomized study. Cephalalgia 2004;24(10):888-93. 41. Goldstein J, Silberstein SD, Saper JR, Ryan RE Jr, Lipton RB. Acetaminophen, aspirin, and caffeine in combination versus ibuprofen for acute migraine: results from a multicenter, double-blind, randomized, parallel-group, single-dose, placebo-controlled study. Headache 2006;46(3):444-53. 42. Nebe J, Heier M, Diener HC. Low-dose ibuprofen in self-medication of mild to moderate headache: a comparison with acetylsalicylic acid and placebo. Cephalalgia 1995;15(6):531-5.

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43. Tulunay FC, Ergun H, Gulmez SE, Ozbenli T, Ozmenoglu M, Boz C, et al. The efficacy and safety of dipyrone (Novalgin) tablets in the treatment of acute migraine attacks: a double-blind, cross-over, randomized, placebo-controlled, multi-center study. Functional Neurology 2004;19(3):197-202. 44. Limmroth V, May A, Diener H. Lysine-acetylsalicylic acid in acute migraine attacks. European Neurology 1999;41(2):88-93. 45. Dib M, Massiou H, Weber M, Henry P, Garcia-Acosta S, Bousser MG. Efficacy of oral ketoprofen in acute migraine: a double-blind randomized clinical trial. Neurology 2002;58(11):1660-5. 46. Lange R, Schwarz JA, Hohn M. Acetylsalicylic acid effervescent 1000 mg (Aspirin®) in acute migraine attacks; a multicentre, randomized, double-blind, single dose, placebo-controlled parallel group study. Cephalalgia 2000;20:663-7. 47. Sargent JD, Peters K, Goldstein J, Madison DS, Solbach P. Naproxen sodium for muscle contraction headache treatment. Headache 1988;28:180-2. 48. Chabriat H, Joire JE, Danchot J, Grippon P, Bousser MG. Combined oral lysine acetylsalicylate and metoclopramide in the acute treatment of migraine: a multicentre double- blind placebo controlled study. Cephalalgia 1994;14:297-300. 49. Henry P, Hiesse-Provost O, Dillenschneider A, Ganry H, Insuasty J. Efficacité et tolérance de l'association effervescente aspirine-métoclopramide dans le traitement de la crise de migraine sans aura. Essai randomisé en double aveugle contre placebo. La Presse Médicale 1995;24:254-8. 50. Codispoti JR, Prior MJ, Fu M, Harte CM, Nelson EB. Efficacy of nonprescription doses of ibuprofen for treating migraine headache. a randomized controlled trial. Headache 2001;41(7):665-79. 51. Goldstein J, Silberstein SD, Saper JR, Elkind AH, Smith TR, Gallagher RM, et al. Acetaminophen, aspirin, and caffeine versus sumatriptan succinate in the early treatment of migraine: results from the ASSET trial. Headache 2005;45(8):973-82. 52. Lipton RB, Goldstein J, Baggish JS, Yataco AR, Sorrentino JV, Quiring JN. Aspirin is efficacious for the treatment of acute migraine. Headache 2005;45(4):283-92. 53. MacGregor EA, Dowson A, Davies PT. Mouth-dispersible aspirin in the treatment of migraine: a placebo-controlled study. Headache 2002;42(4):249-55. 54. British National Formulary. 56th edition. London (UK): BMJ Publishing; 2008. [Pharmaceutical compendium.] 55. Electronic Medicines Compendium. Available from: www.medicines.org.uk/emc/ (accessed 4 April 2013). [Online medicine compendium.] 56. Goldstein J, Gawel MJ, Winner P, Diamond S, Reich L, Davidson WJ, et al. Comparison of butorphanol nasal spray and fiorinal with codeine in the treatment of migraine. Headache 1998;38(7):516-22. 57. Hoffert MJ, Couch JR, Diamond S, Elkind AH, Goldstein J, Kohlerman NJ III, et al. Transnasal butorphanol in the treatment of acute migraine. Headache 1995;35(2):65-9.

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58. Elenbaas RM, Iacono CU, Koellner KJ, Pribble JP, Gratton M, Racz G, et al. Dose effectiveness and safety of butorphanol in acute migraine headache. Pharmacotherapy 1991;11(1):56-63. 59. Diamond S, Freitag FG, Diamond ML, Urban G. Transnasal butorphanol in the treatment of migraine headache pain. Headache Quarterly 1992;3(2):164-71. [Unable to identify study type— abstract not available.] 60. Adam EI. A treatment for the acute migraine attack. The Journal of International Medical Research 1987;15(2):71-5. 61. Gawel MJ, Szalai JF, Stiglick A, Aimola N, Weiner M. Evaluation of analgesic agents in recurring headache compared with other clinical pain models. Clinical Pharmacology and Therapeutics 1990;47(4):504-8. 62. Somerville BW. Treatment of migraine attacks with an analgesic combination (Mersyndol). Medical Journal of Australia 1976;1(23):865-6. 63. Carasso RL, Yehuda S. The prevention and treatment of migraine with an analgesic combination. British Journal of Clinical Practice 1984;38(1):25-7. 64. Uzogara E, Sheehan DV, Manschreck TC, Jones KJ. A combination drug treatment for acute common migraine. Headache 1986;26(5):231-6. 65. Migraine treated with an antihistamine–analgesic combination. Practitioner 1973;211(263):357- 61. 66. Lane PL, McLellan BA, Baggoley CJ. Comparative efficacy of chlorpromazine and meperidine with dimenhydrinate in migraine headache. Annals of Emergency Medicine 1989;18(4):360-5. 67. Stiell IG, Dufour DG, Moher D, Yen M, Beilby WJ, Smith NA. Methotrimeprazine versus meperidine and dimenhydrinate in the treatment of severe migraine: a randomized, controlled trial. Annals of Emergency Medicine 1991;20(11):1201-5. 68. Klapper JA, Stanton J. Current emergency treatment of severe migraine headaches. Headache 1993;33(10):560-2. 69. Scherl ER, Wilson JF. Comparison of dihydroergotamine with metoclopramide versus meperidine with promethazine in the treatment of acute migraine. Headache 1995;35(5):256-9. 70. Belgrade MJ, Ling LJ, Schleevogt MB, Ettinger MG, Ruiz E. Comparison of single-dose meperidine, butorphanol, and dihydroergotamine in the treatment of vascular headache. Neurology 1989;39(4):590-2. 71. Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache 2001;41(10):976-80. 72. Leniger T, Pageler L, Stude P, Diener HC, Limmroth V. Comparison of intravenous valproate with intravenous lysine-acetylsalicylic acid in acute migraine attacks. Headache 2005;45(1):42-6. 73. Silberstein SD, Freitag FG, Rozen TD, Kudrow DB, Hewitt DJ, Jordan DM, et al. Tramadol/acetaminophen for the treatment of acute migraine pain: findings of a randomized, placebo-controlled trial. Headache 2005;45(10):1317-27.

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74. Soyka D, Taneri Z, Oestreich W, Schmidt R. Flunarizine i.v. in the acute treatment of the migraine attack. A double-blind placebo-controlled study. Cephalalgia 1988;8 Suppl 8:35-40. 75. Leplège A, Ecosse E, Verdier A, Perneger TV. The French SF-36 health survey: translation, cultural adaptation and preliminary psychometric evaluation. Journal of Clinical Epidemiology 1998;51(11):1013-23. [Methodological paper] 76. Katsarava Z, Schneeweiss S, Kurth T, Kroener U, Fritsche G, Eikermann A, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004;62(5):788-90. 77. Kangasniemi P, Kaaja R. Ketoprofen and ergotamine in acute migraine. Journal of Internal Medicine 1992;231(5):551-4. 78. Waters WE. A randomized controlled trial of ergotamine tartrate. British Journal of Preventive & Social Medicine 1970;24(1):65. 79. Friedman AP, Di Serio FJ, Hwang DS. Symptomatic relief of migraine: multicenter comparison of Cafergot P-B, Cafergot, and placebo. Clinical Therapy 1989;11(1):170-82. 80. Ryan RE. Double-blind clinical evaluation of the efficacy and safety of ergostine-caffeine, ergotamine-caffeine, and placebo in migraine headache. Headache 1970;9(4):212-20. 81. Kinnunen E, Erkinjuntti T, Farkkila M, Palomaki H, Porras J, Teirmaa H, et al. Placebo- controlled double-blind trial of pirprofen and an ergotamine tartrate compound in migraine attacks. Cephalalgia 1988;8(3):175-9. 82. Hakkarainen H, Allonen H. Ergotamine vs. metoclopramide vs. their combination in acute migraine attacks. Headache 1982;22(1):10-2. 83. The Multinational Oral Sumatriptan and Cafergot Comparative Study Group. A randomized, double-blind comparison of sumatriptan and Cafergot in the acute treatment of migraine. European Neurology 1991;31(5):314-22. 84. Behan PO. Isometheptene compound in the treatment of vascular headache. Practitioner 1978;221(1326):937-9. 85. McCrory DC, Goslin RE, Gray RN. Evidence Report: butalbital-containing compounds for the treatment of tension-type and migraine headache. Duke University Center for Health Policy Research: Raleigh (NC); 1998. [Unable to identify study type—abstract not available.] 86. Gray RN, Mc Crory DC, Eberlein K, Westman EC, Hasselblad V. Self-Administered Drug Treatments for Acute Migraine Headache. Technical Review, 2.4. Prepared for the Agency for Health Care Policy and Research under Contract No. 290-94-2025: Rockville (MD); 1999. [Study type: technical review.] 87. Gray RN, Mc Crory DC, Eberlein K, Westman EC, Hasselblad V. Parenteral Drug Treatments for Acute Migraine Headache. Technical Review, 2.5 Prepared for the Agency for Health Care Policy and Research under Contract No. 290-94-2025: Rockville (MD); 1999. [Study type: technical review.] 88. Ostfeld AM. A study of migraine pharmacotherapy. American Journal of Medical Science 1961;241:192-8. [Unable to identify study type—abstract not available.]

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89. Yuill GM, Swinburn WR, Liversedge LA. A double-blind crossover trial of isometheptene mucate compound and ergotamine in migraine. British Journal of Clinical Practice 1972;26(2):76-9. [Unable to identify study type—abstract not available.] 90. Carleton SC, Shesser RF, Pietrzak MP, Chudnofsky CR, Starkman S, Morris DL, et al. Double- blind, multicenter trial to compare the efficacy of intramuscular dihydroergotamine plus hydroxyzine versus intramuscular meperidine plus hydroxyzine for the emergency department treatment of acute migraine headache. Annals of Emergency Medicine 1998;32(2):129-38. 91. Callaham M, Raskin N. A controlled study of dihydroergotamine in the treatment of acute migraine headache. Headache 1986;26(4):168-71. 92. Klapper J, Stanton J. The emergency treatment of acute migraine headache; a comparison of intravenous dihydroergotamine, dexamethasone, and placebo. Cephalalgia 1991;11(Suppl 11):159-60. [Unable to identify study type—abstract not available.] 93. Hirt D, Lataste X, Taylor P. A comparison of DHE nasal spray and Cafergot in acute migraine. Cephalalgia 1989;9(Suppl 10):410-1. 94. Dihydroergotamine Nasal Spray Multicenter Investigators. Efficacy, safety, and tolerability of dihydroergotamine nasal spray as monotherapy in the treatment of acute migraine. Headache 1995;35(4):177-84. 95. Ziegler D, Ford R, Kriegler J, Gallagher RM, Peroutka S, Hammerstad J, et al. Dihydroergotamine nasal spray for the acute treatment of migraine. Neurology 1994;44(3 Pt 1):447-53. 96. Touchon J, Bertin L, Pilgrim AJ, Ashford E, Bes A. A comparison of subcutaneous sumatriptan and dihydroergotamine nasal spray in the acute treatment of migraine. Neurology 1996;47(2):361-5. 97. Gallagher RM; Dihydroergotamine Working Group. Acute treatment of migraine with dihydroergotamine nasal spray. Archives of Neurology 1996;53(12):1285-91. 98. Tulunay FC, Karan O, Aydin N, Culcuoglu A, Guvener A. Dihydroergotamine nasal spray during migraine attacks. A double-blind crossover study with placebo. Cephalalgia 1987;7(2):131-3. 99. Bousser MG, Loria Y. Efficacy of dihydroergotamine nasal spray in the acute treatment of migraine attacks. Cephalalgia 1985;5(Suppl 3):554-5. [Unable to identify study type—abstract not available.] 100. Krause KH, Bleicher MA. Dihydroergotamine nasal spray in the treatment of migraine attacks. Cephalalgia 1985;5(Suppl 3):138-9. [Unable to identify study type—abstract not available.] 101. Massiou H. Dihydroergotamine nasal spray in prevention and treatment of migraine attacks: two controlled trials versus placebo. Cephalalgia 1987;7(Suppl 6):440-1. [Unable to identify study type—abstract not available.] 102. Paiva T, Esperanca P, Marcelino L, Assis G. A double-blind trial with dihydroergotamine nasal spray in migraine crisis. Cephalalgia 1985;5(Suppl 3):140-1. [Unable to identify study type— abstract not available.]

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103. Rohr J, Dufresne JJ. Dihydroergotamine nasal spray for the treatment of migraine attacks: a comparative double-blind crossover study with placebo. Cephalalgia 1985;5(Suppl 3):142-3. [Unable to identify study type—abstract not available.] 104. Diener HC, Jansen JP, Reches A, Pascual J, Pitei D, Steiner TJ. Efficacy, tolerability and safety of oral eletriptan and ergotamine plus caffeine (Cafergot) in the acute treatment of migraine: a multicentre, randomised, double-blind, placebo-controlled comparison. European Neurology 2002;47(2):99-107. 105. Christie S, Gobel H, Mateos V, Allen C, Vrijens F, Shivaprakash M. Crossover comparison of efficacy and preference for rizatriptan 10 mg versus ergotamine/caffeine in migraine. European Neurology 2003;49(1):20-9. 106. Lainez MJ, Galvan J, Heras J, Vila C. Crossover, double-blind clinical trial comparing almotriptan and ergotamine plus caffeine for acute migraine therapy. European Journal of Neurology 2007;14(3):269-75. 107. Evers S, Gralow I, Bauer B, Suhr B, Buchheister A, Husstedt IW, et al. Sumatriptan and ergotamine overuse and drug-induced headache: a clinicoepidemiologic study. Clinical Neuropharmacology 1999;22(4):201-6. 108. Tfelt-Hansen P, Saxena PR, Dahlof C, Pascual J, Lainez M, Henry P, et al. Ergotamine in the acute treatment of migraine: a review and European consensus. Brain 2000;123(Pt 1):9-18. [Study type: consensus development conference report.] 109. Winner P, Ricalde O, Le Force B, Saper J, Margul B. A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine. Archives of Neurology 1996;53(2):180-4. 110. Loder E. Fixed drug combinations for the acute treatment of migraine: place in therapy. CNS Drugs 2005;19(9):769-84. 111. Akpunonu BE, Mutgi AB, Federman DJ, Volinsky FG, Brickman K, Davis RL, et al. Subcutaneous sumatriptan for treatment of acute migraine in patients admitted to the emergency department: a multicenter study. Annals of Emergency Medicine 1995;25(4):464-9. 112. Bates D, Ashford E, Dawson R, Ensink FB, Gilhus NE, Olesen J, et al. Subcutaneous sumatriptan during the migraine aura. Sumatriptan Aura Study Group. Neurology 1994;44(9):1587-92. 113. Bousser MG, D'Allens H, Richard A; Early-Morning Migraine Sumatriptan Study Group. Efficacy of subcutaneous sumatriptan in the acute treatment of early-morning migraine: a placebo-controlled trial. Journal of Internal Medicine 1993;234(2):211-6. 114. Cady RK, Dexter J, Sargent JD, Markley H, Osterhaus JT, Webster CJ. Efficacy of subcutaneous sumatriptan in repeated episodes of migraine. Neurology 1993;43(7):1363-8. 115. Cady RK, Wendt JK, Kirchner JR, Sargent JD, Rothrock JF, Skaggs H Jr. Treatment of acute migraine with subcutaneous sumatriptan. JAMA 1991;265(21):2831-5. 116. Cady RC, Ryan R, Jhingran P, O'Quinn S, Pait DG. Sumatriptan injection reduces productivity loss during a migraine attack: results of a double-blind, placebo-controlled trial. Archives of Internal Medicine 1998;158(9):1013-8.

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117. Gross ML, Kay J, Turner AM, Hallett K, Cleal AL, Hassani H. Sumatriptan in acute migraine using a novel cartridge system self-injector. United Kingdom Study Group. Headache 1994;34(10):559-63. 118. Mathew NT, Dexter J, Couch J, Flamenbaum W, Goldstein J, Rapoport A, et al. Dose ranging efficacy and safety of subcutaneous sumatriptan in the acute treatment of migraine. US Sumatriptan Research Group. Archives of Neurology 1992;49(12):1271-6. 119. Russell MB, Holm-Thomsen OE, Rishoj NM, Cleal A, Pilgrim AJ, Olesen J. A randomized double-blind placebo-controlled crossover study of subcutaneous sumatriptan in general practice. Cephalalgia 1994;14(4):291-6. 120. The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. New England Journal of Medicine 1991;325(5):316-21. 121. The Sumatriptan Auto-Injector Study Group. Self-treatment of acute migraine with subcutaneous sumatriptan using an auto-injector device. European Neurology 1991;31(5):323-31. 122. Carpay HA, Matthijsse P, Steinbuch M, Mulder PG. Oral and subcutaneous sumatriptan in the acute treatment of migraine: an open randomized cross-over study. Cephalalgia 1997;17(5):591- 5. 123. Gruffydd-Jones K, Hood CA, Price DB. A within-patient comparison of subcutaneous and oral sumatriptan in the acute treatment of migraine in general practice. Cephalalgia 1997;17(1):31-6. 124. Cull RE, Price WH, Dunbar A. The efficacy of subcutaneous sumatriptan in the treatment of recurrence of migraine headache. Journal of Neurology, Neurosurgery, and Psychiatry 1997;62(5):490- 5. 125. Cutler N, Mushet GR, Davis R, Clements B, Whitcher L. Oral sumatriptan for the acute treatment of migraine: evaluation of three dosage strengths. Neurology 1995;45(8 Suppl 7):S5- S9. 126. Nappi G, Sicuteri F, Byrne M, Roncolato M, Zerbini O. Oral sumatriptan compared with placebo in the acute treatment of migraine. Journal of Neurology 1994;241(3):138-44. 127. The Oral Sumatriptan International Multiple-Dose Study Group. Evaluation of a multiple- dose regimen of oral sumatriptan for the acute treatment of migraine. European Neurology 1991;31(5):306-13. 128. Sargent J, Kirchner JR, Davis R, Kirkhart B. Oral sumatriptan is effective and well tolerated for the acute treatment of migraine: results of a multicenter study. Neurology 1995;45(8 Suppl 7):S10-S14. 129. Visser WH, Terwindt GM, Reines SA, Jiang K, Lines CR, Ferrari MD. Rizatriptan vs sumatriptan in the acute treatment of migraine. A placebo-controlled, dose-ranging study. Dutch/US Rizatriptan Study Group. Archives of Neurology 1996;53(11):1132-7. 130. Teall J, Tuchman M, Cutler N, Gross M, Willoughby E, Smith B, et al. Rizatriptan (MAXALT) for the acute treatment of migraine and migraine recurrence. A placebo-controlled, outpatient study. Rizatriptan 022 Study Group. Headache 1998;38(4):281-7.

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131. Rapoport AM, Ramadan NM, Adelman JU, Mathew NT, Elkind AH, Kudrow DB, et al; The 017 Clinical Trial Study Group. Optimizing the dose of zolmitriptan (Zomig, 311C90) for the acute treatment of migraine. A multicenter, double-blind, placebo-controlled, dose range- finding study. Neurology 1997;49(5):1210-8. 132. Solomon GD, Cady RK, Klapper JA, Earl NL, Saper JR, Ramadan NM; The 042 Clinical Trial Study Group. Clinical efficacy and tolerability of 2.5 mg zolmitriptan for the acute treatment of migraine. Neurology 1997;49(5):1219-25. 133. Visser WH, Klein KB, Cox RC, Jones D, Ferrari MD. 311C90, a new central and peripherally acting 5-HT1D receptor agonist in the acute oral treatment of migraine: a double-blind, placebo-controlled, dose-range finding study. Neurology 1996;46(2):522-6. 134. Klassen A, Elkind A, Asgharnejad M, Webster C, Laurenza A; Naratriptan S2WA3001 Study Group. Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled, parallel-group study. Headache 1997;37(10):640-5. 135. Mathew NT, Asgharnejad M, Peykamian M, Laurenza A; The Naratriptan S2WA3003 Study Group. Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled, crossover study. Neurology 1997;49(6):1485-90. 136. Ferrari MD, James MH, Bates D, Pilgrim A, Ashford E, Anderson BA, et al. Oral sumatriptan: effect of a second dose, and incidence and treatment of headache recurrences. Cephalalgia 1994;14(5):330-8. 137. Rapoport AM, Visser WH, Cutler NR, Alderton CJ, Paulsgrove LA, Davis RL, et al. Oral sumatriptan in preventing headache recurrence after treatment of migraine attacks with subcutaneous sumatriptan. Neurology 1995;45(8):1505-9. 138. Cady RK, Rubino J, Crummett D, Littlejohn TW III. Oral sumatriptan in the treatment of recurrent headache. Archives of Family Medicine 1994;3(9):766-72. 139. Dowson A. Can oral 311C90, a novel 5-HT1D agonist, prevent migraine headache when taken during an aura? European Neurology 1996;36 Suppl 2:28-31. 140. The Finnish Sumatriptan Group and the Cardiovascular Clinical Research Group. A placebo- controlled study of intranasal sumatriptan for the acute treatment of migraine. European Neurology 1991;31(5):332-8. 141. Salonen R, Ashford E, Dahlof C, Dawson R, Gilhus NE, Luben V, et al; International Intranasal Sumatriptan Study Group. Intranasal sumatriptan for the acute treatment of migraine. Journal of Neurology 1994;241(8):463-9. 142. Diamond S, Elkind A, Jackson RT, Ryan R, DeBussey S, Asgharnejad M. Multiple-attack efficacy and tolerability of sumatriptan nasal spray in the treatment of migraine. Archives of Family Medicine 1998;7(3):234-40. 143. Ryan R, Elkind A, Baker CC, Mullican W, DeBussey S, Asgharnejad M. Sumatriptan nasal spray for the acute treatment of migraine. Results of two clinical studies. Neurology 1997;49(5):1225-30.

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144. Kelly AM, Ardagh M, Curry C, D'Antonio J, Zebic S. Intravenous chlorpromazine versus intramuscular sumatriptan for acute migraine. Journal of Accident & Emergency Medicine 1997;14(4):209-11. 145. Tepper SJ, Cochran A, Hobbs S, Woessner M. Sumatriptan suppositories for the acute treatment of migraine. S2B351 Study Group. International Journal of Clinical Practice 1998;52(1):31-5. 146. Facchinetti F, Bonellie G, Kangasniemi P, Pascual J, Shuaib A; The Sumatriptan Menstrual Migraine Study Group. The efficacy and safety of subcutaneous sumatriptan in the acute treatment of menstrual migraine. Obstetrics and Gynecology 1995;86(6):911-6. 147. Henry P, D'Allens H; French Migraine Network Bordeaux-Lyon-Grenoble. Subcutaneous sumatriptan in the acute treatment of migraine in patients using dihydroergotamine as prophylaxis. Headache 1993;33(8):432-5. 148. Jensen K, Tfelt-Hansen P, Hansen EW, Krois EH, Pedersen OS. Introduction of a novel self- injector for sumatriptan. A controlled clinical trial in general practice. Cephalalgia 1995;15(5):423-9. 149. The Oral Sumatriptan Dose-Defining Study Group. Sumatriptan—an oral dose-defining study. European Neurology 1991;31(5):300-5. 150. Pfaffenrath V, Cunin G, Sjonell G, Prendergast S. Efficacy and safety of sumatriptan tablets (25 mg, 50 mg, and 100 mg) in the acute treatment of migraine: defining the optimum doses of oral sumatriptan. Headache 1998;38(3):184-90. 151. Pini LA, Sternieri E, Fabbri L, Zerbini O, Bamfi F; The Oral Sumatriptan Italian Study Group. High efficacy and low frequency of headache recurrence after oral sumatriptan. The Journal of International Medical Research 1995;23(2):96-105. 152. Cutler NR, Claghorn J, Sramek JJ, Block G, Panebianco D, Cheng H, et al. Pilot study of MK- 462 in migraine. Cephalalgia 1996;16(2):113-6. 153. Gijsman H, Kramer MS, Sargent J, Tuchman M, Matzura-Wolfe D, Polis A, et al. Double- blind, placebo-controlled, dose-finding study of rizatriptan (MK-462) in the acute treatment of migraine. Cephalalgia 1997;17(6):647-51. 154. Scott RJ, Aitchison WR, Barker PR, McLaren GI. Oral sumatriptan in the acute treatment of migraine and migraine recurrence in general practice. QJM: Monthly Journal of the Association of Physicians 1996;89(8):613-22. 155. Cabarrocas F. For and on behalf of the Almotriptan Subcutaneous Study Group. First efficacy data on subcutaneous almotriptan, a novel 5HT1D agonist. Cephalalgia 1997;17:Poster 421. [Study type: conference abstract.] 156. Jackson NC. A comparison of oral eletriptan (UK-116,044) (20-80 mg) and oral sumatriptan (100 mg) in the acute treatment of migraine. Cephalalgia 1996;16:368-99. [Unable to identify study type—abstract not available.] 157. Färkkilä M. A dose-finding study of eletriptan (UK-116,044) (5-30 mg) for the acute treatment of migraine. Cephalalgia 1996;16:387-8. [Unable to identify study type—abstract not available.]

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158. Cabarrocas X, Zayas JM. Efficacy data on oral almotriptan, a novel 5-HT1B/1D agonist. Headache 1998;38(5):377. [Unable to identify study type—abstract not available.] 159. Ryan R, Keywood C. A preliminary study of frovatriptan (VML251), a potent cerebroselective 5-hydroxytryptamine (5-HT)1B/1D agonist for the acute treatment of migraine. Abstract MTH1. European Journal of Neurology 1998;5(Suppl 3): S46. [Study type: conference abstract.] 160. Goldstein J, Keywood C. A study of the efficacy and safety of low doses of frovatriptan (VML251), a potent cerebroselective 5-hydroxytryptamine (5-HT)1B/1D agonist in the acute treatment of migraine. Abstract MTH2. European Journal of Neurology 1998;5(Suppl 3): S46-S47. [Study type: conference abstract.] 161. Rapoport A. The dose range characteristics of frovatriptan (VML251) a potent cerebroselective 5-hydroxytryptamine (5-HT)1B/1D agonist in the acute treatment of migraine. Abstract 4.1. Cephalalgia 1998;18:384. [Study type: conference abstract.] 162. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001;358(9294):1668- 75. 163. Geraud G, Keywood C, Senard JM. Migraine headache recurrence: relationship to clinical, pharmacological, and pharmacokinetic properties of triptans. Headache 2003;43(4):376-88. 164. Goadsby PB, Lipton RB, Ferrari MD. Migraine: current understanding and management. New England Journal of Medicine 2002;346(4):257-70. 165. Welch KM, Mathew NT, Stone P, Rosamond W, Saiers J, Gutterman D. Tolerability of sumatriptan: clinical trials and post-marketing experience. Cephalalgia 2000;20(8):687-95. 166. Tfelt-Hansen P. Sumatriptan for the treatment of migraine attacks—a review of controlled clinical trials. Cephalalgia 1993;13(4):238-44. 167. Markus F, Mikko K. Frovatriptan review. Expert Opinion on Pharmacotherapy 2007;8(17):3029-33. 168. Tfelt-Hansen P, Ryan RE, Jr. Oral therapy for migraine: comparisons between rizatriptan and sumatriptan. A review of four randomized, double-blind clinical trials. Neurology 2000;55(9 Suppl 2):S19-S24. 169. Geraud G, Compagnon A, Rossi A. Zolmitriptan versus a combination of acetylsalicylic acid and metoclopramide in the acute oral treatment of migraine: a double-blind, randomised, three-attack study. European Neurology 2002;47(2):88-98. 170. Diener HC; The ASASUMAMIG Study Group. Efficacy and safety of intravenous acetylsalicylic acid lysinate compared to subcutaneous sumatriptan and parenteral placebo in the acute treatment of migraine. A double-blind, double-dummy, randomized, multicenter, parallel group study. Cephalalgia 1999;19(6):581-8. 171. Cady R, Martin V, Mauskop A, Rodgers A, Hustad CM, Ramsey KE, et al. Efficacy of Rizatriptan 10 mg administered early in a migraine attack. Headache 2006;46(6):914-24. 172. Dowson AJ, Massiou H, Lainez JM, Cabarrocas X. Almotriptan improves response rates when treatment is within 1 hour of migraine onset. Headache 2004;44(4):318-22.

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173. Cady R, Martin V, Mauskop A, Rodgers A, Hustad CM, Ramsey KE, et al. Symptoms of cutaneous sensitivity pre-treatment and post-treatment: results from the rizatriptan TAME studies. Cephalalgia 2007;27(9):1055-60. 174. Brandes JL, Kudrow D, Stark SR, O'Carroll CP, Adelman JU, O'Donnell FJ, et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA 2007;297(13):1443-54. 175. The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. New England Journal of Medicine 1991;325(5):316-21. 176. Bigal M, Sheftell F, Tepper S, Tepper D, Ho TW, Rapoport A. A randomized double-blind study comparing rizatriptan, dexamethasone, and the combination of both in the acute treatment of menstrually related migraine. Headache 2008;48(9):1286-93. 177. Charlesworth BR, Dowson AJ, Purdy A, Becker WJ, Boes-Hansen S, Farkkila M. Speed of onset and efficacy of zolmitriptan nasal spray in the acute treatment of migraine: a randomised, double-blind, placebo-controlled, dose-ranging study versus zolmitriptan tablet. CNS Drugs 2003;17(9):653-67. 178. Diener HC, Gendolla A, Gebert I, Beneke M. Almotriptan in migraine patients who respond poorly to oral sumatriptan: a double-blind, randomized trial. Headache 2005;45(7):874-82. 179. Olesen J, Diener HC, Schoenen J, Hettiarachchi J. No effect of eletriptan administration during the aura phase of migraine. European Journal of Neurology 2004;11(10):671-7. 180. Stark S, Spierings EL, McNeal S, Putnam GP, Bolden-Watson CP, O'Quinn S. Naratriptan efficacy in migraineurs who respond poorly to oral sumatriptan. Headache 2000;40(7):513-20. 181. Goldstein J, Ryan R, Jiang K, Getson A, Norman B, Block GA, et al; Rizatriptan Protocol 046 Study Group. Crossover comparison of rizatriptan 5 mg and 10 mg versus sumatriptan 25 mg and 50 mg in migraine. Headache 1998;38(10):737-47. 182. Tfelt-Hansen P, Teall J, Rodriguez F, Giacovazzo M, Paz J, Malbecq W, et al; Rizatriptan 030 Study Group. Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Headache 1998;38(10):748-55. 183. Goadsby PJ, Zanchin G, Geraud G, de Klippel N, Diaz-Insa S, Gobel H, et al. Early vs. non- early intervention in acute migraine-'Act when Mild (AwM)'. A double-blind, placebo- controlled trial of almotriptan. Cephalalgia 2008;28(4):383-91. 184. Dahlof C, Cady R, Poole AC. Speed of onset and efficacy of sumatriptan fast- disintegrating/rapid release tablets: results of two replicate randomised, placebo-controlled studies. Headache Care 2004;1:277-80. 185. Linde M, Mellberg A, Dahlof C. Subcutaneous sumatriptan provides symptomatic relief at any pain intensity or time during the migraine attack. Cephalalgia 2006;26(2):113-21. 186. Ferrari M. How to assess and compare drugs in the management of migraine: success rates in terms of response and recurrence. Cephalalgia 1999;19 Suppl 23:2-4. 187. Velentgas P, Cole JA, Mo J, Sikes CR, Walker AM. Severe vascular events in migraine patients. Headache 2004;44(7):642-51.

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188. Hall GC, Brown MM, Mo J, MacRae KD. Triptans in migraine: the risks of stroke, cardiovascular disease, and death in practice. Neurology 2004;62(4):563-8. 189. Katsarava Z, Fritsche G, Muessig M, Diener HC, Limmroth V. Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Neurology 2001;57(9):1694-8. 190. Diamond ML, Hettiarachchi J, Hilliard B, Sands G, Nett R. Effectiveness of eletriptan in acute migraine: primary care for Excedrin nonresponders. Headache 2004;44(3):209-16. 191. Pascual J, Cabarrocas X. Within-patient early versus delayed treatment of migraine attacks with almotriptan: the sooner the better. Headache 2002;42(1):28-31. 192. Burstein R, Collins B, Jakubowski M. Defeating migraine pain with triptans: a race against the development of cutaneous allodynia. Annals of Neurology 2004;55(1):19-26. 193. O'Quinn S, Davis RL, Gutterman DL, Pait GD, Fox AW. Prospective large-scale study of the tolerability of subcutaneous sumatriptan injection for acute treatment of migraine. Cephalalgia 1999;19(4):223-31. 194. Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache 2008;48(8):1157-68. [Study type: longitudinal study.] 195. Limmroth V, Kazarawa Z, Fritsche G, Diener HC. Headache after frequent use of serotonin agonists zolmitriptan and naratriptan. Lancet 1999;353(9150):378. [Unable to identify study type—abstract not available.] 196. Goadsby PJ. Role of naratriptan in clinical practice. Cephalalgia 1997;17:472-3. [Unable to identify study type—abstract not available.] 197. Becker WJ on behalf of the Study Group. A placebo-controlled, dose-defining study of sumatriptan nasal spray in the acute treatment of migraine. Cephalalgia 1995;15(Suppl 14):271- 6. [Unable to identify study type—abstract not available.] 198. Cady RK, Lipton RB, Hall C, Stewart WF, O'Quinn S, Gutterman D. Treatment of mild headache in disabled migraine sufferers: Results of the Spectrum Study. Headache 2000;40(10):792-7. 199. Klapper JA, Charlesworth B, Cheshire M, et al. Treatment of mild migraine with oral zolmitriptan 2.5 mg prevents progression to more severe pain and reduces the impact on normal activities in patients with significant migraine-related disability. Neurology 2002;58(Suppl 3):291-2. [Unable to identify study type—abstract not available.] 200. Belsey J. The clinical and financial impact of oral triptans in the management of migraine in the UK: a systematic review. Journal of Medical Economics 2000;3:35-47. 201. Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia 2002;22(8):633-58. 202. Pascual J, Mateos V, Roig C, Sanchez-Del-Rio M, Jimenez D. Marketed oral triptans in the acute treatment of migraine: a systematic review on efficacy and tolerability. Headache 2007;47(8):1152-68.

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203. Poolsup N, Leelasangaluk V, Jittangtrong J, Rithlamlert C, Ratanapantamanee N, Khanthong M. Efficacy and tolerability of frovatriptan in acute migraine treatment: systematic review of randomized controlled trials. Journal of Clinical Pharmacy and Therapeutics 2005;30(6):521-32. 204. Edmeads J. Defining response in migraine: which endpoints are important? European Neurology 2005;53 Suppl 1:22-8. 205. Mannix LK. Effect of triptans on the quality of life of patients with migraine. Headache Quarterly; 2002;13(3):11-21. 206. Diener HC. Efficacy of almotriptan 12.5 mg in achieving migraine-related composite endpoints: a double-blind, randomized, placebo-controlled study in patients controlled study in patients with previous poor response to sumatriptan 50 mg. Current Medical Research and Opinion 2005;21(10):1603-10. 207. Amery WK, Waelkens J. Prevention of the last chance: an alternative pharmacologic treatment of migraine. Headache 1983;23(1):37-8. 208. Jones J, Pack S, Chun E. Intramuscular prochlorperazine versus metoclopramide as single- agent therapy for the treatment of acute migraine headache. American Journal of Emergency Medicine 1996;14(3):262-4. 209. Cameron JD, Lane PL, Speechley M. Intravenous chlorpromazine vs intravenous metoclopramide in acute migraine headache. Academic Emergency Medicine 1995;2(7):597-602. 210. Tfelt-Hansen P, Olesen J, Aebelholt-Krabbe A, Melgaard B, Veilis B. A double blind study of metoclopramide in the treatment of migraine attacks. Journal of Neurology, Neurosurgery, and Psychiatry 1980;43(4):369-71. 211. Coppola M, Yealy DM, Leibold RA. Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache. Annals of Emergency Medicine 1995;26(5):541-6. 212. Ellis GL, Delaney J, DeHart DA, Owens A. The efficacy of metoclopramide in the treatment of migraine headache. Annals of Emergency Medicine 1993;22(2):191-5. 213. Tek DS, McClellan DS, Olshaker JS, Allen CL, Arthur DC. A prospective, double-blind study of metoclopramide hydrochloride for the control of migraine in the emergency department. Annals of Emergency Medicine 1990;19(10):1083-7. 214. Jones EB, Gonzalez ER, Boggs JG, Grillo JA, Elswick RK Jr. Safety and efficacy of rectal prochlorperazine for the treatment of migraine in the emergency department. Annals of Emergency Medicine 1994;24(2):237-41. 215. Rowat BM, Merrill CF, Davis A, South V. A double-blind comparison of granisetron and placebo for the treatment of acute migraine in the emergency department. Cephalalgia 1991;11(5):207-13. 216. Chappell AS, Bay JM, Botzum GD, Cohen ML. Zatosetron, a 5-HT3 receptor antagonist in a multicenter trial for acute migraine. Neuropharmacology 1994;33(3-4):509-13. 217. Waelkens J. Dopamine blockade with domperidone: bridge between prophylactic and abortive treatment of migraine? A dose-finding study. Cephalalgia 1984;4(2):85-90.

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218. Friedman BW, Corbo J, Lipton RB, Bijur PE, Esses D, Solorzano C, et al. A trial of metoclopramide vs sumatriptan for the emergency department treatment of migraines. Neurology 2005;64(3):463-8. 219. Ross-Lee LM, Eadie MJ, Heazlewood V, Bochner F, Tyrer JH. Aspirin pharmacokinetics in migraine. The effect of metoclopramide. European Journal of Clinical Pharmacology 1983;24(6):777- 85. 220. Schulman EA, Dermott KF. Sumatriptan plus metoclopramide in triptan-nonresponsive migraineurs. Headache 2003;43(7):729-33. 221. Chabriat H, Danchot J, Hugues FC, Joire JE. Combined aspirin and metoclopramide in the acute treatment of migraine attacks: a review. Headache Quarterly 1997;8(2):118-21. 222. Dowson A, Ball K, Haworth D. Comparison of a fixed combination of domperidone and paracetamol (Domperamol) with sumatriptan 50 mg in moderate to severe migraine: a randomised UK primary care study. Current Medical Research and Opinion 2000;16(3):190-7. 223. Colman I, Brown MD, Innes GD, Grafstein E, Roberts TE, Rowe BH. Parenteral metoclopramide for acute migraine: meta-analysis of randomised controlled trials. BMJ 2004;329(7479):1369-73. 224. Honkaniemi J, Liimatainen S, Rainesalo S, Sulavuori S. Haloperidol in the acute treatment of migraine: a randomized, double-blind, placebo-controlled study. Headache 2006;46(5):781-7. 225. Diamond S, Medina JL. Isometheptene—a non-ergot drug in the treatment of migraine. Headache 1975;15(3):211-3. 226. Ryan RE. A study of midrin in the symptomatic relief of migraine headache. Headache 1974;14(1):33-42. [Unable to identify study type—abstract not available.] 227. Ogden HD. Controlled studies of a new agent in vascular headache. Headache 1963;3:29-31. [Unable to identify study type—abstract not available.] 228. Kozubski W. Metamizole and hydrocortisone for the interruption of a migraine attack— preliminary study. Headache Quarterly 1992;3(3):326-8. [Unable to identify study type—abstract not available.] 229. Maizels M, Scott B, Cohen W, Chen W. Intranasal lidocaine for treatment of migraine: a randomized, double-blind, controlled trial. JAMA 1996;276(4):319-21. 230. Maizels M. Intranasal lidocaine for migraine in an outpatient population. Headache 1998;38(5):391. [Study type: conference abstract.] 231. Reutens DC, Fatovich DM, Stewart-Wynne EG, Prentice DA. Is intravenous lidocaine clinically effective in acute migraine? Cephalalgia 1991;11(6):245-7. 232. Bell R, Montoya D, Shuaib A, Lee MA. A comparative trial of three agents in the treatment of acute migraine headache. Annals of Emergency Medicine 1990;19(10):1079-82.

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Inventory of Guideline Recommendations - Pharmacological Interventions for Menstrual Migraine and Migraine in Pregnancy Table G.2b: Acute menstrual migraine - pharmacological interventions Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Simple analgesics G4 (UK) (Main guideline p. 39; BMJ summary p. 1233) 1 1 Patients with acute menstrual migraine can be treated with mefenamic acid or a 1 2 combination of acetylsalicylic acid, acetaminophen, and caffeine. Triptans G4 (UK) (Main guideline p. 39; BMJ summary p. 1233) 3 1 If attacks don’t respond to simple analgesics, sumatriptan, zolmitriptan, naratriptan, 3-5 6 and rizatriptan are recommended. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.2c: Acute migraine in pregnancy - pharmacological interventions Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Simple analgesics G2 (Europe) (p. 974) Not provided If migraine occurs during pregnancy, only paracetamol is allowed during the whole period. NSAIDs can be given in the second trimester. G4 (UK) (Main guideline p. 38; BMJ summary p. 1233) Based on the clinical experience of the guideline development group Where possible, the use of medication in pregnancy should be avoided, particularly (Background studies cited: Other7-11) in the first trimester. Acetaminophen 1000 mg is the treatment of choice in pregnancy for all patients with migraine when the pain is sufficient to require analgesia. If acetaminophen provides insufficient analgesia aspirin 300 mg or ibuprofen 400 mg can be used in the first and second trimester of pregnancy. As with any medication used during pregnancy, acetaminophen should be taken at the lowest effective dose for the shortest time necessary. Aspirin is contraindicated during the third trimester of pregnancy. Long-term exposure or exposure to high doses of ibuprofen in late pregnancy is associated with an increased risk of fetal complications. Triptans G2 (Europe) (p. 974) Not provided Triptans and ergot alkaloids are contraindicated. Administration of triptans in the first trimester of pregnancy is recommended by Based on the clinical experience of the guideline development group expert consensus if the child is more at risk by severe attacks with vomiting than by (Background studies cited: SR12,13; NR14; NRCS15-17) the potential impact of the triptan. G4 (UK) (Main guideline p. 38; BMJ summary p. 1233) Based on the clinical experience of the guideline development group There is insufficient evidence to advocate the use of triptans in pregnancy. (Background studies cited: SR12,18; NR14) CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; NSAIDs - non-steroidal anti-inflammatory drugs; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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References 1. Silberstein SD, Armellino JJ, Hoffman HD, Battikha JP, Hamelsky SW, Stewart WF, et al. Treatment of menstruation-associated migraine with the nonprescription combination of acetaminophen, aspirin, and caffeine: results from three randomized, placebo-controlled studies. Clinical Therapeutics 1999;21(3):475-91. 2. Al-Waili NS. Treatment of menstrual migraine with prostaglandin synthesis inhibitor mefenamic acid: double-blind study with placebo. European Journal of Medical Research 2000;5(4):176-82. 3. Loder E, Silberstein SD, Abu-Shakra S, Mueller L, Smith T. Efficacy and tolerability of oral zolmitriptan in menstrually associated migraine: a randomized, prospective, parallel-group, double-blind, placebo-controlled study. Headache 2004;44(2):120-30. 4. Massiou H, Jamin C, Hinzelin G, Bidaut-Mazel C. Efficacy of oral naratriptan in the treatment of menstrually related migraine. European Journal of Neurology 2005;12(10):774-81. 5. Nett R, Landy S, Shackelford S, Richardson MS, Ames M, Lener M. Pain-free efficacy after treatment with sumatriptan in the mild pain phase of menstrually associated migraine. Obstetrics and Gynecology 2003;102(4):835-42. 6. Silberstein SD, Massiou H, McCarroll KA, Lines CR. Further evaluation of rizatriptan in menstrual migraine: retrospective analysis of long-term data. Headache 2002;42(9):917-23. 7. British National Formulary. 56th edition. London (UK): BMJ Publishing; 2008. [Pharmaceutical compendium.] 8. Briggs G, Freeman RK, Yalle SJ. Drugs in pregnancy and lactation. 7th edition. Philadelphia (PA): Lippincott Williams and Wilkins; 2005. [Book.] 9. Lee A, Inch S, Finnigan D, editors. Therapeutics in pregnancy and lactation. Abingdon (UK): Radcliffe Medical Press; 2000. [Book.] 10. Rubin P, editor. Prescribing in pregnancy. London (UK): BMJ Publishing; 2000. [Book.] 11. Schaefer D, editor. Drugs during pregnancy and lactation. 1st edition. Amsterdam: Elsevier Science BV; 2001. [Book.] 12. Loder E. Safety of sumatriptan in pregnancy: a review of the data so far. CNS Drugs 2003;17(1):1-7. 13. Evans EW, Lorber KC. Use of 5-HT1 agonists in pregnancy. Annals of Pharmacotherapy 2008;42(4):543-9. 14. Fox AW, Chambers CD, Anderson PO, Diamond ML, Spierings EL. Evidence-based assessment of pregnancy outcome after sumatriptan exposure. Headache 2002;42(1):8-15. 15. O'Quinn S, Davis RL, Gutterman DL, Pait GD, Fox AW. Prospective large-scale study of the tolerability of subcutaneous sumatriptan injection for acute treatment of migraine. Cephalalgia 1999;19(4):223-31. 16. Olesen C, Steffensen FH, Sorensen HT, Nielsen GL, Olsen J. Pregnancy outcome following prescription for sumatriptan. Headache 2000;40(1):20-4.

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17. Källén B, Lygner PE. Delivery outcome in women who used drugs for migraine during pregnancy with special reference to sumatriptan. Headache 2001;41(4):351-6. 18. Hilaire ML, Cross LB, Eichner SF. Treatment of migraine headaches with sumatriptan in pregnancy. Annals of Pharmacotherapy 2004;38(10):1726-30.

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Inventory of Guideline Recommendations for Migraine - Non-Pharmacological Interventions Table G.3a: Migraine - non-pharmacological interventions Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other General statements G1 (USA) (Summary guideline for clinicians) Not provided The following non-pharmacologic headache treatments may be used alone or combined with preventive drug therapy to achieve additional clinical improvement: • relaxation training; • thermal biofeedback with relaxation training; • electromyographic (EMG) biofeedback; • cognitive-behavioural therapy. (AAN Encounter Kit Headache) These non-pharmacologic therapies may be particularly well-suited as treatment options for patients with one or more of the following: • history of long-term, frequent, or excessive use of analgesic or acute medications that can aggravate headache problems or lead to decreased responsiveness to other pharmacotherapies; • insufficient or no response to pharmacologic therapy; • medical contraindications to specific pharmacologic treatments; • preference for non-pharmacologic interventions; • pregnancy, planned pregnancy, or nursing; • significant stress, deficient stress-coping skills. G1 (USA) (AAN Encounter Kit Headache) Not provided Professional/patient interaction • Involve the patient in a long-term management plan to improve patient compliance • Create realistic goals • Be flexible and sensitive to the patient’s desires regarding various modalities of treatment • Share evidence-based findings • Be able to discuss non-proven or potentially harmful modalities (i.e. cervical manipulation in the elderly) • Recognize that combining behavioural and physical treatments with the use of conventional pharmacologic agents may improve the efficacy of both modalities

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Table G.3a: Migraine - non-pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Psychological G1 (USA) (p. 9-10, p. 17) 2 1 1 therapy Behavioural therapy (i.e. relaxation, biofeedback) may be combined with preventive 1,2 3 4 drug therapy (i.e. propranolol, amitriptyline) for patients to achieve additional clinical Some difference (G1 improvement for migraine relief. and G3 vs G4) with G1 (USA) (p. 7-9, p. 16-17) Relaxation 1 3 1 respect to cognitive Relaxation training (progressive muscle relaxation, autogenic training 5 6-8 9 behavioural therapy, training, and meditation or passive relaxation), thermal relaxation therapy, Thermal 4 3 1 biofeedback combined with relaxation training, EMG biofeedback, 5,10,11,12 7,13,14 9 and biofeedback biofeedback + and cognitive-behavioural therapy may be considered as treatment relaxation options for prevention of migraine. Specific recommendations training regarding which of these to use for specific patients cannot be made. EMG 1 2 biofeedback 11 7,15 Cognitive- 2 1 2 behavioural 16,17 8 9,18 therapy G3 (France) (Summary [English] p. 1314; Main guideline [French] p. 84-86) 1 Relaxation, biofeedback, and cognitive and behavioural therapies for stress 19 management have been shown to be effective in the prophylactic treatment of migraine and can be considered in some patients, depending on their psychological profile. G4 (UK) (Main guideline p. 43; BMJ summary p. 1233) Based on the clinical experience of the guideline development group No good quality contemporary evidence was identified for cognitive behavioural (Background studies cited: RCT20; G21) therapy or any specific relaxation therapy or biofeedback technique in the management of headache. Hypnosis G1 (USA) (p. 7-8, p. 10-13, p. 17-18) 1 Evidence-based treatment recommendations are not yet possible regarding the use 22 of hypnosis as preventive or acute therapy for migraine.

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Table G.3a: Migraine - non-pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Acupuncture G1 (USA) (p. 7-8, p. 10-13, p. 17-18) 2 2 1 2 Evidence-based treatment recommendations are not yet possible regarding the use 23,24 25,26 27 18,28 Some difference (G1 of acupuncture as preventive or acute therapy for migraine. and G3 vs G4) with G3 (France) (Summary [English] p. 1314; Main guideline [French] p. 86) 1 respect to acupuncture Data in the literature is insufficient to draw conclusion about the efficacy of 29 acupuncture for the prevention of migraine. G4 (UK) (Main guideline p. 45; BMJ summary p. 1233) 2 5 Acupuncture can help reduce migraine frequency and severity and should be 29,30 31-35 considered for preventive management in patients with migraine. However, sham acupuncture (superficial needling at non-acupuncture points) can be equally as effective. Cervical G1 (USA) (p. 7-8, p. 10-13, p. 17-18) 1 manipulation Evidence-based treatment recommendations are not yet possible regarding the use 36 of cervical manipulation as preventive or acute therapy for migraine. G3 (France) (Summary [English] p. 1312; Main guideline [French] p. 87-88) 1 Data in the literature is insufficient to draw conclusion about the efficacy of cervical 37 manipulation for the prevention of migraine. Homeopathy G2 (Europe) (p. 973) 3 No efficacy in migraine prophylaxis has been shown for homeopathic remedies. 38-40 G3 (France) (Summary [English] p. 1314; Main guideline [French] p. 86-87) 1 Data in the literature is insufficient to draw conclusion about the efficacy of 41 homeopathy for the prevention of migraine. G4 (UK) (Main guideline p. 47; BMJ summary p. 1233) Based on the clinical experience of the guideline development group Homeopathy is not effective as a migraine prophylaxis. (Background studies cited: SR41)

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Table G.3a: Migraine - non-pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Hyperbaric oxygen G1 (USA) (p. 7-8, p. 10-13, p. 17-18) 1 Evidence-based treatment recommendations are not yet possible regarding the use 42 of hyperbaric oxygen as preventive or acute therapy for migraine. Massage G4 (UK) (Main guideline p. 45) 1 There is insufficient evidence to make a recommendation on the use of massage in 20 the treatment of patients with headache. Occlusal G1 (USA) (p. 7-8, p. 10-13, p. 17-18) 1 adjustment Evidence-based treatment recommendations are not yet possible regarding the use 43 of occlusal adjustment as preventive or acute therapy for migraine. Oral rehabilitation G4 (UK) (Main guideline p. 46) Based on the clinical experience of the guideline development group No good quality evidence was found to determine whether the use of acrylic splints is effective for patients with migraine. Spinal G4 (UK) (Main guideline p. 44) 1 manipulation The evidence of effectiveness is too limited to lead to a recommendation. 44 Transcutaneous G1 (USA) (p. 7-8, p. 10-13, p. 17-18) 1 1 electrical nerve Evidence-based treatment recommendations are not yet possible regarding the use 45 46 stimulation of TENS as preventive or acute therapy for migraine. (TENS) G4 (UK) (Main guideline p. 45) 1 1 There is insufficient evidence to make a recommendation on the use of TENS in the 44 47 treatment of patients with headache. Diet G4 (UK) (Main guideline p. 41; BMJ summary p. 1233) 1 1 1 1 1 No good quality evidence was found to support the notion that specific foods trigger 48 49 50 51 52 migraine. Expert opinion suggests that missing meals may be a factor. Patients with migraine should be encouraged not to miss meals. Stress management G4 (UK) (Main guideline p. 42; BMJ summary p. 1233) 1 1 1 Stress management should be considered as part of a combined treatment program 20 50 53 (including group exercise and relaxation classes) to help patients reduce the frequency and severity of migraine headaches. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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References 1. Holroyd KA, France JL, Cordingley GE, Rokicki LA, Kvaal SA, Lipchik GL, et al. Enhancing the effectiveness of relaxation-thermal biofeedback training with propranolol hydrochloride. Journal of Consulting and Clinical Psychology 1995;63(2):327-30. 2. Mathew NT. Prophylaxis of migraine and mixed headache. A randomized controlled study. Headache 1981;21(3):105-9. 3. Sovak M, Kunzel M, Sternbach RA, Dalessio DJ. Mechanism of the biofeedback therapy of migraine: volitional manipulation of the psychophysiological background. Headache 1981;21(3):89-92. 4. Penzien D, Johnson C, Carpenter D, Holroyd K. Drug vs. behavioral treatment of migraine: long-acting propranolol vs. home-based self-management training. Headache 1990;30(5):300. [Study type: conference abstract.] 5. Blanchard EB, Theobald DE, Williamson DA, Silver BV, Brown DA. Temperature biofeedback in the treatment of migraine headaches: a controlled evaluation. Archives of General Psychiatry 1978;35(5):581-8. 6. Brown JM. Imagery coping strategies in the treatment of migraine. Pain 1984;18(2):157-67. 7. Daly EJ, Donn PA, Galliher MJ, Zimmerman JS. Biofeedback applications to migraine and tension headaches: a double-blinded outcome study. Biofeedback and Self-regulation 1983;8(1):135- 52. 8. Sorbi M, Tellegen B. Differential effects of training in relaxation and stress-coping in patients with migraine. Headache 1986;26(9):473-81. 9. Barrios FX. Social skills training and psychosomatic disorders. In: Rathjen DP, Foreyt JP, editors. Social competence: Interventions for children and adults. New York (NY): Pergamon; 1980. p. 271-301. [Book.] 10. Blanchard EB, Appelbaum KA, Radnitz CL, Morrill B, Michultka D, Kirsch C, et al. A controlled evaluation of thermal biofeedback and thermal biofeedback combined with cognitive therapy in the treatment of vascular headache. Journal of Consulting and Clinical Psychology 1990;58(2):216-24. 11. Lake A, Rainey J, Papsdorf JD. Biofeedback and rational-emotive therapy in the management of migraine headache. Journal of Applied Behavioral Analysis 1979;12(1):127-40. 12. McGrady A, Wauquier A, McNeil A, Gerard G. Effect of biofeedback-assisted relaxation on migraine headache and changes in cerebral blood flow velocity in the middle cerebral artery. Headache 1994;34(7):424-8. 13. Blanchard EB, Appelbaum KA, Nicholson NL, Radnitz CL, Morrill B, Michultka D, et al. A controlled evaluation of the addition of cognitive therapy to a home-based biofeedback and relaxation treatment of vascular headache. Headache 1990;30(6):371-6. 14. Blanchard EB, Nicholson NL, Radnitz CL, Steffek BD, Appelbaum KA, Dentinger MP. The role of home practice in thermal biofeedback. Journal of Consulting and Clinical Psychology 1991;59(4):507-12.

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15. Bild R, Adams HE. Modification of migraine headaches by cephalic blood volume pulse and EMG biofeedback. Journal of Consulting and Clinical Psychology 1980;48(1):51-7. 16. Richardson GM, McGrath PJ. Cognitive-behavioral therapy for migraine headaches: a minimal-therapist-contact approach versus a clinic-based approach. Headache 1989;29(6):352-7. 17. Sorbi M, Tellegen B. Multimodal migraine treatment: does thermal feedback add to the outcome? Headache 1984;24(5):249-55. 18. Wittchen H, Holroyd KA, Schlote B, Zenz B. A biobehavioral treatment program (SEP) for chronic migraine patients. In: Wittchen H, Holroyd KA, Schlote B, Zenz B, editors. Perspectives in research on headache. Toronto (ON): Hogrefe; 1993. p. 183-97. [Book chapter.] 19. Campbell JK, Penzien DB, Wall EM. Evidence-based guidelines in primary care setting. St Paul (MN): American Academy of Neurology; 2000. 20. Lemstra M, Stewart B, Olszynski WP. Effectiveness of multidisciplinary intervention in the treatment of migraine: a randomized clinical trial. Headache 2002;42(9):845-54. 21. US Headache Consortium. Evidence-based guidelines for migraine headache: behavioural and physical treatments. Available from: www.aan.com/professionals/practice/pdfs/g (accessed 4 April 2013). 22. Anderson JA, Basker MA, Dalton R. Migraine and hypnotherapy. The International Journal of Clinical and Experimental Hypnosis 1975;23(1):48-58. 23. Hesse J, Mogelvang B, Simonsen H. Acupuncture versus metoprolol in migraine prophylaxis: a randomized trial of trigger point inactivation. Journal of Internal Medicine 1994;235(5):451-6. 24. Vincent CA. A controlled trial of the treatment of migraine by acupuncture. Clinical Journal of Pain 1989;5(4):305-12. 25. Dowson DI, Lewith GT, Machin D. The effects of acupuncture versus placebo in the treatment of headache. Pain 1985;21(1):35-42. 26. Lenhard L, Waite PM. Acupuncture in the prophylactic treatment of migraine headaches: pilot study. New Zealand Medical Journal 1983;96(738):663-6. 27. Loh L, Nathan PW, Schott GD, Zilkha KJ. Acupuncture versus medical treatment for migraine and muscle tension headaches. Journal of Neurology, Neurosurgery, and Psychiatry 1984;47(4):333-7. 28. Cecherelli F, Ambrosio F, Avila M, Duse G, Giron GP. Acupuncture vs. placebo in the common migraine: a double blind study. Cephalalgia 1987;7(Suppl 6):499-500. [Unable to identify study type—abstract not available.] 29. Melchart D, Linde K, Fischer P, Berman B, White A, Vickers A, et al. Acupuncture for idiopathic headache. Cochrane Database of Systematic Reviews 2001;(Issue 1):CD001218. 30. Griggs C, Jensen J. Effectiveness of acupuncture for migraine: critical literature review. Journal of Advanced Nursing 2006;54(4):491-501. 31. Diener HC, Kronfeld K, Boewing G, Lungenhausen M, Maier C, Molsberger A, et al. Efficacy of acupuncture for the prophylaxis of migraine: a multicentre randomised controlled clinical trial. Lancet Neurology 2006;5(4):310-6.

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32. Karst M, Reinhard M, Thum P, Wiese B, Rollnik J, Fink M. Needle acupuncture in tension- type headache: a randomized, placebo-controlled study. Cephalalgia 2001;21(6):637-42. 33. Melchart D, Streng A, Hoppe A, Brinkhaus B, Witt C, Wagenpfeil S, et al. Acupuncture in patients with tension-type headache: randomised controlled trial. BMJ 2005;331(7513):376-82. 34. Vickers AJ, Rees RW, Zollman CE, McCarney R, Smith CM, Ellis N, et al. Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis. Health Technology Assessment 2004;8(48):1-35. 35. Alecrim-Andrade J, Maciel-Junior JA, Cladellas XC, Correa-Filho HR, Machado HC. Acupuncture in migraine prophylaxis: a randomized sham-controlled trial. Cephalalgia 2006;26(5):520-9. 36. Parker GB, Tupling H, Pryor DS. A controlled trial of cervical manipulation of migraine. Australian and New Zealand Journal of Medicine 1978;8(6):589-93. 37. Tuchin PJ, Pollard H, Bonello R. A randomized controlled trial of chiropractic spinal manipulative therapy for migraine. Journal of Manipulative and Physiological Therapeutics 2000;23:91- 5. 38. Straumsheim P, Borchgrevink C, Mowinckel P, Kierulf H, Hafslund O. Homeopathic treatment of migraine: a double blind, placebo controlled trial of 68 patients. The British Homeopathic Journal 2000;89(1):4-7. 39. Walach H, Haeusler W, Lowes T, Mussbach D, Schamell U, Springer W, et al. Classical homeopathic treatment of chronic headaches. Cephalalgia 1997;17(2):119-26. 40. Whitmarsh TE, Coleston-Shields DM, Steiner TJ. Double-blind randomized placebo- controlled study of homoeopathic prophylaxis of migraine. Cephalalgia 1997;17(5):600-4. 41. Ernst E. Homeopathic prophylaxis of headaches and migraine? A systematic review. Journal of Pain Symptom and Management 1999;18(5):353-7. 42. Myers DE, Myers RA. A preliminary report on hyperbaric oxygen in the relief of migraine headache. Headache 1995;35(4):197-9. 43. Forssell H, Kirveskari P, Kangasniemi P. Changes in headache after treatment of mandibular dysfunction. Cephalalgia 1985;5(4):229-36. 44. Bronfort G, Nilsson N, Haas M, Evans R, Goldsmith CH, Assendelft WJ, et al. Non-invasive physical treatments for chronic/recurrent headache. Cochrane Database of Systematic Reviews 2004;(3):CD001878. 45. Solomon S, Guglielmo KM. Treatment of headache by transcutaneous electrical stimulation. Headache 1985;25(1):12-5. 46. Sheftell F, Rapoport A, Kudrow L. Efficacy of cranial electrotherapy stimulation in the prophylactic treatment of migraine and chronic muscle contraction headaches. Cephalalgia 1989;9(Suppl 10):379-80. [Unable to identify study type—abstract not available.] 47. Allais G, De Lorenzo C, Quirico PE, Lupi G, Airola G, Mana O, et al. Non-pharmacological approaches to chronic headaches: transcutaneous electrical nerve stimulation, laser therapy and acupuncture in transformed migraine treatment. Neurological Sciences 2003;24(Suppl 2):S138- S142.

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48. Crawford P, Simmons M, Hoock J. Clinical inquiries. What dietary modifications are indicated for migraines? Journal of Family Practice 2006;55(1):62-3,66. 49. Pradalier A, Bakouche P, Baudesson G, Delage A, Cornaille-Lafage G, Launay JM, et al. Failure of omega-3 polyunsaturated fatty acids in prevention of migraine: a double-blind study versus placebo. Cephalalgia 2001;21(8):818-22. 50. Wober C, Brannath W, Schmidt K, Kapitan M, Rudel E, Wessely P, et al. Prospective analysis of factors related to migraine attacks: the PAMINA study. Cephalalgia 2007;27(4):304-14. 51. British Association for the Study of Headache (BASH). Guidelines for all healthcare professionals in the diagnosis and management of migraine, tension-type, cluster and medication-overuse headache. 3rd edition. Hull (UK): BASH; 2007. Available from: http://216.25.88.43/upload/NS_BASH/BASH_guidelines_2007.pdf (accessed 4 April 2013). 52. Wober C, Holzhammer J, Zeitlhofer J, Wessely P, Wober-Bingol C. Trigger factors of migraine and tension-type headache: experience and knowledge of the patients. Journal of Headache and Pain 2006;7(4):188-95. [Study type: cross-sectional study.] 53. Vos J, Passchier J. Reduced impact of migraine in everyday life: an observational study in the Dutch Society of Headache Patients. Headache 2003;43(6):645-50. [Study type: cross-sectional study.]

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Inventory of Guideline Recommendations for Migraine Prophylaxis Table G.4a: Migraine prophylaxis - pharmacological interventions Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Prophylaxis G1 (USA) (p. 21-23) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs (general Medication use statements) • Initiate therapy with the lowest effective dose. Begin with a low dose of the chosen pharmacological agent and increase the dose slowly until clinical benefits are achieved in the absence of adverse events or until limited by adverse events. • Give each treatment an adequate trial. A clinical benefit may take as long as 2 to 3 months to manifest itself. • Avoid interfering medications (e.g. overuse of certain acute medications such as ergotamine). • Use of a long-acting formulation may improve compliance. Patient education • Maximize compliance. Discuss with the patient the rationale for a particular treatment, when and how to use it, and what adverse events are likely. • Address patient expectations. Discuss with the patient the expected benefits of therapy and how long it will take to achieve them. • Create a formal management plan. Evaluation • Monitor patients’ headaches by having them keep headache diaries. Diaries help to track headache and related symptoms from one clinic visit to another. By consensus, they are considered the “gold standard” in headache attack evaluation. Diaries should be user-friendly and should measure attack frequency, severity, duration, disability, response to type of treatment, and adverse effects of medication. • Re-evaluate therapy. After a period of stability, consider tapering or discontinuing treatment. Coexisting conditions Some conditions are more common in patients with migraine. Take into account the presence of coexisting diseases. These include stroke, myocardial infarction, (continued over page) Raynaud’s phenomenon, epilepsy, affective disorders, and anxiety disorders. Coexisting diseases present both treatment opportunities and limitations.

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Prophylaxis For example: Consensus achieved by the US Headache Consortium in the absence of relevant RCTs (general • once the coexisting condition has been identified, select a pharmacological statements) agent that will treat both disorders; (cont’d) • establish that the coexisting condition is not a contraindication for the selected migraine therapies (e.g. beta-blockers are contraindicated in patients with asthma); • establish that the treatments being used for coexisting conditions do not exacerbate migraine; • beware of interactions between pharmacological agents used for migraine and those used for other conditions; • direct special attention to women who are pregnant or want to become pregnant. Preventive medications may have teratogenic effects. If treatment is absolutely necessary, select a treatment with the lowest risk of adverse effects to the fetus.

G1 (USA) (Summary guideline for clinicians) Not provided Guide to preventive therapy Consider preventive therapies when any of these are present: • frequent headaches (>2 per week); • migraine significantly interferes with patient’s daily routines, despite acute treatment; • contraindication to acute therapies or failure, adverse effects, or overuse of acute therapies; • patient preference; • presence of uncommon migraine conditions, including hemiplegic migraine, basilar migraine, migraine with prolonged aura, or migrainous infarction. Goals of preventive therapies (continued over page) • Reduce attack frequency, severity, and duration. • Improve responsiveness to acute treatment. • Improve function and reduce disability.

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Prophylaxis G1 (USA) (Summary guideline for clinicians) Not provided (general Guide to preventive medication use statements) • Use medication with best efficacy and fewest adverse events. (cont’d) • Take coexisting conditions into account.

• Select a drug that will treat more than one condition, if possible • Be sure that the coexistent disease is not a contraindication to the migraine treatment.

• Be sure that the treatments used for coexistent conditions do not exacerbate migraine.

• Beware of drug interactions. • Start low and increase dose slowly until benefits are achieved or limited side effects occur.

• Give the drug an adequate trial at adequate dose (2 to 3 months). • Avoid interfering medications (e.g. overuse of acute medications). • Consider a long-acting formulation, which may improve compliance. • Monitor the patient’s headache diary. • Re-evaluate therapy. If headache is controlled at 6 months, consider tapering or discontinuing treatment. G2 (Europe) (p. 971-2) Based on expert opinion of the guideline development group Prophylactic drug treatment of migraine should be considered and discussed with the patient when: • the quality of life, business duties, or school attendance are severely impaired; • frequency of attacks is ≥2 per month; • migraine attacks do not respond to acute drug treatment;

• frequent, very long, or uncomfortable auras can occur.

A migraine prophylaxis is regarded as successful if the frequency of migraine attacks (continued over page) per month is decreased by at least 50% within 3 months. For therapy evaluation, a migraine diary is extremely useful.

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Prophylaxis G3 (France) (Summary [English] p. 1313; Main guideline [French] p. 70-84; Professional consensus (general Summary [French] p. 11-13) (Background studies cited: NR1; CS2;3; G4; Other5) statements) When to use pharmacologic prophylaxis (cont’d) It is recommended to start prophylactic treatment in two situations: • as a function not only of the frequency and the intensity of the attacks but also of the activities of daily living disability caused by them; • when a patient has taken 6 to 8 doses of acute migraine medication per month for ≥3 consecutive months, even if the medication is effective, to avoid medication overuse (this applies to migraine-specific and/or non- specific agents). The introduction of preventive treatment should be combined with patient education. The patient should be advised that preventive treatment does not eliminate migraine attacks but does limit their frequency and intensity. Keeping an attack diary is helpful for assessing the efficacy of the prophylactic treatment. Drugs to use in prophylaxis No compound has been shown to be more efficacious in migraine prophylaxis compared with the others. Thus, the choice of drug depends on the risk-benefit ratio, including adverse effects, contraindications, drug-to-drug interactions, and any comorbidity the patient may have. Starting treatment Prophylaxis should begin with a single drug at a low dose. The dose should be increased progressively until the optimal dose is achieved, with adverse effects taken into account. Evaluation of efficacy The efficacy of migraine prophylaxis should be assessed after 3 months of treatment. Treatment is considered to be effective if the frequency of migraine attacks is reduced by at least 50%. It is also important to take into account reductions in the consumption of acute-treatment medications and the intensity and duration of the attacks as measured in the migraine diary. Alternative prophylaxis If prophylactic treatment is unsuccessful, and the patient has not experienced any adverse effects, the dose can be increased. Alternatively, a different prophylactic drug (continued over page) can be used. After each prophylactic monotherapy has been tried, two drugs may be combined, each at a low dose to reduce the risk for adverse effects with either drug.

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Prophylaxis Discontinuation (general If successful, prophylactic treatment should be continued for 6 months to 1 year. statements) The dose should then be decreased slowly (over 3 to 6 months) prior to (cont’d) discontinuation. The same treatment can be restarted if the frequency of the attacks increases again. G4 (UK) (Main guideline p. 24; BMJ summary p. 1232) Based on expert opinion of the guideline development group Preventive pharmacological treatment of migraine should be considered in patients with recurring migraines that significantly interfere with their daily routine, in the presence of contraindication to, failure of, or overuse of acute therapies and in uncommon forms of migraine (hemiplegic migraine, basilar artery migraine, or migraine with prolonged aura). The goal of preventive therapy is to reduce the attack frequency, severity, and duration, improve responsiveness to treatment of acute attacks, and reduce migraine associated disability. Preventive pharmacological treatment will not stop all migraine and may not be effective in patients with medication overuse headache. Choice depends on comorbidities, potential drug interactions, and patient preference. General principles for preventive treatment for migraine Based on the clinical experience of the guideline development group 6 7 • Most preventive drugs should be titrated slowly to an effective or maximum (Background studies cited: RCT ; G ) dose in order to minimise side effects. • Preventive medication should be given a trial of at least 6 to 8 weeks following dose titration. • The choice of preventive medications should be guided by their side effect profile and the patient’s comorbid conditions. • After 6 to 12 months of effective prophylaxis, gradual withdrawal should be considered. Alongside preventive migraine treatment patients should also have access to appropriate mediations for treatment of acute attacks of migraine.

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Group 1 therapies G1 (USA) (p. 44) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs No recommendations can be made regarding dosing regimens. Dose ranges are presented for reference purposes only. No dosing information is provided for treatments lacking relevant RCTs. (p. 4-20, 24, 44-55) The following preventive medications have proven high efficacy and mild-to- moderate adverse events. Amitriptyline 3 3 (Doses tested: 25 mg to 150 mg/day; efficacious doses in clinical trials: 30 mg 8-10 11-13 to 150 mg/day) Common adverse events: drowsiness, weight gain, and anticholinergic adverse events; long-term weight gain can be troublesome. Risk of drug interaction between cisapride and amitriptyline. Divalproex sodium (DS); sodium valproate (SV) 5 3 1 (DS: doses tested - 500 mg to 1500 mg/day; serum level - 70 mg/L to 120 14-18 19,20,21 22 mg/L; efficacious doses in clinical trials - 500 mg to 1500 mg/day.) (SV: doses tested - 800 mg to 1500 mg/day; serum level - 50 mg/L; efficacious doses in clinical trials - 800 mg to 1500 mg/day.) Common adverse events: nausea, asthenia, somnolence, vomiting, tremor, alopecia, weight gain, neural tube defects, and teratogenic potential. Not recommended in patients with liver disease. Lisuride 5 1 (Doses tested: 0.075 mg to 0.225 mg/day; efficacious doses in clinical trials: 23-27 28 0.075 to 0.15 mg/day.) Propranolol; timolol 16 16 1 2 (Propranolol: doses tested - 40 mg to 240 mg/day; efficacious doses in clinical 9,10,18, 29-41 42-57 58 22,59 trials - 80 mg to 240 mg/day.) (Timolol: doses tested - 20 mg to 30 mg/day; efficacious doses in clinical trials - 20 mg to 30 mg/day.) Infrequent adverse events include: fatigue, depression, nausea, dizziness, and insomnia. When used in conjunction with rizatriptan, a lower dose of rizatriptan should be given. Should not be used in patients with coexistent asthma, cardiac insufficiency, or Raynaud’s disease. May exacerbate depression.

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Group 2 therapies G1 (USA) (p. 44) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs No recommendations can be made regarding dosing regimens. Dose ranges are presented for reference purposes only. No dosing information is provided for treatments lacking relevant RCTs. (p. 4-20, 24, 44-55) 8 10 2 The following preventive medications have efficacy (lower than those listed in group 29,31,60-65 44,66-74 22,75 1) and mild-to-moderate adverse events. Aspirin (Doses tested: 325 mg every other day, 1300 mg/day; efficacious doses in clinical trials: 1300 mg/day.)

Aspirin plus dipyridamole

(Doses tested: Aspirin 975 mg to 1300 mg + Dipiridamole 75 mg/day; efficacious doses in clinical trials: 975 mg + 75 mg/day.) Fenoprofen (Doses tested: 600 mg to 1800 mg/day; efficacious doses in clinical trials: 1800 mg/day.) Flurbiprofen (Doses tested: 200 mg/day; efficacious doses in clinical trials: 200 mg/day.) Indobufen (Doses tested: 400 mg/day; efficacious doses in clinical trials: 400 mg/day.)

Ketoprofen

(Doses tested: 150 mg/day; efficacious doses in clinical trials: 150 mg/day.)

Lornoxicam (Doses tested: 12 mg/day; efficacious doses in clinical trials: 12 mg/day.) Mefenamic acid (Doses tested: 1500 mg/day; efficacious doses in clinical trials: 1500 mg/day.) Naproxen (Doses tested: 500 mg/day; efficacious doses in clinical trials: not established in placebo-controlled trials.) Naproxen sodium (Doses tested: 1100 mg/day; efficacious doses in clinical trials: 1100 mg/day.)

Tolfenamic acid (Doses tested: 300 mg/day; efficacious doses in clinical trials: 300 mg/day.) Common adverse events NSAIDs: abdominal discomfort, gastritis, nausea, vomiting, occult gastrointestinal bleed. (continued over page)

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Group 2 therapies Atenolol 5 13 1 1 (cont’d) (Doses tested: 100 mg/day; efficacious doses in clinical trials: 100mg/day.) 76-80 55,66,81-91 58 92 Metoprolol (Doses tested: 50 mg to 300 mg/day; efficacious doses in clinical trials: 200 mg/day.) Nadolol (Doses tested: 80 mg to 240 mg/day; efficacious doses in clinical trials: 80 mg to 240 mg/day.) Adverse events: tiredness, fatigue, dizziness, and insomnia. Should not be used in patients with coexistent asthma, cardiac insufficiency, or Raynaud’s disease. May exacerbate depression. Cyclandelate 8 9 (Doses tested: 1200 mg to 1600 mg/day; efficacious doses in clinical trials: not 40,41,93,94, 95, 57, 99, 100-106 established in placebo-controlled trials.) 96-98 Adverse events: infrequent dizziness, oedema, flushing, and constipation. Verapamil (Doses tested: 240 mg/day; efficacious doses in clinical trials: 240 mg/day.) Common adverse events: constipation. Do not use if conduction block is present. Nimodipine (Doses tested: 60 mg to 120 mg/day; efficacious doses in clinical trials: 120 mg/day.) Common adverse events: abdominal discomfort. Fluoxetine (racemic), S-fluoxetine 3 1 (Doses tested: 20 mg every other day to 40 mg/day; efficacious doses in clinical 107-109 22 trials: 20 mg every other day to 40 mg/day.) (continued over page) Common adverse events: insomnia, fatigue, tremor, and stomach pain. Consider use in patients with coexistent depression.

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Group 2 therapies Gabapentin 2 (cont’d) (Doses tested: 900 mg to 2400 mg/day; efficacious doses in clinical trials: 900 110,111 mg to 2400 mg/day.) Adverse events: dizziness or giddiness and drowsiness. Guanfacine 1 (Doses tested: 0.5 mg to 1 mg/day; efficacious doses in clinical trials: 1 112 mg/day.) Feverfew 3 1 (Doses tested: 50 mg to ~82 mg/day; efficacious doses in clinical trials: 50 mg 113-115 116 to ~82 mg/day.) Mild adverse events. Withdrawal of feverfew may be associated with increased frequency of headaches. Magnesium 2 1 (Doses tested: 400 mg to 600 mg/day; efficacious doses in clinical trials: 400 mg 117,118 119 to 600 mg/day. Use of non-chelated formulation is associated with significant diarrhoea at clinically effective doses. Vitamin B2 (riboflavin) 1 (Doses tested: 400 mg/day; efficacious doses in clinical trials: 400 mg/day.) 120 Group 3a G1 (USA) (p. 44) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs therapies No recommendations can be made regarding dosing regimens. Dose ranges are presented for reference purposes only. No dosing information is provided for treatments lacking relevant RCTs. (p. 4-20, 24, 44-55) The following medications are clinically efficacious based on consensus and clinical experience and have mild-to-moderate adverse events: • cyproheptadine (Common adverse events: weight gain and fatigue); • bupropion; • mirtazepine; • trazodone; • venlafaxine; • (continued over page) diltiazem; • doxepin; • imipramine;

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Group 3a • nortriptyline; therapies • protriptyline; (cont’d) • fluvoxamine, paroxetine, sertraline (Common adverse events: insomnia, fatigue, tremor, and stomach pain); • ibuprofen (Common adverse events: abdominal discomfort, gastritis, nausea, vomiting, occult gastrointestinal bleed); • tiagabine; topiramate (Occasional central nervous system adverse events with both agents; kidney stones and weight loss with topiramate. Sedation could occur at doses of topiramate required to achieve efficacy.). (Efficacious doses in clinical trials: not established in placebo-controlled trials.) Group 3b G1 (USA) (p. 44) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs therapies No recommendations can be made regarding dosing regimens. Dose ranges are presented for reference purposes only. No dosing information is provided for treatments lacking relevant RCTs. (p. 4-20, 24, 44-55) The following medications are clinically efficacious based on consensus and clinical experience and have side effect concerns: • methylergonovine (methylergometrine); • phenelzine (Requires complex management with special dietary restrictions. High potential for drug interactions.). (Efficacious doses in clinical trials: not established in placebo-controlled trials.)

Group 4 therapies G1 (USA) (p. 44) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs No recommendations can be made regarding dosing regimens. Dose ranges are presented for reference purposes only. No dosing information is provided for treatments lacking relevant RCTs. (p. 4-20, 24, 44-55) The following medications have medium to high efficacy but with frequent or severe adverse events (or safety concerns) or complex management issues (special diets, (continued over page) high potential for severe adverse drug interactions).

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Group 4 therapies Methysergide 2 13 1 (cont’d) (Doses tested: 2 mg to 10 mg/day, based on body weight; efficacious doses in 121,122 23,53,55,123- 133 132 clinical trials: 6 mg/day.) Common adverse events: gastrointestinal - including nausea, vomiting, abdominal pain, and diarrhoea; leg symptoms (restlessness or pain); dizziness, giddiness, drowsiness, lassitude, and paresthesia. Serious adverse events include retroperitoneal or retropleural fibrosis, which may be associated with uninterrupted use. Manufacturer’s labelling suggests that methysergide be discontinued for 3 to 4 weeks after each 6-month course of treatment. Pizotifen 4 20 2 (Doses tested: 0.5 mg to 6 mg/day; efficacious doses in clinical trials: 1.5 to 6 63,94,96,121 21,26,88, 146,147 mg/day.) 100,101, Adverse events: substantial weight gain, tiredness, and drowsiness. 125,127,131, 134,135-145 Dihydroergotamine (TR-DHE oral) 2 4 1 (Doses tested: 10 mg/day; efficacious doses in clinical trials: 10 mg/day.) 148,149 12,150-152 153 Common adverse events: gastrointestinal symptoms including dyspepsia, epigastric pain, nausea, and vomiting. Flunarizine 6 13 1 (Doses tested: 3 mg to 15 mg/day; efficacious doses in clinical trials: 10 37,77,93,96, 50-52,100, 163 mg/day.) 154,155 101,123,156- Common adverse events: sedation, weight gain, and abdominal pain. Depression and 162 extrapyramidal symptoms can be observed, usually in elderly patients. Group 5 therapies G1 (USA) (p. 44) Consensus achieved by the US Headache Consortium in the absence of relevant RCTs No recommendations can be made regarding dosing regimens. Dose ranges are presented for reference purposes only. No dosing information is provided for treatments lacking relevant RCTs. (p. 4-20, 24, 44-55) 1 3 1 The following medications have evidence indicating limited or no efficacy over 164 165-167 168 placebo: • acebutolol, alprenolol, oxprenolol, pindolol Adverse events: fatigue, depression, nausea, dizziness, and insomnia. (continued over page) • carbamazepine (Doses tested: 600 mg/day; efficacious doses in clinical trials: 1 1 not established in placebo-controlled trials.) (Common adverse events: vertigo, 169 170 giddiness, and drowsiness.);

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Group 5 therapies • vigabatrin (Doses tested: 1000 mg to 2000 mg/day; efficacious doses in 3 (cont’d) clinical trials: not established in placebo-controlled trials.) (Safety concerns with 171-173 visual field constriction.); • clomipramine; 1 1 76 174

• clonazepam (Adverse events: dizziness or giddiness and drowsiness.); 1 175

• clonidine (Doses tested: 0.05 mg to 0.225 mg/day; efficacious doses in clinical 1 12 1 2 trials: 0.075 mg to 0.15 mg/day.) (Common adverse events: central nervous system, 176 21,112,170, 186 187,188 drowsiness, tiredness.); 177-185 • dihydroergokryptine (Doses tested: 20 mg/day; efficacious doses in clinical 1 3 trials: not established in placebo-controlled trials.) (Common adverse events: 149 129,162,189 gastrointestinal symptoms including dyspepsia, epigastric pain, nausea, and vomiting.); • femoxetine; 2 1 190,191 46

• flumedroxone (Doses tested: 10 mg to 30 mg/day; efficacious doses in 3 clinical trials: 10 to 30 mg/day.) (Common adverse events: in men -drowsiness, 126,192,193 dyspepsia, and decreased libido; in women - nausea, mastitis, polymenorrhea and other menstrual disturbances.); • indomethacin; 1 194 • lamotrigine; 1 195

• mianserin; 1 196

• nabumetone; 1 197

• nifedipine, nicardipine (Adverse events: dizziness, oedema, flushing, and constipation.); 3 2 1 39,198,199 200,201 58

(continued over page) • oxitriptan, iprazochrome, tropisetron. 2 5 122,202 132,138,203- 205

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other First line drug (p. 972) G2 (Europe) 1 1 21 8 1 4 therapy • Betablockers - metoprolol 50 mg to 200 mg; propranolol 40 mg to 240 mg. 206 207 14,18,32,34,37,77, 48,51,84,90, 222 223-226 • Calcium channel blockers - flunarizine 5 mg to 10 mg; female patients seem 85,86,93,208-219 157,163,220, Some difference (G2 to benefit from lower doses than male patients. 221 versus G3) with • Antiepileptic drugs - valproic acid 500 mg to 1800 mg; topiramate 25 mg to respect to first line 100 mg. drug therapy G3 (France) (Summary [English] p. 1312-1313; Main guideline [French] p. 70-84); 2 Summary [French] p. 11-13) 5,227 Taking into account the risk-benefit ratio, the following drugs can be used: • propranolol HCl - 40 mg to 240 mg/day (oral); • metoprolol succinate -100 mg to 200 mg/day (oral); • timolol maleate - 10 mg to 20 mg/day (oral); • atenolol - 100 mg/day (oral); • nadolol - 80 to 240 mg/day (oral). Common adverse effects: asthenia, poor exercise tolerance. Rare adverse effects (<1% of attacks): insomnia, nightmares, impotence, depression, hypoglycemia. Contraindications: asthma, heart failure, atrioventricular block, bradycardia. (Note: possible aggravation of migraine with aura). • oxetorone fumarate - 60 mg to 180 mg/day (1 to 3 tablets) (Common adverse effects: somnolence. Rare adverse effects (Bisoprolol 5 mg to 10 mg

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Second line drug G3 (France) (Summary [English] p. 1312-1313; Main guideline [French] p. 70-84); 1 2 therapy Summary [French] p. 11-13) 215 5,227 (cont’d) Taking into account the risk-benefit ratio, the following drugs can be used. Pizotifen 0.5 mg to 1.5 mg/day (progressive dosage to 3 tablets/day) Some difference (G2 Common adverse effects: sedation, weight gain. Rare adverse effects (<1% of attacks): digestive versus G3) with disorders, vertigo, muscle pain, asthenia. respect to second line Contraindications: glaucoma, urethroprostatic disorders. drug therapy Flunarizine HCl 10 mg (1 tablet in the evening); ≤6 months consecutively Common adverse effects: somnolence, weight gain. Rare adverse effects (<1% of attacks): depression, extrapyramidal syndrome. Contraindications: depression, extrapyramidal syndrome. Valproate sodium 500 mg to 1000 mg/day (oral) Adverse effects: nausea, weight gain, somnolence, tremor, alopecia, abnormal liver function test results. Contraindications: liver disease. Gabapentin 1200 mg to 2400 mg/day (oral) Adverse effects: nausea, vomiting, convulsion, somnolence, ataxia, vertigo. Contraindications: hypersensitivity to gabapentin. Topiramate 50 mg to 200 mg/day (oral) Adverse effects: vertigo, ataxia, somnolence, dysarthria, paresthesia, irritability, asthenia, weight loss. Contraindications: hypersensitivity to one of the active compounds and/or to sulfamides. Indoramin 50 mg/day (oral) Adverse effects: Somnolence, nasal congestion, dry mouth, ejaculation disorders. Contraindications: hypersensitivity to one of the active compounds; Parkinson’s disease; severe heart, liver, and/or kidney failure.

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other

Third line drug G2 (Europe) (p. 972) 1 1 11 234 235 117,118,120, 236- therapy • Acetylsalicylic acid 300 mg 243 • Gabapentin 1200 mg to 1600 mg Some difference (G2 • Oral magnesium 24 mmol versus G3) with • respect to third line Feverfew (Tanacetum parthenium) 3 x 6.25 mg drug therapy • Riboflavin 400 mg • Coenzyme Q10 - 300 mg • Candesartan 16 mg • Lisinopril 20 mg • Methysergide 4 mg to 12 mg; short-term use only (maximum 6 months per treatment period) because of potentially severe side effects G3 (France) (Summary [English] p. 1312-1313; Main guideline [French] p. 70-84); 2 Summary [French] p. 11-13) 5,227 Taking into account the risk-benefit ratio, the following drugs can be used. Methysergide maleate 2 mg to 6 mg (1 to 3 tablets); discontinuation required for 1 month every 6 months. Common adverse effects: nausea, vertigo, insomnia. Rare adverse effects (<1% of attacks): retroperitoneal fibrosis. Contraindications: hypertension, coronary insufficiency, arteriopathy, gastric ulcer, liver and/or kidney failure. (Note: should be reserved for patients with severe migraine resistant to other treatments.) Dihydroergotamine 10 mg to 20 mg/day (Note: dihydroergotamine is widely used for first line prophylaxis in France and is well tolerated. However, its efficacy remains to be confirmed.)

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Beta blockers G4 (UK) (p. 25) 1 1 Propranolol (80 mg to 240 mg per day) is recommended as first line therapy for 244 245 prophylaxis in patients with migraine. Timolol, atenolol, nadolol, and metoprolol can be used as alternatives to propranolol as Based on the clinical experience of the guideline development group prophylaxis in patients with migraine. (Background studies cited: G245) Atenolol is not licensed for use in migraine. When propranolol is prescribed to a patient using rizatriptan, the patient should be Based on the clinical experience of the guideline development group advised to halve the dose of rizatriptan and, in addition, not to take rizatriptan within (Background studies cited: Other246) 2 hours of taking propranolol. Use beta blockers with caution in patients with (not an exhaustive list) asthma, 1 1 diabetes, bradycardia, peripheral vascular disease, or comorbid depression. May be 7 246 preferred in patients with comorbid anxiety. Antiepileptics G4 (UK) (p. 26) 1 1 9 Topiramate 247 248 210,211,249-255 In patients with episodic migraine and chronic migraine, topiramate 50 mg to 200 mg per day is recommended to reduce headache frequency and severity. Use topiramate with caution in patients with (not an exhaustive list) renal stones, 1 1 angle closure glaucoma, or pregnancy. May be preferred in patients with comorbid 7 246 obesity. Sodium valproate 1 2 In patients with episodic migraine sodium valproate 800 mg to 1500 mg per day is 247 251,254 recommended to reduce headache frequency and severity. Use valproate with caution in patients with (not an exhaustive list) obesity, liver 1 1 disease, or pregnancy. May be preferred in patients with comorbid depression. 7 246 Gabapentin 1 Patients with episodic and chronic migraine can be treated with gabapentin 1200 mg 236 to 2400 mg per day to reduce headache frequency. When considering antiepileptic medication for prophylaxis of migraine in women of Based on the clinical experience of the guideline development group reproductive age, advice and counselling regarding the potential teratogenic side effects of these drugs should be given.

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Table G.4a: Migraine prophylaxis - pharmacological interventions (cont’d) Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Antidepressants G4 (UK) (p. 27) 2 Selective serotonin reuptake inhibitors are not recommended in the prophylaxis of 256,257 migraine. Amitriptyline 25 mg to 150 mg per day is recommended for patients requiring 1 1 prophylaxis of migraine. 230 245 Venlafaxine 75 mg to 150 mg per day is an effective alternative to tricyclic 2 antidepressants for prophylaxis of migraine. 228,230 Use tricyclic antidepressants with caution in patients with (not an exhaustive list) 1 1 angle closure glaucoma. May be preferred in patients with comorbid depression, 7 246 comorbid tension-type headache, or sleep disturbance. Feverfew G4 (UK) (Main guideline p. 47; BMJ summary p. 1233) 1 1 Some difference (G1, Feverfew is not recommended for preventive treatment of patients with migraine. 234 239 G2 versus G4) with respect to feverfew Other drugs G2 (Europe) (p. 973) 3 No efficacy in migraine prophylaxis has been shown for montelukast, acetazolamide 258-260 (500 mg per day), or lanepitant. G4 (UK) (Main guideline p. 28) Based on the clinical experience of the guideline development group Pizotifen (Background studies cited: RCT261) Pizotifen is of limited value in prophylaxis of migraine. Methysergide Based on the clinical experience of the guideline development group Methysergide should only be used under specialist supervision. (Background studies cited: G245; Other246) Botulinum toxin A 1 Botulinum toxin A is not recommended for the prophylactic treatment of migraine. 262 G4 (UK) (Main guideline p. 47; BMJ summary p. 1233) Based on the clinical experience of the guideline development group Evidence is limited for the use of herbs, vitamins, and minerals. (Background studies cited: SR263; RCT120,229,238,264) CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta- analysis. Statements in italics relate to harm. These statements were sourced from the recommendations or elsewhere in the seed guidelines.

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Table G.4b: Menstrual migraine - prophylaxis Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other General G4 (UK) (Main guideline p. 39) Based on expert opinion of the guideline development group statements Specific menstrual migraine prophylaxis should only be considered in women with regular and predictable menstrual cycles. Hormone G4 (UK) (Main guideline p. 40; BMJ summary p. 1233) Based on the clinical experience of the guideline development group replacement HRT can be prescribed to menopausal and perimenopausal women with migraine. (Background studies cited: NR265-267; RCT268,269; Other270,271) therapy (HRT) If a patient taking HRT experiences worsening migraine, HRT should be considered as a possible cause. If the patient is using oral HRT and experiences worsening migraine, transdermal HRT should be considered. Phytoestrogens G4 (UK) (Main guideline p. 39) 1 1 There is insufficient evidence to make any recommendations on the use of 272 273 phytoestrogens. Triptans G4 (UK) (Main guideline p. 40) 3 Frovatriptan (2.5 mg per day) or naratriptan (1 mg twice daily) taken 2 days before 274-276 day 1 of the menstrual cycle then for a further 4 or 5 days, respectively, is recommended for the prophylaxis of menstrual migraine. Oral G4 (UK) (Main guideline p. 38; BMJ summary p. 1233) 3 1 3 contraception Do not prescribe combined oral contraceptives to women who have migraine with 277-279 280 281-283 aura as this increases the risk of ischemic stroke (relative risk 8.72 [95% confidence interval 5.05 to 15.05]). Patients with migraine without aura who are over the age of 35 years should not use a combined oral contraceptive pill. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta- analysis

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Table G.4.C: Migraine in pregnancy - prophylaxis Supporting Evidence Item Guideline/Country/Synopsis of Recommendations SR/MA NR RCT NRCS CS G Other Drug therapy G2 (Europe) (p. 974) 1 Only magnesium and metoprolol are recommended during pregnancy. 284 CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta- analysis

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32. Tfelt-Hansen P, Standnes B, Kangasneimi P, Hakkarainen H, Olesen J. Timolol vs propranolol vs placebo in common migraine prophylaxis: a double-blind multicenter trial. Acta Neurologica Scandinavica 1984;69(1):1-8. 33. Wideroe TE, Vigander T. Propranolol in the treatment of migraine. BMJ 197429;2(5921):699- 701. 34. Stellar S, Ahrens SP, Meibohm AR, Reines SA. Migraine prevention with timolol. A double- blind crossover study. JAMA 1984;252(18):2576-80. 35. Al-Qassab HK, Findley LJ. Comparison of propranolol LA 80 mg and propranolol LA 160 mg in migraine prophylaxis: a placebo controlled study. Cephalalgia 1993;13(2):128-31. 36. Carroll JD, Reidy M, Savundra PA, Cleave N, McAinsh J. Long-acting propranolol in the prophylaxis of migraine: a comparative study of two doses. Cephalalgia 1990;10(2):101-5. 37. Gawel MJ, Kreeft J, Nelson RF, Simard D, Arnott WS. Comparison of the efficacy and safety of flunarizine to propranolol in the prophylaxis of migraine. Canadian Journal of Neurological Sciences1992;19(3):340-5. 38. Kjaersgard Rasmussen MJ, Holt LB, Borg L, Soelberg SP, Hansen PE. Tolfenamic acid versus propranolol in the prophylactic treatment of migraine. Acta Neurologica Scandinavica 1994;89(6):446-50. 39. Albers GW, Simon LT, Hamik A, Peroutka SJ. Nifedipine versus propranolol for the initial prophylaxis of migraine. Headache 1989;29(4):215-8. 40. Gerber WD, Schellenberg R, Thom M, Haufe C, Bolsche F, Wedekind W, et al. Cyclandelate versus propranolol in the prophylaxis of migraine—a double-blind placebo-controlled study. Functional Neurology 1995;10(1):27-35. 41. Diener HC, Foh M, Iaccarino C, Wessely P, Isler H, Strenge H, et al; The Study Group. Cyclandelate in the prophylaxis of migraine: a randomized, parallel, double-blind study in comparison with placebo and propranolol. Cephalalgia 1996;16(6):441-7. 42. Borgesen SE, Nielsen JL, Moller CE. Prophylactic treatment of migraine with propranolol. A clinical trial. Acta Neurologica Scandinavica 1974;50(5):651-6. 43. Forssman B, Henriksson KG, Johannsson V, Lindvall L, Lundin H. Propranolol for migraine prophylaxis. Headache 1976;16(5):238-45. 44. Johnson RH, Hornabrook RW, Lambie DG. Comparison of mefenamic acid and propranolol with placebo in migraine prophylaxis. Acta Neurologica Scandinavica 1986;73(5):490-2. 45. Pita E, Higueras A, Bolanos J, Perez N, Mundo A. Propranolol and migraine. A clinical trial. Archivos de Farmacología y Toxicología 1977;3(3):273-8. 46. Kangasniemi PJ, Nyrke T, Lang AH, Petersen E. Femoxetine—a new 5-HT uptake inhibitor—and propranolol in the prophylactic treatment of migraine. Acta Neurologica Scandinavica 1983;68(4):262-7. 47. Stensrud P, Sjaastad O. Short-term clinical trial of phopranolol in racemic form (Inderal), D- propranolol and placebo in migraine. Acta Neurologica Scandinavica 1976;53(3):229-32.

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48. Havanka-Kanniainen H, Hokkanen E, Myllyla VV. Long acting propranolol in the prophylaxis of migraine. Comparison of the daily doses of 80 mg and 160 mg. Headache 1988;28(9):607-11. 49. Ahuja GK, Verma AK. Propranolol in prophylaxis of migraine. Indian Journal of Medical Research 1985;82:263-5. 50. Lucking CH, Oestreich W, Schmidt R, Soyka D. Flunarizine vs. propranolol in the prophylaxis of migraine: two double-blind comparative studies in more than 400 patients. Cephalalgia 1988;8 Suppl 8:21-6. 51. Ludin HP. Flunarizine and propranolol in the treatment of migraine. Headache 1989;29(4):219- 24. 52. Shimell CJ, Fritz VU, Levien SL. A comparative trial of flunarizine and propranolol in the prevention of migraine. South African Medical Journal 1990;77(2):75-7. 53. Behan PO, Reid M. Propranolol in the treatment of migraine. Practitioner 1980;224(1340):201-3. 54. Briggs RS, Millac PA. Timolol in migraine prophylaxis. Headache 1979;19(7):379-81. 55. Steardo L, Bonuso S, Di SE, Marano E. Selective and non-selective beta-blockers: are both effective in prophylaxis of migraine? A clinical trial versus methysergide. Acta Neurologica (Napoli) 1982;4(3):196-204. 56. Kuritzky A, Hering R. Prophylactic treatment of migraine with long acting propranolol: a comparison with placebo. Cephalalgia 1987;7(Suppl 6):457-78. 57. Solomon GD. Verapamil and propranolol in migraine prophylaxis: a double-blind crossover study. Headache 1986;26:325. 58. Gerber WD, Diener HC, Scholz E, Niederberger U. Responders and non-responders to metoprolol, propranolol and nifedipine treatment in migraine prophylaxis: a dose-range study based on time-series analysis. Cephalalgia 1991;11(1):37-45. 59. Dahlöf C. No clearcut longterm prophylactic effect of one month of treatment with propranolol in migraineurs. Cephalalgia 1987;7(Suppl 6):7459-60. [Unable to identify study type—abstract not available.] 60. Ryan RE Sr, Ryan RE Jr. Migraine prophylaxis: a new approach. Laryngoscope 1981;91(9 Pt 1):1501-6. 61. Solomon GD, Kunkel RS. Flurbiprofen in the prophylaxis of migraine. Cleveland Clinic Journal of Medicine 1993;60(1):43-8. 62. Carrieri PB, Orefice G, Sorge F. A double-blind placebo-controlled trial of indobufen in the prophylaxis of migraine. Acta Neurologica Scandinavica 1988;77(6):433-6. 63. Bellavance AJ, Meloche JP. A comparative study of naproxen sodium, pizotyline and placebo in migraine prophylaxis. Headache 1990;30(11):710-5. 64. Lindegaard KF, Ovrelid L, Sjaastad O. Naproxen in the prevention of migraine attacks. A double-blind placebo-controlled cross-over study. Headache 1980;20(2):96-8. 65. Welch KM, Ellis DJ, Keenan PA. Successful migraine prophylaxis with naproxen sodium. Neurology 1985;35(9):1304-10.

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66. Stensrud P, Sjaastad O. Clinical trial of a new anti-bradykinin, anti-inflammatory drug, ketoprofen (19.583 r.p.) in migraine prophylaxis. Headache 1974;14(2):96-100. 67. O'Neill BP, Mann JD. Aspirin prophylaxis in migraine. Lancet 1978;2(8101):1179-81. 68. Masel BE, Chesson AL, Peters BH, Levin HS, Alperin JB. Platelet antagonists in migraine prophylaxis. A clinical trial using aspirin and dipyridamole. Headache 1980;20(1):13-8. 69. Sances G, Martignoni E, Fioroni L, Blandini F, Facchinetti F, Nappi G. Naproxen sodium in menstrual migraine prophylaxis: a double-blind placebo controlled study. Headache 1990;30(11):705-9. 70. Diamond S, Solomon GD, Freitag FG, Mehta ND. Fenoprofen in the prophylaxis of migraine: a double-blind, placebo controlled study. Headache 1987;27(5):246-9. 71. Ziegler DK, Ellis DJ. Naproxen in prophylaxis of migraine. Archives of Neurology1985;42(6):582- 4. 72. Mikkelsen BM, Falk JV. Prophylactic treatment of migraine with tolfenamic acid. A comparative double-blind crossover study between tolfenamic acid and placebo. Acta Neurologica Scandinavica 1982;66(1):105-11. 73. Szekely B, Merryman S, Croft H, Post G. Prophylactic effects of naproxen sodium on perimenstrual headache: a double-blind, placebo-controlled study. Cephalalgia 1989;9(Suppl 10):452-3. 74. Sternieri E, Bussone G, Manzoni GC, Martucci N, Nappi G. Lornoxicam, a new nonsteroidal anti-inflammatory drug, in migraine prophylaxis: a double-blind multicenter study. Cephalalgia 1991;11(Suppl 11):11154-5. 75. Couch JR, Bearss CM, Verhulst S. Fenoprofen in migraine prophylaxis. Headache 1987;27(5):289. [Study type: conference abstract.] 76. Langohr HD, Gerber WD, Koletzki E, Mayer K, Schroth G. Clomipramine and metoprolol in migraine prophylaxis—a double-blind crossover study. Headache 1985;25(2):107-13. 77. Sorensen PS, Larsen BH, Rasmussen MJ, Kinge E, Iversen H, Alslev T, et al. Flunarizine versus metoprolol in migraine prophylaxis: a double-blind, randomized parallel group study of efficacy and tolerability. Headache 1991;31(10):650-7. 78. Ryan RE Sr. Comparative study of nadolol and propranolol in prophylactic treatment of migraine. American Heart Journal 1984;108(4 Pt 2):1156-9. 79. Sudilovsky A, Elkind AH, Ryan RE Sr, Saper JR, Stern MA, Meyer JH. Comparative efficacy of nadolol and propranolol in the management of migraine. Headache 1987;27(8):421-6. 80. Olerud B, Gustavsson CL, Furberg B. Nadolol and propranolol in migraine management. Headache 1986;26(10):490-3. 81. Andersson PG, Dahl S, Hansen JH, Hansen PE, Hedman C, Kristensen TN, et al. Prophylactic treatment of classical and non-classical migraine with metoprolol—a comparison with placebo. Cephalalgia 1983;3(4):207-12. 82. Kangasniemi P, Andersen AR, Andersson PG, Gilhus NE, Hedman C, Hultgren M, et al. Classic migraine: effective prophylaxis with metoprolol. Cephalalgia 1987;7(4):231-8.

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83. Freitag FG, Diamond S. Nadolol and placebo comparison study in the prophylactic treatment of migraine. Journal of the American Osteopathic Association 1984;84(4):343-7. 84. Steiner TJ, Joseph R, Hedman C, Rose FC. Metoprolol in the prophylaxis of migraine: parallel- groups comparison with placebo and dose-ranging follow-up. Headache 1988;28(1):15-23. 85. Kangasniemi P, Hedman C. Metoprolol and propranolol in the prophylactic treatment of classical and common migraine. A double-blind study. Cephalalgia 1984;4(2):91-6. 86. Olsson JE, Behring HC, Forssman B, Hedman C, Hedman G, Johansson F, et al. Metoprolol and propranolol in migraine prophylaxis: a double-blind multicentre study. Acta Neurologica Scandinavica 1984;70(3):160-8. 87. Grotemeyer KH, Scharafinski HW, Schlake HP, Husstedt IW. Acetylsalicylic acid vs. metoprolol in migraine prophylaxis—a double-blind cross-over study. Headache 1990;30(10):639-41. 88. Vilming S, Standnes B, Hedman C. Metoprolol and pizotifen in the prophylactic treatment of classical and common migraine. A double-blind investigation. Cephalalgia 1985;5(1):17-23. 89. Forssman B, Lindblad CJ, Zbornikova V. Atenolol for migraine prophylaxis. Headache 1983;23(4):188-90. 90. Johannsson V, Nilsson LR, Widelius T, Javerfalk T, Hellman P, Akesson JA, et al. Atenolol in migraine prophylaxis a double-blind cross-over multicentre study. Headache 1987;27(7):372-4. 91. Ryan RE Sr, Ryan RE Jr, Sudilovsky A. Nadolol: its use in the prophylactic treatment of migraine. Headache 1983;23(1):26-31. 92. Sudilovsky A, Stern MA, Meyer JH. Nadolol: the benefits of an adequate trial duration in the prophylaxis of migraine. Headache 1986;26:325. [Unable to identify study type—abstract not available.] 93. Nappi G, Sandrini G, Savoini G, Cavallini A, de Rysky C, Micieli G. Comparative efficacy of cyclandelate versus flunarizine in the prophylactic treatment of migraine. Drugs 1987;33 Suppl 2:103-9. 94. Mastrosimone F, Iaccarino C, de Caterina G. Efficacy and tolerance of cyclandelate versus pizotifen in the prophylaxis of migraine. Journal of Medicine 1992;23(1):1-16. 95. Solomon GD, Steel JG, Spaccavento LJ. Verapamil prophylaxis of migraine. A double-blind, placebo-controlled study. JAMA 1983;250(18):2500-2. 96. Louis P, Spierings EL. Comparison of flunarizine (Sibelium) and pizotifen (Sandomigran) in migraine treatment: a double-blind study. Cephalalgia 1982;2(4):197-203. 97. Migraine-Nimodipine European Study Group (MINES). European multicenter trial of nimodipine in the prophylaxis of classic migraine (migraine with aura). Headache 1989;29(10):639-42. 98. Migraine-Nimodipine European Study Group (MINES). European multicenter trial of nimodipine in the prophylaxis of common migraine (migraine without aura). Headache 1989;29(10):633-8.

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99. Markley HG, Cheronis JC, Piepho RW. Verapamil in prophylactic therapy of migraine. Neurology 1984;34(7):973-6. 100. Cerbo R, Casacchia M, Formisano R, Feliciani M, Cusimano G, Buzzi MG, et al. Flunarizine- pizotifen single-dose double-blind cross-over trial in migraine prophylaxis. Cephalalgia 1986;6(1):15-8. 101. Rascol A, Montastruc JL, Rascol O. Flunarizine versus pizotifen: a double-blind study in the prophylaxis of migraine. Headache 1986;26(2):83-5. 102. Ansell E, Fazzone T, Festenstein R, Johnson ES, Thavapalan M, Wilkinson M, et al. Nimodipine in migraine prophylaxis. Cephalalgia 1988;8(4):269-72. 103. Gelmers HJ. Nimodipine, a new calcium antagonist, in the prophylactic treatment of migraine. Headache 1983;23(3):106-9. 104. Havanka-Kanniainen H, Hokkanen E, Myllyla VV. Efficacy of nimodipine in the prophylaxis of migraine. Cephalalgia 1985;5(1):39-43. 105. Bussone G, Baldini S, D'Andrea G, Cananzi A, Frediani F, Caresia L, et al. Nimodipine versus flunarizine in common migraine: a controlled pilot trial. Headache 1987;27(2):76-9. 106. Formisano R, Falaschi P, Cerbo R, Proietti A, Catarci T, D'Urso R, et al. Nimodipine in migraine: clinical efficacy and endocrinological effects. European Journal of Clinical Pharmacology 1991;41(1):69-71. 107. Adly C, Straumanis J, Chesson A. Fluoxetine prophylaxis of migraine. Headache 1992;32(2):101- 4. 108. Saper JR, Silberstein SD, Lake AE III, Winters ME. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache 1994;34(9):497-502. 109. Steiner TJ, Ahmed F, Findley LJ, MacGregor EA, Wilkinson M. S-fluoxetine in the prophylaxis of migraine: a phase II double-blind randomized placebo-controlled study. Cephalalgia 1998;18(5):283-6. 110. Wessely P, Baumgartner C, Klingler D, et al. Preliminary results of a double-blind study with the new migraine prophylactic drug Gabapentin. Cephalalgia 1987;7(Suppl 6):477-8. 111. Mathew N, Saper J, Magnus-Miller L. Efficacy and safety of gabapentin (Neurontin®) in migraine prophylaxis. San Diego (CA): 17th Annual Meeting of the American Pain Society; 5 to 8 November 1998. Abstract no. 645. 112. Elkind AH, Webster C, Herbertson RK. Efficacy of guanfacine in a double-blind parallel study for migraine prophylaxis. Cephalalgia 1989;9(Suppl 10):369-70. 113. Murphy JJ, Heptinstall S, Mitchell JR. Randomised double-blind placebo-controlled trial of feverfew in migraine prevention. Lancet 1988;2(8604):189-92. 114. Palevitch D, Earon G, Carusso R. Feverfew (Tanacetum parthenium) as a prophylactic treatment for migraine: a double-blind placebo-controlled study. Phytotherapy Research 1997;11:508-11. 115. De Weerdt CJ, Bootsma HPR, Hendriks H. Herbal medicines in migraine prevention: randomized double-blind placebo-controlled crossover trial of feverfew preparation. Phytomedicine 1996;3:225-30.

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116. Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efficacy of feverfew as prophylactic treatment of migraine. BMJ (Clinical Research Edition) 1985;291(6495):569-73. 117. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia 1996;16(4):257-63. 118. Pfaffenrath V, Wessely P, Meyer C, Isler HR, Evers S, Grotemeyer KH, et al. Magnesium in the prophylaxis of migraine—a double-blind placebo-controlled study. Cephalalgia 1996;16(6):436-40. 119. Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Headache 1991;31(5):298-301. 120. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology 1998;50(2):466-70. 121. Presthus J. BC 105 and methysergide (Deseril) in migraine prophylaxis. Acta Neurologica Scandinavica 1971;47(4):514-8. 122. Titus F, Davalos A, Alom J, Codina A. 5-Hydroxytryptophan versus methysergide in the prophylaxis of migraine. Randomized clinical trial. European Neurology 1986;25(5):327-9. 123. Steardo L, Marano E, Barone P, Denman DW, Monteleone P, Cardone G. Prophylaxis of migraine attacks with a calcium-channel blocker: flunarizine versus methysergide. Journal of Clinical Pharmacology 1986;26(7):524-8. 124. Shekelle RB, Ostfeld AM. Methysergide in the migraine syndrome. Clinical Pharmacology and Therapeutics1964;5:201-4. 125. Forssman B, Henriksson KG, Kihlstrand S. A comparison between BC 105 and methysergide in the prophylaxis of migraine. Acta Neurologica Scandinavica 1972;48(2):204-12. 126. Hudgson P, Foster JB, Newell DJ. Controlled trial of demigran in the prophylaxis of migraine. BMJ 1967;2(5544):91-3. 127. Andersson PG. BC-105 and deseril in migraine prophylaxis (a double-blind study). Headache 1973;13(2):71-3. 128. Pedersen E, Moller CE. Methysergide in migraine prophylaxis. Clinical Pharmacology and Therapeutics1966;7(4):520-6. 129. Cangi F, Boccuni M, Zanotti A, Mailland F, Sicuteri F. Dihydroergokryptine (DEK) in migraine prophylaxis in a double-blind study vs. methysergide. Cephalalgia 1989;9(Suppl 10):448-9. 130. Lance JW, Fine RD, Curran DA. An evaluation of methysergide in the prevention of migraine and other vascular headaches. Medical Journal of Australia 1963;50(1):814-8. 131. Ryan RE. Double-blind crossover comparison of bc-105, methysergide and placebo in the prophylaxis of migraine headache. Headache 1968;8(3):118-26. 132. Sicuteri F. The ingestion of serotonin precursors (L-5-hydroxytryptophan and L-tryptophan) improves migraine headache. Headache 1973;13(1):19-22.

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133. Barrie MA, Fox WR, Weatherall M, Wilkinson MI. Analysis of symptoms of patients with headaches and their response to treatment with ergot derivatives. The Quarterly Journal of Medicine 1968;37(146):319-36. [Unable to identify study type—abstract not available.] 134. Sjaastad O, Stensrud P. Appraisal of BC-105 in migraine prophylaxis. Acta Neurologica Scandinavica 1969;45(5):594-600. 135. Carroll JD, Maclay WP. Pizotifen (BC 105) in migraine prophylaxis. Current Medical Research and Opinion 1975;3(2):68-71. 136. Hughes RC, Foster JB. BC 105 in the prophylaxis of migraine. Current Therapeutic Research, Clinical and Experimental 1971;13(1):63-8. 137. Krakowski AJ, Engisch R. A new agent for chemotherapy of migraine headaches: a controlled study. Psychosomatics 1973;14(5):302-8. 138. Osterman PO. A comparison between placebo, pizotifen and 1-isopropyl-3-hydroxy-5- semicarbazono-6-oxo-2.3.5.6-tetrahydroindol (Divascan) in migraine prophylaxis. Acta Neurologica Scandinavica 1977;56(1):17-28. 139. Kangasniemi P. Placebo, 1-isopropylnoradrenochrome-5-monosemicarbazono and pizotifen in migraine prophylaxis. Headache 1979;19(4):219-22. 140. Havanka-Kanniainen H, Hokkanen E, Myllyla VV. Efficacy of nimodipine in comparison with pizotifen in the prophylaxis of migraine. Cephalalgia 1987;7(1):7-13. 141. Hubbe P. The prophylactic treatment of migraine with an antiserotonin pizotifen. Acta Neurologica Scandinavica 1973;49(1):108-14. 142. Arthur GP, Hornabrook RW. The treatment of migraine with BC 105 (pizotifen): a double blind trial. New Zealand Medical Journal 1971;73(464):5-9. 143. Ryan RE. BC-105 a new preparation for the interval treatment of migraine—a double blind evaluation compared with a placebo. Headache 1971;11(1):6-18. 144. Gawel M. A double-blind, cross-over study of nimodipine versus pizotyline in common and classical migraine. Cephalalgia 1987;7(Suppl 6):453-4. 145. Micieli G, Trucco M, Agostinis, Mancuso A, Papalia F, Sinforiani E. Nimodipine vs. pizotifen in common migraine: results of a double-blind cross-over trial. Cephalalgia 1985;5(Suppl 3):532- 3. 146. Lance JW, Anthony M. Clinical trial of a new serotonin antagonist, BC105, in the prevention of migraine. Medical Journal of Australia 1968;1(2):54-5. [Unable to identify study type—abstract not available.] 147. Bono G, Criscuoli M, Martignoni E, Salmon S, Nappi G. Serotonin precursors in migraine prophylaxis. Advances in Neurology 1982;33:357-63. [Unable to identify study type—abstract not available.] 148. Martucci N, Manna V, Mattesi P, Troiani G, Manzoni GC, Lanfranchi M, et al. Ergot derivatives in the prophylaxis of migraine: a multicentric study with a timed-release dihydroergotamine formulation. Cephalalgia 1983;3 Suppl 1:151-5.

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149. Frediani F, Grazzi L, Zanotti A, Mailland F, Zappacosta BM, Bussone G. Dihydroergokryptine versus dihydroergotamine in migraine prophylaxis: a double-blind clinical trial. Cephalalgia 1991;11(3):117-21. 150. Neuman M, Demarez JP, Harmey JL, Le Bastard B, Cauquil J. Prevention of migraine attacks through the use of dihydroergotamine. International Journal of Clinical Pharmacology Research 1986;6(1):11-3. 151. Bousser MG, Chick J, Fuseau E, Soisson T, Thevenet R. Combined low-dose acetylsalicylic acid and dihydroergotamine in migraine prophylaxis. A double-blind, placebo-controlled crossover study. Cephalalgia 1988;8(3):187-92. 152. Autret A, De Chasteigner C. DHE methane sulfonate with programmed liberation: preliminary results of a controlled study in common migraine. Cephalalgia 1987;7(Suppl 6):451- 2. 153. Buscaino GA, Sorge F, Bussone G, Frediani F. Preventive treatment of headache with slow- release dihydroergotamine: comparison of dosage protocols. Current Therapeutic Research 1991;49(6):925-35. 154. Sorensen PS, Hansen K, Olesen J. A placebo-controlled, double-blind, cross-over trial of flunarizine in common migraine. Cephalalgia 1986;6(1):7-14. 155. Frenken CW, Nuijten ST. Flunarizine, a new preventive approach to migraine. A double-blind comparison with placebo. Clinical Neurology and Neurosurgery 1984;86(1):17-20. 156. al Deeb SM, Biary N, Bahou Y, al Jaberi M, Khoja W. Flunarizine in migraine: a double-blind placebo-controlled study (in a Saudi population). Headache 1992;32(9):461-2. 157. Louis P. A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache 1981;21(6):235-9. 158. Mendenopoulos G, Manafi T, Logothetis I, Bostantjopoulou S. Flunarizine in the prevention of classical migraine: a placebo-controlled evaluation. Cephalalgia 1985;5(1):31-7. 159. Pini LA, Ferrari A, Guidetti G, Galetti G, Sternieri E. Influence of flunarizine on the altered electronystagmographic (ENG) recordings in migraine. Cephalalgia 1985;5 Suppl 2:173-5. 160. Thomas M, Behari M, Ahuja GK. Flunarizine in migraine prophylaxis: an Indian trial. Headache 1991;31(9):613-5. 161. Grotemeyer KH, Schlake HP, Husstedt IW, Rolf LH. Metoprolol versus flunarizine: a double blind cross-over study. Cephalalgia 1987;7(Suppl 6):465-6. 162. Agnoli A, Bussone G, Mailland F, Manzoni GC, Martucci N, Nappi G. Dihydroergokryptine vs. flunarizine in the basic treatment of migraine without aura. Cephalalgia 1991;11(Suppl 11):216-7. 163. Diamond S, Freitag FG. A double blind trial of flunarizine in migraine prophylaxis. Headache Quarterly 1993;4:169-72. [Unable to identify study type—abstract not available.] 164. Ekbom K. Alprenolol for migraine prophylaxis. Headache 1975;15(2):129-32. 165. Ekbom K, Zetterman M. Oxprenolol in the treatment of migraine. Acta Neurologica Scandinavica 1977;56(2):181-4.

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166. Sjaastad O, Stensrud P. Clinical trial of a beta-receptor blocking agent (LB 46) in migraine prophylaxis. Acta Neurologica Scandinavica 1972;48(1):124-8. 167. Nanda RN, Johnson RH, Gray J, Keogh HJ, Melville ID. A double blind trial of acebutolol for migraine prophylaxis. Headache 1978;18(1):20-2. 168. Ekbom K, Lundberg PO. Clinical trial of LB-46 (d, 1-4-(2-hydroxy-3-isopropylaminopropoxy) indol. An adrenergic beta-receptor blocking agent in migraine prophylaxis. Headache 1972;12(1):15-7. [Unable to identify study type—abstract not available.] 169. Rompel H, Bauermeister PW. Aetiology of migraine and prevention with carbamazepine (Tegretol): results of a double-blind, cross-over study. South African Medical Journal 1970;44(4):75-80. 170. Anthony M, Lance JW, Somerville B. A comparative trial of prindolol, clonidine and carbamazepine in the interval therapy of migraine. Medical Journal of Australia 1972;1(26):1343- 6. 171. Ghose K, Niven B, McLeod A, Berry D. Vigabatrin in the prophylaxis of drug resistant migraine: a double blind crossover comparison with placebo. Abstract 330. Cephalalgia 1996;16:367. [Study type: conference abstract.] 172. Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. BMJ 1997;314(7075):180-1. [Study type: case reports.] 173. Mackenzie R, Klistorner A. Severe persistent visual field constriction associated with vigabatrin. Asymptomatic as well as symptomatic defects occur with vigabatrin. BMJ 1998;316(7126):233. [Study type: letter.] 174. Noone JF. Clomipramine in the prevention of migraine. Journal of International Medical Research 1980;8 Suppl 3:49-52. 175. Stensrud P, Sjaastad O. Clonazepam (rivotril) in migraine prophylaxis. Headache 1979;19(6):333-4. 176. Bredfeldt RC, Sutherland JE, Kruse JE. Efficacy of transdermal clonidine for headache prophylaxis and reduction of narcotic use in migraine patients. A randomized crossover trial. Journal of Family Practice 1989;29(2):153-6. 177. Boisen E, Deth S, Hubbe P, Jansen J, Klee A, Leunbach G. Clonidine in the prophylaxis of migraine. Acta Neurologica Scandinavica 1978;58(5):288-95. 178. Das SM, Ahuja GK, Narainaswamy AS. Clonidine in prophylaxis of migraine. Acta Neurologica Scandinavica 1979;60(4):214-7. 179. Kallanranta T, Hakkarainen H, Hokkanen E, Tuovinen T. Clonidine in migraine prophylaxis. Headache 1977;17(4):169-72. 180. Mondrup K, Moller CE. Prophylactic treatment of migraine with clonidine. A controlled clinical trial. Acta Neurologica Scandinavica 1977;56(5):405-12. 181. Ryan RE Sr, Diamond S, Ryan RE Jr. Double blind study of clonidine and placebo for the prophylactic treatment of migraine. Headache 1975;15(3):202-10.

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182. Shafar J, Tallett ER, Knowlson PA. Evaluation of clonidine in prophylaxis of migraine. Double-blind trial and follow-up. Lancet 1972;1(7747):403-7. 183. Stensrud P, Sjaastad O. Clonidine (Catapresan)-double-blind study after long-term treatment with the drug in migraine. Acta Neurologica Scandinavica 1976;53(3):233-6. 184. Louis P, Schoenen J, Hedman C. Metoprolol v. clonidine in the prophylactic treatment of migraine. Cephalalgia 1985;5(3):159-65. 185. Kass B, Nestvold K. Propranolol (Inderal) and clonidine (Catapressan) in the prophylactic treatment of migraine. A comparative trial. Acta Neurologica Scandinavica 1980;61(6):351-6. 186. Sjaastad O, Stensrud P. 2-(2.6-dichlorophenylamino)-2-imidazoline hydrochloride (ST 155 or Catapresan) as a prophylactic remedy against migraine. Acta Neurologica Scandinavica 1971;47(1):120-2. 187. Adam EI, Gore SM, Price WH. Double blind trial of clonidine in the treatment of migraine in a general practice. Journal of the Royal College of General Practitioners 1978;28(195):587-90. [Unable to identify study type—abstract not available.] 188. Wilkinson M. Preliminary report on the use of clonidine (Boehringer Ingelheim) in the treatment of migraine. Research and Clinical Studies in Headache 1970;3:315-20. [Study type: pharmacological report.] 189. Fioroni L, Sances G, Martignoni E, Facchinetti F, Nappi G, Genazzani AR. Perimenstrual headache prophylaxis with dihydroergokriptine. Cephalalgia 1991;11(Suppl 11):199-200. 190. Orholm M, Honore PF, Zeeberg I. A randomized general practice group-comparative study of femoxetine and placebo in the prophylaxis of migraine. Acta Neurologica Scandinavica 1986;74(3):235-9. 191. Zeeberg I, Orholm M, Nielsen JD, Honore PL, Larsen JJ. Femoxetine in the prophylaxis of migraine—a randomised comparison with placebo. Acta Neurologica Scandinavica 1981;64(6):452-9. 192. Bradley WG, Hudgson P, Foster JB, Newell DJ. Double-blind controlled trial of a micronized preparation of flumedroxone (Demigran) in prophylaxis of migraine. BMJ 1968;3(5617):531-3. 193. Lundberg PO. Prophylactic treatment of migraine with flumedroxone. Acta Neurologica Scandinavica 1969;45(3):309-26. 194. Anthony M, Lance JW. Indomethacin in migraine. Medical Journal of Australia 1968;1(2):56-7. 195. Steiner TJ, Findley LJ, Yuen AW. Lamotrigine versus placebo in the prophylaxis of migraine with and without aura. Cephalalgia 1997;17(2):109-12. 196. Monro P, Swade C, Coppen A. Mianserin in the prophylaxis of migraine: a double-blind study. Acta Psychiatrica Scandinavica. Supplementum 1985;320:98-103. 197. Diamond S, Freitag FG, Diamond ML, Urban GJ, Pepper B. A double-blind placebo controlled trial of nabumetone in the prophylaxis of migraine. Headache Quarterly 1996;7(4):326- 9.

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198. Shukla R, Garg RK, Nag D, Ahuja RC. Nifedipine in migraine and tension headache: a randomised double blind crossover study. Journal of the Association of Physicians of India 1995;43(11):770-2. 199. Lamsudin R, Sadjimin T. Comparison of the efficacy between flunarizine and nifedipine in the prophylaxis of migraine. Headache 1993;33(6):335-8. 200. McArthur JC, Marek K, Pestronk A, McArthur J, Peroutka SJ. Nifedipine in the prophylaxis of classic migraine: a crossover, double-masked, placebo-controlled study of headache frequency and side effects. Neurology 1989;39(2 Pt 1):284-6. 201. Leandri M, Rigardo S, Schizzi R, Parodi CI. Migraine treatment with nicardipine. Cephalalgia 1990;10(3):111-6. 202. Ferrari MD, Wilkinson M, Hirt D, Lataste X, Notter M. Efficacy of ICS 205-930, a novel 5- hydroxytryptamine3 (5-HT3) receptor antagonist, in the prevention of migraine attacks. A complex answer to a simple question. ICS 205-930 Migraine Study Group. Pain 1991;45(3):283-91. 203. De Benedittis G, Massei R. 5-HT precursors in migraine prophylaxis: a double-blind cross- over study with L-5-hydroxytryptophan versus placebo. Clinical Journal of Pain 1986;2(2):123-9. 204. Kangasniemi P, Falck B, Langvik VA, Hyyppa MT. Levotryptophan treatment in migraine. Headache 1978;18(3):161-5. 205. Mathew NT. 5-Hydroxytryptophan in the prophylaxis of migraine: a double-blind study. Headache 1978;18:111. 206. Holroyd KA, Penzien DB, Cordingley GE. Propranolol in the management of recurrent migraine: a meta-analytic review. Headache 1991;31(5):333-40. 207. Diamond S, Schenbaum H. Flunarizine, a calcium channel blocker, in the prophylactic treatment of migraine. Headache 1983;23(1):39-42. 208. Diamond S, Medina JL. Double blind study of propranolol for migraine prophylaxis. Headache 1976;16(1):24-7. 209. Diener HC, Matias-Guiu J, Hartung E, Pfaffenrath V, Ludin HP, Nappi G, et al. Efficacy and tolerability in migraine prophylaxis of flunarizine in reduced doses: a comparison with propranolol 160 mg daily. Cephalalgia 2002;22(3):209-21. 210. Diener HC, Tfelt-Hansen P, Dahlof C, Lainez MJ, Sandrini G, Wang SJ, et al. Topiramate in migraine prophylaxis—results from a placebo-controlled trial with propranolol as an active control. Journal of Neurology 2004;251(8):943-50. 211. Silberstein SD, Lipton RB, Dodick DW, Freitag FG, Ramadan N, Mathew N, et al. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache 2007;47(2):170-80. 212. Worz R, Reinhardt-Benmalek B, Grotemeyer KH. Bisoprolol and metoprolol in the prophylactic treatment of migraine with and without aura—a randomized double-blind cross- over multicenter study. Cephalalgia 1991;11(Suppl 11):152-3. 213. Van de Ven, LL, Franke CL, Koehler PJ. Prophylactic treatment of migraine with bisoprolol: a placebo-controlled study. Cephalalgia 1997;17(5):596-9.

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214. Bassi P, Brunati L, Rapuzzi B, Alberti E, Mangoni A. Low dose flunarizine in the prophylaxis of migraine. Headache 1992;32(8):390-2. 215. Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA 2004;291(8):965-73. 216. Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia 2007;27(7):814-23. 217. Freitag FG, Collins SD, Carlson HA, Goldstein J, Saper J, Silberstein S, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology 2002;58(11):1652-9. 218. Mei D, Capuano A, Vollono C, Evangelista M, Ferraro D, Tonali P, et al. Topiramate in migraine prophylaxis: a randomised double-blind versus placebo study. Neurological Sciences 2004;25(5):245-50. 219. Silberstein SD, Neto W, Schmitt J, Jacobs D. Topiramate in migraine prevention: results of a large controlled trial. Archives of Neurology 2004;61(4):490-5. 220. Amery WK, Caers LI, Aerts TJ. Flunarizine, a calcium entry blocker in migraine prophylaxis. Headache 1985;25(5):249-54. 221. Freitag FG, Diamond S, Diamond M. A placebo controlled trial of flunarizine in migraine prophylaxis. Cephalalgia 1991;11((Suppl 11)):157-8-158. 222. Bono G, Manzoni GC, Martucci N, Baldrati A, Farina S, Cassabgi F, et al. Flunarizine in common migraine: Italian cooperative trial. II. Long-term follow-up. Cephalalgia 1985;5 Suppl 2:155-8. 223. Nadelmann JW, Phil M, Stevens J, Saper JR. Propranolol in the prophylaxis of migraine. Headache 1986;26(4):175-82. [Unable to identify study type—abstract not available.] 224. Centonze V, Tesauro P, Trizio T, Magrone D, Vino M, Macinagrossa G, et al. Efficacy and tolerability of flunarizine in the prophylaxis of migraine. Cephalalgia 1985;5 Suppl 2:165-8. [Unable to identify study type—abstract not available.] 225. Balkan S, Aktekin B, Onal Z. Efficacy of flunarizine in the prophylactic treatment of migraine. Gazi Medical Journal 1994;5:81-4. [Unable to identify study type—abstract not available.] 226. Silberstein SD, Collins SD, Carlson H. Safety and efficacy of once-daily, extended-release divalproex sodium monotherapy for the prophylaxis of migraine headaches. Cephalalgia 2000;20:269. [Unable to identify study type—abstract not available.] 227. Institut National de la Santé et de la Recherche Médicale. (INSERM: National Institute of Health andMedical Research). Migraine: Descriptive knowledge, treatment, and prevention [French]. Paris: INSERM; 1998. [Study type: report.] 228. Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache 2005;45(2):144-52. 229. Lipton RB, Gobel H, Einhaupl KM, Wilks K, Mauskop A. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology 2004;63(12):2240-4.

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230. Bulut S, Berilgen MS, Baran A, Tekatas A, Atmaca M, Mungen B. Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clinical Neurology and Neurosurgery 2004;107(1):44-8. 231. Ziegler DK, Hurwitz A, Preskorn S, Hassanein R, Seim J. Propranolol and amitriptyline in prophylaxis of migraine. Pharmacokinetic and therapeutic effects. Archives of Neurology1993;50(8):825-30. 232. Diener HC, Rahlfs VW, Danesch U. The first placebo-controlled trial of a special butterbur root extract for the prevention of migraine: reanalysis of efficacy criteria. European Neurology 2004;51(2):89-97. 233. Adelman LC, Adelman JU, Von SR, Mannix LK. Venlafaxine extended release (XR) for the prophylaxis of migraine and tension-type headache: A retrospective study in a clinical setting. Headache 2000;40(7):572-80. 234. Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane Database of Systematic Reviews 2004, Issue 1. Art. No.: CD002286. DOI: 10.1002/14651858.CD002286.pub2. 235. Silberstein SD. Methysergide. Cephalalgia 1998;18(7):421-35. 236. Mathew NT, Rapoport A, Saper J, Magnus L, Klapper J, Ramadan N, et al. Efficacy of gabapentin in migraine prophylaxis. Headache 2001;41(2):119-28. 237. Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA 2003;289(1):65-9. 238. Sandor PS, Di CL, Coppola G, Saenger U, Fumal A, Magis D, et al. Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Neurology 2005;64(4):713-5. 239. Diener HC, Pfaffenrath V, Schnitker J, Friede M, Henneicke-von Zepelin HH. Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention--a randomized, double-blind, multicentre, placebo-controlled study. Cephalalgia 2005;25(11):1031-41. 240. Buring JE, Peto R, Hennekens CH. Low-dose aspirin for migraine prophylaxis. JAMA 1990;264(13):1711-3. 241. Peto R, Gray R, Collins R, Wheatley K, Hennekens C, Jamrozik K, et al. Randomised trial of prophylactic daily aspirin in British male doctors. BMJ (Clinical Research Edition) 1988;296(6618):313-6. 242. Pfaffenrath V, Diener HC, Fischer M, Friede M, Henneicke-von Zepelin HH. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis—a double-blind, multicentre, randomized placebo-controlled dose-response study. Cephalalgia 2002;22(7):523- 32. 243. Schrader H, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo-controlled, crossover trial. BMJ 2001;322(7277):19-22. 244. Linde K, Rossnagel K. Propranolol for migraine prophylaxis. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD003225. DOI: 10.1002/14651858.CD003225.pub2.

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245. Ramadan NM, Silberstein SD, Freitag F, Gilbert TT, Frishberg BM. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. St Paul (MN): US Headache Consortium; 2000. 246. British National Formulary. 56th edition. London (UK): BMJ Publishing; 2008. [Pharmaceutical compendium.] 247. Chronicle E, Mulleners W. Anticonvulsant drugs for migraine prophylaxis. Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD003226. DOI: 10.1002/14651858.CD003226.pub2. 248. Nadin C. Topiramate: the evidence for its therapeutic value in the prevention of migraine. Report No. 1(2). Knutsford, UK: Core Evidence; 2005. 249. Edwards KR, Potter DL, Wu SC, Kamin M, Hulihan J. Topiramate in the preventive treatment of episodic migraine: a combined analysis from pilot, double-blind, placebo- controlled trials. CNS Spectrums 2003;8(6):428-32. 250. Mei D, Ferraro D, Zelano G, Capuano A, Vollono C, Gabriele C, et al. Topiramate and triptans revert chronic migraine with medication overuse to episodic migraine. Clinical Neuropharmacology 2006;29(5):269-75. 251. Bartolini M, Silvestrini M, Taffi R, Lanciotti C, Luconi R, Capecci M, et al. Efficacy of topiramate and valproate in chronic migraine. Clinical Neuropharmacology 2005;28(6):277-9. 252. Diamond M, Dahlof C, Papadopoulos G, Neto W, Wu SC. Topiramate improves health- related quality of life when used to prevent migraine. Headache 2005;45(8):1023-30. 253. Limmroth V, Biondi D, Pfeil J, Schwalen S. Topiramate in patients with episodic migraine: reducing the risk for chronic forms of headache. Headache 2007;47(1):13-21. 254. Shaygannejad V, Janghorbani M, Ghorbani A, Ashtary F, Zakizade N, Nasr V. Comparison of the effect of topiramate and sodium valporate in migraine prevention: a randomized blinded crossover study. Headache 2006;46(4):642-8. 255. Silberstein SD, Loder E, Forde G, Papadopoulos G, Fairclough D, Greenberg S. The impact of migraine on daily activities: effect of topiramate compared with placebo. Current Medical Research and Opinion 2006;22(6):1021-9. 256. Moja PL, Cusi C, Sterzi RR, Canepari C. Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database of Systematic Reviews 2005, Issue 3. Art. No.: CD002919. DOI: 10.1002/14651858.CD002919.pub2. 257. Tomkins GE, Jackson JL, O'Malley PG, Balden E, Santoro JE. Treatment of chronic headache with antidepressants: a meta-analysis. American Journal of Medicine 2001;111(1):54-63. 258. Brandes JL, Visser WH, Farmer MV, Schuhl AL, Malbecq W, Vrijens F, et al. Montelukast for migraine prophylaxis: a randomized, double-blind, placebo-controlled study. Headache 2004;44(6):581-6. 259. Goldstein DJ, Offen WW, Klein EG, Phebus LA, Hipskind P, Johnson KW, et al. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia 2001;21(2):102-6.

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260. Vahedi K, Taupin P, Djomby R, El-Amrani M, Lutz G, Filipetti V, et al. Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomised placebo-controlled trial. Journal of Neurology 2002;249(2):206-11. 261. Cleland PG, Barnes D, Elrington GM, Loizou LA, Rawes GD. Studies to assess if pizotifen prophylaxis improves migraine beyond the benefit offered by acute sumatriptan therapy alone. European Neurology 1997;38(1):31-8. 262. Relja M, Poole AC, Schoenen J, Pascual J, Lei X, Thompson C. A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches. Cephalalgia 2007;27(6):492-503. 263. Prousky J, Seely D. The treatment of migraines and tension-type headaches with intravenous and oral niacin (nicotinic acid): systematic review of the literature. Nutrition Journal 2005;4:3. 264. Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache 2004;44(9):885-90. 265. MacGregor EA. Migraine and the menopause. Journal of the British Menopause Society 2006;12(3):104-8. 266. Silberstein SD. Headache and female hormones: what you need to know. Current Opinion in Neurology 2001;14(3):323-33. 267. Kittner SJ, Bousser MG. Post-menopausal hormone replacement therapy and stroke risk. Cephalalgia 2000;20(3):208-13. 268. Nappi RE, Cagnacci A, Granella F, Piccinini F, Polatti F, Facchinetti F. Course of primary headaches during hormone replacement therapy. Maturitas 2001;38(2):157-63. 269. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA 2002;288(3):321-33. 270. Tzourio C, Iglesias S, Hubert JB, Visy JM, Alperovitch A, Tehindrazanarivelo A, et al. Migraine and risk of ischaemic stroke: a case-control study. BMJ 1993;307(6899):289-92. [Study type: case-control study.] 271. Misakian AL, Langer RD, Bensenor IM, Cook NR, Manson JE, Buring JE, et al. Postmenopausal hormone therapy and migraine headache. Journal of Women’s Health 2003;12(10):1027-36. [Study type: cross-sectional study.] 272. MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A. Prevention of menstrual attacks of migraine: a double-blind placebo-controlled crossover study. Neurology 2006;67(12):2159-63. 273. Pringsheim T, Davenport WJ, Dodick D. Acute treatment and prevention of menstrually related migraine headache: evidence-based review. Neurology 2008;70(17):1555-63. 274. Mannix LK, Savani N, Landy S, Valade D, Shackelford S, Ames MH, et al. Efficacy and tolerability of naratriptan for short-term prevention of menstrually related migraine: data from two randomized, double-blind, placebo-controlled studies. Headache 2007;47(7):1037-49.

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275. Newman L, Mannix LK, Landy S, Silberstein S, Lipton RB, Putnam DG, et al. Naratriptan as short-term prophylaxis of menstrually associated migraine: a randomized, double-blind, placebo-controlled study. Headache 2001;41(3):248-56. 276. Silberstein SD, Elkind AH, Schreiber C, Keywood C. A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine. Neurology 2004;63(2):261-9. 277. Etminan M, Takkouche B, Isorna FC, Samii A. Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. BMJ 2005;330(7482):63. 278. Curtis KM, Mohllajee AP, Peterson HB. Use of combined oral contraceptives among women with migraine and nonmigrainous headaches: a systematic review. Contraception 2006;73(2):189- 94. 279. Mendizabal JE, Herbert DE. Risk of ischemic stroke in migraineurs: a meta-analysis. Headache & Pain: Diagnostic Challenges, Current Therapy 2004;15(4):197-200. 280. MacGregor EA. Migraine and use of combined hormonal contraceptives: a clinical review. The Journal of Family Planning and Reproductive Health Care 2007;33(3):159-69. 281. Chang CL, Donaghy M, Poulter N. Migraine and stroke in young women: case-control study. The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. BMJ 1999;318(7175):13-8. [Study type: case-control study.] 282. Faculty of Family Planning and Reproductive Health Care. UK medical eligibility criteria for contraceptive use 2005/2006. London (UK): Royal College of Obstetricians and Gynaecologists; 2006. Available from: www.fsrh.org/admin/uploads/archive/UKMEC2005_06.pdf (accessed 4 April 2013). [Study type: expert consensus report.] 283. Buse DC, Loder EW, Golub JR. Use of oral contraceptives in women with migraine. Headache Care 2005;2(3):183-94. [Unable to identify study type—abstract not available.] 284. Goadsby PJ, Goldberg J, Silberstein SD. The pregnant migraineur: what can be done? BMJ 2008;336:1502-4. [Unable to identify study type—abstract not available.]

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Inventory of Guideline Recommendations for Tension-Type Headache (TTH) Table G.5a: Tension-type headache (TTH) - patient education

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other Patient education/ G6 (Europe) (p. 1, 3) Not Not provided reassurance Information, reassurance and identification of trigger factors applicable may be rewarding. It should be explained to the patient that frequent TTH only seldom can be cured, but that a meaningful improvement often can be obtained with the combination of drug and nondrug treatments. *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.5b: Tension-type headache (TTH) - pharmacological prophylaxis

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other Drugs G4 (UK) (p. 30, BMJ summary p. 1233) A 2 Tricyclic antidepressants, particularly amitriptyline, 25 mg to 150 mg per 2,3 day, are recommended as the agents of choice where prophylactic treatment is being considered in a patient with chronic TTH. G6 (Europe) (p. 1, 6) 1 1 15 1 1 3 4 1,5-18 19 20 Amitriptyline is drug of first choice for the prophylactic treatment of chronic TTH. Mirtazapine and venlafaxine are drugs of second choice. The efficacy of the prophylactic drugs is often limited, and treatment may be hampered by side effects. The following drugs are recommended for prophylactic therapy of TTH. Drug of first choice: • amitryptyline (30 mg to 75 mg) - side effects include dry mouth, A drowsiness, dizziness, obstipation and weight gain. Drugs of second choice: • mirtazapine (30 mg) - major side effects are drowsiness and weight B gain;

• venlafaxine (150 mg) - major side effects are vomiting, nausea, dizziness and loss of libido. Drugs of third choice: B • clomipramine (75 mg to 150 mg); • maprotiline (75 mg); • mianserin (30 mg to 60 mg). Botulinum toxin A G4 (UK) (p. 31) B 1 Botulinum toxin A is not recommended for the preventive treatment of 21 chronic TTH. *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Refer to Table G.8 for explanation of ratings. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.5c: Tension-type headache (TTH) - acute pharmacological treatment

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other Drugs G4 (UK) (p. 30, BMJ summary p. 1233) A 1 Aspirin and acetaminophen are recommended for acute treatment in 22 patients with TTH. Doses included: aspirin: 500 mg and 1000 mg; acetaminophen 1000 mg. G6 (Europe) (p. 1, 5) 2 19 8 2 23,24 22,25-42 43-50 51,52 Simple analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) A for all are recommended for the treatment of episodic TTH. except Combination analgesics containing caffeine are drugs of second choice. caffeine Triptans, muscle relaxants and opioids should not be used. combina-tion It is crucial to avoid frequent and excessive use of analgesics to prevent (B) the development of medication-overuse headache. The following drugs are recommended for the acute treatment of TTH. • Ibuprofen (200 mg to 800 mg) - gastrointestinal side effects, risk of bleeding • Ketoprofen (25 mg) - side effects as for ibuprofen • Aspirin (500 mg to 1000 mg) - side effects as for ibuprofen • Naproxen (375 mg to 550 mg) - side effects as for ibuprofen • Diclofenac (12.5 mg to 100 mg), only doses of 12.5 mg to 25 mg tested in TTH - side effects as for ibuprofen • Acetaminophen (1000 mg oral) - less risk of gastrointestinal side effects compared with NSAIDs • Caffeine combination (65 mg to 200 mg) - combination with caffeine (65 mg to 200 mg) increases the efficacy of ibuprofen and acetaminophen, but possibly also the risk for developing medication overuse headache *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Refer to Table G.8 for explanation of ratings. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.5d: Tension-type headache (TTH) - non-pharmacological treatment

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other Psycho- G6 (Europe) (p. 8) 2 53,54 behavioural Non-drug management should always be considered although the A treatments scientific basis is limited. Information, reassurance and identification of trigger factors may be rewarding. Electromyography biofeedback has a documented effect in TTH. Cognitive-behavioural therapy and relaxation training most likely are C 1 1 2 effective, but there is no convincing evidence. 53 4 9,55 Physical therapy G6 (Europe) (p. 8) C 7 1 7 1 1 and acupuncture Physical therapy and acupuncture may be valuable options for patients 56-62 4 63-69 70 71 with frequent TTH, but there is no robust scientific evidence for efficacy. Massage G4 (UK) (p.45) Not 1 There is insufficient evidence to make a recommendation on the use of applicable 72 massage in the treatment of patients with headache. TENS G4 (UK) (p.45) Not 1 There is insufficient evidence to make a recommendation on the use of applicable 58 TENS in the treatment of patients with headache. *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Refer to Table G.8 for explanation of ratings. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.5e: Tension-type headache (TTH) in pregnancy - treatment

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other Simple analgesics G4 (UK) (Main guideline p. 38; BMJ summary p. 1233) Not applicable Based on clinical experience of guideline development group Where possible, the use of medication in pregnancy should be avoided, (Background studies cited: Other73-76) particularly in the first trimester. Acetaminophen 1000 mg is the treatment of choice in pregnancy for all patients with TTH when the pain is sufficient to require analgesia. If acetaminophen provides insufficient analgesia aspirin 300 mg or ibuprofen 400 mg can be used in the first and second trimester of pregnancy. As with any medication used during pregnancy, acetaminophen should be taken at the lowest effective dose for the shortest time necessary. Aspirin is contraindicated during the third trimester of pregnancy. Long-term exposure or exposure to high doses of ibuprofen in late pregnancy is associated with an increased risk of fetal complications. *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Refer to Table G.8 for explanation of ratings. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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47. Harden RN, Rogers D, Fink K, Gracely RH. Controlled trial of ketorolac in tension-type headache. Neurology 1998;50(2):507-9. 48. Ward N, Whitney C, Avery D, Dunner D. The analgesic effects of caffeine in headache. Pain 1991;44(2):151-5. 49. Scher AI, Lipton RB, Stewart WF, Bigal M. Patterns of medication use by chronic and episodic headache sufferers in the general population: results from the frequent headache epidemiology study. Cephalalgia 2010;30(1):321-8. 50. Langman MJ, Weil J, Wainwright P, Lawson DH, Rawlins MD, Logan RF, et al. Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;343(8905):1075-8. 51. Lipton RB, Cady RK, Stewart WF, Wilks K, Hall C. Diagnostic lessons from the spectrum study. Neurology 2002;58(9 Suppl 6):S27-S31. [Study type: cross-sectional study] 52. Brennum J, Brinck T, Schriver L, et al. Sumatriptan has no clinically relevant effect in the treatment of episodic tension-type headache. European Journal of Neurology 1996;(3):23-8. [Unable to identify study type—abstract not available.] 53. Verhagen AP, Damen L, Berger MY, Passchier J, Koes BW. Behavioral treatments of chronic tension-type headache in adults: are they beneficial? CNS Neuroscience & Therapeutics 2009;15(2):183-205. 54. Nestoriuc Y, Rief W, Martin A. Meta-analysis of biofeedback for tension-type headache: efficacy, specificity, and treatment moderators. Journal of Consulting and Clinical Psychology 2008;76(3):379-96. 55. Holroyd KA, Nash JM, Pingel JD, Cordingley GE, Jerome A. A comparison of pharmacological (amitriptyline HCL) and nonpharmacological (cognitive-behavioral) therapies for chronic tension headaches. Journal of Consulting and Clinical Psychology 1991;59(3):387-93. 56. Carlsson J, Fahlcrantz A, Augustinsson LE. Muscle tenderness in tension headache treated with acupuncture or physiotherapy. Cephalalgia 1990;10(3):131-41. 57. Fricton J, Velly A, Ouyang W, Look JO. Does exercise therapy improve headache? a systematic review with meta-analysis. Current Pain and Headache Reports 2009;13(6):413-9. 58. Bronfort G, Nilsson N, Haas M, Evans R, Goldsmith CH, Assendelft WJ, et al. Non-invasive physical treatments for chronic/recurrent headache. Cochrane Database Systematic Reviews 2004;(3):CD001878. 59. Biondi DM. Physical treatments for headache: a structured review. Headache 2005;45(6):738-46. 60. Lenssinck ML, Damen L, Verhagen AP, Berger MY, Passchier J, Koes BW. The effectiveness of physiotherapy and manipulation in patients with tension-type headache: a systematic review. Pain 2004;112(3):381-8. 61. Davis MA, Kononowech RW, Rolin SA, Spierings EL. Acupuncture for tension-type headache: a meta-analysis of randomized, controlled trials. Journal of Pain 2008;9(8):667-77. 62. Linde K, Allais G, Brinkhaus B, Manheimer E, Vickers A, White AR. Acupuncture for tension-type headache. Cochrane Database Systematic Reviews 2009;(1):CD007587.

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63. Boline PD, Kassak K, Bronfort G, Nelson C, Anderson AV. Spinal manipulation vs. amitriptyline for the treatment of chronic tension-type headaches: a randomized clinical trial. Journal of Manipulative and Physiological Therapeutics 1995;18(3):148-54. 64. Bove G, Nilsson N. Spinal manipulation in the treatment of episodic tension-type headache: a randomized controlled trial. JAMA 1998;280(18):1576-9. 65. Soderberg E, Carlsson J, Stener-Victorin E. Chronic tension-type headache treated with acupuncture, physical training and relaxation training. Between-group differences. Cephalalgia 2006;26(11):1320-9. 66. Torelli P, Jensen R, Olesen J. Physiotherapy for tension-type headache: a controlled study. Cephalalgia 2004;24(1):29-36. 67. Van Ettekoven H, Lucas C. Efficacy of physiotherapy including a craniocervical training programme for tension-type headache; a randomized clinical trial. Cephalalgia 2006;26(8):983- 91. 68. Melchart D, Streng A, Hoppe A, Brinkhaus B, Witt C, Wagenpfeil S, et al. Acupuncture in patients with tension-type headache: randomised controlled trial. BMJ 2005;331(7513):376-82. 69. Jena S, Witt CM, Brinkhaus B, Wegscheider K, Willich SN. Acupuncture in patients with headache. Cephalalgia 2008;28(9):969-79. 70. Leinisch-Dahlke E, Jurgens T, Bogdahn U, Jakob W, May A. Greater occipital nerve block is ineffective in chronic tension type headache. Cephalalgia 2005;25(9):704-8. 71. Hoyt WH, Shaffer F, Bard DA, Benesler JS, Blankenhorn GD, Gray JH, et al. Osteopathic manipulation in the treatment of muscle-contraction headache. Journal of the American Osteopathic Association 1979;78(5):322-5. [Unable to identify study type—abstract not available.] 72. Fernandez-de-Las-Penas C, Alonso-Blanco C, Cuadrado ML, Miangolarra JC, Barriga FJ, Pareja JA. Are manual therapies effective in reducing pain from tension-type headache?: a systematic review. Clinical Journal of Pain 2006;22(3):278-85. 73. Briggs G, Freeman RK, Yalle SJ. Drugs in pregnancy and lactation. 7th edition. Philadelphia (PA): Lippincott Williams and Wilkins; 2005. [Book] 74. Lee A, Inch S, Finnigan D, editors. Therapeutics in pregnancy and lactation. Abingdon (UK): Radcliffe Medical Press; 2000. [Book] 75. Rubin P, editor. Prescribing in pregnancy. London (UK): BMJ Publishing; 2000. [Book] 76. Schaefer D, editor. Drugs during pregnancy and lactation. 1st edition. Amsterdam: Elsevier Science BV; 2001. [Book]

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Inventory of Guideline Recommendations for Medication-Overuse Headache Table G.6a: Medication-overuse headache - general statements, definitions, and assessment

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other General G1 (USA) (Guideline p. 23-24, Summary guideline for clinicians) Not applicable Consensus achieved by the US Headache Consortium statements Guard against medication-overuse headache. (“Rebound headache” or (Background studies cited: Other1,2) “drug-induced headache” are sometime used interchangeably with “medication-overuse headache”) (see Glossary in Table G.10). To decrease the risk of medication-overuse headaches, many experts suggest limiting acute therapy for patients who have more than two headache days per week on a regular basis. Attempt to limit acute therapy to 2 days per week. G3 (France) (Summary [English] p. 1309; Summary recommendations Not applicable Professional consensus [French] p. 10) (Background study cited: Other3) For all patients with migraine, the total number of doses taken per month should be counted, using a diary, to identify excessive use of medication (≥10 days/month for > 3 months). Excessive use occurs frequently in patients with migraine and can lead to the development of chronic daily headache related to medication overuse. This is true for all of the migraine medications. G4 (UK) (Quick reference guide p. 8) Not applicable Not provided Medication overuse headache is described as: headache which is present for 15 days or more per month and which has developed while taking regular symptomatic medication. Definitions and G4 (UK) (Main guideline p. 35) D 3 assessment Medication overuse headache must be excluded in all patients with 4-6 chronic daily headache (headache ≥15 days per month for >3 months). (Main guideline p. 35) G4 (UK) D 1 5 3 Clinicians should be aware that patients using any acute or symptomatic 7 8-12 6,13,14 headache treatment are at risk of medication overuse headache. Patients with migraine, frequent headache and those using opioid-containing medications or overusing triptans are at most risk. G4 (UK) (Main guideline p. 35) C 1 When diagnosing medication overuse headache, psychiatric comorbidity 15 and dependence behaviour should be considered. *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Refer to Table G.8 for explanation of ratings. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.6b: Medication-overuse headache - pharmacological prophylaxis

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other General statements G1 (USA) (Guideline p. 23-24) Not applicable Consensus achieved by the US Headache Consortium In patients with suspected medication overuse or patients at risk of medication overuse, consider preventive therapy. G4 (UK) (Main guideline p. 37) D 1 2 1 If frequent headache persists after symptomatic medication have been 16 24,25 20 withdrawn, prophylactic agents may be effective and should be considered. Topiramate G4 (UK) (Main guideline p. 37) C 3 In patients with medication overuse headache, topiramate may be 24,26,27 considered in order to reduce the total number of headache days. *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Refer to Table G.8 for explanation of ratings. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.6c: Medication-overuse headache - treatment

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other General statement G4 (UK) (Main guideline p. 36) Not applicable Based on clinical experience of guideline development group Medication withdrawal should be attempted in all patients with medication overuse headache. Abruptly withdraw G4 (UK) (Main guideline p. 36, BMJ summary p. 1232) C 2 2 1 4 (from treatment Patients with medication overuse headache caused by simple analgesics or 7,16 17,18 19 20-23 with simple triptans should be advised to abruptly withdraw the overused medication. analgesics or In the majority of patients this can be as an outpatient with structured triptans) advice (such as an explanation about how medications cause headache, warning about withdrawal headache and other withdrawal symptoms, and the expectation that headache frequency will reduce and preventive treatments will regain their effectiveness). (Main guideline p. 36, Quick reference guide p. 8) Not applicable 1 1 1 NB Abrupt withdrawal from medication initially results in worsening of 16 19 21 headache. Gradual withdraw G4 (UK) (Main guideline p. 36) D 2 (from treatment Patients with medication overuse headache caused by opioids and opioid- 7,16 with opioids and containing analgesics should be considered for gradual withdrawal of the opioid-containing overused medications. analgesics) (BMJ summary p. 1232) Not applicable Not provided For most patients this can be done in the outpatient department. *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Refer to Table G.8 for explanation of ratings. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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References 1. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Headache Classification Committee of the International Headache Society. Cephalalgia 1988;8 Suppl 7:1-96. [Study type: operational diagnostic criteria] 2. Silberstein SD, Lipton RB. Chronic daily headache. In: Goadsby PJ, Silberstein SD, editors. Blue books of practical neurology: Headache. Boston (MA): Butterworth-Heinemann: 1997. p. 201- 25. [Book] 3. Lantéri-Minet M, Muray JP, EI Hasnaoui A, Dartiques JF, Duru G, Henry P, et al. Prevalence and description of chronic daily headache in the general population in France. Pain 2003;102(1-2):143-9. [Study type: survey] 4. International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24 Suppl 1:9-160. [Study type: operational diagnostic criteria] 5. Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 2006;26(6):742-6. [Study type: operational diagnostic criteria] 6. Silberstein SD, Olsen J, Bousser MG, Diener HC, Dodick D, First M, et al. The International Classification of Headache Disorders, 2nd Edition (ICHD-II) – revision of criteria for 8.2 Medication-overuse headache. Cephalalgia 2005;25(6):460-5. [Study type: operational diagnostic criteria] 7. Paemeleire K, Crevits L, Goadsby PJ, Kaube H. Practical management of medication-overuse headache. Acta Neurologica Belgica 2006;106(2):43-51. 8. Cohen AS, Matharu MS, Goadsby PJ. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) or cranial autonomic features (SUNA)—a prospective clinical study of SUNCT and SUNA. Brain 2006;129(Pt 10):2746-60. 9. Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener HC. Features of medication overuse headache following overuse of different acute headache drugs. Neurology 2002;59(7):1011-4. 10. Paemeleire K, Bahra A, Evers S, Matharu MS, Goadsby PJ. Medication-overuse headache in patients with cluster headache. Neurology 2006;67(1):109-13. 11. Katsarava Z, Schneeweiss S, Kurth T, Kroener U, Fritsche G, Eikermann A, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004;62(5):788-90. 12. Zwart JA, Dyb G, Hagen K, Svebak S, Holmen J. Analgesic use: a predictor of chronic pain and medication overuse headache: the Head-HUNT Study. Neurology 2003;61(2):160-4. 13. Bahra A, Walsh M, Menon S, Goadsby PJ. Does chronic daily headache arise de novo in association with regular use of analgesics? Headache 2003;43(3):179-90. [Study type: survey] 14. Williams D, Cahill T, Dowson A, Fearon H, Lipscombe S, O'Sullivan E, et al. Usage of triptans among migraine patients: an audit in nine GP practices. Current Medical Research and Opinion 2002;18(1):1-9. [Study type: survey, audit]

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15. Atasoy HT, Atasoy N, Unal AE, Emre U, Sumer M. Psychiatric comorbidity in medication overuse headache patients with pre-existing headache type of episodic tension-type headache. European Journal of Pain 2005;9(3):285-91. 16. Zed PJ, Loewen PS, Robinson G. Medication-induced headache: overview and systematic review of therapeutic approaches. Annals of Pharmacotherapy 1999;33(1):61-72. 17. Krymchantowski AV, Moreira PF. Out-patient detoxification in chronic migraine: comparison of strategies. Cephalalgia 2003;23(10):982-93. 18. Rossi P, Di LC, Faroni J, Cesarino F, Nappi G. Advice alone vs. structured detoxification programmes for medication overuse headache: a prospective, randomized, open-label trial in transformed migraine patients with low medical needs. Cephalalgia 2006;26(9):1097-105. 19. Katsarava Z, Fritsche G, Muessig M, Diener HC, Limmroth V. Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Neurology 2001;57(9):1694-8. 20. Zeeberg P, Olesen J, Jensen R. Discontinuation of medication overuse in headache patients: recovery of therapeutic responsiveness. Cephalalgia 2006;26(10):1192-8. 21. Zeeberg P, Olesen J, Jensen R. Probable medication-overuse headache: the effect of a 2- month drug-free period. Neurology 2006;66(12):1894-8. 22. Katsarava Z, Limmroth V, Finke M, Diener HC, Fritsche G. Rates and predictors for relapse in medication overuse headache: a 1-year prospective study. Neurology 2003;60(10):1682-3. 23. Andrasik F, Grazzi L, Usai S, D'Amico D, Kass S, Bussone G. Disability in chronic migraine with medication overuse: treatment effects at 3 years. Headache 2007;47(9):1277-81. 24. Mei D, Ferraro D, Zelano G, Capuano A, Vollono C, Gabriele C, et al. Topiramate and triptans revert chronic migraine with medication overuse to episodic migraine. Clinical Neuropharmacology 2006;29(5):269-75. 25. Descombes S, Brefel-Courbon C, Thalamas C, Albucher JF, Rascol O, Montastruc JL, et al. Amitriptyline treatment in chronic drug-induced headache: a double-blind comparative pilot study. Headache 2001;41(2):178-82. 26. Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia 2007;27(7):814-23. 27. Silvestrini M, Bartolini M, Coccia M, Baruffaldi R, Taffi R, Provinciali L. Topiramate in the treatment of chronic migraine. Cephalalgia 2003;23(8):820-4.

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Inventory of Guideline Recommendations for Cluster Headache Table G.7a: Trigeminal autonomic cephalalgias – diagnosis

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation SR/MA NR RCT NRCS CS G Other Cluster G5 (Europe) (p. 1067) Not applicable 1 headache The International Classification of Headache Disorders diagnostic criteria1: 1 A: At least five headache attacks fulfilling criteria B–D; B: Severe or very severe unilateral orbital, supraorbital and/or temporal headache attacks, which last untreated for 15–180 min. During part (but less than half) of the time course of the cluster headache, attacks may be less severe, less frequent or of shorter or longer duration; C: The headache is accompanied by at least one of the following symptoms ipsilateral to the pain: 1. Conjunctival injection or lacrimation; 2. Nasal congestion and/or rhinorrhoea; 3. Eyelid oedema; 4. Forehead and facial sweating; 5. Miosis and/or ptosis; 6. A sense of restlessness and agitation. D: The attacks have a frequency from one every other day to 8 per day; E: History or physical and neurological examination do not suggest any other disorder and/or they are ruled out by appropriate investigations. Episodic cluster headache: at least two cluster periods lasting 7 days to 1 year separated by pain-free periods lasting ≥1 month. Chronic cluster headache: attacks occur for more than 1 year without remission or with remission <1 month. Probable cluster headache: attacks fulfilling all but one criterion for cluster headache. G5 (Europe) (p. 1067-8) Not applicable 2 1 Electrophysiological and laboratory examinations including examination of the 2,3 4 cerebrospinal fluid are not helpful. For the initial diagnosis, and in the case of an abnormal neurological examination, a cranial computed tomography scan and a cranial magnetic resonance imaging scan should be considered in order to exclude abnormalities of the brain. Particularly in older patients, mass lesions or malformations in the midline have been described to be associated with symptomatic cluster headache or in SUNCT where lesions involving the posterior fossa or region of the pituitary gland need to be considered.

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Table G.7a: Trigeminal autonomic cephalalgias – diagnosis (cont’d)

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation SR/MA NR RCT NRCS CS G Other Paroxysmal G5 (Europe) (p. 1068) Not applicable 1 hemicrania The International Classification of Headache Disorders diagnostic criteria1: 1 A. At least 20 attacks fulfilling criteria B–D; B. Attacks of severe unilateral orbital, supraorbital or temporal pain lasting 2 to 30 minutes; C. Headache is accompanied by at least one of the following: 1. ipsilateral conjunctival injection and/or lacrimation; 2. ipsilateral nasal congestion and/or rhinorrhoea; 3. ipsilateral eyelid oedema; 4. ipsilateral forehead and facial sweating; 5. ipsilateral miosis and/or ptosis. D. Attacks have a frequency above 5 per day for more than half the time, although periods with lower frequency may occur; E. Attacks are prevented completely by therapeutic doses of indomethacin; F. Not attributed to another disorder. SUNCT G5 (Europe) (p. 1068) Not applicable 1 1 (short-lasting The International Classification of Headache Disorders diagnostic criteria1: 5 1 unilateral A. At least five attacks fulfilling criteria B–D; neuralgiform B. Attacks of unilateral orbital, supraorbital or temporal stabbing or headache pulsating pain lasting 5–240 seconds; attacks with conjunctival C. Pain is accompanied by ipsilateral conjunctival injection and injection and lacrimation; tearing) D. Attacks occur with a frequency from 3 to 200 per day; syndrome E. Not attributed to another disorder. The most important differential diagnosis is the classical trigeminal neuralgia. In trigeminal neuralgia, unlike in SUNCT syndrome, autonomic symptoms are not prominent and triggered attacks have a clear refractory period. *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Refer to Table G.8 for explanation of ratings. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.7b: Cluster headache – acute treatment

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other Triptans G4 (UK) (Main guideline p. 32) A 5 2 Subcutaneous injection of sumatriptan 6 mg is recommended as the first 6-10 11,12 choice treatment for the relief of acute attacks of cluster headache. Nasal sumatriptan or zolmitriptan is recommended for treatment of acute attacks of cluster headache in patients who cannot tolerate subcutaneous sumatriptan. G5 (Europe) (p.1069, 1072) A 2 5 1 4 The drug of first choice is subcutaneous injection of sumatriptan 6 mg. 13,14 6-8,15,16 17 11,12, An alternative would be sumatriptan 20 mg nasal spray or zolmitriptan 5 mg 18,19 nasal spray, with the disadvantage of a slower onset and the advantage of being able to treat more attacks in 24 hours than with injected sumatriptan. The following, while not a recommendation, was mentioned in G5 with respect to potential harm: Subcutaneous injection of sumatriptan is safe, with no evidence of tachyphylaxis or rebound headache in most patients. The most uncomfortable side effects are chest pain and distal paresthesia. Oxygen G4 (UK) (Main guideline p. 32) Not applicable Based on clinical experience of guideline development group 100% oxygen (7 to 12 litres per minute) should be considered for the (Background study cited: NRCS20) treatment of acute attacks in all patients with cluster headache. G5 (Europe) (p.1069, 1072) A 2 3 The first option for the treatment of acute attacks of cluster headache should 21,22 20,23, be the inhalation of 100% oxygen with at least 7 litres per minute over 15 24 minutes. The following, while not a recommendation, was mentioned in G5 with respect to potential harm: Oxygen is safe and without side effects. Lidocaine G4 (UK) (Main guideline p. 32) Not applicable Based on clinical experience of guideline development group For patients whose attacks of cluster headache are not well relieved by (Background studies cited: NRCS25) subcutaneous or nasal triptan and inhaled 100% oxygen, 10% intranasal lidocaine drops can be considered to help speed relief for acute attacks. G5 (Europe) (p.1072) B 1 1 1 Intranasal lidocaine (4%) can be tried for treating acute cluster headache 26 27 28 attacks if level A medication (oxygen, triptan) is ineffective or contraindicated.

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Table G.7b: Cluster headache – acute treatment (cont’d)

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other Octreotide G5 (Europe) (p.1072) B 1 Subcutaneous octreotide 100 μg can be tried for treating acute cluster 29 headache attacks if level A medication (oxygen, triptan) is ineffective or contraindicated. Zolmitriptan G5 (Europe) (p.1072) B 1 Oral administration of zolmitriptan at 5 mg to 10 mg is effective in some 10 patients, but high doses produce more side effects and limit practical use. *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Refer to Table G.8 for explanation of ratings. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.7c: Cluster headache – pharmacological prophylaxis

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other Verapamil G4 (UK) (Main guideline p. 33; BMJ Summary p. 1233) B 1 1 1 Verapamil 240 mg to 960 mg is recommended as the first choice for the 2 30 31(G5) prophylaxis of cluster headache. G5 (Europe) (p. 1071, 1072) A 2 1 1 3 Prophylaxis of cluster headache should be tried first with verapamil at a 2,32 30 33 34-36 daily dose of at least 240 mg (maximum dose depends on efficacy or tolerability; echocardiographic controls are obligatory with increasing doses). The following, while not a recommendation, was mentioned in G5 with respect to potential harm: Side effects of verapamil are bradycardia, ankle edema, constipation, gastrointestinal discomfort, gingival hyperplasia, and dull headache. Steroids G4 (UK) (Main guideline p. 33; BMJ Summary p. 1233) Not applicable 1 1 In addition to verapamil, steroids (60 mg prednisolone for five days then 37 31(G5) reduced by 10 mg every two days till stopped) can be given at the start of a cluster bout to abort it. G5 (Europe) (p.1072) A 1 1 Although no class I or II* trials are available, steroids are clearly effective 38 39 for treating cluster headache. Corticosteroids can be used for short periods where bouts are short or to help establish another medication. The use of at least 100 mg methylprednisone (or equivalent corticosteroid) given orally or up to 500 mg intravenously per day over 5 days (then tapering down) is recommended. The maximum dose depends on efficacy and tolerability. Methysergide G5 (Europe) (p.1072) B 3 2 4 1 and lithium Methysergide and lithium are drugs of second choice if verapamil is 22,38,40 33,41 42-45 46 ineffective or contraindicated. For methysergide, the maximum dose depends on efficacy and tolerability. The following, while not a recommendation, was mentioned in G5 with respect to potential harm: For methysergide, as there is a definite incidence of pulmonary and retroperitoneal fibrosis under long-term use, the continuous use of methysergide is limited to 6 months. For lithium, the major side effects are hyperthyreosis, tremor, and renal dysfunction.

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Table G.7c: Cluster headache – pharmacological prophylaxis (cont’d)

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other Melatonin G5 (Europe) (p.1072) B 1 1 Melatonin is useful in some patients. The maximum dose depends on 47 48 efficacy and tolerability. Ergotamine G5 (Europe) (p.1072) B 1 2 tartrate Ergotamine tartrate is recommended for short-term prophylaxis. 49 50,51 Pizotifen and G5 (Europe) (p.1072) B 2 3 intranasal Despite positive class II studies, pizotifen and intranasal capsaicin should 52,53 54-56 capsaicin only be used in rare cases because of side effects. The following, while not a recommendation, was mentioned in G5 with respect to potential harm: For pizotifen, the side effects include tiredness and weight gain. Topiramate G5 (Europe) (p.1072) B 2 1 1 Topiramate is promising, but only open trials exist at this point. 57,58 59 60 Recommended dose is at least 100 mg/day, with a starting dose of 25 mg. The following, while not a recommendation, was mentioned in G5 with respect to potential harm: Side effects include cognitive disturbances, paresthesia and weight loss. Baclofen and G5 (Europe) (p.1072) C 2 2 valproic acid Baclofen 15 mg to 30 mg and valproic acid showed possible efficacy and 61,62 63,64 can be tried as drugs of third choice. *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Refer to Table G.8 for explanation of ratings. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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Table G.7d: Paroxysmal hemicrania, hemicrania continua, and SUNCT – acute treatment

Rating of Supporting Evidence Item Guideline/Country/Synopsis of Recommendations Recommen- dation* SR/MA NR RCT NRCS CS G Other Indomethacin G4 (UK) (Main guideline p. 34) D 1 Indomethacin up to 225 mg is recommended for the prophylaxis of 2 paroxysmal hemicrania and hemicrania continua. G5 (Europe) (p.1073) 1 2 5 1 Paroxysmal hemicrania is to be treated with indomethacin up to 200 mg. A 65 66,67 68-72 73 Alternatively, verapamil and other NSAIDs can be tried. C Lamotrigine G5 (Europe) (p.1073) Not stated 2 5 1 Recent large case series outcomes suggest that lamotrigine is the most 74,75 76-80 81 effective preventive agent in SUNCT, followed by topiramate and gabapentin. Intravenous G5 (Europe) (p.1066) Not stated 1 lidocaine Intravenous lidocaine may also be helpful as an acute therapy when patients 82 are extremely distressed and disabled by frequent attacks. *After consultation with the Steering Committee, the strength of the recommendations, as stated by the seed guidelines, was added to the evidence inventory tables for recommendations on tension-type, cluster, and medication-overuse headache. Refer to Table G.8 for explanation of ratings. CS – case series study; G – guideline; NR – non-systematic/narrative review; NRCS – non-randomized comparative study; RCT – randomized controlled trial; SR/MA – systematic review/meta-analysis

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17. Gregor N, Schlesiger C, Akova-Ozturk E, Kraemer C, Husstedt IW, Evers S. Treatment of cluster headache attacks with less than 6 mg subcutaneous sumatriptan. Headache 2005;45(8):1069-72. 18. Paemeleire K, Bahra A, Evers S, Matharu MS, Goadsby PJ. Medication-overuse headache in patients with cluster headache. Neurology 2006;67(1):109-13. 19. Schuh-Hofer S, Reuter U, Kinze S, Einhaupl KM, Arnold G. Treatment of acute cluster headache with 20 mg sumatriptan nasal spray—an open pilot study. Journal of Neurology 2002;249(1):94-9. 20. Kudrow L. Response of cluster headache attacks to oxygen inhalation. Headache 1981;21(1):1-4. 21. Ekbom K. Treatment of cluster headache: clinical trials, design and results. Cephalalgia 1995;15(Suppl 15):33-6. 22. May A. Cluster headache: pathogenesis, diagnosis, and management. Lancet 2005;366(9488):843-55. 23. Fogan L. Treatment of cluster headache. A double-blind comparison of oxygen v air inhalation. Archives of Neurology 1985;42(4):362-3. 24. Gallagher RM, Mueller L, Ciervo CA. Analgesic use in cluster headache. Headache 1996;36(2):105-7. 25. Costa A, Pucci E, Antonaci F, Sances G, Granella F, Broich G, et al. The effect of intranasal cocaine and lidocaine on nitroglycerin-induced attacks in cluster headache. Cephalalgia 2000;20(2):85-91. 26. Markley HG. Topical agents in the treatment of cluster headache. Current Pain and Headache Reports 2003;7(2):139-43. 27. Robbins L. Intranasal lidocaine for cluster headache. Headache 1995;35(2):83-4. 28. Mills TM, Scoggin JA. Intranasal lidocaine for migraine and cluster headaches. Annals of Pharmacotherapy 1997;31(7-8):914-5. [Unable to identify study type—abstract not available.] 29. Matharu MS, Levy MJ, Meeran K, Goadsby PJ. Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study. Annals of Neurology 2004;56(4):488-94. 30. Leone M, D'Amico D, Frediani F, Moschiano F, Grazzi L, Attanasio A, et al. Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology 2000;54(6):1382-5. 31. May A, Leone M, Afra J, Linde M, Sandor PS, Evers S, et al. EFNS guidelines on the treatment of cluster headache and other trigeminal-autonomic cephalalgias. European Journal of Neurology 2006;13(10):1066-77. 32. May A. Headaches with (ipsilateral) autonomic symptoms. Journal of Neurology 2003;250(11):1273-8. 33. Bussone G, Leone M, Peccarisi C, Micieli G, Granella F, Magri M, et al. Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache 1990;30(7):411- 7.

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34. Gabai IJ, Spierings EL. Prophylactic treatment of cluster headache with verapamil. Headache 1989;29(3):167-8. 35. Cohen A, Matharu M, Goadsby P. ECG abnormalities on verapamil in cluster headache. Cephalalgia 2005;25:1200. 36. Matharu MS, Van Vliet JA, Ferrari MD, Goadsby PJ. Verapamil induced gingival enlargement in cluster headache. Journal of Neurology, Neurosurgery, and Psychiatry 2005;76(1):124-7. 37. Ambrosini A, Vandenheede M, Rossi P, Aloj F, Sauli E, Pierelli F, et al. Suboccipital injection with a mixture of rapid- and long-acting steroids in cluster headache: a double-blind placebo- controlled study. Pain 2005;118(1-2):92-6. 38. Ekbom K, Hardebo JE. Cluster headache: aetiology, diagnosis and management. Drugs 2002;62(1):61-9. 39. Mir P, Alberca R, Navarro A, Montes E, Martinez E, Franco E, et al. Prophylactic treatment of episodic cluster headache with intravenous bolus of methylprednisolone. Neurological Sciences 2003;24(5):318-21. 40. Dodick DW, Capobianco DJ. Treatment and management of cluster headache. Current Pain and Headache Reports 2001;5(1):83-91. 41. Steiner TJ, Hering R, Couturier EG, Davies PT, Whitmarsh TE. Double-blind placebo- controlled trial of lithium in episodic cluster headache. Cephalalgia 1997;17(6):673-5. 42. Ekbom K. Lithium for cluster headache: review of the literature and preliminary results of long-term treatment. Headache 1981;21(4):132-9. 43. Manzoni GC, Bono G, Lanfranchi M, Micieli G, Terzano MG, Nappi G. Lithium carbonate in cluster headache: assessment of its short- and long-term therapeutic efficacy. Cephalalgia 1983;3(2):109-14. 44. Graham JR, Suby HI, LeCompte PR, Sadowsky NL. Fibrotic disorders associated with methysergide therapy for headache. New England Journal of Medicine 1966;274(7):359-68. 45. Muller R, Weller P, Chemaissani A. [Pleural fibrosis as a side effect of years-long methysergide therapy]. Deutsche Medizinische Wochenschrift 1991;116(38):1433-6. 46. Curran D, Hinterberger H, Lance J. Methysergide. Research and Clinical Studies in Headache 1967;1:74-122. [Unable to identify study type—abstract not available.] 47. Leone M, D'Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia 1996;16(7):494-6. 48. Pringsheim T, Magnoux E, Dobson CF, Hamel E, Aube M. Melatonin as adjunctive therapy in the prophylaxis of cluster headache: a pilot study. Headache 2002;42(8):787-92. 49. Dodick DW, Rozen TD, Goadsby PJ, Silberstein SD. Cluster headache. Cephalalgia 2000;20(9):787-803. 50. Magnoux E, Zlotnik G. Outpatient intravenous dihydroergotamine for refractory cluster headache. Headache 2004;44(3):249-55.

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51. Ekbom K. Ergotamine tartrate orally in Horton's histaminic cephalalgia (also called Harris's ciliary neuralgia). Acta Psychiatrica Scandinavica 1947;46:106. 52. Fusco BM, Marabini S, Maggi CA, Fiore G, Geppetti P. Preventative effect of repeated nasal applications of capsaicin in cluster headache. Pain 1994;59(3):321-5. 53. Marks DR, Rapoport A, Padla D, Weeks R, Rosum R, Sheftell F, et al. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia 1993;13(2):114- 6. 54. Ekbom K. Prophylactic treatment of cluster headache with a new serotonin antagonist, BC 105. Acta Neurologica Scandinavica 1969;45(5):601-10. 55. Speight TM, Avery GS. Pizotifen (BC-105): a review of its pharmacological properties and its therapeutic efficacy in vascular headaches. Drugs 1972;3(3):159-203. 56. Sicuteri F, Fusco BM, Marabini S, Campagnolo V, Maggi CA, Geppetti P, et al. Beneficial effect of capsaicin application to the nasal mucosa in cluster headache. Clinical Journal of Pain 1989;5(1):49-53. 57. McGeeney BE. Topiramate in the treatment of cluster headache. Current Pain and Headache Reports 2003;7(2):135-8. 58. Rozen TD. Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia. Headache 2001;41 Suppl 1:S25-S32. 59. Leone M, Dodick D, Rigamonti A, D'Amico D, Grazzi L, Mea E, et al. Topiramate in cluster headache prophylaxis: an open trial. Cephalalgia 2003;23(10):1001-2. 60. Forderreuther S, Mayer M, Straube A. Treatment of cluster headache with topiramate: effects and side-effects in five patients. Cephalalgia 2002;22(3):186-9. 61. Gallagher RM, Mueller LL, Freitag FG. Divalproex sodium in the treatment of migraine and cluster headaches. Journal of the American Osteopathic Association 2002;102(2):92-4. 62. El Amrani M, Massiou H, Bousser MG. A negative trial of sodium valproate in cluster headache: methodological issues. Cephalalgia 2002;22(3):205-8. 63. Hering R, Kuritzky A. Sodium valproate in the treatment of cluster headache: an open clinical trial. Cephalalgia 1989;9(3):195-8. 64. Hering-Hanit R, Gadoth N. The use of baclofen in cluster headache. Current Pain and Headache Reports 2001;5(1):79-82. 65. Sjaastad O, Apfelbaum R, Caskey W, Christoffersen B, Diamond S, Graham J, et al. Chronic paroxysmal hemicrania (CPH). The clinical manifestations. A review. Upsala Journal of Medical Sciences. Supplement 1980;31:27-33. 66. Evers S, Husstedt IW. Alternatives in drug treatment of chronic paroxysmal hemicrania. Headache 1996;36(7):429-32. 67. Matharu MS, Cohen AS, Frackowiak RS, Goadsby PJ. Posterior hypothalamic activation in paroxysmal hemicrania. Annals of Neurology 2006;59(3):535-45.

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68. Sjaastad O, Stovner LJ, Stolt-Nielsen A, Antonaci F, Fredriksen TA. CPH and hemicrania continua: requirements of high indomethacin dosages—an ominous sign? Headache 1995;35(6):363-7. 69. Boes CJ, Dodick DW. Refining the clinical spectrum of chronic paroxysmal hemicrania: a review of 74 patients. Headache 2002;42(8):699-708. 70. Shabbir N, McAbee G. Adolescent chronic paroxysmal hemicrania responsive to verapamil monotherapy. Headache 1994;34(4):209-10. 71. Warner JS, Wamil AW, McLean MJ. Acetazolamide for the treatment of chronic paroxysmal hemicrania. Headache 1994;34(10):597-9. 72. Sjaastad O, Antonaci F. A piroxicam derivative partly effective in chronic paroxysmal hemicrania and hemicrania continua. Headache 1995;35(9):549-50. 73. Sjaastad O, Dale I. Evidence for a new (?), treatable headache entity. Headache 1974;14(2):105- 8. [Unable to identify study type—abstract not available.] 74. Matharu MS, Cohen AS, Boes CJ, Goadsby PJ. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome: a review. Current Pain and Headache Reports 2003;7(4):308-18. 75. Pareja JA, Caminero AB, Sjaastad O. SUNCT Syndrome: diagnosis and treatment. CNS Drugs 2002;16(6):373-83. 76. D'Andrea G, Granella F, Cadaldini M. Possible usefulness of lamotrigine in the treatment of SUNCT syndrome. Neurology 1999;53(7):1609. 77. D'Andrea G, Granella F, Ghiotto N, Nappi G. Lamotrigine in the treatment of SUNCT syndrome. Neurology 2001;57(9):1723-5. 78. Hunt CH, Dodick DW, Bosch EP. SUNCT responsive to gabapentin. Headache 2002;42(6):525-6. 79. Matharu MS, Boes CJ, Goadsby PJ. SUNCT syndrome: prolonged attacks, refractoriness and response to topiramate. Neurology 2002;58(8):1307. 80. Porta-Etessam J, Benito-Leon J, Martinez-Salio A, Berbel A. Gabapentin in the treatment of SUNCT syndrome. Headache 2002;42(6):523-4. 81. Cohen A, Matharu M, Goadsby P. Suggested guidelines for treating SUNCT and SUNA. Cephalalgia 2005;25:1200. [Unable to identify study type—abstract not available.] 82. Matharu MS, Cohen AS, Goadsby PJ. SUNCT syndrome responsive to intravenous lidocaine. Cephalalgia 2004;24(11):985-92.

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Table G.8: Recommendation ratings used by seed guidelines

Recommendation G4 G5, G6 Rating

A • At least one high quality meta-analysis, systematic review of randomised Established as effective, ineffective, or harmful: requires at least one convincing controlled trials, or randomised controlled trial with a very low risk of bias class I* study or at least two consistent, convincing class II studies and directly applicable to the target population; or • A body of evidence consisting principally of well conducted meta-analyses, systematic reviews of randomised controlled trials, or randomised controlled trials with a low risk of bias directly applicable to the target population, and demonstrating overall consistency of results

B • A body of evidence including studies rated as high quality systematic reviews Probably effective, ineffective, or harmful: requires at least one convincing class of case-control or cohort studies, and high quality case-control or cohort II* study or overwhelming class III evidence studies with a very low risk of confounding or bias and a high probability that the relation is causal and which are directly applicable to the target population, and with overall consistency of results; or • Extrapolated evidence from studies described in A C • A body of evidence including well conducted case-control or cohort studies Possibly effective, ineffective, or harmful: rating requires at least two convincing with a low risk of confounding or bias and a moderate probability that the class III* studies relation is causal and which are directly applicable to the target population and with overall consistency of results; or • Extrapolated evidence from studies described in B D • Non-analytic studies, such as case reports, case series, expert opinion; or • Extrapolated evidence from studies described in C *Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required: (a) randomization concealment; (b) primary outcome(s) is/are clearly defined; (c) exclusion/inclusion criteria are clearly defined; (d) adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias; (e) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e. Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment. Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion.

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Table G.9: Diagnosis criteria for migraine extracted from the seed guidelines* G3 (France) (Summary [English] p. 1307, Main guideline [French] p. 16-29) Diagnostic criteria of migraine without aura (code 1.1; adapted from IHS classification†): A. ≥5 attacks fulfilling criteria B to D B. Migraine attacks lasting 4 to 72 hours (untreated or unsuccessfully treated) C. Headache with ≥2 of the following characteristics: - Unilateral localization - Pulsating quality - Moderate or severe pain intensity (as measured using a 4-item pain-intensity scale (0=none, 1=mild, 2=moderate, 3=severe) - Aggravation by or causing avoidance of routine physical activity (e.g. walking, climbing stairs) D. The presence of ≥1 of the following symptoms occurs during the headache: - Nausea and/or vomiting - Photosensitivity and phonosensitivity E. Physical examination between attacks is unremarkable. In case of doubt, organic diseases should be ruled out using appropriate investigations. If one of the criteria listed in A to D is not fulfilled, the diagnosis is probable migraine without aura (code 1.6.1). (Summary [English] p. 1307, Main guideline [French] p. 16-29) Diagnostic criteria of typical aura with migraine headache (code 1.2.1; adapted from IHS classification†): A. ≥2 attacks fulfilling criteria B to D B. Aura consisting of ≥1 of the following, but not motor weakness: Fully reversible visual symptoms, including positive features (e.g. flickering lights, spots, or lines) and/or negative features (e.g. loss of vision) Fully reversible sensory symptoms, including positive features (e.g. “pins and needles”) and/or negative features (e.g. numbness) Fully reversible dysphasic speech disturbance C. ≥2 of the following: Homonymous visual symptoms and/or unilateral sensory symptoms ≥1 aura symptom developing gradually over ≥5 minutes and/or different aura symptoms occurring in succession over ≥5 minutes Each symptom lasts 5 to 60 minutes D. Headache fulfilling criteria B to D for IHS migraine classification Migraine without aura (see diagnostic criteria) begins during the aura or follows aura within 60 minutes E. Physical examination between attacks is unremarkable. In case of doubt, organic diseases should be ruled out using appropriate investigations. ICHD-II code 1.6.1 Probable migraine without aura† Diagnostic criteria: A. Attacks fulfilling all but one of criteria A to D for Migraine without aura. B. Not attributed to another disorder. Comment: Do not code as 1.6.1. Probable migraine without aura if the patient fulfills the criteria for Chronic migraine or Status migrainosus. G4 (UK) (p. 1, Quick reference guide) Characteristics of migraine (bold indicates the most helpful for distinguishing migraine from other headache) • episodic moderate to severe headache that causes disability • unilateral • pulsating • builds up over minutes to hours • moderate to severe in intensity

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• associated with nausea and/or vomiting and/or sensitivity to light and/or sensitivity to sound • aggravated by routine physical activity • typical aura (in 15 to 33% of patients with migraine) • exacerbation by physical activity • sensitivity to light between attacks • positive family history of migraine (p. 63-71) Selected Diagnostic Criteria from IHS Classification (ICHD-II)†‡

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ICHD - International Classification of Headache Disorders; IHS - International Headache Society *The information presented here is taken entirely, without any content modification, from the seed guidelines (G3 and G4) and the International Classification of Headache Disorders, 2nd edition (see citation below). References for the seed guidelines are available in Appendix E. †International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24 Suppl 1:9- 160. ‡Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 2006;26(6):742-6.

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Table G.10: Definitions of terms extracted from the seed guidelines* Term Definition Chronic headache (G4) Occurs on more than 15 days per month for more than 3 months. Medication-overuse headache (G1) Medication-overuse headache results from frequent use of acute medications and is a pattern of increasing headache frequency often resulting in daily headaches. (G4) A headache which is present for 15 days or more per month and which has developed or worsened while taking regular symptomatic medication. Non-acute headache (G1) All headache syndromes that have occurred for at least 4 weeks during a patient’s lifetime. Primary headache disorders (G4) Headaches not associated with an underlying pathology, e.g. migraine, tension-type headache, and cluster headache. Rebound headache (G1) Rebound headache is distinct from medication-overuse headache in that rebound headache is associated with withdrawal of analgesics or abortive migraine medication. Our understanding of this phenomenon is based on strong clinical impression and limited research. There is no uniform agreement about which agents can cause rebound headache, although ergotamine (not dihydroergotamine), opiates, triptans, NSAIDs, simple and mixed analgesics containing butalbital, caffeine, or isometheptene are generally thought to do so. There is less uniform opinion about other antimigraine agents. Red flags (G4) Warning signs for potential secondary headache that requires further investigation. Rescue medication (G1) A rescue medication is used at home when other treatments fail. It permits the patient to achieve relief without the discomfort and expense of a visit to the physician’s office or emergency department. Secondary headache disorders (G4) Headache attributed to an underlying pathological condition. Includes any head pain of infectious, neoplastic, vascular, or drug-induced origin. Thunderclap headache (G4) Defined by the ICHD-II (see Table G.9) as a high-intensity headache or rapid onset mimicking a subarachnoid haemorrhage from a ruptured aneurysm, with maximum intensity being reached in less than a minute. In most patients thunderclap headache peaks instantaneously. Thunderclap headache may be primary or secondary. Trigeminal autonomic (G4) Characterized by attacks of severe unilateral pain in a trigeminal distribution. cephalalgias (TAC) TACs include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). ICHD - International Classification of Headache Disorders; NSAIDs - non-steroidal anti-inflammatory drugs *References for the seed guidelines are available in Appendix E.

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APPENDIX H: SUMMARY OF PARKING LOT ITEMS RECOMMENDATIONS ACCEPTED OR REJECTED BY THE GDG BASED ON SUPPLEMENTARY INFORMATION REVIEWED AND DISCUSSED IN SUBCOMMITTEE MEETINGS Table H.1: Headache diagnosis and investigation*

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source History-taking 30 May2011. SC: Check for 30 May 2011. Review statements from Neurology 24 October 2011. GDG accepted G4 (UK) recommendation on history-taking in G4 based on one guideline.1 Psychology, pain management recommendation. seed guidelines. Recommendation on headache history HTA research Based on GDG expert opinion. prepared by the GDG co-chair (neurologist). EO (GDG) July 2011 to July 2012. SC meeting (26 Neurology July 2012) and email correspondence Family medicine, chronic pain (3 July 2012, and 26 July 2011 to 5 management August 2011): Prepare headache Psychology, pain management history tool for use by primary care practitioners. HTA research Examination Physical examination 17 August 2010. No SR found on Neurology (two participants) 19 October 2010. GDG accepted G4 (UK) 22 March 2010. Supplementary search physical/clinical examination or Psychology, pain management recommendation. neurological examination for for SRs on physical/clinical HTA research G4 + minor modification. headache. Information on clinical and examination and neurological CS (G4) examination for headache.§ neurological examination was reviewed from seven NRs3-9 and one qSR.2 Refine list of neurological examinations Subcommittee decision: Accept G4 in patients presenting with headache recommendation with minor provided by G4. modifications drafted by the GDG co- Review study cited by the GDG.2 chair (neurologist). Screening neurological examination 10 June 2010. Refined draft 19 October 2010. GDG accepted recommendation based on G4. recommendation Based on expert opinion from G4 EO (G4)

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Table H.1: Headache diagnosis and investigation (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Examination Neck examination 10 June 2010. Refined draft 19 October 2010. GDG accepted G4 (UK) recommendation based on G4. recommendation. (cont’d) 27 September 2010. Subcommittee Based on NRCS from G4 + decision: Accept recommendation on GDG expert opinion. neck examination drafted by GDG co- NRCS (G4) chair (neurologist) based on G4. 30 May 2011. E-mail correspondence: Musculoskeletal chronic pain Recommendations reviewed by two management GDG members after applying the Primary care GLIA tool.10,11 Examination for 6 June 2011. SC: Quick literature search 10 June 2010. Refined draft Neurology (two participants—one by 19 October 2011. GDG accepted temporoman- for TMD guidelines, particularly clinical recommendation written by GDG co- email) recommendation. dibular disorders examination of patients with potential chair (neurologist). Manual therapy, acupuncture, Based on GDG expert opinion. (TMD) TMD. 27 September 2010. Subcommittee intramuscular stimulation, therapeutic EO (GDG) New decision: Accept recommendation on exercise (by email) recommendation neck examination drafted by GDG co- Spinal biomechanics chair (neurologist). Physical therapy Psychology, pain management Musculoskeletal chronic pain management HTA research 7 July 2011. Review information and Neurology recommendations extracted from six HTA research TMD guidelines.12-17 30 May 2011. E-mail correspondence: Neurology Recommendations reviewed by two Musculoskeletal chronic pain GDG members after applying the (continued management GLIA tool.10,11 over page) Primary care

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Table H.1: Headache diagnosis and investigation (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Examination for 17 January 2011. SC: Search for videos 1 July 2011 to 28 July 2011. Email Neurology 28 July 2011. Decision to use temporoman- on temporomandibular, neck, and correspondence: Discussions about Psychology, pain management video as practical tool for dibular disorders neurological examination. video.18 temporomandibular examination. Musculoskeletal chronic pain (TMD) management New Manual therapy, acupuncture, recommendation intramuscular stimulation, therapeutic (cont’d) exercise HTA research Primary headache 22 March 2010. GDG: What are the 17 August 2010. Review studies2,19,20 Neurology (two participants) 28 September 2010. GDG accepted diagnosis appropriate diagnostic criteria for cited by the GDG. Review IHS criteria Psychology, pain management G4 recommendation with migraine? Include shortcut criteria (e.g., and G4 statement, as well as modifications and expert opinion. Migraine HTA research studies.19,20), full International recommendation drafted by the GDG G1 (USA) G4 + GDG expert opinion. Headache Society (IHS) diagnostic co-chair (neurologist). Four options G3 (France) criteria cited in G4, or adopt G4 were discussed: (a) SIGN criteria; (b) NRCS (G4) G4 (UK) statement. SIGN criteria without severe 28 September 2010. GDG: Reword headaches (only light sensitivity or recommendations to make them more nausea); (c) IHS criteria; (d) client-centered. Merge (b) and (d) (see Identification of Migraine (ID next column) into one Migraine) criteria. Subcommittee recommendation. decision: go with options (b) and (d) and ask opinion of family physicians. Primary headache 22 March 2010. GDG: Review G3 and 10 April 2010. Email correspondence: Neurology (two participants) 28 March 2011. GDG accepted diagnosis G4 recommendations and IHS GDG co-Chair (neurologist) drafted Psychology, pain management recommendation. diagnostic criteria cited in G4. recommendation. Tension-type HTA research Based on studies cited in G4 + headache (TTH) 28 September 2010. GDG: Reword 17 August 2010. Subcommittee GDG expert opinion. G3 (France) recommendations to make them more decision: accept recommendation CS (G4) client-centered. drafted by GDG co-Chair. G4 (UK)

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Table H.1: Headache diagnosis and investigation (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Primary headache 22 March 2010. GDG: Review G4 10 April 2010. Email correspondence: Neurology (two participants) 28 March,2011. GDG accepted diagnosis recommendation and IHS diagnostic GDG co-chair (neurologist) drafted Psychology, pain management recommendation. criteria cited in G4. recommendation. Cluster headache HTA research Based on studies cited in G4 + G4 (UK) 28 September 2010. GDG: Reword 17 August 2010. Subcommittee GDG expert opinion. recommendations to make them more decision: accept recommendation CS (G4) client-centered. drafted by GDG co-chair. Primary headache 22 March 2010. GDG: Review G4 10 April 2010. Email correspondence: Neurology (two participants) 28 March 2011. GDG accepted diagnosis recommendation and IHS diagnostic GDG co-chair (neurologist) drafted Psychology, pain management recommendation. criteria cited in G4. recommendation. Hemicrania HTA research Based on GDG expert opinion. continua 28 September 2010. GDG: Reword 17 August 2010. Subcommittee EO (GDG) G4 (UK) recommendations to make them more decision: accept recommendation client-centered. drafted by GDG co-chair. Primary headache 22 March 2010. GDG: Review G4 10 April 2010. Neurologist drafted Neurology (two participants) 28 March 2011. GDG accepted diagnosis recommendation and IHS diagnostic recommendation (email Psychology, pain management recommendation. criteria cited in G4. correspondence). New daily HTA research Based on clinical experience from persistent 28 September 2010. GDG: Reword 17 August 2010. Reviewed and G4 + GDG expert opinion. headache recommendations to make them more accepted by subgroup. EO (G4) G4 (UK) client-centered.

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Table H.1: Headache diagnosis and investigation (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Cervicogenic 22 March 2012. GDG: Review 17 August 2010. Add information Neurology (two participants) 27 September 2010. GDG accepted headache— references from G4. Supplementary about assessment of jaw movements Psychology, pain management recommendation proposed by co- clinical and search for SRs on clinical and (palpation of head and jaw; palpation chair and SC. HTA research neurological neurological examination for of temporal arteries) when addressing Based on GDG expert opinion. examination; cervicogenic headache and whiplash- cervicogenic headache. EO (GDG) whiplash- associated disorders§. Review article 27 September 2010. Review four Neurology (two participants by email) associated written and cited by one member of the studies cited in G41,22-24 and one SR25 disorders GDG.21 Psychology, pain management found by search, but in the SR study Musculoskeletal chronic pain G4 (UK) population was not stated and the management reviewed studies included data from children and adolescents. A summary Manual therapy, acupuncture, of the conclusions from qSRs26,27 and intramuscular stimulation, therapeutic NRs28-33 was also reviewed. Review exercise (by email) recommendation drafted by GDG co- Spinal biomechanics chair (neurologist). HTA research 30 May 2011. Email correspondence: Musculoskeletal chronic pain Recommendations reviewed by two management GDG members after applying the Primary care GLIA tool.10,11

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Table H.1: Headache diagnosis and investigation (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Diagnosis and 22 March 2010. GDG: Review the list 22 March 2010. Review options and Neurology (two participants) 28 March 2011. GDG accepted neuroimaging in of red flags from G4. Decide how best approaches for development of Family medicine, chronic pain recommendations. the emergent/ to organize the information for use by recommendations. management (by email, 22 March Emergency red flags urgent setting primary care physicians—group by level 17 August 2010. Review 2010) Thunderclap headache of emergency. Red flags and recommendations drafted by the Psychology, pain management EO (GDG) & CS (G4) referral 28 September 2010. GDG: Use red GDG co-chair (neurologist), based on HTA research Meningismus G4 (UK) flags only for emergency and urgent recommendations from G4 and situations. information from one CS,35 two CS (G4) 36,37 38 Papillo-oedema 29 November 2010. SC: Decision to NRs, and one NRCS. NRCS (G4) create a neuroradiology subcommittee 11 July 2011. Diagnostic imaging Radiology for red flags and diagnostic imaging recommendations reviewed by an Acute angle-closure glaucoma recommendations. Involve an external external expert in radiology. CS (G4) consultant/expert to review the Urgent red flags Radiology recommendations reviewed Radiology radiology recommendations. Signs of systemic illness by one external expert in radiology and Primary care 22 February 2011: SC: Send one primary care physician from the G (G4) Neurology recommendation to external radiology GDG. Temporal arteritis expert. NR (G4) 29 March 2011. SC: Send 28 July 2011. Review Neurology Papillo-oedema without focal signs recommendations to an recommendations from Ontario Psychology, pain management EO (GDG) ophthalmologist for review. report. HTA research Elderly patients 28 July 2011. SC: Review Ontario EO (GDG) Health Technology Advisory 17 June 2012. Recommendations Emergency medicine Committee report.34 reviewed by two external experts, one Neurology in emergency medicine and the other Ophthalmology in ophthalmology.

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Table H.1: Headache diagnosis and investigation (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Neuroimaging 22 March 2010. GDG: Review G1, G3, 13 September 2010. No SR found on Neurology (two participants) 28 March 2011. GDG accepted and diagnosis in and G4 recommendations. indications for neuroimaging. Psychology, pain management recommendations. the outpatient Supplementary search for SRs on Information extracted from qSR2 cited Family medicine, chronic pain Imaging in typical migraine setting diagnostic imaging§. Review study2 cited by GDG was discussed. Review management CS (G4) + qSR (IHE database) by the GDG. recommendations drafted by the G1 (USA) Sinus and cervical spine X-ray GDG co-chair (neurologist). HTA research G3 (France) 13 September 2010. SC: Seek the EO (G3) opinion of a neuroradiologist. G4 (UK) Atypical headaches EO (G1) Unexplained focal signs CS (G4) + qSR (IHE database) & G (G4) Unusual headache precipitants CS (G4) + qSR (IHE database) & CS (G4) & EO (GDG) Unusual aura symptoms EO (GDG) Cluster headache and other uncommon primary headache syndromes CS (G4) + qSR (IHE database) Late onset headache NR (G4)

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Table H.1: Headache diagnosis and investigation (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Neuroimaging for 22 March 2010. GDG: Review study 13 September 2010. Review one Neurology (two participants) 13 September 2010. Subcommittee patient cited in G4 recommendation.39 Include RCT39 and one NR.40 Review Psychology, pain management accepted G4 recommendation reassurance a reassuring statement for physicians to recommendation drafted by the GDG and additional information from Family medicine, chronic pain tell patients. Review study cited by the co-chair (neurologist). the NR and subcommittee expert G4 (UK) management GDG.40 opinion. HTA research 28 March 2011. GDG accepted recommendation. G4 + RCT cited in G4 + NR + GDG expert opinion. RCT (G4) Electroencephalo- 22 March 2010. GDG: Review G1 and 29 March 2010. Recommendation NA 29 March 2010. Subcommittee graphy (EEG) G3 recommendations. drafted by the GDG co-chair accepted recommendation based G1 (US) (neurologist). on expert opinion from G1 and G3. G3 (France) 9 May 2011. GDG accepted recommendation. Based on expert opinion from G1 and G3. EO (G1, G3)

CS – case series; EO – expert opinion; G – guideline; GDG – Guideline Development Group (see role and membership in Appendix A and Appendix B); GLIA – GuideLine Implementability Appraisal; HTA – health technology assessment; IHE – Institute of Health Economics; IHS – International Headache Society; NA – not applicable (that is, no parking lot items or other miscellaneous requests); NR – narrative review; NRCS – nonrandomized comparative study; NSAIDs – non-steroidal anti-inflammatory drugs; qSR – quasi-systematic review; RCT – randomized controlled trial; SC – Steering Committee (see role and membership in Appendix A and Appendix B); SIGN – Scottish Intercollegiate Guidelines Network; SR – systematic review Parking lot item – Any activity that involved review of individual studies cited in the seed guideline, systematic reviews published between January 2000 and October 2010, or other requests that were required by the GDG before a final decision could be made. * See Appendix E for the seed guidelines references (G1 to G6). † Interventions are listed in the order in which they were written in the Alberta CPG. See Appendix G for the original recommendations from the seed guidelines. ‡ Detailed information about the searches conducted and about data extraction from studies is available upon request. § The systematic search included systematic reviews that were published between January 2000 and October 2010 and that focused on specific interventions for headache disorders. Note: Over a series of teleconferences and email correspondences held between May 2011 and February 2012, the SC appraised and, where necessary, refined the final wording of each recommendation according to the principles of the GuideLine Implementability Appraisal (GLIA) tool.10,11 The final version of the recommendations was presented to and approved by the GDG on 27 February 2012.

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Table H.2: Management of migraine headache*

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source General approach to management Exercise 27 September 2010. Subcommittee: 27 September 2010. Subcommittee Neurology 14 February 2011. GDG accepted New Supplementary search for SRs on decision: Make a recommendation Manual therapy, acupuncture, recommendation. § recommendation— exercise for migraine . Is there any regarding exercise for migraine. intramuscular stimulation, therapeutic Based on GDG expert opinion. evidence supporting these therapies? developed from 1 October 2010. Review summary of exercise EO (GDG) subcommittee data extracted from two SRs.41,42 Spinal biomechanics discussion 1 October 2010 to 1 November 2011. Physical therapy Email correspondence: Psychology, pain management Recommendation drafted by GDG co-chair (neurologist). Reviewed and Musculoskeletal chronic pain accepted by subcommittee. management HTA research Lifestyle 24 October 2011. Check seed guidelines 29 November 2010. Formation of a Neurology 17 January 2011. GDG accepted factors/specific for commonly reported lifestyle new subcommittee to decide on Manual therapy, acupuncture, food trigger list; decision made to migraine triggers migraine triggers. organization of a potential general intramuscular stimulation, therapeutic include as tool for patients. New lifestyle section. exercise 28 March 2011. GDG accepted recommendation— 22 March 2011. Summary document Psychology, pain management shortened document on lifestyle. developed based on on lifestyle factors prepared by the HTA research 24 October 2011. GDG accepted subcommittee GDG co-chair (neurologist) and sent revised recommendation. discussion to SC for review. Based on GDG expert opinion. Developed two documents for patients on “Commonly Reported EO (GDG) Food Triggers for Migraine Attacks” and “Caffeine Content in Common Drinks and Foods.” Diet 31 May 2010. GDG: Should types of 2 November 2010. Subcommittee Neurology 17 January 2011. GDG decision: A G4 (UK) food triggers for migraine be added to a decision: Accept background Family medicine, chronic pain separate recommendation for diet recommendation? Supplementary statement prepared by GDG co-chair management will not be made. Add search for SRs on diet§. (neurologist). More background recommendation on specific Psychology, pain management 29 November 2010. GDG: Refine information to be added. migraine triggers. recommendation to include specific HTA research triggers.

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Table H.2: Management of migraine headache (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the GDG; Subcommittee and GDG; Guideline) SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Pharmacological interventions NSAIDs and 4 May 2010. GDG: Review RCTs listed in 17 August 2010. Review seven RCTs43-49 Neurology (two participants) 14 February 2011. GDG accepted acetaminophen G3 and G4. Include in the cited in G4 and one RCT50 cited in G3. Pharmacy recommendation. G3 (France) recommendation only the NSAIDs with 23 September 2010. Pharmacist G4 + additional evidence from SR RCT evidence. List dosage amount if Psychology, pain management G4 (UK) provided information on NSAID risks + GDG expert opinion. higher than usual. Add an EO statement and adverse events. HTA research that some patients respond differently, in RCT (G4) + SR (IHE database) which case it is appropriate for these 8 November 2010. Email 51 individuals to trial other forms from short correspondence: Only one SR was list. found on naproxen sodium. Summary of conclusions from two qSRs52,53 and two 17 August 2010. SC: Draft statement NRs54,55 were reviewed. The search also about adverse events. Supplementary identified one SR56 on ibuprofen. The search for SRs on other NSAIDs subcommittee reviewed this, but the (tolfenamic acid, diclofenac, naproxen, information did not change the and flurbiprofen)§. recommendation. Add a 29 November 2010. GDG: Use naproxen recommendation on acetaminophen, as dosage (550 mg) to reflect Canadian in G4. practices. 17 January 2011. GDG: Create a recommendation regarding triptans, if other medications fail. Triptans 4 May 2010. GDG: Review wording of 13 September 2010. Review SRs57-60 and Neurology (two participants) 13 September 2010. Subcommittee G2 (Europe) the triptan recommendations in G2, G3, qSR61 from G3 and G4. Subcommittee Pharmacy accepted G3 and G4 and G4. Retrieve SRs cited in G3 and G4 decision: Accept G4 recommendations recommendation with expert G3 (France) only if relevant. Look for evidence-based for oral triptans, which triptan to use, Psychology, pain management opinion. G4 (UK) Family medicine, chronic pain rationale that suggests which triptan and when to take triptans. Accept the 14 February 2011. GDG accepted variant to start with, based on individual general G3 statement about which management recommendation. differences, and how to modify triptan to use rather than stating the HTA research accordingly. Which triptans are more names of individual triptans. The G3, G4 + GDG expert opinion effective, and are there strong data to recommended doses of the various SR (G3, G4) support this conclusion? Add statement triptans will be listed in the medication about differential benefits. table in the final guideline. 19 October 2010. GDG: Group to wordsmith the background information for this recommendation.

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Table H.2: Management of migraine headache (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Triptans Triptan and NSAID combinations 13 September 2010. Subcommittee G2 (Europe) Subcommittee decision: Accept G4 accepted G4 with modification and expert opinion. G3 (France) statement with modification for drug doses available in Canada. Add 14 February 2011. GDG accepted G4 (UK) background statement that any triptan recommendation. (cont’d) may work with any NSAID. G4 with modification + GDG expert opinion. RCT (G4) Subcutaneous injections 13 September 2010. Subcommittee Subcommittee decision: Accept G2 accepted G2 statement with statement with minor modification of minor modification. wording and addition of dose. 14 February 2011. GDG accepted recommendation. G2 with minor modification + GDG expert opinion. SR (G2) Triptan nasal sprays 18 October 2010. Subcommittee 13 September 2010. Subcommittee accepted revised decision: Accept revised recommendation. recommendation prepared by GDG 14 February 2011. GDG accepted co-chair (neurologist) based on G2. recommendation. 18 October 2010. Revised G2 with minor modification + recommendation prepared by GDG GDG expert opinion co-chair. SR (G2)

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Table H.2: Management of migraine headache (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Antiemetics 4 May 2010. GDG: Refer to G2 13 September 2010. Review five Neurology (two participants) 13 September 2010. Subcommittee G1 (USA) recommendation before reviewing RCTs.62-66 Subcommittee decision: Pharmacy accepted recommendations. RCTs. If guidelines do not provide a Accept revised recommendation for G2 (Europe) Psychology, pain management 19 October 2010. GDG accepted daily dose, then review the RCTs cited metoclopramide prepared by the recommendations. G4 (UK) in G2. GDG co-chair (neurologist). Accept Family medicine, chronic pain management Metoclopramide and domperidone 13 September 2010. Subcommittee: G4 statement for intravenous G2+ additional evidence from Supplementary search for SRs on the metoclopramide. HTA research RCTs cited in G2. use of prochlorperazine§. 26 September 2010. E-mail 21 July 2011. SC GLIA meeting: Check correspondence: No SRs were found. RCT (G2) dosage of domperidone. Intravenous metoclopramide Based on G4 SR (G4) Ergotamine 4 May 2010. GDG: Review SR cited in 17 August 2010. The qSR does not Neurology (two participants) 19 October 2010. GDG accepted G1 (USA) G4 for economic impact. GDG co- include information on economic Pharmacy recommendation. Chair (neurologist) to draft a statement. impact. The subcommittee refined the G4 (UK) Psychology, pain management G4 + GDG expert opinion. Consider adding a statement about not recommendation. recommending ergot alkaloids for acute HTA research SR (G4) migraine although they may be helpful for selected patients. Should a list of when to use ergot alkaloids be included? Should nasal spray be included? The guideline does not cover intravenous administration suitable for other healthcare settings. Butalbital 31 May 2010. GDG: SC to refine 29 March 2011. E-mail Neurology 9 May 2011. GDG accepted G1 (USA) recommendation from G1. correspondence: Recommendation Psychology, pain management recommendation. drafted by GDG co-chair HTA research Based on RCT from G1. (neurologist). Recommendation applies to all medications containing RCT (G1) butalbital, regardless of dose.

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Table H.2: Management of migraine headache (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Dexamethasone 31 May 2010. Query about using 18 October 2010. Two SRs67,68 and Neurology 18 October 2010. Subcommittee and prednisone dexamethasone and prednisone for one qSR69 were identified by the Primary care accepted recommendation G1 + migraine in the emergency room and literature search. Subcommittee additional evidence (SRs). G1 (USA) Psychology, pain management general practice. Supplementary search decision: Accept recommendation 18 October 2011. SC decision not HTA research for SRs on dexamethasone and drafted by GDG co-chair to include recommendation. prednisone for acute migraine§. (neurologist). Add background 24 October 2011. GDG: Consider information about how this can be relevance of adding recommendation. useful for the occasional attack that does not respond to the patient’s usual treatment—it is not meant for routine use. Intravenous 31 May 2010. GDG: Supplementary 18 October 2010. No SR was found. Neurology 18 October 2010. Subcommittee lidocaine search for SRs on intravenous lidocaine Review summary of conclusions from Primary care decision not to include for acute migraine§. two narrative reviews.70,71 Use of recommendation. G1 (USA) Psychology, pain management intravenous lidocaine is not a routine practice. HTA research Menstrual Simple analgesics 18 October 2010. Review one Neurology 19 October 2010. GDG accepted migraine 31 May 2010. GDG: Is mefenamic acid NRCS.72 Review revised Primary care recommendation. recommendation prepared by the G4 (UK) a specific treatment for menstrual Psychology, pain management Based on G4 + additional migraine? Review one study cited in GDG co-chair (neurologist) based on evidence (SR). HTA research G4. G4 recommendation. Add background information about supporting RCT (G4) + SR (IHE

evidence. Subcommittee decision: database) Accept revised recommendation for simple analgesics and triptans based on G4. Triptans 18 October 2010. Review evidence 31 May 2010. GDG: Supplementary from one SR73 and summary of search for SRs on triptans for menstrual conclusions from eight narrative migraine§. reviews.74-81

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Table H.2: Management of migraine headache (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Migraine in pregnancy Simple analgesics 31 May 2010. GDG: Supplementary 18 October 2010. None of the SRs Neurology 29 June 2012. SC accepted G2 (Europe) search for SRs on the use of NSAIDs met the predefined inclusion criteria. Primary care recommendations. during pregnancy§. Check information Review summary of conclusions from G4 (UK) Psychology, pain management 24 October 2011. GDG accepted available on the Motherisk website two qSRs82,83 and four NRs.84-87 recommendations. (www.motherisk.org/women/index.jsp) Review statement from Motherisk HTA research Acetaminophen . Look for SR on contraindication of website. Review a revised using NSAIDs in the third trimester. recommendation drafted by the GDG EO (G2, G4) co-chair (neurologist). Acetaminophen-codeine combination EO (GDG) Triptans 31 May 2010. GDG: Supplementary 18 October 2010. None of the SRs SC Ibuprofen search for SRs on the use of triptans met the predefined inclusion criteria. G2 (Europe) Neurology EO (G4) during pregnancy§. Check information Review summary of conclusions from G4 (UK) Psychology, pain management available on the Motherisk website four quasi-SRs83,89-91 and six NRs.84- Sumatriptan (www.motherisk.org/women/index.jsp) 87,92,93 Review statement based on HTA research EO (G2, G4) . study92 from Motherisk website. Avoid drugs 17 August 2010. SC: Expand and Review a revised recommendation Email correspondence: February EO (G4) update search for new published seed drafted by the GDG co-chair 2011 Ergot alkaloids (neurologist). guidelines and search for guidelines on Neurology EO (G2) headache in pregnancy. 14 February 2011. Email Family medicine 19 October 2010. GDG: Wordsmith correspondence: One new guideline94 the background information. that focused on medications (NSAIDs, Chronic pain management codeine, and opioids) for headache in 14 February 2011. Search the Health Psychology, pain management pregnancy was reviewed. The Canada and the Unites States Food and HTA research Canadian Compendium of Drug Administration websites for Pharmaceuticals and Specialties95 and information on medications in the websites of Health Canada and the pregnancy. United States Food and Drug 21 July 2011. SC: Review one study88 on Administration were searched. triptans in pregnancy cited on the 28 July 2011. Review Norwegian Motherisk website to inform study.88 Results discussed at the SC background. meeting on 29 July 2011. SC decision: 28 July 2011. Subcommittee: Check Add information to the background sumatriptan pregnancy registries to section. inform the recommendation.

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Table H.2: Management of migraine headache (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Triptans 24 October 2011. GDG: 8 August 2011. SC discussed results G2 (Europe) Recommendations approved; include published by the manufacturer in the background information under registry document for sumatriptan.96 G4 (UK) sumatriptan. 11 to 29 June 2012. SC further refined (cont’d) the recommendation based after discussions with TOP on 11 June. Pharmacological prophylactic therapy Nortriptyline 14 June 2010. GDG: Supplementary 2 November 2010. No SRs found. Neurology 29 November 2010. GDG accepted G1 (USA) search for SRs on nortriptyline for Review summary of conclusions from Pharmacy recommendation. prophylactic treatment of migraine§. one qSR97 and eight NRs.98-105 Psychology, pain management Based on expert opinion from G1 Recommendation drafted based on and GDG. expert opinion. HTA research EO (G1) Selective serotonin 14 June 2010. GDG: Supplementary 2 November 2010. Review evidence Neurology 29 November 2010. GDG accepted reuptake search for SRs on SSRIs for from two SRs106,107 cited in G4. Pharmacy recommendation. inhibitors (SSRIs) prophylactic treatment of migraine§. Review summary of conclusions from Psychology, pain management Based on G4. G4 (UK) Extract information from two SRs cited one qSR97 and 14 narrative reviews.98- in G4. 105,108-113 Subcommittee decision: HTA research SR (G4) Accept recommendation based on SRs from G4. Gabapentin 14 June 2010. GDG: Review dosages 13 September 2010. Review RCT114 Neurology 19 October 2010. GDG accepted G1 (USA) for gabapentin from the RCT cited in cited in G4. Subcommittee decision: Pharmacy recommendation. G4. Accept recommendation drafted by G2 (Europe) Family medicine, chronic pain Based on an RCT from G4. GDG co-chair (neurologist). Add management G4 (UK) dosage 900 mg to 24000 mg daily. RCT (G4) Psychology, pain management HTA research

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Table H.2: Management of migraine headache (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Duloxetine and 14 June 2010. GDG: Supplementary November 2010. No SRs found. SC NA November 2010. SC and GDG desvenlafaxine search for SRs on duloxetine or and GDG decision: When new decision: No recommendations New intervention desvenlafaxine for prophylactic interventions are suggested by the on new intervention in the seed suggested by GDG treatment of migraine§. GDG that are not included in the seed guidelines. Do not make a guidelines, no recommendation will be recommendation owing to the made unless there is at least one absence of SRs. relevant SR of the intervention listed in the IHE database. Non-pharmacological therapy Relaxation 31 May 2010. GDG: Supplementary 18 August 2010. Review evidence Psychology, pain management 24 November 2010. GDG accepted training, search for SRs on psychological from six RCTs115-120 cited in G1 and Psychology, chronic pain, chronic recommendation. biofeedback, therapy§. Review six RCTs cited in G1 one SR121 cited in G3. Review headache Based on SR from G3 + cognitive and one SR from G3. Check if there are information from one new SR122 and HTA research information from SR (IHE behavioral any RCTs among the NRCSs cited in its update123 found by the literature database) + GDG expert opinion therapy, G1. search. Review one RCT124 on stress from one NR. stress management cited in G4. Discrepancy Review RCT on stress management SR (G3, IHE database) management cited in G4. between G1 and G3 (supportive of treatment) and G4 (equivocal). Two G1 (USA) 18 August 2010. Subcommittee: potential recommendations were G3 (France) Supplementary search for SRs on stress drafted. G4 (UK) management§. 24 November 2010. No SRs found on stress management. Review summary of information from eight NRs.125-132 Subcommittee decision: Accept one of the two drafted recommendations and add stress management.

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Table H.2: Management of migraine headache (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Acupuncture 31 May 2010. GDG: Supplementary 27 September 2010. Review one Neurology 19 October 2010. GDG accepted G1 (USA) search for SRs on acupuncture§. Assess Cochrane SR133 published in 2009 and Manual therapy, acupuncture, recommendation. the quality of one Cochrane review recommendation drafted by the GDG G3 (France) intramuscular stimulation, therapeutic Based on SR cited in G4 (minor published in 2009. co-chair based on G4. Provide details exercise modification) + SR from IHE G4 (UK) from review about frequency and Physical therapy database. duration of treatment. Psychology, pain management SR (G4, IHE database) 28 September 2010 and 18 October 2010. Email correspondence: Musculoskeletal chronic pain Information extracted from the management Cochrane review discussed. HTA research Homeopathy 21 July 2011. SC: Review SR from G3 21 July 2011. Review evidence from Neurology 21 July 2011. SC decision: “Not G2 (Europe) on homeopathy for prophylactic SR134 cited in G3. Subcommittee Psychology, pain management recommended.” treatment of migraine. decision: Adopt G2 recommendation G3 (France) HTA research Based on RCTs from G2. based on RCTs—“not G4 (UK) recommended.” RCT (G2) Hyperbaric 31 May 2010. GDG: Supplementary 13 September 2010. Review one Neurology (two participants) 19 October 2010. GDG decision: oxygen search for SRs on hyperbaric oxygen Cochrane SR135 found by literature Family medicine, chronic pain Reject recommendation owing to G1 (USA) for migraine§. search on hyperbaric and normobaric management lack of evidence. oxygen for treating and preventing Psychology, pain management 21 July 2011. SC GLIA meeting: migraine. Review and refine Decision to reword HTA research Normobaric recommendations drafted by GDG recommendations for hyperbaric oxygen co-chair (neurologist). and normobaric oxygen. GDG New accepted revised recommendation recommendations. Hyperbaric oxygen Based on G1 + SR from IHE database. RCT (G1) + SR (IHE database) Normobaric oxygen Based on SR from IHE database. SR (IHE database)

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Table H.2: Management of migraine headache (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Spinal 31 May 2010. GDG: Review SR cited in 27 September 2010. Review one SR42 Neurology (two participants—one by 8 July 2011. Insufficient evidence manipulation G4. cited in G4. There is insufficient email) is available to make a G1 (USA) 29 November 2010. GDG: Develop evidence to make a recommendation. Manual therapy, acupuncture, recommendation. Therefore, SC labelled recommendation as “do G3 (France) three recommendations and intramuscular stimulation, therapeutic background statements for exercise (by email) not know.” GDG accepted G4 (UK) recommendation. manipulation, mobilization, and Spinal biomechanics massage. Based on SR from G4 + IHE Physical therapy database. Psychology, pain management SR (G4, IHE database) Musculoskeletal chronic pain management HTA research 31 July 2011. GDG: Review one new 1 to 8 August 2011. Email Neurology published SR on spinal manipulation correspondence and SC meeting Spinal biomechanics for the treatment of migraine. discussion. Decision to consider the Psychology, pain management results from the new SR136 as conflicting evidence. The studies HTA research included in the SR were included in older publications. Hypnotherapy 31 May 2010. GDG: Supplementary 18 August 2010. No SRs were found. Psychology, pain management 19 October 2010. GDG decision: G1 (USA) search for SRs on hypnotherapy§. Review information from three Psychology, chronic pain, chronic Insufficient evidence is available Review NRCS cited in G1. NRs137-139 and the RCT140 cited in G1. headaches to make a recommendation, The NRs are supportive of treatment therefore label as “do not know.” 19 October 19, 2010. GDG: Drafted HTA research background statement. but include a small number of patients. Based on RCT from G1 + GDG Some journals for this area may not be expert opinion based on NRs. captured by the search. Ask GDG if

additional evidence is available that RCT (G1) was not captured.

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Table H.2: Management of migraine headache (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Transcutaneous 31 May 2010. GDG: Check evidence 18 October 2010 to 28 November Neurology 2 November 2010. SC decision: Use electrical nerve source for G1 (NRCS). Retrieve SR 2010. Email correspondence: SR42 Psychology, pain management G4 recommendation with minor stimulation cited in G4; review if migraine is from G4 addressed migraine modification. HTA research (TENS) addressed separately. separately, but only included one low 29 November 2010. GDG G1 (USA) quality quasi-RCT with long-term accepted “do not know” follow up (36 months) on G4 (UK) recommendation. TENS/neurotransmitter modulation. G4 with minor modification. Use a modified G4 recommendation. SR (G4)

EO – expert opinion; G – guideline; GDG – Guideline Development Group (see role and membership in Appendices A and B); GLIA – GuideLine Implementability Appraisal; HTA – health technology assessment; IHE – Institute of Health Economics; NA – not applicable (that is, no parking lot items or other miscellaneous requests); NR – narrative review; NRCS – nonrandomized comparative study; NSAIDs – non-steroidal anti-inflammatory drugs; qSR – quasi-systematic review; RCT – randomized controlled trial; SC – Steering Committee (see role and membership in Appendix A and Appendix B); SR – systematic review Parking lot item – Any activity that involved review of individual studies cited in the seed guideline, systematic reviews published between January 2000 and October 2010, or other requests that were required by the GDG before a final decision could be made. * See Appendix E for the seed guidelines references (G1 to G6). † Interventions are listed in the order in which they were written in the Alberta CPG. See Appendix G for the original recommendations from the seed guidelines. ‡ Detailed information about the searches conducted and about data extraction from studies is available upon request. § The systematic search included systematic reviews that were published between January 2000 and October 2010 and that focused on specific interventions for headache disorders. Note: Over a series of teleconferences and email correspondences held between May 2011 and February 2012, the SC appraised and, where necessary, refined the final wording of each recommendation according to the principles of the GuideLine Implementability Appraisal (GLIA) tool.10,11 The final version of the recommendations was presented to and approved by the GDG on 27 February 2012.

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Table H.3: Management of tension-type headache (TTH)*

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Combination 29 November 2010. GDG: Retrieve 3 May 2011. Review information Neurology 9 May 2011. GDG accepted analgesics studies cited in G6 on combination extracted from seven RCTs141-147 and Pharmacy recommendation. containing drugs for TTH that include caffeine. one population survey148 cited in G6. Family medicine Based on RCTs from G6 with caffeine Subcommittee decision: Accept G6 minor modification. Family medicine, chronic pain G6 (Europe) recommendation with slight modification drafted by GDG co-chair management RCT (G6) (neurologist). Psychology, pain management HTA research Mirtazapine 29 November 2010. GDG: Retrieve 3 May 2011. Review information from Neurology 9 May 2011. GDG accepted 149 150,151 G6 (Europe) studies cited in G6 on mirtazapine for one SR and two RCTs cited in Pharmacy recommendation. TTH. G6. Subcommittee decision: Adopt Family medicine Based on SR and RCTs from G6. G6 recommendation. Family medicine, chronic pain SR (G6) management Psychology, pain management HTA research Venlafaxine 29 November 2010. GDG: Retrieve 3 May 2011. Review information from Neurology 9 May 2011. GDG accepted 152 G6 (Europe) study cited in G6 on venlafaxine for one RCT cited in G6. Pharmacy recommendation. TTH. Subcommittee decision: Adopt G6 Family medicine Based on RCT from G6. recommendation. Family medicine, chronic pain RCT (G6) management Psychology, pain management HTA research Onabotulinum- 29 November 2010. GDG: 3 May 2011. Review information from Neurology 9 May 2011. GDG accepted toxin A Supplementary search for SRs on one SR149 and four NRs153-156 Pharmacy recommendation. (botulinum toxin botulinum toxin A for TTH.§ identified by the search. Subcommittee Family medicine Based on RCT (G4) with A) decision: Accept recommendation modification of wording. from G4 with modification of Family medicine, chronic pain G4 (UK) wording: botulinum toxin A is not management RCT (G4) recommended for the prophylaxis of Psychology, pain management chronic TTH. HTA research

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Table H.3: Management of tension-type headache (TTH) (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Exercise 27 September 2010. Subcommittee: 27 September 2010. Subcommittee Neurology 14 February 2011. GDG accepted New Supplementary search for SRs on decision: Make a recommendation Manual therapy, acupuncture, recommendation. recommendation— exercise for TTH§. Is any evidence regarding exercise for TTH. intramuscular stimulation, therapeutic Based on SRs from IHE database. available to support these therapies? developed from 1 October 2010. Review summary of exercise SR (IHE database) subcommittee data extracted from two SRs.41,42 Spinal biomechanics discussion 1 October 2010 to 1 November 2011. Physical therapy Email correspondence: Psychology, pain management Recommendation drafted by GDG co-chair (neurologist). Reviewed and Musculoskeletal chronic pain accepted by subcommittee. management HTA research Massage 14 February 2011. GDG: Check SR 14 February 2011. Review one SR157 Neurology 28 March 2011: GDG decision: G4 (UK) cited in G4 to see if it provides separate cited in G4. The review provided HTA research Add statement to the background. results for TTH. separate results for TTH. SC GLIA meeting: Accept Subcommittee decision: Accept recommendation as “do not recommendation from G4. know.” Insufficient evidence is available to Based on SR cited in G4. make a recommendation for or against the use of massage in patients with SR (G4) TTH. TENS 14 February 2011. GDG: Check SR 14 February 2011. Review one SR42 Neurology 28 March 2011. GDG decision: G4 (UK) cited in G4 to see if it provides separate cited in G4. The study provided HTA research Accept recommendation as “do results for TTH. separate results for TTH. not know.” Subcommittee decision: Accept Based on SR cited in G4. recommendation from G4.

Insufficient evidence is available to SR (G4) make a recommendation for or against the use of TENS in patients with TTH.

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Table H.3: Management of tension-type headache (TTH) (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source TTH in pregnancy NSAIDs 17 January 2011. GDG: Reword G4 February 2011. Email correspondence: Neurology 28 March 2011. GDG accepted G4 (UK) recommendation. Check for Added information. Family medicine recommendation. acetylsalicylic acid dosages with 14 February 2011. Accept provisional Chronic pain management 9 May 2011. GDG accepted pharmacist and websites. recommendation. wording change to background Psychology, pain management 14 February 2011. GDG: Check for 1 August 2011. Email correspondence: section. HTA research drugs and pregnancy with reference to Changed recommendation on 27 February 2012. GDG accepted acetylsalicylic acid, ibuprofen, and other ibuprofen for increased risk to middle recommendation. NSAIDs. trimester. Based on G4 expert opinion + 28 March 2011. Subcommittee: Remove GDG expert opinion. acetylsalicylic acid from recommendation. EO (G4)

EO – expert opinion; GDG – Guideline Development Group (see role and membership in Appendices A and B); GLIA – GuideLine Implementability Appraisal; HTA – health technology assessment; IHE – Institute of Health Economics; NR – narrative review; NSAIDs – non-steroidal anti-inflammatory drugs; RCT – randomized controlled trial; SC – Steering Committee (see role and membership in Appendix A and Appendix B); SR – systematic review Parking lot item – Any activity that involved review of individual studies cited in the seed guideline, systematic reviews published between January 2000 and October 2010, or other requests that were required by the GDG before a final decision could be made. * See Appendix E for the seed guidelines references (G1 to G6). † Interventions are listed in the order in which they were written in the Alberta CPG. See Appendix G for the original recommendations from the seed guidelines. ‡ Detailed information about the searches conducted and about data extraction from studies is available upon request. § The systematic search included systematic reviews that were published between January 2000 and October 2010 and that focused on specific interventions for headache disorders. Note: Over a series of teleconferences and email correspondences held between May 2011 and February 2012, the SC appraised and, where necessary, refined the final wording of each recommendation according to the principles of the GuideLine Implementability Appraisal (GLIA) tool.10,11 The final version of the recommendations was presented to and approved by the GDG on 27 February 2012.

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Table H.4: Management of other headache disorders*

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Cluster headache Oxygen therapy 28 March 2011. GDG: Check and 14 April 2011 to 2 May 2011. Email Neurology 9 May 2011. GDG accepted G4 (UK) refine recommendation. correspondence: Review one Psychology, pain management recommendation. Cochrane SR135 identified by G5 (Europe) HTA research Based on NRCS cited in G5 + supplementary search for SRs on G4 expert opinion + GDG hyperbaric oxygen for migraine§. The expert opinion. SR also focused on hyperbaric and normobaric oxygen for treating and NRCS (G5) preventing cluster headache. No evidence is available to support the use of normobaric oxygen therapy as a prophylactic measure. Administration of normobaric oxygen to treat acute cluster headache is likely to be effective in more than 70% of cases. Cervicogenic headache Referral 30 May 2011. SC: GDG co-chair 30 May 2011 to 6 June 2011. Email Neurology 11 July 2011. SC accepted New (neurologist) to review seed guidelines correspondence: Recommendation Musculoskeletal chronic pain recommendation. recommendation for information on cervicogenic prepared by the GDG co-chair management 24 October 2011. GDG accepted headache. (neurologist) was reviewed by two Primary care recommendation. GDG members after applying the Based on GDG expert opinion. GLIA tool.10,11 EO (GDG)

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Table H.4: Management of other headache disorders (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Exercise 27 September 2010. Subcommittee: 27 September 2010. Subcommittee Neurology 14 February 2011. GDG accepted New Supplementary search for SRs on decision: Make a recommendation Manual therapy, acupuncture, recommendation. recommendation— exercise for cervicogenic headache§. Is regarding exercise for cervicogenic intramuscular stimulation, therapeutic Based on SRs (IHE database) + developed from any evidence available to support these headache. exercise GDG expert opinion. therapies? subcommittee 1 October 2010. Review summary of Spinal biomechanics SR (IHE database) discussion data extracted from two SRs.41,42 Physical therapy 1 October 2010 to 1 November 2011. Psychology, pain management Email correspondence: Recommendation drafted by GDG Musculoskeletal chronic pain co-chair (neurologist). Reviewed and management accepted by subcommittee. HTA research Cervical spine 27 September 2010. Subcommittee: 29 November 2010 and 10 December Neurology (two participants—one by 14 February 2011. GDG accepted manipulation and Supplementary search for SRs on neck 2010. Email correspondence: Review a email) recommendation with addition of mobilization exercise for cervicogenic headache and summary (comparators, outcomes, Manual therapy, acupuncture, a background sentence. G1 (USA) general exercises§. side effects, and cost) of six RCTs158- intramuscular stimulation, therapeutic Based on SRs from G4 and IHE 165 cited in one SR.166 Some of the G3 (France) 19 October 2010. GDG: Add more exercise (by email) database + GDG expert opinion. information regarding the risks and studies had a very short follow-up. G4 (UK) Spinal biomechanics Cervical spinal manipulation post-whiplash headaches. 30 November 2010. Review Physical therapy SR (G4, IHE database) recommendations drafted by the 17 January 2011. GDG: Expand the Cervical spine mobilization GDG co-chair (neurologist). Psychology, pain management background statements regarding SR (G4, IHE database) cervical manipulation and mobilization. 1 December 2010. Review definitions Musculoskeletal chronic pain for spinal manipulation, spinal management mobilization, and massage prepared by HTA research one member of the GDG. 6 December 2010. Recommendations drafted by the GDG co-chair (neurologist). 1 February 2011. Review and refine draft recommendations based on two SRs.42,166

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Table H.4: Management of other headache disorders (cont’d)

Intervention† Parking Lot Items and Other Subcommittee Meetings Final Decision by the (Source Seed Miscellaneous Requests by the Subcommittee and GDG; Guideline) GDG; SC Actions Review/Discussion/Deliberation‡ Expertise of Participants Evidence Source Headache secondary to temporomandibular disorders Referral 30 May 2011. SC: GDG co-chair 30 May 2011 to 6 June 2011. Email Neurology 11 July 2011. SC accepted New (neurologist) to review seed guidelines correspondence. Recommendation Musculoskeletal chronic pain recommendation. recommendation for information on temporomandibular prepared by the GDG co-chair was management 24 October 2011. GDG accepted disorder. reviewed by two GDG members after Primary care recommendation. applying the GLIA tool.10,11 Based on GDG expert opinion. EO (GDG)

EO – expert opinion; GDG – Guideline Development Group (see role and membership in Appendix A and Appendix B); GLIA – GuideLine Implementability Appraisal; HTA – health technology assessment; IHE – Institute of Health Economics; RCT – randomized controlled trial; SR – systematic review Parking lot item – Any activity that involved review of individual studies cited in the seed guideline, systematic reviews published between January 2000 and October 2010, or other requests that were required by the GDG before a final decision could be made. * See Appendix E for the seed guidelines references. † Interventions are listed in the order in which they were written in the Alberta CPG. See Appendix G for the original recommendations from the seed guidelines. ‡ Detailed information about the searches conducted and about data extraction from studies is available upon request. § The systematic search included systematic reviews that were published between January 2000 and October 2010 and that focused on specific interventions for headache disorders. Note: Over a series of teleconferences and email correspondences held between May 2011 and February 2012, the SC appraised and, where necessary, refined the final wording of each recommendation according to the principles of the GuideLine Implementability Appraisal (GLIA) tool.10,11 The final version of the recommendations was presented to and approved by the GDG on 27 February 2012.

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Table H.5: Other parking lot items

Item Parking Lot Items and Other Subcommittee Meetings Final Decision by the Miscellaneous Requests by the Subcommittee and GDG; GDG; SC Actions Review/Discussion/Deliberation Expertise of Participants Evidence Source New published 11 July 2011. GDG: Review 11 July 2011 to 14 July 2011. Email Neurology 14 July 2011: Subcommittee guideline on recommendations from new guideline correspondence: Review guideline.167 Spinal biomechanics decision not to include the chiropractic cited by member of the GDG. Most of the recommendations, except chiropractic guideline or to alter Psychology, pain management treatment of Compare with Alberta for neck manipulation, are congruent Alberta CPG recommendations. headache recommendations for migraine, with the Alberta CPG HTA research tension-type headache, and cervicogenic recommendations. Review one RCT168 headache. cited in the guideline.

CPG – clinical practice guideline; GDG – Guideline Development Group (see role and membership in Appendix A and Appendix B); HTA – health technology assessment; RCT – randomized controlled trial; SC – Steering Committee (see role and membership in Appendices A and B) Parking lot item – Any activity that involved review of individual studies cited in the seed guideline, systematic reviews published between January 2000 and October 2010, or other requests that were required by the GDG before a final decision could be made.

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79. Nappi G, Johnson EN. The clinical efficacy of zolmitriptan. Reviews in Contemporary Pharmacotherapy 2000;11(2):99-118. 80. Recober A, Geweke LO. Menstrual migraine. Current Neurology & Neuroscience Reports 2005;5(2):93-8. 81. Silberstein SD. Headache and female hormones: what you need to know. Current Opinions & Neurology 2001;14(3):323-33. 82. Koren G, Florescu A, Moldovan Costei A, Boskovic R, Moretti ME. Nonsteroidal anti- inflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: A meta-analysis. The Annals of Pharmacotherapy 2006;40(5):824-9. 83. MacGregor EA. Migraine in pregnancy and lactation: A clinical review. Journal of Family Planning & Reproductive Health Care 2007;33(2):83-93. 84. Brandes JL. Headache related to pregnancy: Management of migraine and migraine headache in pregnancy. Current Treatment Options in Neurology 2008;10(1):12-9. 85. Hansen WF, Peacock AE, Yankowitz J. Safe prescribing practices in pregnancy and lactation. Journal of Midwifery & Women's Health 2002;47(6):409-21. 86. Menon R. Headache and pregnancy. Neurologist 2008;14(2):108-19. 87. Silberstein SD. Headaches in pregnancy. Neurologic Clinics 2004;22(4):727-56. 88. Nezvalova-Henriksen K, Spigset O, Nordeng H. Triptan exposure during pregnancy and the risk of major congenital malformations and adverse pregnancy outcomes: results from the Norwegian mother and child cohort study. Headache 2010;50(4):563-75. 89. Evans EW, Lorber KC. Use of 5-HT1 agonists in pregnancy. Annals of Pharmacotherapy 2008;42(4):543-9. 90. Hilaire ML, Cross LB, Eichner SF. Treatment of migraine headaches with sumatriptan in pregnancy. Annals of Pharmacotherapy 2004;38(10):1726-30. 91. Fox AW, Chambers CD, Anderson PO, Diamond ML, Spierings EL. Evidence-based assessment of pregnancy outcome after sumatriptan exposure. Headache 2002;42(1):8-15. 92. Duong S, Bozzo P, Nordeng H, Einarson A. Safety of triptans for migraine headaches during pregnancy and breastfeeding. Canadian Family Physician 2010;56(6):537-9. 93. Loder E. Safety of sumatriptan in pregnancy: a review of the data so far. CNS Drugs 2003;17(1):1-7. 94. Macintyre PE, Schug SA, Scott DA, Visser EJ, Walker SM; APM:SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine. Acute Pain Management: Scientific Evidence. 3rd edition. Melbourne, Australia: ANZCA and FPM; 2010. Available from: www.anzca.edu.au/resources/books-and-publications/acutepain.pdf (accessed 8 September 2010). 95. Repchinsky, C, editor-in-chief. Compendium of Pharmaceuticals and Specialties. Ottawa (ON): Canadian Pharmacists Association; 2013.

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96. Project conducted by GlaxoSmithKline. The sumatriptan/naratriptan/treximet pregnancy registry. Interim report 1 January 1996 through 31 October 2010. Issued February 2011. Available from: http://pregnancyregistry.gsk.com/documents/sum-nar-trex_interim_report_2011_final.pdf 2011 (accessed 29 July 2011). 97. Koch HJ. Antidepressants in long-term migraine prevention. Drugs 2009;69(1):1-19. 98. Buchanan TM, Ramadan NM. Prophylactic pharmacotherapy for migraine headaches. Seminars in Neurology 2006;26(2):188-98. 99. Griffith JL, Razavi M. Pharmacological management of mood and anxiety disorders in headache patients. Headache 2006;46(SUPPL.3):S133-S41. 100. Loj J, Solomon GD. Migraine prophylaxis: Who, why, and how. Cleveland Clinic Journal of Medicine 2006;73(9):793-816. 101. Punay NC, Couch JR. Antidepressants in the treatment of migraine headache. Current Pain & Headache Reports 2003;7(1):51-4. 102. Sarchielli P, Mancini ML, Calabresi P. Practical considerations for the treatment of elderly patients with migraine. Drugs & Aging 2006;23(6):461-89. 103. Silberstein SD, Young WB. Preventive treatment. CONTINUUM: Lifelong Learning in Neurology 2006;12(6):106-32. 104. Silberstein SD. Treatment recommendations for migraine. Nature Clinical Practice Neurology 2008;4(9):482-9. 105. Sternieri E, Coccia CPR, Pinetti D, Guerzoni S, Ferrari A. Pharmacokinetics and interactions of headache medications, part II: Prophylactic treatments. Expert Opinion On Drug Metabolism & Toxicology 2006;2(6):981-1007. 106. Tomkins GE, Jackson JL, O'Malley PG, Balden E, Santoro JE. Treatment of chronic headache with antidepressants: a meta-analysis. American Journal of Medicine 2001;111(1):54-63. 107. Moja PL, Cusi C, Sterzi RR, Canepari C. Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database of Systematic Reviews 2005;(3):CD002919. 108. Colombo B, Annovazzi POL, Comi G. Therapy of primary headaches: The role of antidepressants. Neurological Sciences 2004;25(SUPPL.3):S171-75. 109. Freeman MC. Migraine-preventive medications: Guidelines for success. Headache & Pain: Diagnostic Challenges, Current Therapy 2006;17(2):83-9. 110. Jackson JL, O'Malley PG, Kroenke K. Antidepressants and cognitive-behavioral therapy for symptom syndromes. CNS Spectrums 2006;11(3):212-22. 111. Stovner LJ, Tronvik E, Hagen K. New drugs for migraine. Journal of Headache & Pain 2009;10(6):395-406. 112. Verdu B, Decosterd I, Buclin T, Stiefel F, Berney A. Antidepressants for the treatment of chronic pain. Drugs 2008;68(18):2611-32. 113. Whyte CA. Adverse effects of medications commonly used in the treatment of migraine. Expert Review of Neurotherapeutics 2009;9(9):1379-91.

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114. Mathew NT, Rapoport A, Saper J, Magnus L, Klapper J, Ramadan N, et al. Efficacy of gabapentin in migraine prophylaxis. Headache 2001;41(2):119-28. 115. Blanchard EB, Appelbaum KA, Radnitz CL, Morrill B, Michultka D, Kirsch C, et al. A controlled evaluation of thermal biofeedback and thermal biofeedback combined with cognitive therapy in the treatment of vascular headache. Journal of Consultation & Clinical Psychology 1990;58(2):216-24. 116. Blanchard EB, Theobald DE, Williamson DA, Silver BV, Brown DA. Temperature biofeedback in the treatment of migraine headaches: a controlled evaluation. Archives of General Psychiatry 1978;35(5):581-8. 117. Lake A, Rainey J, Papsdorf JD. Biofeedback and rational-emotive therapy in the management of migraine headache. Journal of Applied Behaviour Analysis 1979;12(1):127-40. 118. McGrady A, Wauquier A, McNeil A, Gerard G. Effect of biofeedback-assisted relaxation on migraine headache and changes in cerebral blood flow velocity in the middle cerebral artery. Headache 1994;34(7):424-8. 119. Richardson GM, McGrath PJ. Cognitive-behavioral therapy for migraine headaches: a minimal-therapist-contact approach versus a clinic-based approach. Headache 1989;29(6):352-7. 120. Sorbi M, Tellegen B. Multimodal migraine treatment: does thermal feedback add to the outcome? Headache 1984;24(5):249-55. 121. Goslin RE, Gray RN, McCrory DC, Penzien D, Rains J, Hasselblad V. Behavioral and Physical Treatments for Migraine Headache. Technical Review 2.2. Prepared for the Agency for Health Care Policy and Research under Contract No. 290-94-2025: Rockville (MD); 1999. 122. Nestoriuc Y, Martin A. Efficacy of biofeedback for migraine: A meta-analysis. Pain 2007;128(1-2):111-27. 123. Nestoriuc Y, Martin A, Rief W, Andrasik F. Biofeedback treatment for headache disorders: A comprehensive efficacy review. Applied Psychophysiology Biofeedback 2008;33(3):125-40. 124. Lemstra M, Stewart B, Olszynski WP. Effectiveness of multidisciplinary intervention in the treatment of migraine: a randomized clinical trial. Headache 2002;42(9):845-54. 125. Sauro KM, Becker WJ. The stress and migraine interaction. Headache 2009;49(9):1378-86. 126. Buse DC, Andrasik F. Behavioral medicine for migraine. Neurologic Clinics 2009;27(2):445-65. 127. Holroyd KA, Drew JB. Behavioral approaches to the treatment of migraine. Seminars in Neurology 2006;26(2):199-207. 128. Lake III AE. Behavioral medicine for chronic headache: Overview and practical tools for the practicing physician. CONTINUUM: Lifelong Learning in Neurology 2006;12(6):235-58. 129. Scopp AL. Cognitive therapy: An effective tool in headache treatment. Headache & Pain: Diagnostic Challenges, Current Therapy 2003;14(3):115-27. 130. Sheftell FD, Atlas SJ. Migraine and psychiatric comorbidity: From theory and hypotheses to clinical application. Headache 2002;42(9):934-44. 131. Smitherman TA. Anxiety disorders and migraine intractability and progression. Current Pain and Headache Reports 2008;12(3):224-9.

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132. Martin PR, MacLeod C. Behavioral management of headache triggers: Avoidance of triggers is an inadequate strategy. Clinical & Psychology Review 2009;29(6):483-95. 133. Linde K, Allais G, Brinkhaus B, Manheimer E, Vickers A, White AR. Acupuncture for migraine prophylaxis. 2009. Cochrane Database of Systematic Reviews, CD001218(1). 134. Ernst E. Homeopathic prophylaxis of headaches and migraine? A systematic review. Journal of Pain & Symptomatic Management 1999;18(5):353-7. 135. Bennett MH, French C, Schnabel A, Wasiak J, Kranke P. Normobaric and hyperbaric oxygen therapy for migraine and cluster headache. Cochrane Database of Systematic Reviews 2008, Issue 3 Art No: CD005219 2008. 136. Posadzki P, Ernst E. Spinal manipulations for the treatment of migraine: A systematic review of randomized clinical trials. Cephalagia 2011;31(8):964-70. 137. Gruzelier J. Unwanted effects of hypnosis: a review of the evidence and its implications. Contemporary Hypnosis 2000;17(4):163-93. 138. Sandor PS, Afra J. Nonpharmacologic treatment of migraine. Current Pain & Headache Reports 2005;9(3):202-5. 139. Hammond DC. Review of the efficacy of clinical hypnosis with headaches and migraines. International Journal of Clinical Expert Hypnosis 2007;55(2):207-19. 140. Anderson JA, Basker MA, Dalton R. Migraine and hypnotherapy. International Journal of Clinical Expert Hypnosis 1975;23(1):48-58. 141. Pini LA, Del Bene E, Zanchin G, Sarchielli P, Di TG, Prudenzano MP, et al. Tolerability and efficacy of a combination of paracetamol and caffeine in the treatment of tension-type headache: a randomised, double-blind, double-dummy, cross-over study versus placebo and naproxen sodium. Journal of Headache Pain 2008;9(6):367-73. 142. Ward N, Whitney C, Avery D, Dunner D. The analgesic effects of caffeine in headache. Pain 1991;44(2):151-5. 143. Schachtel BP, Thoden WR, Konerman JP, Brown A, Chaing DS. Headache pain model for assessing and comparing the efficacy of over-the-counter analgesic agents. Clinical & Pharmacology Therapy 1991;50(3):322-9. 144. Diener HC, Pfaffenrath V, Pageler L, Peil H, Aicher B. The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single- dose, placebo-controlled parallel group study. Cephalalgia 2005;25(10):776-87. 145. Migliardi JR, Armellino JJ, Friedman M, Gillings DB, Beaver WT. Caffeine as an analgesic adjuvant in tension headache. Clinical & Pharmacology Therapy 1994;56(5):576-86. 146. Diamond S, Balm TK, Freitag FG. Ibuprofen plus caffeine in the treatment of tension-type headache. Clinical & Pharmacology Therapy 2000;68(3):312-9. 147. Cerbo R, Centonze V, Grazioli I, Tavolato B, Trenti T, Uslenghi C, et al. Efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine in the treatment of episodic tension-type headache: a double-blind, randomized, nimesulide-controlled, parallel group, multicentre trial. European Journal of Neurology 2005;12(10):759-67.

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148. Scher AI, Lipton RB, Stewart WF, Bigal M. Patterns of medication use by chronic and episodic headache sufferers in the general population: results from the frequent headache epidemiology study. Cephalalgia 2009. 149. Krishnan A, Silver N. Headache (chronic tension-type). Clinical Evidence 2007;1-21. Available from: http://clinicalevidence.bmj.com/x/systematic-review/1205/overview.html (accessed 11 April 2013). 150. Bendtsen L, Jensen R. Mirtazapine is effective in the prophylactic treatment of chronic tension-type headache. Neurology 2004;62(10):1706-11. 151. Bendtsen L, Buchgreitz L, Ashina S, Jensen R. Combination of low-dose mirtazapine and ibuprofen for prophylaxis of chronic tension-type headache. European Journal of Neurology 2007;14(2):187-93. 152. Zissis NP, Harmoussi S, Vlaikidis N, Mitsikostas D, Thomaidis T, Georgiadis G, et al. A randomized, double-blind, placebo-controlled study of venlafaxine XR in out-patients with tension-type headache. Cephalalgia 2007;27(4):315-24. 153. Freitag FG. Preventative treatment for migraine and tension-type headaches: Do drugs having effects on muscle spasm and tone have a role? CNS Drugs 2003;176(6):373-81. 154. Gobel H, Heinze A, Heinze-Kuhn K, Jost WH. Evidence-based medicine: Botulinum toxin A in migraine and tension-type headache. Journal of Neurology 2001;248(Suppl 1):34-8. 155. Rozen D, Sharma J. Treatment of tension-type headache with botox: A review of the literature. Mount Sinai Journal of Medicine 2006;73(1):493-8. 156. Samton J, Mauskop A. Treatment of headaches with botulinum toxin. Expert Review of Neurotherapeutics 2006;6(3):313-22. 157. Fernandez-de-Las-Penas C, Alonso-Blanco C, Cuadrado ML, Miangolarra JC, Barriga FJ, Pareja JA. Are manual therapies effective in reducing pain from tension-type headache?: a systematic review. Clinical Journal of Pain 2006;22(3):278-85. 158. Chen L, Zhang XL, Ding H, Tao YQ, Zhan HS. Comparative study on effects of manipulation treatment and transcutaneous electrical nerve stimulation on patients with cervicogenic headache. Journal of Chinese Integrative Medicine 2007;5(4):403-6. 159. Bitterli J, Graf R, Robert F, Adler R, Mumenthaler M. Objective criteria for the evaluation of chiropractic treatment of spondylotic headache [Zur Objektivierung der manualtherapeutischen Beeinflussbarkeit des spondylogenen Kopfschmerzes]. Nervenarzt 1977;48(5):159-62. 160. Haas M, Groupp E, Aickin M, Fairweather A, Ganger B, Attwood M, et al. Dose response for chiropractic care of chronic cervicogenic headache and associated neck pain: A randomized pilot study. Journal of Manipulative and Physiological Therapeutics 2004;27(9):547-53. 161. Howe DH, Newcombe RG, Wade MT. Manipulation of the cervical spine—a pilot study. Journal of the Royal College of General Practitioners 1983;33(254):574-9. 162. Hurwitz EL, Morgenstein H, Harber P, Kominski GF, Yu F, Adams AH. A randomized trial of chiropractic manipulation and mobilization for patients with neck pain: Clinical outcomes from the UCLA Neck-Pain Study. Research and Practice 2002;92(10):1634-41.

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163. Nilsson N. A randomized controlled trial of the effect of spinal manipulation in the treatment of cervicogenic headache. Journal of Manipulative and Physiological Therapeutics 1995;18(7):435-40. 164. Nilsson N, Christensen HW, Hartvigsen J. Lasting changes in passive range of motion after spinal manipulation: A randomized, blind, controlled trial. Journal of Manipulative and Physiological Therapeutics 1996;19(3):165-8. 165. Nilsson N, Christensen HW, Hartvigsen J. The effect of spinal manipulation in the treatment of cervicogenic headache. Manipulative and Physiological Therapeutics 1997;20(5):326-30. 166. Gross A, Miller J, D'Sylva J, Burnie SJ, Goldsmith CH, Graham N et al. Manipulation or mobilization for neck pain. Cochrane Database of Systematic Reviews 2010;No.: CD004249(1). 167. Bryans R, Descarreaux M, Duranleau M, Marcoux H, Potter B, Ruegg R, et al. Evidence-based guidelines for the chiropractic treatment of adults with headache. Journal of Manipulative and Physiological Therapeutics 2011;34(5):274-85. 168. Tuchin PJ, Pollard H, Bonello R. A randomized controlled trial of chiropractic spinal manipulative therapy for migraine. Manipulative & Physiology Therapeutics 2000;23:91-5.

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APPENDIX I: SAMPLE OF THE ADDITIONAL INFORMATION PROVIDED TO THE GDG AND SUBCOMMITTEES Ambassador Program – Headache Guideline Parking Lot Items

Triptans

GDG Meeting March 22, 2010. Questions: • Use wording found in G3 Summary in English (p. 1309)? • Single out which triptans are more effective if there are really strong data to support this conclusion • Include a statement from G3 about differential benefits • Should dosages in the G2 list be included? • Should there be a recommendation stating which triptan variants to try first as in G4? • A conclusion paragraph from a meta-analysis regarding which triptan variant is superior to others can be found in the G3 French seed guideline, Volume 2, p. 45; must look for evidence-based rationale that suggests which ones to start with, based on individual differences, and how to modify accordingly. • Endorse statements from G4 about triptan nasal sprays and NSAID combination to use in recommendation, except generalize from sumatriptan to other triptans (considered expert opinion) Actions: Subcommittee to review the following references: • Ferarri et al. (2001) from G3; • Belsey (2000), Ferrari et al. (2002), Loder (2005), Pascual et al. (2007), and Poolsup et al. (2005) from G4, but only if relevant. Additional information for triptans

Section A Wording from the triptan recommendations in G2, G3, and G4.

Section B Information abstracted from systematic reviews requested by the GDG that were cited in guidelines G3 (Table I.1) and G4 (Table I.2) from the pharmaceutical interventions inventory tables.

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Section A Wording in G3 (France) (Summary [English] p. 1309) Triptans are effective for migraine headache, associated gastrointestinal symptoms, and phonosensitivity or photosensitivity. Each triptan has efficacy and tolerability profiles different from the others, but these differences are minimal. A patient who does not respond to one triptan may respond to another. A patient who does not respond to a particular triptan during an initial migraine attack may respond to it in subsequent attacks. Before concluding that a particular triptan is ineffective in a patient, it should be tried for ≥3 attacks, unless it is poorly tolerated. Irrespective of the type of treatment, the patient should take the medication as early as possible after the onset of migraine headache. Delaying administration of an oral triptan after the onset of a migraine headache might reduce the likelihood of complete relief, increase the risk for headache recurrence and adverse effects, and prolong suffering. Concluding paragraph from a meta-analysis (Ferarri et al. 2001) cited in G3 (France) regarding which triptan variant is superior (Volume 2, p. 45) “The authors conclude that, in comparison to sumatriptan 100 mg: • Rizatriptan 10 mg has similar and consistent efficacy, but lower tolerability; • Eletriptan 80 mg has better efficacy and the same durability of effect, but lower tolerability; • Almotriptan 12.5 mg has similar efficacy and durability of effect, but better tolerability; • Sumatriptan 25 mg, naratriptan 2.5 mg, eletriptan 20 mg, and frovatriptan 2.5 mg are less effective but have better tolerability; • Zolmitriptan 2.5 and 5 mg, eletriptan 40 mg, rizatriptan 5 mg, and sumatriptan 50 mg have similar efficacy and tolerability.” Reference G3 (France) Summary guideline: [English] Géraud G, Lantéri-Minet M, Lucas C, Valade D; French Society for the Study of Migraine Headache (SFEMC). French guidelines for the diagnosis and management of migraine in adults and children. Clinical Therapeutics 2004;26(8):1305-18. Summary guideline [French] ANAES Recommandations pour la pratique clinique. Prise en charge diagnostique et thérapeutique de la migraine chez l’adulte et chez l’enfant: aspects cliniques et économiques. Recommandations. Octobre 2002. Available from: http://www.has- sante.fr/portail/jcms/c_272212/prise-en-charge-diagnostique-et-therapeutique-de-la-migraine-chez- ladulte-et-chez-lenfant-aspects-cliniques-et-economiques (accessed April 2, 2013). Main Guideline: [French] ANAES Recommandations pour la pratique clinique. Prise en charge diagnostique et thérapeutique de la migraine chez l’adulte et chez l’enfant: aspects cliniques et économiques. Argumentaire Tome 2: Prise en charge thérapeutique de la migraine chez l’adulte et chez l’enfant, et aspects économiques Octobre 2002. Available from: http://www.has- sante.fr/portail/jcms/c_272212/prise-en-charge-diagnostique-et-therapeutique-de-la-migraine-chez- ladulte-et-chez-lenfant-aspects-cliniques-et-economiques (April 2, 2013).

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Dosages in G2 (Europe) list (p. 968, 970-71) Triptans are recommended for the acute treatment of migraine attacks. The following triptans have efficacy in acute migraine treatment. • Sumatriptan 25 mg, 50 mg, 100 mg (oral including rapid-release); 25 mg (suppository); 10 mg, 20 mg (nasal spray); 6 mg (subcutaneous) – 100 mg sumatriptan is reference for all triptans • Zolmitriptan 2.5 mg, 5 mg (oral including disintegrating form); 2.5 mg, 5 mg (nasal spray) • Naratriptan 2.5 mg (oral) – lesser but longer efficacy than sumatriptan • Rizatriptan 10 mg (oral including 5 mg when taking propranolol wafer form) • Almotriptan 12.5 mg (oral) – probably less side effects than sumatriptan • Eletriptan 20 mg, 40 mg (oral) – 80 mg allowed if 40 mg not effective • Frovatriptan 2.5 mg (oral) – lesser but longer efficacy than sumatriptan In very severe attacks, subcutaneous sumatriptan is recommended. Reference G2 (Europe) Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, et al. EFNS guideline on the drug treatment of migraine--revised report of an EFNS task force. European Journal of Neurology 2009;16(9):968-81. Recommendation in G4 (UK) regarding which triptan to try first (Main guideline p. 20-22; BMJ summary p. 1232) Oral triptans are recommended for acute treatment in patients with all severities of migraine if previous attacks have not been controlled using simple analgesics. Almotriptan 12.5 mg, eletriptan 40-80 mg, or rizatriptan 10 mg are the preferred oral triptans for acute migraine. If a patient does not respond to one triptan an alternative triptan should be offered. Triptans should be taken at, or soon after, the onset of the headache phase of a migraine attack. Triptans are contraindicated in patients with ischemic heart disease, previous myocardial infarction, coronary vasospasm, or uncontrolled or severe hypertension. Triptans should be used with caution in hemiplegic migraine. Triptan nasal sprays/subcutaneous injections Nasal zolmitriptan or subcutaneous sumatriptan should be considered in severe migraine or where vomiting precludes oral route or where oral triptans have been ineffective. Triptan and NSAID combinations For recurrent or prolonged attacks or attacks recurring regularly after successful treatment with a triptan, consider a combination of sumatriptan 50-100 mg and naproxen sodium 500 mg.

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Reference G4 (UK) Main guideline: Scottish Intercollegiate Guidelines Network (SIGN). Diagnosis and management of headache in adults. Edinburgh, Scotland: SIGN; 2008. Available from: http://www.sign.ac.uk/guidelines/fulltext/107/index.html (accessed April 2, 2013). BMJ Summary: Duncan CW, Watson DPB, Stein A, on behalf of the Guideline Development Group. Diagnosis and management of headache in adults: summary of SIGN guideline. BMJ 2008;337:a2329:1231-4. Quick Reference Guide: http://www.sign.ac.uk/pdf/qrg107.pdf (accessed April 2, 2013).

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Section B Table I.1: Summary of data from the systematic review on triptans cited in G3

Review Study Population Comparison/Outcome/ Relevant Results/Authors’ Conclusions Intervention Details Ferarri et al. (2001)1 Included Patients: Comparisons: Mean response rates for sumatriptan 100 mg were 59% (95% confidence interval (CI) The Netherlands, United Total number: Placebo or any triptan type 57% to 60%) for 2-hour headache response; 29% (95% CI 27% to 30%) for 2-hour Kingdom, USA 24,089 Outcomes Measured: pain-free; 20% (95% CI 18% to 21%) for sustained pain-free, and 67% (95% CI 63% to Condition: Headache response at 2 hours, 70%) for consistency. Placebo-subtracted proportions for patients with at least one Objective: adverse event were 13% (95% CI 8% to 18%), for at least one central nervous system To provide evidence-based Acute migraine defined pain-free rates at 2 hours, adverse event 6% (95% CI 3% to 9%), and for at least one chest adverse event 1.9% selection guidelines for by International headache recurrence, sustained (95% CI 1·0% to 2·7%). using triptans in clinical Headache Society pain-free rates, adverse events practice criteria Provider: Not stated Compared with these data, rizatriptan 10 mg showed better efficacy and consistency, and similar tolerability; eletriptan 80 mg showed better efficacy, similar consistency, but Age: 18 to 65 years Not stated Studies Reviewed: Setting: lower tolerability; almotriptan 12·5 mg showed similar efficacy at 2 hours but better Double-blind randomized Race: Not stated Intervention: Sumatriptan 100 other results; naratriptan 2·5 mg and eletriptan 20 mg showed lower efficacy and better controlled trials: 41 Excluded Patients: mg was selected as the tolerability; zolmitriptan 2·5 mg and 5 mg, eletriptan 40 mg, and rizatriptan 5 mg published and 12 Adolescents or reference dose for showed very similar results. unpublished children; data collected comparisons between triptans The results of the 22 trials that directly compared triptans showed the same overall for first attack only Financial support: pattern. At marketed doses, all oral triptans were effective and well tolerated. No formal funding Rizatriptan 10 mg (especially when consistent and rapid freedom from pain is desired), statement, but three of the eletriptan 80 mg (especially when high efficacy and low recurrence were favoured over four authors stated various tolerability), and almotriptan 12·5 mg (especially when high tolerability and good conflicts of interest relating efficacy were favoured) provide the highest likelihood of consistent success. to pharmaceutical companies Sumatriptan 50 mg and 100 mg provide good efficacy and tolerability and by far the longest clinical experience. Naratriptan 2·5 mg offers very good tolerability coupled to a slower onset of improvement; this can be useful in patients with mild or moderate migraine. Zolmitriptan 2·5 mg and 5 mg were good alternatives in many patients; they offer no specific advantages or flaws. Frovatriptan cannot be fully judged in view of the lack of data, but does not seem to offer any particular advantage. All triptans are contraindicated in the presence of cardiovascular disease. Comments: The review did not assess the quality of the included studies and, therefore, does not qualify as a systematic review according to the definition used by the Ambassador Program.

1 Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT1B/1D agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet 2001; 358:1668-75.

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Table I.2: Summary of data from the systematic reviews on triptans cited in G4

Review Study Population Comparison/Outcome/ Relevant Results/Authors’ Conclusions Intervention Details Belsey (2007)2 Included Patients: Comparisons: Based on the numbers needed to treat analysis, significantly more patients achieved United Kingdom Total number: Placebo or any triptan type pain-free status at 2 hours with rizatriptan 10 mg than with sumatriptan 100 mg Not stated Outcomes Measured: (P<0.02), sumatriptan 50 mg (P<0.01) eletriptan 40 mg (P<0.01), zolmitriptan 2.5 Objective: mg (P<0.05), almotriptan 12.5 mg (P<0.01), or naratriptan 2.5 mg (P<0.001). To carry out a systematic Condition: Pain free at 2 hours There was no significant difference between rizatriptan 10 mg, eletriptan 80 mg, review of the evidence base Acute migraine Not stated Provider: and zolmitriptan 5 mg for this endpoint. relating to randomized Age: Not stated Setting: Not stated placebo-controlled trials of Based on acquisition costs alone, there was a statistically significant difference Race: Not stated Any single dose oral triptan therapy in acute Intervention: between the cost-effectiveness ratios of rizatriptan 10 mg (£14.15) and sumatriptan treatment of oral triptan migraine and to ascertain Excluded Patients: 100 mg (£37.61; P<0.001), zolmitriptan 5 mg (£33.26; P<0.001), naratriptan 2.5 Data collected for first aggregate crude efficacy mg (£32.66; P<0.01), sumatriptan 50 mg (£28.71; P<0.001) and eletriptan 80 mg attack only levels for each agent and (£28.17; P<0.001). There was no significant difference between the cost- dose effectiveness ratios calculated for rizatriptan 10 mg and almotriptan 12.5 mg (£15.06), eletriptan 40 mg (£17.37), and zolmitriptan 2.5 mg (£20.22). Studies Reviewed: 29 double-blind randomized Rizatriptan 10 mg is the only agent studied that demonstrated high levels of both controlled trials clinical and cost-effectiveness. It can therefore be considered an ideal first-line treatment choice in the management of the acute migraine attack. Financial support: Unconditional educational grant from Merck Sharp & Dohme Ltd Ferrari MD, Goadsby PJ, Duplicate publication of Ferarri et al. (2001)1 Roon KI, Lipton RB. Triptans (serotonin, 5- HT1B/1D agonists) in migraine: detailed results and methods of a meta- analysis of 53 trials. Cephalalgia 2002;22(8):633- 58. Loder E. Fixed drug Quasi-systematic review (quality of the included studies was not assessed). combinations for the acute Does not contain any information on fixed drug combinations that include a triptan. treatment of migraine: place in therapy. CNS Drugs 2005;19(9):769-84.

2Belsey JD. The clinical and financial impact of oral triptans - an updated meta-analysis. Journal of Medical Economics 2002;5:79-89.

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Table I.2: Summary of data from the systematic reviews on triptans cited in G4 (cont’d)

Review Study Population Comparison/Outcome/ Relevant Results/Authors’ Conclusions Intervention Details Pascual et al. (2007)3 Included Patients: Comparisons: After 30 minutes, fast-dissolving sumatriptan 50 and 100 mg, sumatriptan 50 mg, Spain Total number: Placebo or any triptan type and rizatriptan 10 mg showed significant relief when compared to placebo, Not stated Outcomes Measured: whereas the fast-dissolving formulation of sumatriptan 100 mg was the only oral Objective: triptan that was superior to placebo in meeting the pain-free endpoint. On the To compare the efficacy and Condition: Pain relief and pain free at 30 other hand, fast-dissolving sumatriptan 50 and 100 mg and eletriptan 40 mg tolerability of currently Acute migraine minutes, 1 hour, 2 hours; showed a lower rate of recurrence than placebo, whereas rizatriptan 10 mg was the marketed oral, non- Age: 19 years or older headache recurrence; adverse events only triptan with a recurrence rate greater than that of placebo. reencapsulated triptan Race: Not stated formulations versus placebo Provider: Not stated Adverse events associated with treatment with tablet formulations of sumatriptan in the treatment of Excluded Patients: and zolmitriptan were significantly more frequent than those of the placebo group. Data collected for first Setting: Not stated moderate to severe migraine The influence of reencapsulation on the effectiveness and tolerability data is small. attack only Any of the seven attacks Intervention: currently marketed triptans Studies Reviewed: 38 double-blind randomized controlled trials Financial support: Grant from GSK-Spain; all authors have given paid lectures for the companies launching the triptans analyzed in this paper

3Pascual J, Mateos V, Roig C, Sanchez-Del-Rio M, Jimenez D. Marketed oral triptans in the acute treatment of migraine: a systematic review on efficacy and tolerability. Headache 2007;47(8):1152-68.

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Table I.2: Summary of data from the systematic reviews on triptans cited in G4 (cont’d)

Review Study Population Comparison/Outcome/ Relevant Results/Authors’ Conclusions Intervention Details Poolsup et al. (2005)4 Included Patients: Comparisons: Frovatriptan 2.5 mg was more effective than placebo in rendering the patient pain- Thailand Total number: Placebo free at 2 hours (risk ratio (RR) 3.70, 95% confidence interval (CI) 2.59 to 5.29) and 2866 Outcomes Measured: 4 hours (RR 2.67, 95% CI 2.21 to 3.22). It was also superior to placebo in reducing Objective: headache severity at 2 hours (RR 1.66, 95% CI 1.48 to 1.88) and 4 hours (RR 1.83, To evaluate the efficacy and Condition: Pain free, headache response, 95% CI 1.66 to 2.00) after treatment. tolerability of frovatriptan in Acute migraine headache recurrence, relief of acute migraine treatment Age: Not stated migraine-associated symptoms, In those whose headache was relieved at 4 hours, the risk of headache recurrence adverse effects within 24 hours was reduced by 26% with frovatriptan (P=0.009). Studies Reviewed: Race: Not stated 5 double-blind randomized Provider: Not stated Frovatriptan 2.5 mg was also superior to placebo in improving symptoms Excluded Patients: associated with migraine. At 2 hours after dosing, frovatriptan reduced the risk of controlled trials Not stated Setting: Not stated nausea by 14% (P=0.0005), photophobia by 17% (P<0.0001), and phonophobia

Financial support: Intervention: by 14% (P<0.0001). The corresponding numbers at 4 hours after dosing were 37% Not stated Frovatriptan 2.5 mg (P<0.0001), 34% (P<0.0001), and 30% (P<0.0001). Frovatriptan caused more adverse events than placebo (RR 1.31, 95% CI 1.07 to 1.62). The available evidence suggests that frovatriptan 2.5 mg is more effective, but may cause more adverse events, than placebo in the treatment of acute moderate to severe migraine. It is effective in providing pain relief and reducing the risk of recurrence. 4Poolsup N, Leelasangaluk V, Jittangtrong J, Rithlamlert C, Ratanapantamanee N, Khanthong M. Efficacy and tolerability of frovatriptan in acute migraine treatment: systematic review of randomized controlled trials. Journal of Clinical Pharmacy and Therapeutics 2005;30(6):521-32.

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APPENDIX J: SAMPLE OF THE DOCUMENT USED TO TRACK GDG DELIBERATIONS

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APPENDIX K: PROCESS USED TO FORMULATE RECOMMENDATIONS

Seed Guideline on Headache

Seed Guideline Recommendation

ACCEPT OR ACCEPT WITH ACCEPT BUT SUPPLEMENT REJECT ORIGINAL RECOM- MORE INFORMATION MINOR MODIFICATION (E.G. WITH EXPERT OPINION MENDATION AND CREATE REQUIRED WORDING) Accept original NEW ONE BASED ON EXPERT OPINION Accept original recommendation from recommendation from seed guideline but The original seed guideline with only modify or supplement recommendation was minor wording or other with additional rejected and a new one changes to make it information/recom- was drafted based on applicable to the mendations based on the collective expert Alberta healthcare the collective expert opinion of the system. opinion of the Ambassador Guideline Ambassador Guideline Development Group Development Group. (GDG). ADDITIONAL INFORMATION (GDG). RETRIEVED/CONSIDERED

ACCEPT/CHANGE ORIGINAL ACCEPT/CHANGE ORIGINAL SUPPLEMENT ADDITIONAL REJECT ORIGINAL RECOMMENDATION BASED RECOMMENDATION BASED EVIDENCE WITH EXPERT RECOMMENDATION ONLY ON STUDIES ON ADDITIONAL EVIDENCE OPINION AND CREATE NEW ONE BASED ON INCLUDED IN SEED FROM LITERATURE SEARCH After examining the EXPERT OPINION GUIDELINES The GDG accepted or individual studies cited The GDG accepted or changed the original by the seed guideline or changed the original recommendation after additional systematic recommendation after examining additional reviews on headache examining the systematic reviews on identified by a individual studies cited headache identified by a supplementary literature by the seed guideline as supplementary literature search, the GDG evidence for the original search. An example of modified the original recommendation. this would be the recommendation based addition of a on the collective expert recommendation on opinion of the therapeutic exercise for Ambassador GDG. tension-type headache. This was only added after a subjective assessment of the additional evidence.

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APPENDIX L: RECOMMENDATION CATEGORIES Definitions for Do, Do Not Do, Do Not Know DO When the Guideline Development Group (GDG) accepted the intent of the original recommendation in the seed guideline(s), the original wording was preserved where possible. Thus, recommendations were classified as “Do” when the original guideline recommended or provided a prescriptive direction to perform the action, or used the term “effective” to describe it. The seed guidelines used different systems to grade or categorize the level of evidence supporting each recommendation and the strength or type of recommendation made. However, generally all of the guidelines recommended an action or described it as effective when this statement was supported by: • results from at least one study of strong design for answering the question addressed; • generally consistent results from multiple studies of strong design for answering the question addressed; • the clinical experience of the GDG. When the Ambassador GDG supplemented a recommendation or created a new one based on expert opinion, it was classified “Do” when the collective professional opinion of the GDG supported the action. DO NOT DO (Not Recommended) When the GDG accepted the intent of the original recommendation in the seed guideline(s), the original wording was preserved where possible. Thus, recommendations were classified as “Do Not Do” when the original guideline recommended against or provided a prescriptive direction not to perform the action, used the term “ineffective” to describe it, or stated that the evidence does “not support” it. The seed guidelines used different systems to grade or categorize the level of evidence supporting each recommendation and the strength or type of recommendation made. However, generally all of the guidelines recommended against performing an action or described it as ineffective when this statement was supported by: • results from at least one study of strong design for answering the question addressed; • generally consistent results from multiple studies of strong design for answering the question addressed; • the clinical experience of the GDG. When the Ambassador GDG supplemented a recommendation or created a new one based on expert opinion, it was classified “Do Not Do” when the collective professional opinion of the GDG did not support the action.

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DO NOT KNOW When the GDG accepted the intent of the original recommendation in the seed guideline(s), the original wording was preserved where possible. Thus, recommendations were classified as “Do Not Know” when the original guideline did not recommend for or against the action or stated that there was “no evidence”, “insufficient or conflicting evidence”, or “no good evidence” to support its use. The seed guidelines used different systems to grade or categorize the level of evidence supporting each recommendation and the strength or type of recommendation made. However, generally all of the guidelines stated that evidence for a particular action was lacking or insufficient when: • effectiveness was demonstrated in a general sense but not specifically for back pain; • the studies were of poor quality, inappropriately designed to answer the question addressed, or presented conflicting results, which precluded the determination of effectiveness or the balance of benefits and harms; • only one study of any design was available; • no studies of any design were available. When the Ambassador GDG supplemented a recommendation or created a new one based on expert opinion, it was classified “Do Not Know” when the collective professional opinion of the GDG was equivocal with respect to supporting the action.

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APPENDIX M: FEEDBACK ON GUIDELINE DOCUMENTS Table M.1: Rating of importance of key guideline messages by Guideline Development Group members (n=10 via an online survey in March 2012) and family physicians (n=4 via a focus group in April 2012)

Not at all Slightly Moderately Very Extremely Message important important important important important Neuroimaging is not indicated in patients with recurrent migraine headache, a normal 0 0 2 4 8 neurological examination and no “Red Flags.” Migraine should be considered in patients with recurrent moderate or severe headaches and a 0 0 3 6 5 normal neurological examination. A triptan should be used when NSAIDs are not 0 1 1 8 4 effective. Opioid containing analgesics are not 0 0 2 7 5 recommended for routine use for migraine. Medication overuse should be diagnosed in patients with headache who use combination analgesics, opioids, or triptans on 10 or more 0 0 3 5 6 days per month or acetaminophen or NSAIDs on 15 or more days a month. ASA, NSAIDs, and triptans are the primary 0 1 2 8 3 medications for acute migraine treatment. Patients consulting for bilateral headaches that interfere with their activities are likely to have 0 0 3 9 2 migraine rather than tension-type headache and may require migraine specific medication. Most patients who present to community health 0 1 3 4 2 care providers with headaches have migraine.* Comprehensive migraine therapy includes management of lifestyle factors and triggers, 0 0 5 1 4 acute and prophylactic medications, and migraine self-management strategies.* Patients who do not respond well to one triptan 1 0 6 2 1 may respond to another.* *The family physician focus group was not asked to score this key message.

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Table M.2a: Summary of feedback on the patient information sheets received from Guideline Development Group members (online survey conducted in November 2012)*

Information Sheet Detail Discipline What you should Information is important for patients to know (three strongly agree, three agree). Six participants: know about • The sheet could be edited to read better and be clearer and shorter. Two family headache self- physicians management • Stress section clear and easy to understand. One specialist • Consider substituting "reduce" for "alleviate" in the first bullet. Consider physician substituting "communicating effectively your needs and limitations" instead of "being assertive....". One pharmacist One psychologist • Link to the headache diary in the text at the point where it is recommended? One director • Document lengthy; a single double-sided page is often best. • Remind patients that the headache diary is for self-evaluation and should be abandoned once data are collected as continued use can lead to pain centering and hamper improved function. What you should Information is important for patients to know (four strongly agree). Four participants: know about • Add some of the causes of headaches. One family headache physician • Some language (e.g., intensity and duration) may be at a higher reading level than desired. Maybe: "Migraine is the most common cause of headaches that One specialist last longer or are especially painful." physician • Should mention again that over-the-counter medications are useful in One pharmacist moderation, but should be limited to 10 to 15 days per month. One director What you should Information is important for patients to know (three strongly agree, three agree) Six participants: know about • Add a couple of examples of self-management strategies in the self- Two family medication- management section. physicians overuse One specialist headache • Under the "How is ...Treated" heading: physician - Third bullet: Consider "more than you can comfortably tolerate" instead of "bear." One pharmacist - Final bullet: Consider "Medications that prevent migraine headaches may One psychologist be more effective after the medication overuse has been stopped." One director What you should Information is important for patients to know (five strongly agree, three agree) Eight participants: know about • Too wordy in sections and too much information. Three family migraine physicians headache • Consider using "features" instead of "symptoms" in the first bullet. Second bullet is a run-on sentence followed by a conflicting sentence. Consider One specialist "Patients sometimes confuse recurrent attacks over long periods of time of physician migraine headaches for those related to sinus infections (sinusitis). If the One headache is sinus related, it would be expected to improve with appropriate physiotherapist treatment that may include antibiotics. However, in most cases these One pharmacist headaches are found not to be sinus related and are instead migraine." One psychologist • Information regarding sinusitis seems conflicting and confusing. One director • In the section “Should I take medications for my headache?” consider having bullet #6 say "codeine and other narcotics" and #9 say "or codeine/ narcotic- containing."

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Table M.2a: Summary of feedback on the patient information sheets from Guideline Development Group members (cont’d)

Information Sheet Detail Discipline What you should Information is important for patients to know (five strongly agree, two agree) Seven participants: know about • The initial comment on the first page about self-management strategies with Two family migraine accompanying examples is great. It should be cut and pasted onto other physicians preventive documents that refer to self-management. One specialist medications • The font on this one seems smaller and a lot of higher level vocabulary has physicians been used. One pharmacist • Please add that antidepressants/antianxiety medications can also be used if One psychologist you don't have anxiety or depression (similar to topirimate) One chiropractor • First bullet: Clarify "… preventive medications do not cause rebound or One director medication-overuse headache." Consider: "When your migraines cause enough pain or loss of ability to do normal activities in spite of appropriate use of acute medications for individual attacks." First bullet under “When should I consider …” • The phrasing of the definition is confusing: "They are different from acute or symptomatic medications like the triptans (for example sumatriptan) or painkillers which are taken to treat individual migraine attacks and do not cause rebound or medication-overuse headache." This sounds like painkillers do not cause rebound headache. Perhaps: "They are different from acute or symptomatic medications like the triptans (for example sumatriptan) or painkillers which are taken to treat individual migraine attacks. Preventive medications do not cause rebound or medication-overuse headache." • Should be written at a lower literacy level. Is the bullet point about overweight and topiramate really necessary? What you should Information is important for patients to know (two strongly agree, three agree) Five participants: know about • It says that self-management strategies will be referred to later in the One family tension-type document, but they are not. physician headache • May want to change: “Who is qualified to evaluate me?” to “Who should be One specialist seeing me?” or “Who should I see? “Also, some pictures would be nice. physician • Is the "Who should evaluate me?" section necessary in all the sheets? One pharmacist One psychologist One director * One specialist physician (neurologist), who did not fill in the survey, made further refinements to the patient information sheets after reviewing the suggestions received from the survey participants.

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Table M.2b: Summary of feedback on the patient information sheets from the Institute of Health Economics Lay Committee (n=8 via a focus group conducted in Edmonton, October 2012)

Theme/Information Sheet Detail General opinion • Some sheets are too wordy. Low health literacy populations or individuals for whom English is not their first language (for example, First Nations Elders) may have difficulty reading and comprehending the text. • The sheets do not cover cluster headache, and participants felt information pertaining to even uncommon forms of headaches would be useful. • Participants had some concerns about the accessibility of the patient sheets. For example an electronic form may not be appropriate for a person during an episode of headache, so in such circumstances the information could be more useful in a print form. • Participants stated that they trusted their family physicians and would read information given to them by their physician. • The IHE and TOP logos are fine, but readers who are not familiar with TOP and IHE might not read the information online; a logo from Alberta Health Services would make the information more credible. • Handing all sheets to a patient may be confusing. What you should • Sheet is too wordy; some of the repetitive information could be removed. know about headache • Some participants said they did not want anything that might be useful to be left out; repetition self-management may be good, as not everyone understands the medical terminology. Some visuals or pictures may work. • Participants appreciated the management and holistic approach presented in this sheet (for example, one participant expressed appreciation of the discussion on the emotions that can accompany a headache). • The different types of headache should be explained so that people can distinguish what they should do; for example, whether they need to see a doctor, self-medicate, or need a prescription. • The information is useful for people who do not suffer from headache pain and shows what to do at the onset of a headache, provides a general idea about headache conditions, and provides a better understanding of what people with headache experience. • A person who suffers from an episode of headache needs streamlined information. • Should include: triggers, what to do, different medications (talk to your doctor about what route to go and what type of medications to take), and include some information about drugs and drug interactions. What you should • Participants liked the sheet and found the information useful. They would read the information if know about headache it were handed out by a physician. • The “Seek professional help” section is clear. • Participants also liked the sections about which professionals are qualified to evaluate headache patients and about returning to the physician if the headache pain does not improve.

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Table M.2b: Summary of feedback on the patient information sheets from the Institute of Health Economics Lay Committee (cont’d)

Theme/Information Sheet Detail What you should • Most participants did not know about this condition; they learned a lot from reading the know about information. medication-overuse • The section about treating medication-overuse headache may not need such detail, as this headache should be explained by a physician. However, not all physicians discuss this with patients. • The information about potential addictions is important and may be useful for those who are dealing with addictions to medications and withdrawal symptoms, and for those who do not understand medical terminology and can get easily addicted. Participants emphasized that physicians need to explain potential addiction issues. • Physicians should discuss the content of the sheet when they hand it out and should answer questions about medication interactions and frequency of use. • Withdrawal symptoms should be mentioned in the other sheets as well. • The self-care section is very useful. • Participants were interested to know whether pharmacists will also hand out this sheet, as not all people with headaches go to a physician. Also, massage therapists, chiropractors, and naturopaths could use these sheets. • It would be useful to play the messages from the sheet on screens in pharmacies so people could read them while they are waiting for a prescription; TV advertisements are very useful. Sheets could also include a web address where people can find more information. • Self-medicating can be dangerous because everybody is different. If you overmedicate you can get other problems—ulcers, nausea, etc. A disclaimer would be good. • Patients should speak to a doctor first about what medications are safe for them. What you should • The sheet is informative about what to do if you have a migraine. know about migraine • Explain the migraine types and symptoms. headache • No information is given about comparing migraine with other headaches.

What you should • Is the word “prophylactic” necessary? Could it be avoided? know about migraine • Language is too inaccessible and the sheet is very wordy. It needs a better title. preventive medications • Participants liked that it mentions different medications (i.e., which medication to try). • It would be useful to highlight the diary information at www.headachenetwork.ca. • Participants talked about controlling triggers, but the information about triggers is in a different pamphlet. This one could just have a list of triggers: environmental, dietary, etc. • The pamphlet (especially the last sections) covers information patients need to know. • People need to be directed to a website for more information. • The sheet could combine some of the bullet points in the third section—there are too many bullet points in the first sections. Do not use them with every sentence, only for introducing new concepts. • Pamphlet would have to be identified in some way in order to be accepted as valid.

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Table M.2b: Summary of feedback on the patient information sheets from the Institute of Health Economics Lay Committee (cont’d)

Theme/Information Sheet Detail What you should • Second section—“What is a tension headache?”—could be first. know about tension- • Leave out the word “bilateral”; just say “both sides of your head.” type headache • General agreement was expressed that it’s necessary to mention X-rays or MRIs. • The sheets should use a common format and style. This pamphlet was clearer, more concise, and read better than the others.

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Table M.2c: Summary of feedback on the patient information sheets from the Calgary Headache Assessment & Management Program patients (n=5 via a focus group conducted in Calgary, May 2013)*

Theme/Information Sheet Detail General opinion • Size of the documents and fonts, and their availability in electronic format, may impact readability, especially when patients have a headache. • It is useful to tell people what websites to access. What you should • General comments: There is a lot of helpful information. Managing triggers, stress, and emotions know about headache are very important in headache. self-management • Tips for self-monitoring: Good information. Remove “for at least a month” from the statement “keep up with self-monitoring for at least a month”. • Information in third paragraph, “some people find that if they can react early…”, is important, especially if there are factors (such as stretching) other than the medications that may alleviate the headache, so medication-overuse can be prevented. • The Tips on healthy lifestyle section is redundant and could be deleted or included in the next section. • Minimize the intensity and impact of a migraine: Participants liked the third bullet “avoid negative or catastrophic thinking”, but they did not like “I’ll lose my job, my boyfriend, etc.” as it is too specific. Leave it as “this headache is killing me”. What you should • General comments: Content is good, though grammar needs correcting. A good learning resource know about headache for someone who does not have knowledge about headaches. • Title: Should be “headaches” instead of “headache” as there is more than one type of headache. • Facts about migraine: It is helpful to know that headaches are common and there are medical and non-medical treatments to cope with them. • Will I need X-rays, and MRI or laboratory tests: This section is useful. • What should I do to help myself: Information about headache diaries is important as they are excellent tools. Diary design can be improved by increasing the space in the columns to accommodate more information (triggers, flares-up, activities during the day, medication intake). • Can headaches be prevented? Mention some non-medical treatments. What you should • General comments: Good; nothing missing, and nothing to take out. know about • What is medication-overuse headache? Liked that the medications acetaminophen and ibuprofen are medication-overuse separated from codeine and triptans and that there is an indication of the number of medication headache days that could lead to medication-overuse. • Should I see my doctor? Useful information; gives options and choices. • What can I do to help myself? Using a diary is useful to avoid over-medication. The link to a diary is useful. • Perhaps explain terminology and that medication-overuse is different from addiction. • If I’ve stopped medication: Great section.

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Table M.2c: Summary of feedback on the patient information sheets from the Calgary Headache Assessment & Management Program patients (cont’d)

Theme/Information Sheet Detail What you should • General comments: Information is credible; nothing to remove. know about migraine • Should I take medicines for my headache? The list of medications for acute and preventive treatment headache of migraine is a little overwhelming. There is nothing to take out but the information could be made more user friendly. What should I do to help myself? There is not much information about self-management in the sheet, although there is a separate sheet developed for this. It may be helpful to add interventions that alleviate pain, such as using a barometric pressure therapy device and hyperbaric oxygen. Specify other triggers such as florescent light and weather pressure changes. • Can migraine be prevented or cured? The information that there is no known cure for migraine is depressing; add something like “however, with the right combination of preventive approaches many people are able to live without migraine being a big disruption in their lives.” What you should • General comments: Information is credible; nothing to remove. know about migraine • Which medication should I try? Everyone is different and it is hard to know what works for each preventive individual. Like the inclusion of alternative non-prescription medications. medications • What is likely to happen after I start a migraine preventive medication? The statement “a successful preventive medication will only decrease your migraine frequency by 50%” is quite disturbing. • To prevent/alleviate pain, it may help to use an antiglare screen and drink lots of water. Add life coaching; emphasize lifestyle factors and psychological help. What you should • General comments: Information is credible; nothing to change or remove. know about tension- type headache * Participants were split into two groups, each of which reviewed three patient information sheets

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Table M.3: Suggestions from family physicians for improving the guideline documents (n=4 via a focus group conducted in Calgary, April 2012)

Theme Detail Discipline Presentation of Rated 4 on a scale of 1 (lowest quality) to 5 (highest quality) for organization and Four family main guideline ease of finding information. physicians document • Organized approach; nicely separated into topics, but document is lengthy and it can take a while to find specific information. The checkbox format was easy to understand (do, do not do, do not know). • Thorough document, well organized, although long; like the Motherisk contact information given. Is the diary available as a separate PDF to be distributed to patients? • Bring the information about the medications (lines of treatment, drugs, side effects, and evidence sources) into the recommendation. • Document is hard to navigate. • Add pop-up text when the cursor hovers over text; add bookmarks and hyperlinks to the document; find a way to make searching the document easier; add a function to show where you are in the document (such as a table of contents showing on the left side of the document). • Split the main guideline into chapters and save them in separate documents (e.g., diagnosis, management of migraine and/or tension-type headache). • Link information from the main guideline to the summary guideline and algorithm. • Acronyms for the evidence source need to be explicit on each page. • Add a note to say that additional information about the medications mentioned in the guideline is available in Appendix A: Medication table. Main guideline: Rated 4 on a scale of 1 (lowest quality) to 5 (highest quality) for providing Three family information sufficient information to inform clinical decisions. physicians provided and • Add s specific reference to the latest Canadian guidelines. areas missing • Would like to have medication starting doses in the text of the document, not just in the appendix. • Need clearer recommendations about how to diagnose medication-overuse headache and how to initiate/choose headache prophylaxis—including a timeline on when to expect improvements. • Use a checklist format for red flags, exam findings; include levels of evidence and pediatric recommendations; add an icon for each medication for use in pregnancy; mention other headache conditions such as coital, exertional, hypnic, paroxysmal, and hemicrania. • It’s important that recommendations are described clearly so doctors don’t have to spend a lot of time reading the background. • Add levels of evidence for guideline recommendations. • Evidence source: mention all the type of studies that informed the recommendation, not only the highest. • Rank the evidence source using numbers. • Add information about auras: typical versus atypical. • Add information about use of contraceptives and associated risks with aura symptoms and cerebrovascular disease/stroke.

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Table M.3: Suggestions for improving the guideline documents from physicians (cont’d)

Theme Detail Discipline Guideline Rated 4 by three participants and 5 by one participant on a scale of 1 (lowest Four family recommendations quality) to 5 (highest quality) physicians (clinically sound, • Dosage and titration is required; special pregnancy precautions. appropriate for the intended • Need to add more information about titration of β-blockers for migraine. patients) • Pharmacological prophylaxis for tension-type headache—include information about medications in a table format, add more details about side effects and titrations; information can be included in pop up boxes for those using the electronic format. • Triptan qualifications and doses—add a more specific recommendation on which triptan is recommended to be used first, which second, and so on. • Add symbols (,, ?) in the medication tables in Appendix A. • Add links to provincial resources available for the treatment of headache. Enablers to • Check box format is clear, quick to review. Four family implementing the • Lots of information that is relatively easy to use; clinically useful, especially physicians guideline medication doses. • ,, ? system. Barriers to • Lack of infrastructure/information technology to support guideline use Four family implementing the • Lack of time to use the guideline in the clinical setting physicians guideline • Too lengthy to use on a regular basis; better suited as a reference document • A more tabular treatment option presentation in the main guideline would help. Usability Three participants indicated that they will use the guideline in making professional Three primary decisions and would recommend the guideline for use in practice. care physicians Quick reference Clarity and usefulness of the algorithm Four family algorithm and On a scale of 1 (lowest quality) to 5 (highest quality): rated 4 by three participants physicians medication tables and 5 by one participant for clarity; rated 4 for ease of use by four participants. Four participants said they will use the algorithm. • Should be incorporated into electronic medical record (EMR). • It would be easiest and most practical if it were condensed to one page.

Clarity and usefulness of the medication tables On a scale of 1 (lowest quality) to 5 (highest quality): rated 4 by two participants and 5 by one participant for clarity; rated 4 for ease of use by two participants and 5 by one participant. Two participants indicated that it is worthwhile to have the medication tables included with the algorithm and that they will use them. • Try to minimize appendix references or minimize core document information. • Add hyperlinks to link medication tables with the main guideline medication table. • Add title “selected” or “commonly used” medications instead of “summary” medication table. • Titration information is very important. • Add a note about drugs used in pregnancy (or a symbol to indicate which drugs could be used during pregnancy). • Add more information on triptan qualifications and doses.

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Table M.3: Suggestions for improving the guideline documents from physicians (cont’d)

Theme Detail Discipline Additional The algorithms were considered clear, but one algorithm works best. Four family algorithms • Suggest having one simplified document. physicians developed for • Algorithms are good but people would likely only use/find the information if different combined into one master algorithm. headache • Consolidate them into one page with meds on reverse of sheet for non-EMR conditions users. • Primary Care Network physicians use EMRs; information from EMRs can be easily updated; would like to include the algorithm of the headache guideline. Preference for a • Suggest comments on the electronic version of the document, with hyperlink Four family more detailed capabilities. physicians summary • We may miss some information using only one master summary. guideline that • “Less is more”—cross-reference with the main guideline document. includes key • In the algorithm there is a discontinuation of diagnosing uncommon headache messages and conditions; add arrows to link with diagnosis of common headaches. selected recommendations • Add bookmarks for “Table 1,” “Table 2,” and “Table 3” in the algorithm, to for headache link with the medication tables. assessment and • Use smaller fonts for the practice points. treatment (e.g., a • Add “refer if necessary” for patients with migraine and tension-type headache. six-page • Red flags box: separate/make more distinctive the emergency red flags and document instead urgent red flags—possible indicators of secondary headache; add a time for of a two-page referral: emergency red flags need to be addressed immediately, urgent red flags summary) addressed in hours to days. It would be good to add the questions about assessment of the need to change a patient’s acute migraine medication (from page 16 of the main guideline) to the summary guideline, although this may not work due to space: • Do you have significant relief within 2 hours of taking the medication? • Is the medication well tolerated? • Do you take only one dose? • Can you resume normal occupational, social, and family activities within 2 hours of taking the medication? If the patient says “No” to at least one of these questions, the physician should consider changing the patient’s acute migraine medication, if possible. Other comments • Physicians would prefer to learn how to use the headache guideline via Four family academic detailing or an interactive workshop. Other suggested dissemination physicians methods were mail-out of laminated algorithm/medication tables and integrating with EMRs. • In-person communication of the guideline works best. Emails are sometimes overlooked. Tools can also be disseminated by mail, advertisements in professional magazines, workshops/presentations at conferences, and apps. • More patient handouts would help physicians use the guideline. The headache diary and caffeine handout are very helpful. More patient self-assistance and management tools would also help.

Ambassador Program. Guideline for Management of Primary Headache in Adults. Background Document 276 August, 2013

Table M.4: Suggestions for improving the guideline from Advisory Committee members (December 2011)

Document Detail Main guideline • The guideline does not mention that NSAIDs have been linked to increased risk of heart disease. What would be recommended to patients who have a history of heart disease? Possibly add a background statement about NSAIDs administered to patients with comorbidities (heart disease). • Suggest moving the blood pressure measurement to after the neck examination in the physical examination recommendation, and include a statement about the adverse effects of cervical spinal manipulation. • Question were raised about including the strength of evidence of the recommendations in the Alberta guideline. This information was not included in the Alberta guideline due to variations in the scales used to rate the strength of evidence among the seed guidelines. • The guideline could be used as a tool to support a physician’s decision to not recommend neuroimaging, but the guideline does not state this strongly enough. The guideline cannot take the point of view that we live in a society that demands scanning, while still aiming to reduce unnecessary scanning. Patients may be caused unneeded anxiety after scan results. The guideline could be used to support the family physicians’ decision to not prescribe a scan when the evidence does not support the need for a scan. A short video and/or a short one-pager for physicians on how to approach this topic may be useful. • The guideline may need to list the International Headache Society Diagnostic Classifications as background. • The guideline should be used as a tool to state what interventions are supported by the research evidence, rather than focusing on areas where the evidence is not as strong. The interventions that are supported by strong evidence should be clearly stated. • It was noted that the guideline is missing an education component for new physicians to learn how to utilize guidelines. However, this is a component of the dissemination plan. • It was mentioned that the commonality of various headache types should be emphasized within the guideline. However, this will be addressed in the two-page algorithm and in the medication tables of the guideline. • A decision support tool, which could help reassure the patient, might be a useful addition to the guideline.

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APPENDIX N: DECLARATION OF COMPETING INTEREST FORM

Declaration of Competing Interest

Project Name: Headache Guidelines in Primary Care

1. I agree to have my name acknowledged as a contributor on the development of the guideline on headache. Yes  No 

If not, please be assured that we would respect your preference.

2. If yes, please list name, degrees, position, title and affiliation as you wish them to appear in the guideline.

Name: Degrees: Position Title: Affiliation: Area of expertise:

All contributors are required to disclose circumstances which could be perceived to be a competing interest. Competing interest is considered to be financial interest or non-financial interest, either direct or indirect that could affect the recommendations contained in this guideline. Please note that declaring financial and/or non-financial competing interest helps us to fully inform our stakeholders about this aspect and does not mean that the person would not be in a position to act as an expert, or that his/her contributions would be incorrect or biased. If you have any questions or concerns, please contact Christa Harstall, Project Director HTA, by e-mail at [email protected].

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Potential competing interest NO YES

Ownership of stock, stock options or other financial instruments of a product’s   manufacturer or manufacturers of competitive products (excluding mutual fund ownership).

Honoraria or other compensation from a manufacturer or a special interest group for   writing a publication or participating in the development of the guideline.

Grant, honoraria or other compensation from a manufacturer or a special interest group   for conducting research

Currently, or within the last 2 years:   • Consultancy or employment with a manufacturer or a special interest group. • Speaker fees, educational grants and/or travel assistance provided by a manufacturer or a special interest group. • Any other direct or indirect relationship with a manufacturer or a special interest group which could be perceived to be a competing interest.

If yes to any of the above or if there is any other potential competing interest, please describe below:

Signature Date

Printed Name

Thank you for completing this form. Please return the form by mail or fax to:

Institute of Health Economics Attention: HTA 1200, 10405 Jasper Avenue Edmonton, Alberta, Canada T5J 3N4 Fax: (780) 448-0018

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Table N.1: Competing interests declared by GDG members

Affiliation, Discipline, Area of Expertise Declared Interest Werner Becker MD, BSc, FRCP(C) Served on Medical Advisory Boards for AGA Medical, Allergan, Merck, (co-chair) and Pfizer Professor, Department of Clinical Received speaker’s honoraria from Allergan, Merck, Pfizer, Serono, and Neurosciences Teva University of Calgary Received research support as part of multicenter clinical trials (served as Neurology local principal investigator) from AGA Medical, Allergan, Medtronic, and Merck MD, FRCPC (Neurology), DABPN Received consultant’s fees from Biogen Idec Clinical Assistant Professor, Division of Received travel assistance from Teva Neuroscience Neurology Department of Clinical Neurosciences, University of Calgary Neurology BScPharm Written continuing medical education for pharmacists and presented at Clinical Pharmacist, Alberta Health Services pharmacy educational conferences for a manufacturer or a special Pharmacy, pain management interest group (not specified) BSc, DC, MSc, PhD Chief Scientific Officer and 51% shareholder of VibeDx Associate Professor, Canada Research Chair in Recipient of an operating grant from the Canadian Chiropractic Spinal Function Research Foundation, as well as funds from the Canadian Institutes of University of Alberta Health Research, the Natural Science and Engineering Research Council Spinal biomechanics of Canada, and the National Institutes of Health

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