Guideline Panel Members

i Guideline Panel Members Saudi Expert Panel Dr. Adel Alhazzani Dr. Nasser Alotaibi Dr. Suleiman Mohammed Kojan Dr. Manal Abdulaziz Murad Dr. Mona Obaid McMaster University Working Group Dr. John J Riva, Dr. Ainsley E Moore, Dr. Jan L Brożek, and Dr. Holger J Schünemann, on behalf of the McMaster Guideline Working Group. Acknowledgements We acknowledge Dr. Ali M. Al Khathaami, Dr. Abdullah Al-Humaidan, Dr. Abdul-Hameed Ali Hassan, Dr. Fahmi M. Al-Senani for their contribution to this work. We gratefully acknowledge Dr Rajaa Alraddadi, from the Ministry of Health for peer reviewing this final report. Disclosure of potential conflict of interest: Dr. Suleiman Mohammed Kojan declares that he participated in a headache course sponsored by Janssen-Cilag and received honoraria for his contribution. Other co-authors declare that they have no conflict of interest related to this guideline. Funding: This clinical practice guideline was funded by the Ministry of Health, Saudi Arabia. Address for correspondence: Saudi Center for Evidence Based Health Care E-mail: ebhc@moh.gov.sa Web: http://www.moh.gov.sa/endepts/proofs/pages/home.aspx

ii Contents The Saudi Center for Evidence Based Health Care (EBHC)... iv Executive Summary... 1 Introduction... 1 Methodology... 1 How to use these guidelines... 2 Key Questions... 3 Recommendations... 4 Scope and purpose... 6 Introduction... 6 Methodology... 7 How to use these guidelines... 8 Key questions... 8 Recommendations... 9 Question 1: Should head MRI or CT (with or without contrast) rather than no imaging be done in patients with suspected migraine headache?... 9 Question 2: Should metoclopramide versus NSAIDs be used for acute migraine?... 10 Question 3: Should triptans versus metoclopramide be used for acute migraine?... 11 Question 4: Should triptans versus paracetamol be used for acute migraine?... 12 Question 5: Should triptans, in combination with NSAIDs, versus NSAIDs alone be used for acute migraine?... 13 Question 6: Should triptans, in combination with NSAIDs, versus triptans alone be used for acute migraine?... 14 Question 7: Should beta-blockers versus no beta-blockers be used for prevention of recurrence of migraine?... 15 Question 8: Should topiramate versus no antiepileptics be used for prevention of recurrence of migraine?... 16 Question 9: Should valproate versus no antiepileptics be used for prevention of recurrence of migraine?... 16 Question 10: Should topiramate versus valproate be used for prevention of recurrence of migraine?... 17 Question 11: Should antiepileptics other than topiramate or valproate versus no antiepileptics be used for prevention of recurrence of migraine?... 18 Question 12: Should topiramate versus beta-blockers be used for prevention of recurrence of migraine?... 19 Question 13: Should triptans versus no triptans be used for prevention of recurrence of menstrual-related migraine?... 20 Question 14: Should botulinum toxin A injections versus no injections be used for prevention of recurrence of episodic migraine?... 21 Question 15: Should botulinum toxin A injections versus no injections be used for prevention of recurrence of chronic migraine?... 22 Question 16: Should tricyclic antidepressants versus no antidepressants be used for prevention of recurrence of migraine?... 23

iii Question 17: Should SSRIs versus no antidepressants be used for prevention of recurrence of migraine?... 24 Question 18: Should education and self-management programs versus no such programs (usual care only) be used for prevention of recurrence of migraine?... 24 References... 26 Appendices... 34 Appendix 1: Evidence to Decision Frameworks... 35 01: Should head MRI or CT (with or without contrast) rather than no imaging be done in patients with suspected migraine headache and no other indications?... 35 02: Should metoclopramide versus NSAIDs be used for acute migraine?... 46 03: Should triptans versus metoclopramide be used for acute migraine?... 55 04: Should triptans versus paracetamol be used for acute migraine?... 64 05: Should triptans, in combination with NSAIDs, versus NSAIDs alone be used for acute migraine?... 72 06: Should triptans, in combination with NSAIDs, versus triptans alone be used for acute migraine?... 81 07: Should beta-blockers versus no beta-blockers be used for prevention of recurrence of migraine?... 90 08: Should topiramate versus no antiepileptics be used for prevention of recurrence of migraine?... 99 09: Should valproate versus no antiepileptics be used for prevention of recurrence of migraine?... 106 10: Should topiramate versus valproate be used for prevention of recurrence of migraine?... 114 11: Should antiepileptics other than topiramate or valproate versus no antiepileptics be used for prevention of recurrence of migraine?... 123 12: Should topiramate versus beta-blockers be used for prevention of recurrence of migraine?... 131 13: Should triptans versus no triptans be used for prevention of recurrence of menstrualrelated migraine?... 138 14: Should botulinum toxin A injections versus no injections be used for prevention of recurrence of episodic migraine?... 146 15: Should botulinum toxin A injections versus no injections be used for prevention of recurrence of chronic migraine?... 154 16: Should tricyclic antidepressants versus no antidepressants be used for prevention of recurrence of migraine?... 163 17: Should SSRIs versus no antidepressants be used for prevention of recurrence of migraine?... 170 18: Should education and self-management programs versus no such programs (usual care only) be used for prevention of recurrence of migraine?... 177 Appendix 2: Search Strategies and Results... 186

iv The Saudi Center for Evidence Based Health Care (EBHC) The Saudi Centre for Evidence Based Health Care has managed and supported the coordination of the process of clinical practice guideline (CPG) development between the methodological team from McMaster University and the local clinical expert panel members in Saudi Arabia. The EBHC staff members recruited local clinical experts through contacting Saudi specialist societies and also independent experts interested in developing reliable and most up-to-date CPGs to harmonize the treatment and provide the highest quality of health care in the Kingdom of Saudi Arabia. These experts were health care professionals of multidisciplinary backgrounds. As much as possible, patient s representatives were also included in panels. In an effort to make national recommendations, the participating experts were professionals from the Ministry of Health (MoH), National Guard Hospitals, King Faisal Specialist Hospital and Research Centre (KFSHRC), University Hospitals, Security Forces Hospitals, Prince Sultan Military Medical City (PSMMC) and from some private hospitals. Based on a pre-selection of available evidence syntheses, the EBHC provided a list of potential topics to be addressed in CPGs after thorough consultations with the local stakeholders. These topics were further discussed with the McMaster team for important selection criteria and agreed on 12 topics for wave 2. The guideline panel meetings were held in Riyadh on 15 th -18 th March 2015 where about (96 local experts working in Saudi Arabia participated with the methodological support from 20 experts from McMaster University and its partners from the American University of Beirut, Lebanon, and the University of Freiburg, Germany, in providing high quality recommendations for common and important clinical conditions in the Kingdom. The Saudi Centre for EBHC supports the efforts for dissemination of the CPGs by publishing online the full reports of the CPGs, facilitates writing concise versions of the CPGs for publication in peer reviewed medical journals, sending hard copies to hospitals and health care centers. Finally, a mobile App has been introduced in KSA to facilitate the dissemination efforts of the completed practice guidelines. The staff members at the Saudi Centre for EBHC: Dr Zulfa Al Rayess, Consultant Family Medicine, Head of Saudi Center for EBHC Dr Yaser Adi, Scientific Advisor for the Saudi Centre for EBHC Miss Nourah Al Moufarreh, Project Manager, Saudi Center for EBHC

1 Executive Summary Introduction Migraine headache is very common in society with a prevalence and global burden that ranks third world-wide of all neurological disorders. 7 It also has been argued that current research underestimates the burden of disability associated with migraine. 8 In acute situations, most migrainers report trying more than three acute treatments with over-thecounter acute treatments more commonly reported than use of prescription treatments. 9 Those with more chronic migraine (15 or more migraines per month) tend to have even more debility, lost work time or decreased productivity. 10,11 This chronicity leads to higher headache-related disability, headache impact, typically worse socioeconomic status, worse health-related quality of life, and higher other medical and psychiatric conditions. 12,13 In addition, there is also increased healthcare resource utilization and higher direct and indirect costs. 14 In the context of Saudi Arabia, a 2010 systemic review found a high variability in prevalence across studies done in Arab countries and authors described a deficit in accurate epidemiological data in these countries. 15 This variability was described to pose a challenge in estimating the burden of headache, but also identifies a need and opportunity for research in this area. Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other populationbased surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. 16 More recently, a country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. Authors described poor sleep habits and hot weather as contributing factors. 17 Specific to the population of Saudi Arabia, situational contexts contribute to burden. For example, fasting for approximately one month during the month of Ramadan (i.e. first of Ramadan ) can contribute to headache exacerbation along with the effects of dehydration and caffeine withdrawal. 18 As well, up to 4.7% of traffic accidents were associated with migraine headaches in a survey of 1985 drivers in the United Arab Emirates. 19 While health utility data was not identified relative to Saudi Arabia, all levels of migraine pain severity in other countries have been found to have significantly reduced utility values. As example, in United Kingdom populations, severe migraine pain was considered a health state worse than death. 20 As well, the disutility in United States of America populations for mild migraine pain was estimated to be 0.14 (95% confidence interval (CI): 0.08-0.19), with a disutility for moderate migraine pain of 0.19 (95% CI: 0.16-0.21) and for severe migraine pain of 0.49 (95% CI: 0.41-0.56). 21 Often the clinical approach to the diagnosis of migraine headache includes a decision around head imaging. Determining if the headache is a primary or secondary disorder is considered necessary as secondary headaches often result from underlying pathology such as thrombosis, tumour or abscess. Once a diagnosis of migraine headache is made, management strategies are introduced as either acute or prophylactic approaches based on episodic or chronic frequencies of migraine attacks. Given the importance of this topic, the Ministry of Health of the Kingdom of Saudi Arabia with the support of the McMaster University Working Group produced practice guidelines to assist health care providers in evidencebased decision-making on the diagnosis and management of migraine headache. Methodology This practice guideline is a part of the larger initiative of the Ministry of Health of the King-

2 dom of Saudi Arabia (KSA) to establish a program of rigorous development of guidelines. The ultimate goals are to provide guidance for clinicians and other healthcare decision makers and reduce unnecessary variability in clinical practice across the Kingdom. The guideline panel selected the topic of this guideline and all healthcare questions addressed herein using a formal prioritization process. For all selected questions we updated existing systematic reviews on diagnosis and management of migraine headache that were previously published by the National Institute for Health and Care Excellence (NICE) to support the 2012 guideline, Headaches: Diagnosis and management of headaches in young people and adults. 6 We also conducted additional systematic searches for information that was required to develop full guidelines for the KSA, including searches for information about patients values and preferences, and costs and resource use specific to the Saudi context and for questions not specifically addressed in the previously published systematic review. Based on the systematic reviews we prepared summaries of available evidence supporting each recommendation following the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. 1 We used this information to prepare the GRADE evidence-todecision frameworks that served the guideline panel to follow the structured consensus process and transparently document all decisions made during the meeting (see Appendix 1). The guideline panel met in Riyadh on March 15 & 16, 2015 and formulated all recommendations during this meeting. Potential conflicts of interests of all panel members were managed according to the World Health Organization (WHO) rules. 2 As a quality measure for any practice guideline prior to publication, the final report have been externally peer reviewed by a methodological expert who has not been involved in this guideline development. How to use these guidelines The guideline-working group developed and graded the recommendations and assessed the quality of the supporting evidence according to the GRADE approach. 3 Quality of evidence (confidence in the estimates of effects) is categorized as: high, moderate, low, or very low based on consideration of risk of bias, indirectness, inconsistency, imprecision and publication bias of the estimates as well as factors that lead to upgrading the quality of the evidence. High quality evidence indicates that we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality evidence indicates moderate confidence, and that the true effect is likely close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality evidence indicates that our confidence in the effect estimate is limited, and that the true effect may be substantially different. Finally, very low quality evidence indicates that the estimate of effect of interventions is very uncertain, the true effect is likely to be substantially different from the effect estimate and further research is likely to have important potential for reducing the uncertainty. The strength of recommendations is expressed as either strong ( guideline panel recommends ) or conditional ( guideline panel suggests ) and has explicit implications (see Table 1). 4 Understanding the interpretation of these two grades is essential for sagacious clinical decision-making.

3 Table 1: Interpretation of strong and conditional (weak) recommendations Implications Strong recommendation Conditional (weak) recommendation For patients Most individuals in this situation would want the recommended course of action and only a small proportion would not. Formal decision aids are not likely to be needed to help individuals make decisions consistent with their values and preferences. The majority of individuals in this situation would want the suggested course of action, but many would not. For clinicians For policy makers Most individuals should receive the intervention. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator. The recommendation can be adapted as policy in most situations Recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful helping individuals making decisions consistent with their values and preferences. Policy-making will require substantial debate and involvement of various stakeholders. Key Questions The following is a list of the priority clinical questions selected by the panel and addressed in this guideline and their respective recommendations. Diagnosis 1. Should head MRI or CT (with or without contrast) rather than no imaging be done in patients with suspected migraine headache and no other indications? Acute Pharmacological Management 2. Should metoclopramide versus NSAIDs be used for acute migraine? 3. Should triptans versus metoclopramide be used for acute migraine? 4. Should triptans versus paracetamol be used for acute migraine? 5. Should triptans, in combination with NSAIDs, versus NSAIDs alone be used for acute migraine? 6. Should triptans, in combination with NSAIDs, versus triptans alone be used for acute migraine? Prophylactic Pharmacological Management 7. Should beta-blockers versus no betablockers be used for prevention of recurrence of migraine? 8. Should topiramate versus no antiepileptics be used for prevention of recurrence of migraine? 9. Should valproate versus no antiepileptics be used for prevention of recurrence of migraine? 10. Should topiramate versus valproate be used for prevention of recurrence of migraine? 11. Should antiepileptics other than topiramate or valproate versus no antiepileptics be used for prevention of recurrence of migraine? 12. Should topiramate versus betablockers be used for prevention of recurrence of migraine? 13. Should triptans versus no triptans be used for prevention of recurrence of menstrual-related migraine?

4 14. Should botulinum toxin A injections versus no injections be used for prevention of recurrence of episodic migraine? 15. Should botulinum toxin A injections versus no injections be used for prevention of recurrence of chronic migraine? 16. Should tricyclic antidepressants versus no antidepressants be used for prevention of recurrence of migraine? 17. Should SSRIs versus no antidepressants be used for prevention of recurrence of migraine? Prophylactic Non-Pharmacological Management 18. Should education and selfmanagement programs versus no such programs (usual care only) be used for prevention of recurrence of migraine? Recommendations Diagnosis Recommendation 1: The panel recommends that clinicians do not use head MRI or CT imaging in patients with migraine or suspected of migraine that do not have other indications for imaging. (strong recommendation, very low quality evidence) Acute Pharmacological Management Recommendation 2: The panel suggests either metoclopramide or a NSAID in patients with acute migraine. (conditional recommendation, very low quality evidence) Recommendation 3: The panel suggests metoclopramide rather than a triptan in patients with acute migraine. (conditional recommendation, low quality evidence) Recommendation 4: The panel suggests a triptan rather than parcetamol in patients with acute migraine. (conditional recommendation, very low quality evidence) Recommendation 5: The panel suggests a combination of a triptan with a NSAID rather than a NSAID alone in patients with acute migraine. (conditional recommendation, low quality evidence) Recommendation 6: The panel suggests a combination of a triptan with a NSAID rather than a triptan alone in patients with acute migraine. (conditional recommendation, very low quality evidence) Prophylactic Pharmacological Management Recommendation 7: The panel suggests using beta-blockers for the prevention of migraine attacks. (conditional recommendation, low quality evidence) Recommendation 8: The panel suggests topiramate 50 to 100 mg daily for the prevention of migraine attacks. (conditional recommendation, moderate quality evidence) Recommendation 9: The panel suggests valproate 500 to 1000 mg daily for the prevention of migraine attacks. (conditional recommendation, low quality evidence) Remark: The panel determined that there is not enough evidence to favor one over the other.

5 Recommendation 10: The panel suggests that clinicians use either topiramate or valproate for the prevention of migraine attacks. (conditional recommendation, very low quality evidence) Remark: The panel found not enough evidence to favor one over the other. Recommendation 11: The panel suggests that clinicians do not use antiepileptics other than topiramate or valproate for the prevention of migraine attacks until more research about their efficacy and safety is available. (conditional recommendation, low quality evidence) Recommendation 17: The panel suggests that clinicians do not use SSRIs for the prevention of migraine attacks until more evidence is available. (conditional recommendation, low quality evidence) Prophylactic Non-Pharmacological Management Recommendation 18: The panel suggests that more research is done on effectiveness and cost-effectiveness of education and self-management programs. (conditional recommendation, very low quality evidence) Recommendation 12: The panel suggests that clinicians use either topiramate or beta-blockers for the prevention of migraine attacks. (conditional recommendation, low quality evidence) Recommendation 13: The panel suggests triptans for the prevention of menstrual-related migraine attacks. (conditional recommendation, low quality evidence) Recommendation 14: The panel recommends that clinicians do not use botulinum toxin A for the prevention of migraine attacks in patients with episodic migraine. (strong recommendation, moderate quality evidence) Recommendation 15: The panel suggests botulinum toxin A injections for the prevention of chronic migraine in patients who have not responded to other prophylactic treatments. (conditional recommendation, low quality evidence) Recommendation 16: The panel suggests tricyclic antidepressants for the prevention of migraine attacks. (conditional recommendation, low quality evidence)

6 Scope and purpose The purpose of this document is to provide guidance about the diagnosis and management of migraine headache. The target audience of these guidelines includes primary and specialist care clinicians in the Kingdom of Saudi Arabia (KSA). Other health care professionals and policy makers may also benefit from this guideline. Given the importance of this topic, the Ministry of Health (MoH) of Saudi Arabia with the support of the McMaster University Working Group produced practice guidelines to assist health care providers in evidence-based decision-making. This practice guideline is a part of the larger initiative of the Ministry of Health of Saudi Arabia to establish a program of rigorous adaptation and de novo development of guidelines in the Kingdom; the ultimate goal being to provide guidance for clinicians and other healthcare decision makers and reduce unnecessary variability in clinical practice across the Kingdom. This guideline does not encompass all aspects of diagnosis and management of migraine headache. Due to feasibility, priority questions were identified and addressed in this project. Introduction Migraine headache is very common in society with a prevalence and global burden that ranks third world-wide of all neurological disorders. 7 It also has been argued that current research underestimates the burden of disability associated with migraine. 8 In acute situations, most migrainers report trying more than three acute treatments with over-thecounter acute treatments more commonly reported than use of prescription treatments. 9 Those with more chronic migraine (15 or more migraines per month) tend to have even more debility, lost work time or decreased productivity. 10,11 This chronicity leads to higher headache-related disability, headache impact, typically worse socioeconomic status, worse health-related quality of life, and higher other medical and psychiatric conditions. 12,13 In addition, there is also increased healthcare resource utilization and higher direct and indirect costs. 14 In the context of Saudi Arabia, a 2010 systemic review found a high variability in prevalence across studies done in Arab countries and authors described a deficit in accurate epidemiological data in these countries. 15 This variability was described to pose a challenge in estimating the burden of headache, but also identifies a need and opportunity for research in this area. Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other populationbased surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. 16 More recently, a country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. Authors described poor sleep habits and hot weather as contributing factors. 17 Specific to the population of Saudi Arabia, situational contexts contribute to burden. For example, fasting for approximately one month during the month of Ramadan (ie. first of Ramadan ) can contribute to headache exacerbation along with the effects of dehydration and caffeine withdrawal. 18 As well, up to 4.7% of traffic accidents were associated with migraine headaches in a survey of 1985 drivers in the United Arab Emirates. 19 While health utility data was not identified relative to Saudi Arabia, all levels of migraine pain severity in other countries have been found to have significantly reduced utility values. As example, in United Kingdom populations, severe migraine pain was considered a health state worse than death. 20 As well, the disutility in United States of America populations for mild

7 migraine pain was estimated to be 0.14 (95% confidence interval (CI): 0.08-0.19), with a disutility for moderate migraine pain of 0.19 (95% CI: 0.16-0.21) and for severe migraine pain of 0.49 (95% CI: 0.41-0.56). 21 Often the clinical approach to the diagnosis of migraine headache includes a decision around head imaging. Determining if the headache is a primary or secondary disorder is considered necessary as secondary headaches often result from underlying pathology such as thrombosis, tumour or abscess. Once a diagnosis of migraine headache is made, management strategies are introduced as either acute or prophylactic approaches based on episodic or chronic frequencies of migraine attacks. Methodology To facilitate the interpretation of these guidelines; we briefly describe the methodology we used to develop and grade recommendations and quality of the supporting evidence. The guideline panel selected the topic of this guideline and all health care questions addressed herein using this formal prioritization process. Based on the questions addressed in the 2012 NICE systematic review, a pool of 52 potential research questions was created specific to migraine headache diagnosis and management. Through an online surveybased rating and ranking exercise from July- August 2014, panel members selected their top priority questions from the question pool and also identified new questions to inform a priority list consisting of 15 research questions. In November 2014, panel members through an online survey-based exercise also ranked importance of outcomes as they related to each of the selected priority research questions. As well, panel members provided estimates on KSA specific costs related to specific interventions in their clinical environment. For the selected questions we updated existing systematic reviews on diagnosis and management of migraine headache that were previously published by NICE to support the 2012 guideline, Headaches: Diagnosis and management of headaches in young people and adults. 6. For each question, the McMaster Guideline Working Group updated the search strategy to identify new studies and/or new systematic reviews. When relevant, the metaanalyses were updated. We also conducted systematic searches for information that was required to develop full guidelines for the KSA, including searches for information about patients values and preferences, and costs and resource use specific to the Saudi context (see Appendix 2). Next, we developed for each question an evidence profile and an evidence-to-decision (EtD) table following the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and shared them with the panel members (see Appendix 1). 1,5 The guideline panel was invited to provide additional information, particularly when published evidence was lacking. The final step consisted of an in-person meeting of the guideline panel in Riyadh on March 15 & 16, 2015 to formulate the final recommendations. During the in-person meeting 2 questions were collapsed into one more general question and 3 questions were divided into more specific questions, based on clinical relevance, for a total of 18 questions. We used the GRADE evidence-to-decision frameworks to follow a structured consensus process and transparently document all decisions made during the meeting. Potential conflicts of interests of all panel members were managed according to the World Health Organization (WHO) rules. 2 Grading of the quality of evidence The GRADE working group defines the quality of evidence as the extent of our confidence that the estimate of an effect is adequate to support a particular decision or recommendation. 3 We assessed the quality of evidence using the GRADE approach.

8 Quality of evidence is classified as high, moderate, low, or very low based on decisions about methodological characteristics of the available evidence for a specific health care problem. The definition of each category is as follows: High: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect. Very low: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect. Grading of the strength of recommendations The GRADE working group defines the strength of recommendation as the extent to which we can be confident that desirable effects of an intervention outweigh undesirable effects. According to the GRADE approach, the strength of a recommendation is either strong or conditional (also known as or called weak) and has explicit implications. 4 Understanding the interpretation of these two grades either strong or conditional of the strength of recommendations is essential for sagacious clinical decision-making. (see Table 1) As a quality measure for any practice guideline prior to publication, the final report have been externally peer reviewed by a methodological expert who has not been involved in this guideline development. How to use these guidelines The Ministry of Health of Saudi Arabia and McMaster University Practice Guidelines provide clinicians and their patients with a basis for rational decisions about the diagnosis and management of migraine headache. Clinicians, patients, third-party payers, institutional review committees, other stakeholders, or the courts should never view these recommendations as dictates. As described in other guidelines following the GRADE approach, no guideline or recommendation can take into account all of the often-compelling unique features of individual clinical circumstances. Therefore, no one charged with evaluating clinicians actions should attempt to apply the recommendations from these guidelines by rote or in a blanket fashion. Statements about the underlying values and preferences, resources, feasibility, equity, acceptability as well as other qualifying remarks accompanying each recommendation are its integral parts and serve to facilitate an accurate interpretation. They should never be omitted when quoting or translating recommendations from these guidelines if they influence the strength or direction of the recommendation. Key questions The following is a list of the priority clinical questions selected by the panel and addressed in this guideline. Diagnosis 1. Should head MRI or CT (with or without contrast) rather than no imaging be done in patients with suspected migraine headache and no other indications? Acute Pharmacological Management

9 2. Should metoclopramide versus NSAIDs be used for acute migraine? 3. Should triptans versus metoclopramide be used for acute migraine? 4. Should triptans versus paracetamol be used for acute migraine? 5. Should triptans, in combination with NSAIDs, versus NSAIDs alone be used for acute migraine? 6. Should triptans, in combination with NSAIDs, versus triptans alone be used for acute migraine? Prophylactic Pharmacological Management 7. Should beta-blockers versus no betablockers be used for prevention of recurrence of migraine? 8. Should topiramate versus no antiepileptics be used for prevention of recurrence of migraine? 9. Should valproate versus no antiepileptics be used for prevention of recurrence of migraine? 10. Should topiramate versus valproate be used for prevention of recurrence of migraine? 11. Should antiepileptics other than topiramate or valproate versus no antiepileptics be used for prevention of recurrence of migraine? 12. Should topiramate versus betablockers be used for prevention of recurrence of migraine? 13. Should triptans versus no triptans be used for prevention of recurrence of menstrual-related migraine? 14. Should botulinum toxin A injections versus no injections be used for prevention of recurrence of episodic migraine? 15. Should botulinum toxin A injections versus no injections be used for prevention of recurrence of chronic migraine? 16. Should tricyclic antidepressants versus no antidepressants be used for prevention of recurrence of migraine? 17. Should SSRIs versus no antidepressants be used for prevention of recurrence of migraine? Prophylactic Non-Pharmacological Management 18. Should education and selfmanagement programs versus no such programs (usual care only) be used for the prevention of recurrence of migraine? Recommendations Patient Values and Preferences: Across the 18 recommendations, all panel members agreed the problem of migraine was a priority. Health utility data was not identified specific to Saudi Arabia, yet all levels of migraine pain severity in other countries have been found to have significantly reduced utility values. As example, in United Kingdom populations, severe migraine pain was considered a health state worse than death. 20 As well, the disutility in United States of America populations for mild migraine pain was estimated to be 0.14 (95% confidence interval (CI): 0.08-0.19), with a disutility for moderate migraine pain of 0.19 (95% CI: 0.16-0.21) and for severe migraine pain of 0.49 (95% CI: 0.41-0.56). 21 Cost Effectiveness: Across the 18 recommendations, no cost effectiveness studies were identified specific to Saudi Arabia. Studies from various other countries and studies presented in the 2012 NICE systematic review were identified, 6,57-60,,137,138 but the panel felt these were not relevant to the local context. For each recommendation, panel members provided their estimate of average unit costs for the specific intervention - in Saudi Arabian Riyal (SAR). I. DIAGNOSIS Question 1: Should head MRI or CT (with or without contrast) rather than no imaging be done in patients with suspected migraine headache? Summary of Findings: The MRI imaging section of the question was based on the 2012

10 NICE systematic review including 4 retrospective cohort studies. 32-35 The updated literature search identified no new relevant studies. The CT imaging section of the question was primarily based on the 2012 NICE systematic review including 3 retrospective cohort studies. 36-38 The updated literature search identified one new retrospective cohort study. 39 Benefits and harms of the Option: For MRI, the 4 retrospective cohort studies (total of 1139 participants) were very low quality evidence that could not estimate the absolute effect of head MRI with or without contrast on: identifying a tumour/neoplasm compared to no imaging (5 events per 1000); identifying an abscess compared to no imaging (0 events per 1000); identifying a subdural haematoma compared to no imaging (2 events per 1000); identifying hydrocephalus compared to no imaging (3 events per 1000); identifying an arteriovenous malformation compared to no imaging (2 events per 1000); identifying a stroke (i.e. venous thrombosis) compared to no imaging (0 events per 1000). For CT, the 4 retrospective cohort studies (total of 2287 participants) were very low quality evidence that could not estimate the absolute effect of head CT with or without contrast on: identifying a tumour/neoplasm compared to no imaging (7 events per 1000); identifying an abscess compared to no imaging (0 events per 1000); identifying a subdural haematoma compared to no imaging (0 events per 1000); identifying hydrocephalus compared to no imaging (1 event per 1000); identifying an arteriovenous malformation compared to no imaging (0 events per 1000); identifying a stroke (i.e. venous thrombosis) compared to no imaging (0 events per 1000); identifying venous thrombosis in pregnant women compared to no imaging (63 events per 1000). Resource Use: Panel members estimated a MRI unit cost range of 2000-4500 SAR. Using MRI alone carried an imaging resource cost between 181,800 SAR and 409,050 SAR per serious abnormality detected. Panel members estimated CT unit cost range of 1200-1500 SAR. Using CT or MRI combinations carried an imaging resource cost between 133,312 SAR and 499,950 SAR per serious abnormality detected. Other factors such as outpatient and hospital provider visits, x-rays and labs would also need to be considered. Other considerations: The panel judged MRI or CT imaging to likely be acceptable to patients but uncertain whether also acceptable for policymakers and payers. The panel judged MRI or CT imaging to probably not be a feasibility intervention to implement; and the impact on health inequities to probably increase. Balance between desirable and undesirable consequences: Prevalence of potentially treatable serious head lesions is likely very low. The proportion of false negative and false positive results is not known, but likely to result in substantial anxiety and unnecessary cost of further testing. The resources required would be large. Recommendation 1: The panel recommends that clinicians do not use head MRI or CT imaging in patients with migraine or suspected of migraine that do not have other indications for imaging. (strong recommendation, very low quality evidence) II. ACUTE PHARMACOLOGICAL MANAGMENT Question 2: Should metoclopramide versus NSAIDs be used for acute migraine? Summary of Findings: The question was based on the 2012 NICE systematic review including one randomized controlled trial in only pediatric patients. 45 The updated literature search identified one new trial in adults. 46 Benefits and harms of the Option: Findings from one trial (total of 208 participants) found very low quality evidence that did not rule out a reduction or an increase in headache relief

11 at 2 hours (change in severe or moderate headache to mild or none) for metoclopramide use compared to NSAID use in patients with acute migraine (risk ratio (RR) 1.17; 95% CI 0.93 to 1.47; absolute effect: 91 more events per 1000). Findings from one trial (total of 220 participants) found very low quality evidence that did not rule out a reduction or an increase in headache freedom at 2 hours for metoclopramide use compared to NSAID use in patients with acute migraine (RR 1.15; 95% CI 0.74 to 1.79; absolute effect: 37 more events per 1000). Findings from one trial (total of 218 participants) found very low quality evidence that did not rule out a reduction or an increase in Sustained freedom from headache at 24 hours for metoclopramide use compared to NSAID use in patients with acute migraine (RR 0.71; 95% CI 0.35 to 1.4; absolute effect: 45 fewer events per 1000). Findings from one trial (total of 205 participants) found very low quality evidence that did not rule out a reduction or an increase in Sustained relief from headache at 24 hours (change from severe to moderate to mild or none) for metoclopramide use compared to NSAID use in patients with acute migraine (RR 1.27; 95% CI 0.89 to 1.82; absolute effect: 88 more events per 1000). Findings from one trial (total of 219 participants) found low quality evidence that did not rule out a reduction or an increase in adverse events (dizzy, too drowsy to function, dyspepsia, heartburn, bloating) for metoclopramide use compared to NSAID use in patients with acute migraine (RR 0.71; 95% CI 0.31 to 1.63; absolute effect: 36 fewer events per 1000). Resource Use: Panel members estimated an average monthly cost of 50-100 SAR for NSAIDs and metoclopramide. Other factors such as outpatient and hospital provider visits, hospital stays, x-rays and labs would also need to be considered. Other considerations: The panel judged the use of metoclopramide in patients with acute migraines to be both acceptable and feasible. The panel judged there to be no impact on health inequity. Balance between desirable and undesirable consequences: No evidence of difference in benefits, adverse effects and cost has been identified. Recommendation 2: The panel suggests either metoclopramide or a NSAID in patients with acute migraine. (conditional recommendation, very low quality evidence) Remark: The panel determined that there is not enough evidence to favor one over the other. Research Priorities: The panel suggested that it might be beneficial to conduct more headto-head RCTs that investigate commonly used NSAIDs and other medications used for acute migraine and measure patient-important outcomes. Question 3: Should triptans versus metoclopramide be used for acute migraine? Summary of Findings: The question was based on the 2012 NICE systematic review including one randomized controlled trial. 55 The updated literature search identified no new studies. Benefits and harms of the Option: Findings from one trial (total of 77 participants) found very low quality evidence that: did not rule out a reduction or an increase in freedom from pain at 2 hours (change in severe or moderate headache to mild or none) for triptan use compared to metoclopramide use in patients with acute migraine (RR 0.59; 95% CI 0.35 to 0.97; absolute effect: 246 fewer events per 1000); did not rule out a reduction or an increase in sustained freedom from pain at 24 hours for triptan use compared to metoclopramide use in patients with acute migraine (RR 0.68; 95% CI -0.35 to 1.3; absolute effect: 128 fewer events per 1000); did not rule out a reduction or an increase in adverse events (weakness) for triptan use compared to metoclopramide use in patients with acute migraine (OR 2.25; 95% CI 0.67 to 7.48; abso-

12 lute effect: 118 more events per 1000); did not rule out a reduction or an increase in adverse events (feeling of heaviness / dizziness) for triptan use compared to metoclopramide use in patients with acute migraine (OR 6.09; 95% CI 0.68 to 54.85; absolute effect: 110 more events per 1000); did not rule out a reduction or an increase in adverse events (stiffness or abnormal movements) for triptan use compared to metoclopramide use in patients with acute migraine (OR 2.88; 95% CI 0.69 to 12.09; absolute effect: 114 more events per 1000). Resource Use: Panel members estimated an average monthly cost of 50-100 SAR for metoclopramide and 200-400 SAR for triptans. Other factors such as outpatient and hospital provider visits, hospital stays, x-rays and labs would also need to be considered. Other considerations: The panel judged the use of triptans to be both acceptable and feasible. They judged the impact on inequity to probably increase. Balance between desirable and undesirable consequences: The panel determined that undesirable effects were likely small and favored the control intervention. The quality of available evidence supporting this recommendation is low leaving much uncertainty about the balance of desirable and undesirable consequences. However, use of metoclopramide is less costly. In settings where resources are available, an alternative option (i.e. using triptans) may be equally reasonable. Recommendation 3: The panel suggests metoclopramide rather than a triptan in patients with acute migraine. (conditional recommendation, low quality evidence) Subgroup Considerations: Available evidence is for intravenous administration in emergency departments. It is less clear whether it is applicable to less severe cases and oral administration of these medications. Note: Evidence is available for sumatriptan only. Research Priorities: The panel thought that more research on comparative safety and effectiveness for all routes of administration and types of triptans would be desirable. Question 4: Should triptans versus paracetamol be used for acute migraine? Summary of Findings: The question was based on the 2012 NICE systematic review including one randomized controlled trial. 64 The updated literature search identified no new studies. Benefits and harms of the Option: Findings from one trial (total of 86 participants) found very low quality evidence that: did not rule out a reduction or an increase in headache response at up to 2 hours for triptan use compared to paracetamol use in patients with acute migraine (RR 1.1; 95% CI 0.85 to 1.42; absolute effect: 70 more events per 1000); did not rule out a reduction or an increase in freedom from pain at up to 2 hours for triptan use compared to paracetamol use in patients with acute migraine (RR 1.54; 95% CI 0.82 to 2.9; absolute effect: 138 more events per 1000); did not rule out a reduction or an increase in sustained headache response at up to 24 hours for triptan use compared to paracetamol use in patients with acute migraine (RR 1.19; 95% CI 0.82 to 2.9; absolute effect: 138 more events per 1000); and did not rule out a reduction or an increase in sustained freedom from pain at up to 24 hours for triptan use compared to paracetamol use in patients with acute migraine (RR 1.43; 95% CI 0.6 to 3.4; absolute effect: 70 more events per 1000). Resource Use: The panel estimated that triptans would carry an average monthly cost estimated at 200-400 SAR and paracetamol would carry an average monthly cost estimated at 10-50 SAR. Both outpatient and hospital

13 provider visits would also need to be considered. Other considerations: Based on their unsystematic clinical observations, panel members considered paracetamol as not very effective in acute migraine. However, panel members acknowledged that most of them have experience from tertiary care centers with patients who likely already tried and failed other treatments (including paracetamol). The panel also felt that those with access to specialty clinics are more likely to receive a triptan, while in family care settings it is less likely. The panel judged the use of triptans to be both acceptable and feasible. They judged the impact on inequity to probably increase, as again those with access to specialty clinics are more likely to receive a triptan while in family care setting it is less likely. Balance between desirable and undesirable consequences: Available evidence, though very uncertain, and unsystematic observations in panel members practice suggest larger benefit from triptans compared to paracetamol. One panel member felt that the balance between desirable and undesirable consequences is uncertain because available evidence is of too low quality to be able to make the judgment. Recommendation 4: The panel suggests a triptan rather than parcetamol in patients with acute migraine. (conditional recommendation, very low quality evidence) Subgroup Considerations: Patients with hemiplegic migraine should not receive triptans. Note: Evidence is available only for risatriptan. Question 5: Should triptans, in combination with NSAIDs, versus NSAIDs alone be used for acute migraine? Summary of Findings: The question was based on the 2012 NICE systematic review including 3 randomized controlled trials. 74-76 The updated literature search identified no new studies. Benefits and Harms of the Option: The metaanalysis of 3 trials (total of 1944 participants) found low quality evidence that showed: an increase in freedom from pain at 2 hours for the combination of triptan and NSAID use compared to NSAID use alone in patients with acute migraine (RR 2.03; 95% CI 1.71 to 2.4; absolute effect: 165 more events per 1000); an increase in headache relief at up to 2 hours for the combination of triptan and NSAID use compared to NSAID use alone in patients with acute migraine (RR 1.41; 95% CI 1.3 to 1.54; absolute effect: 180 more events per 1000); an increase in sustained freedom from pain at 24 hours for the combination of triptan and NSAID use compared to NSAID use alone in patients with acute migraine (RR 2.25; 95% CI 1.82 to 2.78; absolute effect: 134 more events per 1000); an increase in sustained headache relief at 24 hours for the combination of triptan and NSAID use compared to NSAID use alone in patients with acute migraine (RR 1.64; 95% CI 1.45 to 1.85; absolute effect: 179 more events per 1000); a reduction in rescue medication use for the combination of triptan and NSAID use compared to NSAID use alone in patients with acute migraine (RR 0.61; 95% CI 0.54 to 0.7; absolute effect: 164 fewer events per 1000); and an increase in adverse events for the combination of triptan and NSAID use compared to NSAID use alone in patients with acute migraine (RR 1.77; 95% CI 1.47 to 2.13; absolute effect: 112 more events per 1000). The meta-analysis of 2 trials (total of 1352 participants) found low quality evidence that showed an increase in relief of functional disability at 2 hours for the combination of triptan and NSAID use compared to NSAID use alone in patients with acute migraine (RR 1.43; 95% CI 1.35 to 1.97; absolute effect: 84 more events per 1000). Resource Use: Panel members estimated an average monthly cost of 50-100 SAR for NSAIDs and 200-400 SAR for triptans. Other factors such as outpatient and hospital pro-

14 vider visits, hospital stays, x-rays and labs would also need to be considered. Other considerations: The panel judged the use of the combination of a triptan and a NSAID to be both acceptable and feasible. They judged the impact on health inequities to be dependent on the availability of resources. Balance between desirable and undesirable consequences: There is a clinically important benefit and no serious adverse effects were observed. Recommendation 5: The panel suggests a combination of a triptan with a NSAID rather than a NSAID alone in patients with acute migraine. (conditional recommendation, low quality evidence) Subgroup Considerations: Patients with hemiplegic migraine should not receive triptans. Question 6: Should triptans, in combination with NSAIDs, versus triptans alone be used for acute migraine? Summary of Findings: The question was based on the 2012 NICE systematic review including 4 randomized controlled trials. 74-76,80 The updated literature search identified no new studies. Benefits and harms of the Option: The metaanalysis of 4 trials (total of 2105 participants) found very low quality evidence that: showed an increase in freedom from pain at 2 hours for the combination of triptan and NSAID use compared to triptan use alone in patients with acute migraine (RR 1.42; 95% CI 1.23 to 1.63; absolute effect: 99 more events per 1000); showed an increase in headache relief at up to 2 hours for the combination of triptan and NSAID use compared to triptan use alone in patients with acute migraine (RR 1.18; 95% CI 1.09 to 1.28; absolute effect: 91 more events per 1000); and did not rule out a reduction or an increase in adverse events for the combination of triptan and NSAID use compared to triptan use alone in patients with acute migraine (RR 1; 95% CI 0.86 to 1.16; absolute effect: 0 fewer events per 1000). The metaanalysis of 3 trials (total of 1925 participants) found low quality evidence that: showed an increase in sustained freedom from pain at 24 hours for the combination of triptan and NSAID use compared to triptan use alone in patients with acute migraine (RR 1.7; 95% CI 1.41 to 2.06; absolute effect: 100 more events per 1000); showed an increase in sustained headache relief at 24 hours for the combination of triptan and NSAID use compared to triptan use alone in patients with acute migraine (RR 1.39; 95% CI 1.24 to 1.55; absolute effect: 129 more events per 1000); and showed a reduction in rescue medication use for the combination of triptan and NSAID use compared to triptan use alone in patients with acute migraine (RR 0.66; 95% CI 0.58 to 0.76; absolute effect: 131 fewer events per 1000). The meta-analysis of 2 trials (total of 1354 participants) found low quality evidence that showed an increase in relief of functional disability at 2 hours for the combination of triptan and NSAID use compared to triptan use alone in patients with acute migraine (RR 1.41; 95% CI 1.18 to 1.69; absolute effect: 93 more events per 1000). Resource Use: Panel members estimated an average monthly cost of 50-100 SAR for NSAIDs and 200-400 SAR for triptans. Other factors such as outpatient and hospital provider visits, hospital stays, x-rays and labs would also need to be considered. Other considerations: The panel judged the use of the combination of triptans and NSAIDs to be both acceptable and feasible. They judged the impact on inequity to not be influenced by the intervention. Balance between desirable and undesirable consequences: There was clinical benefit with small additional cost.

15 Recommendation 6: The panel suggests a combination of a triptan with a NSAID rather than a triptan alone in patients with acute migraine. (conditional recommendation, very low quality evidence) III. PROPHYLACTIC PHARMACOLOGICAL MANAGMENT Question 7: Should beta-blockers versus no beta-blockers be used for prevention of recurrence of migraine? Summary of Findings: The question was based on the 2012 NICE systematic review including 4 randomized controlled trials. 84-87 The updated literature search identified no new studies. Benefits and harms of the Option: The finding of 1 trial (total of 108 participants) found moderate quality evidence that showed a reduction in episodic change in patient reported migraine days per month: follow up 16 months) for the use of beta blockers compared to no beta blocker for prevention of recurrence of migraine (MD 0.6 days per month lower; 95% CI 1.22 lower to 0.22 lower). The finding of 1 trial (total of 75 participants) found low quality evidence that did not rule out a reduction or an increase in episodic responder rate (follow up: 10 months) for the use of beta-blockers compared to no betablocker for prevention of recurrence of migraine (RR 0.94; 95% CI 0.61 to 1.42; absolute effect: 33 fewer events per 1000). The finding of 1 trial (total of 286 participants) found moderate quality evidence that showed an increase in episodic responder rate [>50% reduction] (follow up: 26 weeks) for the use of beta-blockers compared to no beta-blocker for prevention of recurrence of migraine (RR 1.95; 95% CI 1.24 to 3.09; absolute effect: 146 more events per 1000). The meta-analysis of 3 trials (total of 586 participants) found low quality evidence that showed a reduction in episodic change in reported migraine frequency per month (follow up: 26 weeks) for the use of beta-blockers compared to no beta-blocker for prevention of recurrence of migraine (MD 1.37 episodes fewer; 95% CI 1.69 lower to 1.04 lower). The finding of 1 trial (total of 108 participants) found high quality evidence that showed an increase in episodic headache specific quality of life [MSQL score; 100-point scale] (follow up: 16 months) for the use of beta-blockers compared to no beta-blocker for prevention of recurrence of migraine (MD 0.3 higher; 95% CI 0.84 higher to 1.44 higher). The finding of 1 trial (total of 203 participants) found low quality evidence that showed an increase in episodic: Adverse Events - ceasing medications due to side effects (e.g. fatigue) (follow up: 16 months) for the use of beta-blockers compared to no beta-blocker for prevention of recurrence of migraine (OR 1.19; 95% CI 0.37 to 3.9; absolute effect: 10 more events per 1000). Resource Use: Panel members estimated an average monthly cost of 50-100 SAR for betablockers. Other factors such as outpatient provider visits, x-rays and labs would also need to be considered. Other considerations: The panel judged the use of beta-blockers to be both acceptable and feasible. They judged the impact on inequity to be probably reduced by the use of beta-blockers. Balance between desirable and undesirable consequences: The panel thought that the potential benefits outweigh the undesirable effects. Some panel members thought that there is no important uncertainty of variability in how patients would value the main outcomes. Some members were uncertain about the magnitude of benefit and some thought it is probably a large benefit. Recommendation 7: The panel suggests using beta-blockers for the prevention of migraine attacks. (conditional recommendation, low quality evidence)

16 Implementation Considerations: In order to increase compliance and when a decision to use beta-blockers is made, it may be beneficial to remind patients that this intervention does not eliminate migraine attacks but reduces their severity and frequency. Research Priorities: More well designed and performed trials are needed to better establish both benefits and safety. Question 8: Should topiramate versus no antiepileptics be used for prevention of recurrence of migraine? Summary of Findings: The question was originally based on the 2012 NICE systematic review. The updated literature search identified one 2013 Cochrane systematic review by Linde et al. 92 The question was then based on that Cochrane review. Benefits and harms of the Option: The metaanalysis of 9 trials (total of 1246 participants) found moderate quality evidence that showed an increase in responder rate [>50% reduction in headache frequency] for the use of topiramate compared to no antiepileptic use for prevention of recurrence of migraine (RR 2.02; 95% CI 1.57 to 2.6; absolute effect: 237 more events per 1000). The meta-analysis of 9 trials (total of 1793 participants) found moderate quality evidence that showed a reduction in Headache frequency reduction per month for the use of topiramate compared to no antiepileptic use for prevention of recurrence of migraine (MD 1.2 lower; 95% CI 1.59 lower to 0.8 lower). The meta-analysis of 3 trials (total of 993 participants) found low quality evidence that showed a reduction in adverse effects using 50mg or 100mg for the use of topiramate compared to no antiepileptic use for prevention of recurrence of migraine (RR 1.08 episodes fewer; 95% CI 0.96 to 1.22 lower; absolute effect: 47 more events per 1000). Resource Use: Panel members estimated an average monthly cost of 500 SAR for 50mg topiramate. Other factors such as outpatient provider visits, x-rays and labs would also need to be considered. Other considerations: The panel judged the use of topiramate to be both acceptable and feasible. The Panel determined that impact on health inequity would depend on patient income and extended health insurance. Balance between desirable and undesirable consequences: One panel member was uncertain whether benefits outweigh undesirable effects. There is a benefit with some uncertainty about adverse effects. Adverse effects were thought to be small for doses 50-100 mg of topiramate. Recommendation 8: The panel suggests topiramate 50 to 100 mg daily for the prevention of migraine attacks. (conditional recommendation, moderate quality evidence) Implementation Considerations: Availability of resources will have important impact on this recommendation. Question 9: Should valproate versus no antiepileptics be used for prevention of recurrence of migraine? Summary of Findings: The question was originally based on the 2012 NICE systematic review that the panel considered not directly relevant to the question. An updated Medline search was conducted (March 15, 2015) and identified two 2013 Cochrane systematic reviews both by Linde et al. 93-94 The Cochrane review of Pregabalin (also of interest to the panel) did not identify any studies. 93 The question was then based on the one identified Cochrane review on valproate. 94 Benefits and harms of the Option: The metaanalysis of 4 trials (total of 574 participants) found moderate quality evidence that showed an increase in episodic migraine: valproate - divalproex sodium responder rate [>50% re-

17 duction in headache frequency] (12 week follow-up) for the use of valproate compared to no antiepileptic use for prevention of recurrence of migraine (RR 2.18; 95% CI 1.28 to 3.72; absolute effect: 252 more events per 1000). The finding of 1 trial (total of 68 participants) found low quality evidence that showed an increase in episodic migraine: valproate sodium valproate responder rate (>50% reduction in headache frequency] (12 week follow-up) for the use of valproate compared to no antiepileptic use for prevention of recurrence of migraine (RR 2.83; 95% CI 1.27 to 6.31; absolute effect: 390 more events per 1000). The finding of 1 trial (total of 126 participants) found low quality evidence that showed a reduction in episodic migraine: valproate sodium valproate: headache frequency post treatment (12 week follow-up) for the use of valproate compared to no antiepileptic use for prevention of recurrence of migraine (MD 4.31 lower; 95% CI 8.32 lower to 0.30 lower). The meta-analysis of 2 trials (total of 499 participants) found low quality evidence that did not rule out a reduction or an increase in episodic migraine: Valproate any adverse event (e.g. fatigue, dizziness, nausea, tremor, weight gain) (12 week followup) for the use of valproate compared to no antiepileptic use for prevention of recurrence of migraine (RR 1.06; 95% CI 0.90 to 1.27; absolute effect: 37 more events per 1000). Resource Use: Panel members estimated an average monthly cost of 200-500 SAR for valproate. Other factors such as outpatient provider visits, x-rays and labs would also need to be considered. Other considerations: The panel judged the use of valproate to be both acceptable and feasible. The Panel determined that impact on health inequity would be probably reduced with the use of valproate. Balance between desirable and undesirable consequences: There is uncertainty in the effects because of low confidence in estimated effects, but the panel felt that benefits outweigh harms. Recommendation 9: The panel suggests valproate 500 to 1000 mg daily for the prevention of migraine attacks. (conditional recommendation, low quality evidence) Question 10: Should topiramate versus valproate be used for prevention of recurrence of migraine? Summary of Findings: The question was primarily based on the 2012 NICE systematic review including one randomized controlled trial. 102 The updated literature search identified one new trial. 103 Benefits and harms of the Option: The finding of 1 trial (total of 56 participants) found low quality evidence that did not rule out a reduction or an increase in episodic: patientreported migraine frequency for last weeks (follow up: 12 weeks) for the use of topiramate compared to the use of valproate for prevention of recurrence of migraine (MD 0.6 lower; 95% CI 1.57 lower to 0.37 higher). The finding of 1 trial (total of 56 participants) found low quality evidence that showed a reduction in episodic: patient-reported migraine intensity for last weeks (follow up: 12 weeks) for the use of topiramate compared to the use of valproate for prevention of recurrence of migraine (MD 1.1 lower; 95% CI 0.2 lower to 2 lower). The finding of 1 trial (total of 64 participants) found low quality evidence that showed an increase in patient-reported migraine frequency per month (follow up: 8 weeks) for the use of topiramate compared to the use of valproate for prevention of recurrence of migraine (MD 1.2 higher; 95% CI 1.1 higher to 1.3 higher). The finding of 1 trial (total of 64 participants) found very low quality evidence that did not rule out a reduction or an increase in patient-reported migraine intensity VAS (follow up: 8 weeks) for the use of topiramate compared to the use of valproate for prevention of recurrence of migraine (MD 0.1 lower; 95% CI 0 higher to 0.3 lower). The finding of 1 trial (total of 64 participants)

18 found low quality evidence that did not rule out a reduction or an increase in adverse events: (e.g. weight change, paresthesia, somnolence, hair loss) (follow up: 8 weeks) for the use of topiramate compared to the use of valproate for prevention of recurrence of migraine (OR 1.46; 95% CI 0.54 to 3.9; absolute effect: 94 more events per 1000). Resource Use: Panel members estimated an average monthly cost of 200-500 SAR for both medications with topiramate being typically more expensive than valproate. Other factors such as outpatient provider visits, x-rays and labs would also need to be considered. Other considerations: The panel judged the use of topiramate to be both acceptable and feasible. The panel members thought that availability of resources would have an impact on health inequities in this context, as topiramate is more expensive. Balance between desirable and undesirable consequences: Two panel members thought that anticipated undesirable effects are probably small and three were uncertain. There is low confidence in the estimated effects. Efficacy seems to be comparable, but there is higher cost associated with topiramate and more adverse effects associated with valproate. Recommendation 10: The panel suggests that clinicians use either topiramate or valproate for the prevention of migraine attacks. (conditional recommendation, very low quality evidence) Remark: The panel found not enough evidence to favor one over the other. Implementation Considerations: When choosing between these two options one should weigh the higher cost associated with topiramate versus the more adverse effects associated with valproate. Research Priorities: The panel suggests more head-to-head comparison studies. Question 11: Should antiepileptics other than topiramate or valproate versus no antiepileptics be used for prevention of recurrence of migraine? Summary of Findings: The question was based on the 2012 NICE systematic review and individual trials from two 2013 Cochrane systematic reviews, both by Linde et al. 93,95 The updated literature search also identified 2 randomized controlled trials. 96,97 Benefits and harms of the Option: The finding of 1 trial (total of 63 participants) found low quality evidence that showed with gabapentin a reduction in patient-reported migraine frequency for the use of antiepileptics other than topiramate or valproate compared to no antiepileptic use for prevention of recurrence of migraine (MD 1.89 lower; 95% CI 2.37 lower to 1.41 lower). The finding of 1 trial (total of 63 participants) found low quality evidence that showed with gabapentin a reduction in patient-reported migraine intensity for the use of antiepileptics other than topiramate or valproate compared to no antiepileptic use for prevention of recurrence of migraine (MD 0.62 lower; 95% CI 0.91 lower to 0.33 lower). The finding of 1 trial (total of 93 participants) found low quality evidence that showed an increase in carbamapezine responder rate [>50% reduction in migraine frequency for the use of antiepileptics other than topiramate or valproate compared to no antiepileptic use for prevention of recurrence of migraine (OR 11.77; 95% CI 3.92 to 35.32; absolute effect: 474 more events per 1000). The finding of 1 trial (total of 93 participants) found low quality evidence that showed an increase in carbamapezine adverse events for the use of antiepileptics other than topiramate or valproate compared to no antiepileptic use for prevention of recurrence of migraine (RR 2.9; 95% CI 1.66 to 5.09; absolute effect: 435 more events per 1000).

19 The finding of 1 trial (total of 113 participants) found low quality evidence that showed an increase in lamotrigine responder rate [>50% reduction in migraine frequency for the use of antiepileptics other than topiramate or valproate compared to no antiepileptic use for prevention of recurrence of migraine (RR 1.63; 95% CI 0.76 to 3.49; absolute effect: 116 more events per 1000). The finding of 1 trial (total of 26 participants) found low quality evidence that did not rule out a reduction or an increase in levetiracetam responder rate [>%50 reduction in migraine frequency for the use of antiepileptics other than topiramate or valproate compared to no antiepileptic use for prevention of recurrence of migraine (RR 12.75; 95% CI 0.81 to 199.88; intervention: 533 events per 1000; control: 0 events per 1000). The finding of 1 trial (total of 65 participants) found moderate quality evidence that showed a reduction in levetiracetam use for change in migraine frequency (follow up: 4 months) for the use of antiepileptics other than topiramate or valproate compared to no antiepileptic use for prevention of recurrence of migraine (MD 2.25 lower; 95% CI 3.65 lower to 0.85 lower). The finding of 1 trial (total of 65 participants) found moderate quality evidence that did not rule out a reduction or an increase in levetiracetam use for change in symptomatic medications taken (follow up: 4 months) for the use of antiepileptics other than topiramate or valproate compared to no antiepileptic use for prevention of recurrence of migraine (MD 3.98 lower; 95% CI 0 higher to 0 higher). Resource Use: Panel members estimated an average monthly cost of 200-500 SAR for other antiepileptics other than topiramate or valproate. Other factors such as outpatient provider visits, x-rays and labs would also need to be considered. Other considerations: The panel judged the use of antiepileptics, other than topiramate or valproate, to be both acceptable and feasible. The panel determined that impact on health inequity would be probably reduced with the use of antiepileptics other than topiramate or valproate. Balance between desirable and undesirable consequences: Antiepileptics other than topiramate or valproate are sometimes used off label for the prevention of migraine attacks despite there are no experimental studies that investigated their effects. Given the availability of other options for the prevention of migraine attacks, the panel considered it prudent not to use other antiepileptics until evidence for their effectiveness in this setting is available. Recommendation 11: The panel suggests that clinicians do not use antiepileptics other than topiramate or valproate for the prevention of migraine attacks until more research about their efficacy and safety is available. (conditional recommendation, low quality evidence) Research Priorities: Trials of antiepileptics for the prevention of migraine attacks, that properly measure and report patientimportant outcomes, were suggested by the panel. Question 12: Should topiramate versus betablockers be used for prevention of recurrence of migraine? Summary of Findings: The question was based on the 2012 NICE systematic review including one randomized controlled trial. 106 The updated literature search identified no new studies. Benefits and harms of the Option: The finding of 1 trial (total of 56 participants) found moderate quality evidence that showed an increase in patient-reported migraine days (follow up: 26 weeks) for the use of topiramate compared to the use of beta-blockers for prevention of recurrence of migraine (MD 0.35 higher; 95% CI 0.25 higher to 0.95 higher). The

20 finding of 1 trial (total of 56 participants) found low quality evidence that did not rule out a reduction or an increase in responder rate [>50% reduction] (follow up: 26 weeks) for the use of topiramate compared to the use of beta-blockers for prevention of recurrence of migraine (RR 0.85; 95% CI 0.62 to 1.17; absolute effect: 45 fewer events per 1000). The finding of 1 trial (total of 56 participants) found moderate quality evidence that showed an increase in patient-reported migraine frequency (follow up: 26 weeks) for the use of topiramate compared to the use of beta-blockers for prevention of recurrence of migraine (MD 0.25 higher; 95% CI 0.26 higher to 0.76 higher). The finding of 1 trial (total of 56 participants) found moderate quality evidence that showed an increase in use of acute pharmacological treatment (follow up: 26 weeks) for the use of topiramate compared to the use of beta-blockers for prevention of recurrence of migraine (MD 0.4 higher; 95% CI 0.1 higher to 0.9 higher). Resource Use: Panel members estimated an average monthly cost of 300-500 SAR with topiramate and 50-100 SAR for beta-blockers. Other factors such as outpatient provider visits, x-rays and labs would also need to be considered. Other considerations: The panel judged the use of topiramate to be both acceptable and feasible. The panel judged the impact on inequity to vary depending on context. Balance between desirable and undesirable consequences: The panel found there was not enough evidence to favor one over the other. No difference in effectiveness was found in one trial with serious limitations. Use of topiramate would require larger resources. Availability of resources will have important impact on this choice. Recommendation 12: The panel suggests that clinicians use either topiramate or beta-blockers for the prevention of migraine attacks. (conditional recommendation, low quality evidence) Research Priorities: The panel suggests more head-to-head comparison studies. Question 13: Should triptans versus no triptans be used for prevention of recurrence of menstrual-related migraine? Summary of Findings: The question was based on the 2012 NICE systematic review including three randomized controlled trials. 111-113 The updated literature search identified no new studies. Benefits and harms of the Option: The finding of 1 trial (total of 244 participants) found low quality evidence that showed an increase in responder rate [>50% reduction in migraine frequency] for the use of a triptan compared to no triptan use for prevention of recurrence of menstrual-related migraine (RR 1.49; 95% CI 1.1 to 2.03; absolute effect: 188 more events per 1000). The finding of 1 trial (total of 410 participants) found low quality evidence that showed a reduction in use of acute pharmacological treatment [% of patients treated] for the use of a triptan compared to no triptan use for prevention of recurrence of menstrual-related migraine (RR 0.78; 95% CI 0.7 to 0.87; absolute effect: 188 fewer events per 1000). The finding of 1 trial (total of 244 participants) found low quality evidence that showed a reduction in use of acute pharmacological treatment [% of breakthrough attacks treated] for the use of a triptan compared to no triptan use for prevention of recurrence of menstrual-related migraine (RR 0.83; 95% CI 0.69 to 0.99; absolute effect: 126 fewer events per 1000). The meta-analysis of 2 trials (total of 654 participants) found low quality evidence that did not rule out a reduction or an increase in adverse events for the use of a triptan compared to no triptan use for prevention of recurrence of menstrual-related migraine (OR 0.58; 95% CI 0.04 to 9.35; absolute effect: 2 fewer events per 1000). The finding of 1 trial (total of 272 participants) found low quality evidence that did not rule

21 out a reduction or an increase in frovatriptan twice daily freedom from menstrual-migraine per menstrual period (follow up: 6 days) compared to no triptan use for prevention of recurrence of menstrual-related migraine (MD 0.92 higher; 95% CI 0.11 lower to 1.95 higher). Resource Use: Panel members estimated an average monthly cost of 67-133 SAR with triptans. Other factors such as outpatient provider visits, x-rays and labs would also need to be considered. From health system perspective resources may be small, from individual perspective, out of the pocket cost may not be small. Other considerations: The panel judged the use of triptans in patients to be both acceptable and feasible. The panel judged the impact on inequity to probably increase with the use of triptans for the prevention of recurrence of menstrual-related migraine. Balance between desirable and undesirable consequences: One panel member was uncertain if the desirable anticipated effects were large. Panel members judged that desirable consequences probably outweigh undesirable consequences in most settings. Recommendation 13: The panel suggests triptans for the prevention of menstrual-related migraine attacks. (conditional recommendation, low quality evidence) Implementation Considerations: Treatment is used only during the menstrual period but needs to be timed to start treatment before period starts. Subgroup Considerations: In women with irregular menstrual period, it is uncertain if this will be effective because of feasibility of determining when to start treatment. Question 14: Should botulinum toxin A injections versus no injections be used for prevention of recurrence of episodic migraine? Summary of Findings: The NICE 2012 systematic review did not address this topic. The question was based on a 2012 systematic review and meta-analysis by Jackson et al. 136 including 18 randomized controlled trials in migraine populations. 118-135 Outcomes for adverse events were a pooled value that included both migraine and tension-type headache populations across 25 trials. The updated literature search identified no new studies. Benefits and harms of the Option: The metaanalysis of 9 trials (total of 1838 participants) found moderate quality evidence that did not rule out a reduction or an increase in number of headache episodes per month (follow up: range 84-270 days) for the use of botulinum toxin A injections compared to no injection use for prevention of recurrence of episodic migraine (MD 0.95 higher; 95% CI 026 lower to 0.36 higher). The meta-analysis of 2 trials (total of 421 participants) found moderate quality evidence that did not rule out a reduction or an increase in 50% reduction in number of monthly headaches (follow up: range 84-270 days) for the use of botulinum toxin A injections compared to no injection use for prevention of recurrence of episodic migraine (RR 1; 95% CI 0.85 to 1.18; absolute effect: 0 fewer events per 1000). The meta-analysis of 25 trials (total of 5711 participants) found moderate quality evidence that showed an increase in adverse events (e.g. blepharoptosis, dizziness, muscle weakness, nausea, neck pain, parasthesia) for the use of botulinum toxin A injections compared to no injection use for prevention of recurrence of episodic migraine (RR 1.25; 95% CI 1.14 to 1.36; absolute effect: 115 more events per 1000). Resource Use: Panel members estimated an average monthly cost of 1000-1500 SAR with botulinum toxin A injections. Other factors such as outpatient provider visits and training would also need to be considered. Other considerations: The panel judged the use of botulinum toxin A injections to be both acceptable and feasible. The panel judged the

22 impact on inequity to increase with the use of botulinum toxin A injections for prevention of recurrence of episodic migraine. Balance between desirable and undesirable consequences: There is no evidence of benefit and there is a potential harm and large cost. Recommendation 14: The panel recommends that clinicians do not use botulinum toxin A for the prevention of migraine attacks in patients with episodic migraine. (strong recommendation, moderate quality evidence) Question 15: Should botulinum toxin A injections versus no injections be used for prevention of recurrence of chronic migraine? Summary of Findings: The NICE 2012 systematic review did not address this topic. The question was based on a 2012 systematic review and meta-analysis by Jackson et al., 136 including 18 randomized controlled trials in migraine populations. 118-135 Outcomes for adverse events were a pooled value that included both migraine and tension-type headache populations across 25 trials. The updated literature search identified no new studies. Benefits and harms of the Option: The metaanalysis of 5 trials (total of 1508 participants) found low quality evidence that showed a reduction in number of monthly headaches (follow up: range 84-168 days) for the use of botulinum toxin A injections compared to no injection use for prevention of recurrence of chronic migraine (MD 2.3 lower; 95% CI 3.66 lower to 0.94 lower). The meta-analysis of 2 trials (total of 92 participants) found low quality evidence that showed an increase in 50% reduction in number of monthly headaches (follow up: range 84-112 days) for the use of botulinum toxin A injections compared to no injection use for prevention of recurrence of chronic migraine (RR 2.21; 95% CI 1.3 to 3.78; absolute effect: 309 more events per 1000). The findings of 1 trial (total of 1005 participants) found moderate quality evidence that showed an increase in functioning and health related quality of life clinically important improvement (follow up: 24 weeks) for the use of botulinum toxin A injections compared to no injection use for prevention of recurrence of chronic migraine (RR 1.73; 95% CI 1.44 to 2.07; absolute effect: 185 more events per 1000). The findings of 1 trial (total of 904 participants) found moderate quality evidence that showed an increase in responders (>50% reduction in moderate/severe headache days) (follow up: 24 weeks) for the use of botulinum toxin A injections compared to no injection use for prevention of recurrence of chronic migraine (RR 1.35; 95% CI 1.16 to 1.58; absolute effect: 126 more events per 1000). The meta-analysis of 25 trials (total of 5711 participants) found low quality evidence that did not rule out a reduction or an increase in adverse events (e.g. blepharoptosis, dizziness, muscle weakness, nausea, neck pain, parasthesia) for the use of botulinum toxin A injections compared to no injection use for prevention of recurrence of chronic migraine (RR 1.25; 95% CI 1.14 to 1.36; absolute effect: 115 more events per 1000). Resource Use: Panel members estimated an average monthly cost of 1000-1500 SAR with botulinum toxin A injections. Other factors such as outpatient provider visits and training would also need to be considered. Other considerations: The panel judged the use of botulinum toxin A injections to be both acceptable and feasible with barriers to implementation, which include large costs and required experience to perform the procedure. The panel judged the impact on inequity to probably increase with the use of botulinum toxin A injections for prevention of recurrence of chronic migraine. Balance between desirable and undesirable consequences: Two of five panel members were uncertain whether the anticipated desirable effects were large and whether they were large relative to undesirable effects. There is possibly a benefit but cost is large

23 likely resulting in an increase in inequity in access to health care. There is also requirement for special training of clinicians who would perform the procedure. Two of the five panel members thought that desirable consequences probably outweigh undesirable consequences in most settings and three of five panel members felt the balance between desirable and undesirable consequences is closely balanced. Recommendation 15: The panel suggests botulinum toxin A injections for prevention or recurrence of chronic migraine in patients who have not responded to other prophylactic treatments. (conditional recommendation, low quality evidence) Implementation Considerations: Injections of botulinum toxin A require specific skills and following a specific injection protocol. If the procedure is done, clinicians performing it need specific training. Monitoring and evaluation: Optimum duration of treatment and indications for discontinuation in patients with no response is currently not known. Research Priorities: Additional research is needed to clarify the required duration of treatment and criteria for its discontinuation. Comparative studies of different botulinum toxin preparations may be beneficial. Question 16: Should tricyclic antidepressants versus no antidepressants be used for prevention of recurrence of migraine? Summary of Findings: The NICE 2012 systematic review did not address this topic in migraine populations. The question was based on a 2010 systematic review and metaanalysis. 145 The updated literature search identified no new studies. Benefits and harms of the Option: The metaanalysis of 9 trials (total of 495 participants) found low quality evidence that showed a reduction in the burden of headache (follow up: range 4-26 weeks) for the use of tricyclic antidepressants compared to no tricyclic antidepressants use for prevention of recurrence of migraine (SMD 0.96 lower; 95% CI 1.39 lower to 0.53 lower). The meta-analysis of 4 trials (total of 480 participants) found low quality evidence that showed an increase in responder rate (50% reduction) (follow up: range 4-12 weeks) for the use of tricyclic antidepressants compared to no tricyclic antidepressants use for prevention of recurrence of migraine (RR 1.8; 95% CI 1.24 to 2.62; absolute effect: 181 more events per 1000). The meta-analysis of 7 trials (total of 690 participants) found high quality evidence that showed an increase in adverse events (e.g. anxiety, blurred vision, constipation, weight gain, nausea, dry mouth) for the use of tricyclic antidepressants compared to no tricyclic antidepressants use for prevention of recurrence of migraine (RR 1.89; 95% CI 1.18 to 3.02; absolute effect: 442 more events per 1000). Resource Use: Panel members estimated an average monthly cost of 50-100 SAR with tricyclic antidepressants. Other factors such as outpatient provider visits would also need to be considered. Other considerations: The panel judged the use of the use of tricyclic antidepressants to be both acceptable and feasible. The panel judged the impact on inequity to probably be reduced with the use of tricyclic antidepressants for prevention of recurrence of migraine. Balance between desirable and undesirable consequences: The panel felt desirable consequences probably outweigh undesirable consequences in most settings.

24 Recommendation 16: The panel suggests tricyclic antidepressants for the prevention of migraine attacks. (conditional recommendation, low quality evidence) Implementation Considerations: Most evidence is available for amitriptyline. Question 17: Should SSRIs versus no antidepressants be used for prevention of recurrence of migraine? Summary of Findings: The NICE 2012 systematic review did not address this topic in migraine populations. The question was based on a 2005 Cochrane systematic review by Moja et al. 147 The updated literature search identified no new studies. Benefits and harms of the Option: The metaanalysis of 3 trials (total of 86 participants) found low quality evidence that did not rule out a reduction or an increase in the headache index change (follow up: 8 weeks) for the use of SSRIs compared to no antidepressants use for prevention of recurrence of migraine (SMD 0.14 higher; 95% CI 0.57 lower to 0.3 higher). The meta-analysis of 4 trials (total of 161 participants) found low quality evidence that showed an increase in adverse events for the use of SSRIs compared to no antidepressants use for prevention of recurrence of migraine (OR 1.25; 95% CI 1.36 to 4.35; absolute effect: 15 more events per 1000). Resource Use: Panel members estimated an average monthly cost of 50-100 SAR with SSRI antidepressants having further increased costs with newer drugs. Other factors such as outpatient provider visits would also need to be considered. Other considerations: The panel judged the use of the use of SSRIs to be both acceptable and feasible. The panel judged the impact on inequity to probably be reduced with the use of SSRIs for prevention of recurrence of migraine. Balance between desirable and undesirable consequences: The panel was uncertain about the balance between desirable and undesirable consequences. Panel members were uncertain whether the incremental cost is small relative to benefits for SSRIs as newer drugs are much more expensive. Recommendation 17: The panel suggests that clinicians do not use SSRIs for the prevention of migraine attacks until more evidence is available. (conditional recommendation, low quality evidence) Research Priorities: The panel suggested more studies be done with an adequate length of follow-up and reporting that captures all patient-important outcomes. IV. PROPHYLACTIC NON-PHARMACOLOGICAL MANAGEMENT Question 18: Should education and selfmanagement programs versus no such programs (usual care only) be used for prevention of recurrence of migraine? Summary of Findings: The question was based one trial identified in the 2012 NICE systematic review. 157 The updated literature search also identified 2 new trials. 158,159 Benefits and harms of the Option: The findings of 1 trial (total of 51 participants) found very low quality evidence that showed an increase in the change in patient-reported migraine frequency (follow up: 3 months) for the use of education and self-management programs compared to no use of such a program for prevention of recurrence of migraine (RR 4.61; 95% CI 1.76 to 12.09; absolute effect: 498 more events per 1000). The findings of 1 trial (total of 51 participants) found very low quality evidence that did not rule out a reduction or an increase in the Use of acute pharmacological treatment [mean doses per week]

25 (follow up: 3 months) for the use of education and self-management programs compared to no use of such a program for prevention of recurrence of migraine (mean 2.5 lower). The findings of 1 trial (total of 368 participants) found low quality evidence that did not rule out a reduction or increase in intervention responder [>50% clinically significant improvement) (follow up: 3 months) for the use of education and self-management programs compared to no use of such a program for prevention of recurrence of migraine (RR 1.14; 95% CI 0.87 to 1.48; absolute effect: 54 more events per 1000). The findings of 1 trial (total of 368 participants) found low quality evidence that did not rule out a reduction or increase in migraine attack frequency (follow up: mean 3 months) for the use of education and self-management programs compared to no use of such a program for prevention of recurrence of migraine (mean 0.7 lower; 95% CI 2.33 lower to 0.95 higher). The findings of 1 trial (total of 368 participants) found low quality evidence that did not rule out a reduction or increase in migraine-specific quality of life [80-point scale] (follow up: 3 months) for the use of education and self-management programs compared to no use of such a program for prevention of recurrence of migraine (mean 0.8 higher; 95% CI 7.55 lower to 9.15 higher). The findings of 1 trial (total of 368 participants) found low quality evidence that did not rule out a reduction or increase in headache days per month (follow up: 3 months) for the use of education and selfmanagement programs compared to no use of such a program for prevention of recurrence of migraine (mean 2.3 lower; 95% CI 6.1 lower to 1.5 higher). The findings of 1 trial (total of 189 participants) found very low quality evidence that did not rule out a reduction or increase in patient global rating of improvement (much improved) (follow up: 6 months) for the use of education and self-management programs compared to no use of such a program for prevention of recurrence of migraine (RR 1.43; 95% CI 0.72 to 2.83; absolute effect: 54 more events per 1000). Resource Use: The average cost per month of such programs was estimated between 100-500 SAR by panel members. Outpatient provider visits would also need to be considered. Other considerations: The panel judged the use of educational programs to probably not be feasible as implementation would require setting up websites, creating educational materials, training psychologists; although the program probably would be acceptable by key stakeholders. The panel judged the impact on inequity to probably be increased for prevention of recurrence of migraine. Balance between desirable and undesirable consequences: The panel thought that desirable and undesirable consequences were closely balanced. The panel found no evidence of effectiveness but also no evidence of ineffectiveness and it is possible that there is a benefit from these educational programs. However, possibly substantial resources would be required in order to implement such programs. Recommendation 18: The panel suggests that more research is done on effectiveness and cost-effectiveness of education and self-management programs. (conditional recommendation, very low quality evidence)

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33 141. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007; 68: 343-9. 142. Botney M, Fields JL. Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system. Ann Neurol 1983; 13: 160-4. 143. Eberhard G, Von Knorring L, Nilsson HL, Sundequist U, Wahlander L. Predictors for the outcome of treatment with antidepressants inpatients with idiopathic pain syndromes. Nord Psykiatr Tidsskr 1989; 43: 114-20. 144. Dharmshaktu P, Tayal V, Kalra B. Efficacy of antidepressants as analgesics: a review. J Clin Pharmacol. 2012; 52: 6-17. 145. Jackson JL, Shimeall W, Sessums L, Dezee KJ, Becher D, Diemer M, Berbano E, O'Malley PG. Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ. 2010 Oct 20;341:c5222. doi: 10.1136/bmj.c5222. 146. Anderson ED. An ascending serotoninergic pain modulation pathway from the dorsal raphe nucleus to the parafascicularis nucleus of the thalamus. Brain Res 1983;269:67-77. 147. Moja PL, Cusi C, Sterzi RR, Canepari C. Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database Syst Rev 2005; (3): CD002919. 148. Lipton RB, Bigal ME, Amatniek JC, Stewart WF. Tools for diagnosing migraine and measuring its severity. Headache 2004; 44: 387-98. 149. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. On behalf of the AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology 2007; 68:343-9. 150. Wenzel R, Dortch M, Cady R, et al. Migraine headache misconceptions: barriers to effective care. Pharmacotherapy 2004a; 24: 638-48. 151. Kol CM, Dekker F, Neven AK, et al. Acceptance or rejection of prophylactic medicine in patients with migraine: a cross- sectional study. Br J Gen Pract 2008; 58: 98-101. 152. Abu-Salameh I, Plakht Y, Ifergane G. Migraine exacerbation during Ramadan fasting. J Headache Pain 2010; 11: 513-7. 153. Bener A, Dunn EV, Achan NV, Moussa NA, Abu Azab I. Migraine associated with road traffic accidents in United Arab Emirates. Neurosciences (Riyadh) 2001; 6: 33-7. 154. Blumenfeld AM, Bloudek LM, Becker WJ, Buse DC, Varon SF, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache 2013 Apr; 53: 644-55. 155. Hepp Z, Bloudek LM, Varon SF. Systematic review of migraine prophylaxis adherence and persistence. J Manag Care Pharm 2014; 20: 22-33. 156. Penzien DB, Rains JC, Andrasik F. Behavioral management of recurrent headache: three decades of experience and empiricism. Appl Psychophysiol Biofeedback 2002; 27: 163-81. 157. Kohlenberg RJ, Cahn T. Self-help treatment for migraine headaches: A controlled outcome study. Headache 1981; 21: 196-200. 158. Bromberg J, Wood ME, Black RA, Surette DA, Zacharoff KL, Chiauzzi EJ. A randomized trial of a web-based intervention to improve migraine self-management and coping. Headache 2012; 52: 244-61. 159. Kleiboer A, Sorbi M, van Silfhout M, Kooistra L, Passchier J. Short-term effectiveness of an online behavioral training in migraine self-management: a randomized controlled trial. Behav Res Ther 2014; 61: 61-9.

34 Appendices 1. Appendix 1: Evidence-to-Decision Frameworks 2. Appendix 2: Search Strategies and Results

35 Appendix 1: Evidence to Decision Frameworks 01: Should head MRI or CT (with or without contrast) rather than no imaging be done in patients with suspected migraine headache and no other indications? Population Intervention Comparison Outcomes Those with suspected migraine headaches and no other historical findings, signs and/or symptoms being an indication for head imaging MRI or CT Imaging No imaging serious abnormalities: tumour/neoplasm, abscess, subdural haematoma, hydrocephalus, arterio-venous malformations, venous thrombosis, and stroke Clinical Background: In migraine headache diagnosis, determining if the headache is a primary or secondary disorder is considered necessary. Secondary headaches often result from underlying pathology. Common causes of secondary headache are serious abnormalities such as thrombosis, tumour or abscess. Most often, the presentation is that of migraine headache, which carries lifetime prevalence is 18% and occurs moreso in women. 22 In children, a systematic review of 17 observational studies found patient management was altered in only 2.5% of 3260 children who received CT or MRI imaging. Additionally, of these 2.5% of children identified only 4 had normal findings on neurological examination. 23 While these findings are not surprising in young populations, the presence of both abnormal 24 or incidential 25 findings identified through imaging, is known to increase with age. An abnormal neurological examination during a headache workup often prompts imaging and some have been suggested that requesitions for imaging should not occur prior to the completion of a neurological examination. 26 As example of resource implications, the related costs to identify brain tumours via CT have been found to be 10 fold greater when done after a normal neurological examination. 27 In the case of MRI, referring speciality or even specialist experience had little bearing on cost-effectiveness outcomes. 28 As well as the implication of high resource costs, some patients may be claustrophobic, require sedation, or occasionally need a general anesthetic. In most instances, patients will be conveyed non-serious findings, which may still worry a proportion of patients who conclude that there is still something wrong with them. 29 A randomized controlled trial of 150 patients with migraine and oth-

36 er headaches assigned to either to receiving MRI or no imaging reported only the outcomes of anxiety and reasurance and found a signficant health resource cost reduction in the specific sub-group of patients with higher pyschiatric co-morbidity. 30 Lastly, defensive medicine by clinicians, patient pressure for completeness, clinical site of care protocols and available insurance to fund the costs further add to the complexity of the decision. 31 This recommendation question specifically relates to those patients who the clinician suspects have a migraine headache, rather than those who have a suspected serious abnormality or other indication suggesting imaging is required. Evidence summary for MRI and CT imaging: Potential Sources: NICE 2012 systematic review McMaster observational study literature search (Medline, Embase, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date Of potential MRI imaging literature sources, one new trial was identified that did not capture a critical outcome of interest; but did report on the implications of MRI use in chronic daily headache patients. 30 The available evidence available relates to only retrospective cohort studies identified by the NICE 2012 systematic review. There were 4 studies identified that measured serious abnormalities detected via MRI in adults with various types of headache. 32-35 Across studies (n=1139), identification of serious adverse events ranged from none (abscess or stroke) to 5 per 1000 for tumour/neoplasm (number needed to image with MRI = 200) in the best case. Of potential CT imaging literature sources, the available evidence was combined from the NICE 2012 systematic review and one new observational study from McMaster literature searches. Three retrospective cohort studies used combinations of CT and MRI in adults with various types of headache. 36-38 One additional case series was identified, with a very small population (n=63) of primarily African American pregnant women ranging from ages 15 to 41 who presented to emergency with severe headaches at various times throughout their pregnancy. 39 There were no studies that exclusively used CT alone as a method of detection of serious abnormalities. Venous thrombosis was particularly of interest to the KSA panel and this outcome was presented for the populations of both adults and pregnant women. Across studies (n=2287), identification of serious adverse events ranged from none (abscess or subdural haematoma) to 7 per 1000 for tumour/neoplasm (number needed to image with CT/MRI combinations = 143) in the best case.

37 No cost-effectiveness or patient values & preferences information was identified specifically related to KSA. A crude resource cost per serious abnormality detected was calculated. The certainty of the available benefits and harms evidence was overall very low. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. What is the overall certainty of this evidence? included studies Very low Low Moderate High The relative importance or values of the main outcomes of interest: Outcome Tumour / Neoplasm identified Relative importance Certainty of theevidence (GRADE) VERY LOW Benefits & harms of the options Is there important uncertainty about how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of Abscess identified Subdural Haematoma identified Hydrocephalus identified Arteriovenous Malformation identified VERY LOW VERY OW VERY LOW VERY LOW

38 Criteria Judgements Research evidence Additional considerations variability known undesirable Stroke (e.g. venous thrombosis) identified VERY LOW Are the desirable anticipated effects large? Are the undesirable anticipated effects small? Probably no Yes Probably no Yes Summary of findings: MRI imaging Outcome Tumor / Neoplasm identified 5 per 1000 Abscess identified With head MRI (with or without contrast) 0 identified SubduralHematoma identified 2 per 1000 Hydrocephalus identified 3 per 1000 Arteriovenous Malformation identified 2 per 1000 Stroke (e.g. venous thrombosis) identified 0 identified Are the desirable effects large relative to undesirable effects? Probably no Yes Summary of findings: CT imaging Outcome Tumor / Neoplasm identified 7 per 1000 Abscess identified Withhead CT (with or without contrast) 0 identified Subdural Hematoma identified 0 identified Hydrocephalus identified 8 per 10,000

39 Criteria Judgements Research evidence Additional considerations Arteriovenous Malformation identified 4 per 10,000 Stroke (e.g. venous thrombosis) identified 4 per 10,000 Pregnant women: Venous Thrombosis identified 63 per 1000 Resource use Are the resources required small? No Yes MRI unit cost range: 2000-4500 SR. Using MRI alone carries an imaging resource cost between 181,800SR and 409,050 SR per serious abnormality detected. CT unit cost range: 1200-1500. Using CT or MRI combinations carries an imaging resource cost between 133,312 SR and 499,950 SR per serious abnormality detected. Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist -Hospital: ER/urgent care visit, inpatient hospital stay per day -Labs & x-rays -Blood tests Is the incremental cost small relative to the net benefits? Probably no Yes No evidence identified specific to KSA Equity What would be the impact on health inequities? Increased Probably increased No evidence identified specific to KSA

40 Criteria Judgements Research evidence Additional considerations Probably reduced Reduced Acceptability Is the option acceptable to key stakeholders? Yes Varies No evidence identified specific to KSA Likely acceptable to patients but uncertain whether also acceptable for policymakers and payers. Feasibility Is the option feasible to implement? Probably no Yes No evidence identified specific to KSA

41 Recommendation Should head MRI or CT imaging (with or without contrast) vs. no imaging be used in patients with suspected migraine headache and no other indications? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel recommends that clinicians do not use head MRI or CT imaging in patients with migraine or suspected of migraine that do not have other indications for imaging. Prevalence of potentially treatable serious head lesions is likely very low. Proportion of false negative and false positive results is not known, but likely to result in substantial anxiety and unnecessary cost of further testing. Resources required would be large. None None None None

42 Evidence Profile: Should head MRI or CT (with or without contrast) rather than no imaging be done in patients with suspected migraine headache? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations head MRI (with or without contrast) no imaging Relative (95% CI) Absolute (95% CI) Quality Importance Tumour / Neoplasm identified 4 observational studies very serious not serious serious 2 serious 3 none 6/1139 (0.5%) not estimable 1 not estimable VERY LOW Abscess identified 4 observational studies very serious not serious serious 2 serious 3 none 0/1139 (0.0%) not estimable 1 not estimable VERY LOW Subdural Haematoma identified 4 observational studies very serious not serious serious 2 serious 3 none 2/1139 (0.2%) not estimable 1 not estimable VERY LOW Hydrocephalus identified 4 observational studies very serious not serious serious 2 serious 3 none 3/1139 (0.3%) not estimable 1 not estimable VERY LOW Arteriovenous Malformation identified 4 observational studies very serious not serious serious 2 serious 3 none 2/1139 (0.2%) not estimable 1 not estimable VERY LOW Stroke (e.g. venous thrombosis) identified 4 observational studies very serious not serious serious 2 serious 3 none 0/1139 (0.0%) not estimable 1 not estimable VERY LOW MD mean difference, RR relative risk 1. nature of abnormality is not detailed; unclear on specific imaging procedure done 2. unclear if populations potentially could have secondary headaches 3. retrospective reporting of events only available

43 Bibliography: Grimaldi D, Nonino F, Cevoli S, Vandelli A, D'Amico R, Cortelli P. Risk stratification of non-traumatic headache in the emergency department. Journal of Neurology 2009; 256: 51-7. Jordan JE, Ramirez GF, Bradley WG, Chen DY, Lightfoote JB, Song A. Economic and outcomes assessment of magnetic resonance imaging in the evaluation of headache. Journal Natl Med Assoc 2000; 92: 573-8. Tsushima Y, Endo K. MR imaging in the evaluation of chronic or recurrent headache. Radiology 2005; 235: 575-9. 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: 405-8.

44 Evidence Profile: Head CT (with or without contrast) compared to no imaging for diagnosis of suspected migraine headache Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations head CT (with or without contrast) no imaging Relative (95% CI) Absolute (95% CI) Quality Importance Tumour / Neoplasm identified 4 observational studies very serious not serious serious 2 serious 3 none 16/2287 1 (0.7%) not estimable not estimable VERY LOW Abscess identified 4 observational studies very serious not serious serious 2 serious 3 none 0/2287 (0.0%) not estimable not estimable 1 VERY LOW Subdural Haematoma identified 4 observational studies Hydrocephalus identified 4 observational studies very serious not serious serious 2 serious 3 none 0/2287 (0.0%) not estimable not estimable 1 VERY LOW very serious not serious serious 2 serious 3 none 2/2287 (0.1%) not estimable not estimable 1 VERY LOW Arteriovenous Malformation identified 4 observational studies very serious not serious serious 2 serious 3 none 1/2287 (0.0%) not estimable not estimable 1 VERY LOW Stroke (e.g. venous thrombosis) identified 4 observational studies very serious not serious serious 2 serious 3 none 1/2287 (0.0%) not estimable not estimable 1 VERY LOW Pregnant women: Venous Thrombosis identified 1 observational studies serious 1 not serious serious 2 very serious 3 4 none 4/63 (6.3%) not estimable not estimable VERY LOW

45 MD mean difference, RR relative risk 1. nature of abnormality is not detailed; unclear on specific imaging procedure done 2. unclear if populations potentially could have secondary headaches 3. different combinations and ordering of MRI and CT used 4. very small sample size Bibliography: Cull RE. Investigation of late-onset migraine. Scottish Medical Journal 1995; 40: 50-2. Demaerel P, Boelaert I, Wilms G, Baert AL. The role of cranial computed tomography in the diagnostic work-up of headache. Headache 1996; 36: 347-8. 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: 30-5. Ramchandren S, Cross BJ, Liebeskind DS. Emergent headaches during pregnancy: correlation between neurologic examination and neuroimaging. AJNR Am J Neuroradiol 2007; 28:1085-7.

46 02: Should metoclopramide versus NSAIDs be used for acute migraine? Population Intervention Comparison Those with acute migraine headaches metoclopramide NSAIDs Outcomes of Interest Time to freedom from pain Headache response at up to 2 hours Freedom from pain at up to 2 hours Sustained headache response at 24 hours Sustained freedom from pain at 24 hours Headache specific quality of life Functional health status and health related quality of life Incidence of serious adverse events Clinical background: Metoclopramide has long been used as an intervention to treat nausea associated with migraine. As well, it is known to have the potential to enhance absorption of other analgesics by relieving gastric stasis. 40 Studies have also suggested its dopamine antagonist properties might also make it effective as a single agent in acute migraine. 41 A systematic review of 13 placebo-controlled trials across 655 adult patients found a significant reduction in migraine pain (OR=2.84; 95%CI 1.05 to 7.68) and concluded its effectiveness as a single or combined agent for acute migraine use (number needed to treat =4). 42 As a control group treatment, in prophylaxis and specific to KSA, a placebo-controlled trial of 222 participants, the NSAID (etoricoxib) was evaluated and determined effective as a means to reduce the incidence of first of Ramadan onset of fasting headaches (OR=3.19; 95%CI: 1.68 to 6.06) during the first 5 days of month. 43 In acute situations, a systematic review of 8 trials across 321 patients of ketorolac found NSAIDs effective as an alternative agent for anti-emetics for acute migraine, although suggesting that it may not be as effective as the anti-emetic metoclopramide. 44 This overall leads to some uncertainty around the choice between anti-emetics and NSAIDs in acute migraine patients.

47 Evidence summary for metoclopramide versus NSAID use in acute migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date Of potential sources, the available evidence was combined from the NICE 2012 systematic review and one new study from McMaster literature searches. The available evidence in specifically acute migraine headache populations relates to 2 randomized controlled trials, one in children (ages 5-18) 45 and one in adults, 46 that specifically compared the anti-emetics (intravenous prochlorperazine or metoclopramide: 10 mg) to the NSAID (intravenous ketorolac: 30 mg). In children, there was an absolute benefit to 264 per 1000 (number needed to treat = 4) more with anti-emetics and in adults, there was an absolute benefit of headache relief at 2 hours to 91 per 1000 (number needed to treat = 11) more compared to NSAIDs with 36 per 1000 (number needed to harm = 28) more experiencing adverse events (e.g. dizziness, drowsiness, dyspepsia). No evidence was identified related to cost-effectiveness or values & preferences. Generally, the certainty of the benefits and harms evidence was very low. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide crosssectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95%

48 Criteria Judgements Research evidence Additional considerations CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. What is the overall certainty of this evidence? included studies Very low Low Moderate High The relative importance or values of the main outcomes of interest: Outcome Headache relief at 2 hours (Change from severe or moderate tomild or none) Relative importance Certainty of the evidence (GRADE) VERY LOW Benefits & harms of the options Is there important uncertainty about how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known Headache freedom at 2 hours Sustained freedom from headache at 24 hours Sustained relief from headache at 24 hours (change from severe to moderate to mild or nne) Adverse Events (Dizzy, too drowsy to function, dyspepsia, heartburn, bloating) IMPORTANT VERY LOW VERY LOW VERY LOW LOW

49 Criteria Judgements Research evidence Additional considerations Are the desirable anticipated effects large? Are the undesirable anticipated effects small? undesirable Probably no Yes Probably yes Yes Summary of findings: NSAIDs Outcome Headache relief a 2 hours (Change from severe or moderate to mild or none) Headache freedom at 2 hours With NSAIDs 538 per 1000 245 per 1000 With antiemetics 629 per 1000 (500 to 790) 282 per 1000 (182 to 439) Difference (95% CI) 91 more per 1000 (from 38 fewer to 253 more) 37 more per 1000 (from 64 fewer to 194 more) Relative effect (RR) (95% CI) RR 1.17 (0.93 to 1.47) RR 1.15 (0.74 to 1.79) Are the desirable effects large relative to undesirable effects? Uncertain Yes Sustained freedom from headache at 24 hours Sustained relief from headache at 24 hours (change from severe to moderate to mild or none) Adverse Events (Dizzy, too drowsy to function, dyspepsia, heartburn, bloating) 156 per 1000 327 per 1000 136 per 1000 111 per 1000 (55 to 218) 415 per 1000 (291 to 595) 101 per 1000 (47 to 205) 45 fewer per 1000 (from 62 more to 101 fewer) 88 more per 1000 (from 36 fewer to 268 more) 36 fewer per 1000 (from 68 more to 90 fewer) RR 0.71 (0.35 to 1.4) RR 1.27 (0.89 to 1.82) OR 0.71 (0.31 to 1.63)

50 Criteria Judgements Research evidence Additional considerations Resource use Are the resources required small? Yes NSAIDs: average monthly cost estimated at 50-100 SAR by panel members. Anti-emetics: average monthly cost estimated at 50-100 SAR by panel members. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist -Hospital: ER/urgent care visit, inpatient hospital stay per day Is the incremental cost small relative to the net benefits? Yes No evidence identified specific to KSA Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced No impact No evidence identified specific to KSA Acceptability Is the option acceptable to key No evidence identified specific to KSA

51 Criteria Judgements Research evidence Additional considerations stakeholders? Yes Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA

52 Recommendation Should anti-emetics vs. NSAIDs be used in acute migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel suggests either metoclopramide or NSAID in patients with acute migraine. The panel determined that there is not enough evidence to favor one over the other. No evidence of difference in benefits, adverse effects and cost has been identified. None None None The panel suggested that it might be beneficial to conduct more head-to-head RCTs that investigate commonly used NSAIDs and other medications used for acute migraine and measure patient-important outcomes.

53 Evidence Profile: Should metoclopramide versus NSAIDs be used for acute migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations metoclopramide NSAIDs Relative (95% CI) Absolute (95% CI) Quality Importance Headache relief at 2 hours (Change from severe or moderate to mild or none) 1 randomised trials not serious not serious serious 3 very serious 2 none 64/102 (62.7%) 57/106 (53.8%) RR 1.17 (0.93 to 1.47) 91 more per 1000 (from 38 fewer to 253 more) VERY LOW Headache freedom at 2 hours 1 randomised trials not serious not serious serious very serious 2 none 31/110 (28.2%) 27/110 (24.5%) RR 1.15 (0.74 to 1.79) 37 more per 1000 (from 64 fewer to 194 more) VERY LOW Sustained freedom from headache at 24 hours 1 randomised trials not serious not serious serious very serious 2 none 12/109 (11.0%) 17/109 (15.6%) RR 0.71 (0.35 to 1.4) 45 fewer per 1000 (from 62 more to 101 fewer) VERY LOW Sustained relief from headache at 24 hours (change from severe to moderate to mild or none) 1 randomised trials not serious not serious serious very serious 2 none 42/101 (41.6%) 34/104 (32.7%) RR 1.27 (0.89 to 1.82) 88 more per 1000 (from 36 fewer to 268 more) VERY LOW Adverse Events (Dizzy, too drowsy to function, dyspepsia, heartburn, bloating) 1 randomised trials not serious serious serious 2 none 11/109 (10.1%) 15/110 (13.6%) OR 0.71 (0.31 to 1.63) 36 fewer per 1000 (from 68 more to 90 fewer) LOW not serious IM- PORTANT 1. confidence interval crosses minimally important difference making effect size uncertain 2. confidence interval crosses both minimally important differences making outcome effect very uncertain 3. the study that used ketorolac IV that is not available in KSA

54 Bibliography: Friedman BW, Garber L, Yoon A, Solorzano C, Wollowitz A, Esses D, Bijur PE, Gallagher EJ. Randomized trial of IV valproate vs metoclopramide vs ketorolac for acute migraine. Neurology 2014; 82: 976-83.

55 03: Should triptans versus metoclopramide be used for acute migraine? Population Intervention Comparison Those with acute migraine headaches Triptans Metoclopramide Outcomes of Interest Time to freedom from pain Headache response at up to 2 hours Freedom from pain at up to 2 hours Sustained headache response at 24 hours Sustained freedom from pain at 24 hours Headache specific quality of life Functional health status and health related quality of life Incidence of serious adverse events Clinical background: Acute migraine is often debilitating with severe attacks of headache pain and autonomic dysfunction. 47 It is usually accompanied with other symptoms such as nausea, vomiting. 48 As triptans are highly migraine-specific, they are usually used as first-line treatment for mild to moderate attacks that are unresponsive to nonspecific analgesics. 49,50 As discussed previously, metoclopramide as a comparison group treatment has long been used to treat nausea associated with migraine. As well, it has the potential to enhance absorption of other analgesics by relieving gastric stasis. 51 Also, studies have suggested its dopamine antagonist properties might make it an effective single agent in acute migraine. 52 A systematic review of 13 trials across 655 adult patients found a significant reduction in migraine pain (OR=2.84; 95%CI 1.05 to 7.68) and concluded its effectiveness as a single or combined agent for acute migraine (number needed to treat = 4). 42 Additionally, consideration of combining triptans with the anti-emetic promethazine was given in a trial of 242 patients that reported primary headache-free response at 2 hours more effective (OR=2.83; 95%CI: 1.03 to 3.26) to solely sumatriptan monotherapy. 53 However, contraindications and side-effects complicate the clinical situation. 54 Therefore, this requires at times a decision between a specific monotherapy, either triptans or anti-emetics. Evidence summary for triptan versus metoclopramide use in acute migraine:

56 Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date Of potential sources, the available evidence was derived from the NICE 2012 systematic review. The available evidence, in specifically acute migraine headache populations, relates to one randomized controlled trial (n=77) that specifically compared the triptans (sumatriptan 6 mg subcutaneous) and the anti-emetic (IV metoclopramide 20 mg up to 4 doses every 30 minutes with 2 separate IV infusions of 25 mg diphenhydramine). 55 For the outcome of achieving pain free status at 2 hours, the absolute effect was 246 per 1000 fewer benefiting and 110 per 1000 experiencing more adverse events (e.g. weakness, heaviness, dizziness) when using triptans compared to metroclopramide. The mean age was 34 (range 31-37) with 86% of participants in the trial being female. One systematic review of Cochrane reviews also summarized best routes of sumatriptan administration although not direct to this specific metoclopramide comparator. 56 Four triptan cost-effectiveness studies were identified although the comparisons were indirect. 57-60 Generally, the certainty of the benefits and harms evidence was low. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly

57 Criteria Judgements Research evidence Additional considerations reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. What is the overall certainty of this evidence? included studies Very low Low Moderate High The relative importance or values of the main outcomes of interest: Outcome Pain free at 2 hours Relative importance Certainty of the evidence (GRADE) MODERATE The panel determined that undesirable effects were likely small and favored control intervention. Benefits & harms of the options Is there important uncertainty about how much people value the main outcomes? Are the desirable anticipated effects Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable Probably no Sustained pain free at 24 hours LOW Adverse Event: Weakness IMPORTANT LOW Adverse Events: Feeling of Heaviness / Dizziness Adverse Events: Stiffness or Abnormal Movements Summary of findings: anti-emetics Outcome With antiemetics Pain free at 2 hours 600 per 1000 IMPORTANT MPORTANT With triptans 354 per 1000 (210 to LOW LOW Difference (95% CI) 246 fewer per 1000 (from 18 fewer to 390 fewer) Relative effect (RR) (95% CI) RR 0.59 (0.35 to 0.97)

58 Criteria Judgements Research evidence Additional considerations large? Yes Sustained pain free at 24 hours 400 per 1000 582) 272 per 1000 (-140 to 520) 128 fewer per 1000 (from 120 more to 540 fewer) RR 0.68 (-0.35 to 1.3) Adverse Events: Weakness 125 per 1000 243 per 1000 (87 to 517) 118 more per 1000 (from 38 fewer to 392 more) OR 2.25 (0.67 to 7.48) Are the undesirable anticipated effects small? Are the desirable effects large relative to undesirable effects? Probably yes Yes Probably no Yes Adverse Events: Feeling of Heaviness / Dizziness Adverse Events: Stiffness or Abnormal Movements 25 per 1000 75 per 1000 135 per 1000 (17 to 584) 189 per 1000 (53 to 495) 110 more per 1000 (from 8 fewer to 559 more) 114 more per 1000 (from 22 fewer to 420 more) OR 6.09 (0.68 to 54.85) OR 2.88 (0.69 to 12.09) Resource use Are the resources required small? Probably no Triptans: average monthly cost estimated at 200-400 SR by panel members. Anti-emetics: average monthly cost estimated at 50-100 SR by panel members. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN,

59 Criteria Judgements Research evidence Yes Additional considerations Pain specialist, Psychologist, Psychiatrist -Hospital: ER/urgent care visit, inpatient hospital stay per day Is the incremental cost small relative to the net benefits? Probably no Yes No evidence identified specific to KSA. Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced No evidence identified specific to KSA Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA

60 Criteria Judgements Research evidence Additional considerations Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA.

61 Recommendation Should triptans vs. metoclopramide be used for acute migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel suggests metoclopramide rather than a triptan in patients with acute migraine. The quality of available evidence supporting this recommendation is low leaving much uncertainty about the balance of desirable and undesirable consequences. However, use of metoclopramide is less costly. In settings where resources are available an alternative option (i.e. using triptans) may be equally reasonable. Available evidence is for intravenous administration in emergency department. It is less clear whether it is applicable to less severe cases and oral administration of medications. Note: evidence is available for sumatriptan only. None None The panel thought that more research on comparative safety and effectiveness for all routes of administration and types of triptans would be desirable.

62 Evidence Profile: Should triptans versus metoclopramide be used for acute migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations triptans metoclopramide Relative (95% CI) Absolute (95% CI) Quality Importance Pain free at 2 hours 1 randomised trials not serious not serious not serious serious 1 none 13/37 (35.1%) 24/40 (60.0%) RR 0.59 (0.35 to 0.97) 246 fewer per 1000 (from 18 fewer to 390 fewer) MODERATE Sustained pain free at 24 hours 1 randomised trials not serious not serious not serious very serious 2 none 10/37 (27.0%) 16/40 (40.0%) RR 0.68 (-0.35 to 1.3) 128 fewer per 1000 (from 120 more to 540 fewer) LOW Adverse Events: Weakness 1 randomised trials not serious not serious not serious very serious 3 none 9/37 (24.3%) 5/40 (12.5%) OR 2.25 (0.67 to 7.48) 118 more per 1000 (from 38 fewer to 392 more) LOW IMPORTANT Adverse Events: Feeling of Heaviness / Dizziness 1 randomised trials not serious not serious not serious very serious 3 none 4/37 (10.8%) 0/40 (0.0%) OR 6.09 (0.68 to 54.85) 110 more per 1000 (from 8 fewer to 559 more) LOW IMPORTANT Averse Events: Stiffness or Abnormal Movements 1 randomised trials not serious not serious not serious very serious 3 none 7/37 (18.9%) 3/40 (7.5%) OR 2.88 (0.69 to 12.09) 114 more per 1000 (from 22 fewer to 420 more) LOW IMPORTANT MD mean difference, RR relative risk

63 1. confidence interval crosses minimally importance difference 2. confidence interval crosses null value making outcomes uncertain 3. small sample size Bibliography: 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: 463-8.

64 04: Should triptans versus paracetamol be used for acute migraine? Population Those with acute migraine headaches Intervention triptans Comparison paracetamol Outcomes of Interest Time to freedom from pain Headache response at up to 2 hours Freedom from pain at up to 2 hours Sustained headache response at 24 hours Sustained freedom from pain at 24 hours Headache specific quality of life Functional health status and health related quality of life Incidence of serious adverse events Clinical background: The triptans are considered first-line agents in the treatment of acute migraine for those with disabling migraine. However, for those whose acute headaches are not typically disabling, the use of over-the-counter agents such as acetaminophen may prove sufficient. In acute situations, most patients with migraine report trying often more than three medication types, with over-the-counter acute medication use being more commonly reported than even prescription treatments. 61 In one randomized controlled trial of 140 patients, paracetamol (e.g. Tylenol) was found to significantly more effective than placebo in reducing pain intensity at 2-hours and reducing functional disability with no serious adverse events reported. 62 As well, paracetamol represents a cost-effective over-the-counter option for those with less disabling acute migraines or for those not able or who do not wish to seek medical care. 63 Evidence summary for triptan versus paracetamol use in acute migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014

65 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date Of potential sources, the available evidence was derived from the NICE 2012 systematic review. The available evidence, in specifically acute migraine headache, relates to one randomized controlled trial (n=173) that compared a triptan (rizatriptan 10 mg tablets) versus paracetamol (1000 mg tablets) administered within 4 hours of migraine onset in adults (mean age 43), who were primarily (88%) female participants. 64 While paracetamol did offer benefit, triptans afforded an absolute pain free at 2 hours benefit to 138 of 1000 (number needed treat = 7) more when compared to paracetamol. No serious adverse events were identified as an outcome. One systematic review also summarized best routes of sumatriptan administration. 56 Four triptan cost-effectiveness studies were identified although the comparisons were indirect. 57-60 Generally, the certainty of the benefits and harms evidence was very low. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the options What is the overall certainty of this evidence? included studies Very low Based on their unsystematic clinical observations panel members considered paracetamol as not very effective

66 Criteria Judgements Research evidence Additional considerations Is there important uncertainty about how much people value the main outcomes? Low Moderate High Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable The relative importance or values of the main outcomes of interest: Outcome Headache response at up to 2 hours Pain free at up to 2 hour Sustained headache response at 24 hours Sustained freedom from pain at 24 hours Summary of findings: paracetamol Outcome With paracetamol Relative importance Withtriptans Certainty of the evidence (GRADE) VERY LOW VERY LOW VERY LOW VERY LOW Difference (95% CI) Relative effect (RR) (95% CI) in acute migraine. However, panel members acknowledged that most of them have experience form tertiary care centers with patients who likely already tried and failed other treatments (including paracetamol). Are the desirable anticipated effects large? Uncertain Yes Headache response at up to 2 hours Pain free at up to 2 hour 698 per 1000 256 per 1000 767 per 1000 (593 to 991) 394 per 1000 (210 to 742) 70 more per 1000 (from 105 fewer to293 more) 138 more per 1000 (from 46 fewer to 486 more) RR 1.1 (0.85 to 1.42) RR 1.54 (0.82 to 2.9) Are the undesirable

67 Criteria Judgements Research evidence Additional considerations anticipated effects small? Are the desirable effects large relative to undesirable effects? Probably yes Yes Probably yes Yes Sustained headache response at 24 hours Sustained freedom from pain at 24 hours 419 per 1000 163 per 1000 498 per 1000 (318 to 774) 233 per 1000 (98 to 553) 80 more per 1000 (from 100 fewer to 356 more) 70 more per 1000 (from 65 fewer to 391 more) RR 1.19 (0.76 to 1.85) RR 1.43 (0.6 to 3.4) Resource use Are the resources required small? Is the incremental cost small relative to the net benefits? Probably no Yes Uncertain Yes Triptans: average monthly cost estimated at 200-400 SR by panel members. Paracetamol: average monthly cost estimated at 10-50 SR by panel members. No evidence identified specific to KSA. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist -Hospital: ER/urgent care visit, inpatient hospital stay per day Equity What would be the impact on health inequities? Increased Probably increased No evidence identified specific to KSA Those with access to specialty clinic are more likely to receive triptans. In family care setting it is less likely.

68 Criteria Judgements Research evidence Additional considerations Probably reduced Reduced Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA.

69 Recommendation Should triptans vs. paracetamol be used for acute migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel suggests triptans rather than parcetamol in patients with acute migraine. Available evidence, though very uncertain, and unsystematic observations in panel members practice suggest larger benefit from triptans compared to paracetamol. One panel member felt that the balance between desirable and undesirable consequences is uncertain because available evidence is of too low quality to be able to make the judgment. Patients with hemiplegic migraine should not receive triptans. Note: evidence is available only for risatriptan. None None None

70 Evidence Profile: Should triptans versus paracetamol be used for acute migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations triptan paracetamol Relative (95% CI) Absolute (95% CI) Quality Importance Headache response at up to 2 hours 1 randomised trials very serious not serious not serious serious 2 none 33/43 2 (76.7%) 30/43 (69.8%) RR 1.1 (0.85 to 1.42) 70 more per 1000 (from 105 fewer to 293 more) VERY LOW Pain free at up to 2 hour 1 randomised trials very serious not serious not serious serious 2 none 17/43 2 (39.5%) 11/43 (25.6%) RR 1.54 (0.82 to 2.9) 138 more per 1000 (from 46 fewer to 486 more) VERY LOW Sustained headache response at 24 hours 1 randomised trials very serious not serious not serious serious 2 none 23/43 1 (53.5%) 18/43 (41.9%) RR 1.19 (0.76 to 1.85) 80 more per 1000 (from 100 fewer to 356 more) VERY LOW Sustained freedom from pain at 24 hours 1 randomised trials very serious not serious not serious serious 2 none 10/43 2 (23.3%) 7/43 (16.3%) RR 1.43 (0.6 to 3.4) 70 more per 1000 (from 65 fewer to 391 more) VERY LOW MD mean difference, RR relative risk 1. unclear allocation concealment and blinding; not all outcome data available 2. confidence interval crosses minimally important difference

71 Bibliography: Freitag F, Diamond M, Diamond S, Janssen I, Rodgers A, Skobieranda F. Efficacy and tolerability of coadministration of rizatriptan and acetaminophen vs rizatriptan or acetaminophen alone for acute migraine treatment. Headache 2008; 48: 921-30.

72 05: Should triptans, in combination with NSAIDs, versus NSAIDs alone be used for acute migraine? Population Intervention Comparison Those with acute migraine headaches triptans in combination with NSAIDs NSAIDs only Outcomes of Interest Time to freedom from pain Headache response at up to 2 hours Freedom from pain at up to 2 hours Sustained headache response at 24 hours Sustained freedom from pain at 24 hours Headache specific quality of life Functional health status and health related quality of life Incidence of serious adverse events Clinical background: In acute migraine, both medication classes of triptans and NSAIDs are known to reduce pain intensity and disability and also are associated with a reduction in the risk for chronic migraine onset. 65,66 Often triptans and NSAIDs are used concurrently and appear to have synergistic benefits in acute migraine. 67 Both reduce neurogenic inflammation with triptans offering, as well, some protective benefit for specifically allodynia. 68,69 Monotherapy is not uniformly effective and failures can lead to an increased risk of episodic migraines becoming chronic when disabling pain is not disrupted. 70,71 Likewise, combination regimes in acute migraine can also increase the risk of the development of chronic migraine. 65 Due to several neural pathways become sequentially activated and sensitized during an acute migraine, 72 it may be challenging to optimize the best combination of therapeutic medication approaches. 73 Evidence summary for triptans, in combination with NSAIDs, for use in acute migraine:

73 Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date Of potential sources, the available evidence was derived from the NICE 2012 systematic review. The available evidence, in specifically acute migraine headache populations, relates to 3 randomized controlled trials across 1976 patients that specifically compared the combination of triptans and NSAIDs versus NSAIDs alone. 74-76 All trials represented adults who were primarily (79-90%) female participants. Dosing across trials was sumatriptan (50-85 mg) plus naproxen sodium (500 mg). For the outcome of achieving freedom from pain free at 2 hours, there was an absolute benefit of 165 per 1000 (number needed to treat = 6) more with 112 per 1000 (number needed to harm = 9) more adverse events when using triptans, in combination with NSAIDs versus NSAIDs alone. Additionally, there was also one pilot study of 28 patients suggesting a subset of patients may be responsive to high doses of naproxen acutely with subsequent prophylactic benefit. 77 One systematic review also summarized the best routes of sumatriptan administration 56 and two studies identified that medication timing (early or late) in acute onset had similar efficacy results and improved patient satisfaction over monotherapy. 78,79 Four triptan cost-effectiveness studies were identified although the comparisons were indirect. 57-60 Generally, the certainty of the evidence was low. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender.

74 Criteria Judgements Research evidence Additional considerations The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the options What is the overall certainty of this evidence? Is there important uncertainty about how much people value the main outcomes? included studies Very low Low Moderate High Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important The relative importance or values of the main outcomes of interest: Outcome Relative importance Certainty ofthe evidence (GRADE) Pain free at 2 hours Headache relief at up to 2 hours Sustained pain free at24 hour Sustained headache relief at 24 hours Rescue MedicationUse Relief of functional disability at 2 hours IMPORTANT LOW LOW LOW LOW LOW LOW

75 Criteria Judgements Research evidence Additional considerations uncertainty of variability known undesirable Adverse events IMPORTANT Summary of findings: Triptans in combination with NSAIDs LOW Are the desirable anticipated effects large? Yes Outcome Pain free t 2 hours Headache relief at up to 2 hours With only NSAIDs 160 per 100 440 per 1000 With triptans, in combination with NSAIDs 325 per 1000 (274 to 384) 621 per 1000 (572 to 678) Difference (95% CI) 165 more per 1000 (from 114 more to 224 more) 180 more per 1000 (from 132 more to 238 more) Relative effect (RR)(95%CI) RR 2.03 (1.71 to 2.4) RR 1.41 (1.3 to 1.54) Are the undesirable anticipated effects small? Are the desirable effects large relative to undesirable effects? Probably yes Yes Sustained pain free at 24 hours Sustained headache relief at 24 hours Rescue Medication Use 107 per 1000 280 per 1000 420 per 1000 242 per 1000 (196 to 299) 459 per 1000 (406 to 518) 256 per 1000 (227 to 294) 134 more per 1000 (from 88 more to 191 more) 179 more per 1000 (from 126 more to 238 more) 164 fewer per 1000 (from 126 fewer to 193 fewer) RR 2.25 (1.82 to 2.78) RR 1.64 (1.45 to 1.85) RR 0.61 (0.54 to 0.7)

76 Criteria Judgements Research evidence Additional considerations Yes Relief of functional disability at 2 hours 196 per 1000 281 per 1000 (265 to 387) 84 more per 1000 (from 69 more to 191 more) RR 1.43 (1.35 to 1.97) Adverse events 146 per 1000 258 per 1000 (214 to 310) 112 more per 1000 (from 68 more to 165 more) RR 1.77 (1.47 to 2.13) No severe adverse effects were reported. No evidence identified specific to KSA. Resource use Are the resources required small? Probably no Yes Triptans: average monthly cost estimated at 200-400 SR by panel members. NSAIDs: average monthly cost estimated at 50-100 SR by panel members. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist -Hospital: ER/urgent care visit, inpatient hospital stay per day Is the incremental cost small relative to the net benefits? Probably yes Yes No evidence identified specific to KSA.

77 Criteria Judgements Research evidence Additional considerations Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced Varies No evidence identified specific to KSA Panel members thought that the impact on health equities is dependent on the availability of resources. Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement? Yes

78 Recommendation Should triptans, in combination with NSAIDs, vs. NSAIDs alone be used for acute migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel suggests a combination of triptans with NSAID rather than NSAID alone in patients with acute migraine. There is a clinically important benefit and no serious adverse effects were observed. Patients with hemiplegic migraine should not receive triptans. None None None

79 Evidence Profile: Should triptans, in combination with NSAIDs, versus NSAIDs alone be used for acute migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations triptans, in combination with NSAIDs, NSAIDs alone Relative (95% CI) Absolute (95% CI) Quality Importance Pain free at 2 hours 3 randomised trials very not serious not serious not serious none 317/976 serious 1 (32.5%) 155/968 (16.0%) RR 2.03 (1.71 to 2.4) 165 more per 1000 (from 114 more to 224 more) LOW Headache relief at up to 2 hours 3 randomised trials very not serious not serious not serious none 607/976 serious 1 (62.2%) 426/968 (44.0%) RR 1.41 (1.3 to 1.54) 180 more per 1000 (from 132 more to 238 more) LOW Sustained pain free at 24 hours 3 randomised trials very not serious not serious not serious none 236/976 serious 1 (24.2%) 104/968 (10.7%) RR 2.25 (1.82 to 2.78) 134 more per 1000 (from 88 more to 191 more) LOW Sustained headache relief at 24 hours 3 randomised trials very not serious not serious not serious none 447/976 serious 1 (45.8%) 271/968 (28.0%) RR 1.64 (1.45 to 1.85) 179 more per 1000 (from 126 more to 238 more) LOW Rescue Medication Use 3 randomised trials very not serious not serious not serious none 252/976 serious 1 (25.8%) 407/968 (42.0%) RR 0.61 (0.54 to 0.7) 164 fewer per 1000 (from 126 fewer to 193 fewer) LOW Relief of functional disability at 2 hours

80 2 randomised trials very not serious not serious not serious none 220/685 serious 1 (32.1%) 131/667 (19.6%) RR 1.43 (1.35 to 1.97) 84 more per 1000 (from 69 more to 191 more) LOW IMPORTANT Adverse events 3 randomised trials very not serious not serious not serious none 225/988 serious 1 (22.8%) 143/982 (14.6%) RR 1.77 (1.47 to 2.13) 112 more per 1000 (from 68 more to 165 more) LOW IMPORTANT MD mean difference, RR relative risk 1. unclear randomization, allocation concealment and investigator blinding Bibliography: 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: 1443-54. Landy S, DeRossett SE, Rapoport A, Rothrock J, AmesMH, McDonald SA, et al. Two double-blind, multicentre, randomized, placebo-controlled, single-dose studies of sumatriptan/naproxen sodium in the acute treatment of migraine: function, productivity and satisfaction outcomes. Medscape General Medicine 2007; 9: 53. Smith TR, Sunshine A, Stark SR, Littlefield DE, Spruill SE, Alexander WJ. Sumatriptan and naproxen sodium for the acute treatment of migraine. Headache 2005; 45: 983-91.

81 06: Should triptans, in combination with NSAIDs, versus triptans alone be used for acute migraine? Population Intervention Comparison Those with acute migraine headaches triptans in combination with NSAIDs triptans only Outcomes of Interest Time to freedom from pain Headache response at up to 2 hours Freedom from pain at up to 2 hours Sustained headache response at 24 hours Sustained freedom from pain at 24 hours Headache specific quality of life Functional health status and health related quality of life Incidence of serious adverse events Clinical background: As described previously in Q5, In acute migraine, both medication classes of triptans and NSAIDs are known to reduce pain intensity and disability and also are associated with a reduction in the risk of chronic migraine onset. 65,66 Often triptans and NSAIDs are used concurrently and appear to have synergistic benefits in acute migraine. 67 Both reduce neurogenic inflammation with triptans offering additionally some protective benefit for specifically allodynia. 68,69 Monotherapy is not uniformly effective and failures can lead to an increased risk of episodic migraines becoming chronic when disabling pain is not disrupted. 70,71 Likewise, combination regimes in acute migraine can also increase the risk of the development of chronic migraine. 65 Due to several neural pathways become sequentially activated and sensitized during an acute migraine, 72 it is challenging to optimize the best combination of therapeutic medication approaches. 73 Evidence summary for triptans, in combination with NSAIDs, for use in acute migraine: Potential Sources: NICE 2012 systematic review

82 McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date Of potential sources, the available evidence was derived from the NICE 2012 systematic review. The available evidence, in specifically acute migraine headache populations, relates to 4 randomized controlled trials across 1952 patients that specifically compared the combination of triptans and NSAIDs versus triptans alone. 74-76,80 All studies consisted of adult populations of primarily female (over 80%) participants. Dosing in 3 trials consisted of sumatriptan (50-85 mg) plus naproxen sodium (500 mg). The forth trial (n=90) had a slightly younger age (mean 38) of participants and used almotriptan (12.5 mg) plus acelofenac (100 mg) as the intervention. For the outcome of achieving freedom of pain free at 2 hours, there was an absolute benefit of 99 per 1000 (number needed to treat = 10) more with no more adverse events when using triptans, in combination with NSAIDs versus triptans alone. One systematic review also summarized best routes of sumatriptan administration 56 and two studies identified that medication timing (early or late) in acute onset had similar efficacy results and improved patient satisfaction over monotherapy. 78,79 Four triptan cost-effectiveness studies were identified although the comparisons were indirect. 57-60 Generally, the certainty of the benefits and harms evidence was low to very low. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly

83 Criteria Judgements Research evidence Additional considerations reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the options What is the overall certainty of this evidence? Is there important uncertainty about how much people value the main outcomes? included studies Very low Low Moderate High Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable The relative importance or values of the main outcomes of interest: Outcome Pain free at 2 hours Headache relief at 2 hours Sustained pain free at 24 hours Sustained headache relief at 24 hours Rescue medication use Relative importance Certainty of the evidence (GRADE) IMPORTANT VERY LOW VERY LOW LOW LOW LOW Relief of functional disability at 2 hours IMPORTANT LOW Adverse events IMPORTANT Summary of findings: Triptans in combination with NSAIDs VERY LOW Are the desirable anticipated effects Outcome With trip- With triptans, in Difference (95% CI) Relative effect

84 Criteria Judgements Research evidence Additional considerations large? Are the undesirable anticipated effects small? Probably yes Yes Probably yes Yes Pain free at 2hours Headache relief at 2 hours Sustained pain free at 24 hours tans only 235 per100 507 per 1000 142 per 1000 combination with NSAIDs 333 per 1000 (289 to 383) 599 per 1000 (553 to 649) 242 per 1000 (201 to 293) 99 more per 1000 (from 54 more to 148 more) 91 more per 1000 (from 46 more to 142 more) 100 more per 1000 (from 58 more to 151 more) (RR) (95% CI) RR 1.42 (1.23 to 1.63) RR 1.18 (1.09 to 1.28) RR 1.7 (1.41 to 2.06) Sustained headache relief at 24 hours 331 per 1000 460 per 1000 (410 to 513) 129 more per 1000 (from 79 more to 182 more) RR 1.39 (1.24 to 1.55) Are the desirable effects large relative to undesirable effects? Probably yes Yes Rescue medication use Relief of functional disability at 2 hours 387 per 1000 227 per 1000 255 per 1000 (224 to 294) 320 per 1000 (268 to 384) 131 fewer per 1000 (from 93 fewer to 162 fewer) 93 more per 1000 (from 41 more to 157 more) RR 0.66 (0.58 to 0.76) RR 1.41 (1.18 to 1.69) Adverse events 258 per 1000 258 per 1000 (222 to 300) 0 fewer per 1000 (from 36 fewer to 41 more) RR 1 (0.86 to 1.16)

85 Criteria Judgements Research evidence Additional considerations No evidence identified specific to KSA. Resource use Are the resources required small? Yes NSAIDs: average monthly cost estimated at 50-100 SR by panel members. Triptans: average monthly cost estimated at 200-400 SR by panel members. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist -Hospital: ER/urgent care visit, inpatient hospital stay per day Is the incremental cost small relative to the net benefits? Probably yes Yes No evidence identified specific to KSA. Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced not applicable No evidence identified specific to KSA. Panel members thought that equity would not be influenced.

86 Criteria Judgements Research evidence Additional considerations Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA. Feasibility Is the option feasible to implement? Yes

87 Recommendation Should triptans, in combination with NSAIDs, vs. triptans alone be used for acute migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel suggests a combination of a triptan with an NSAID rather than a triptan alone in patients with acute migraine. There was clinical benefit with small additional cost. None None None None

88 Evidence Profile: Should triptans, in combination with NSAIDs, versus triptans alone be used for acute migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations triptan in combination with NSAIDs, triptan alone Relative (95% CI) Absolute (95% CI) Quality Importance Pain free at 2 hours 4 randomised trials very not serious not serious serious 2 none 354/1066 serious 1 (33.2%) 244/1039 (23.5%) RR 1.42 (1.23 to 1.63) 99 more per 1000 (from 54 more to 148 more) VERY LOW Headache relief at 2 hours 4 randomised trials very not serious not serious serious 2 none 639/1066 serious 1 (59.9%) 527/1039 (50.7%) RR 1.18 (1.09 to 1.28) 91 more per 1000 (from 46 more to 142 more) VERY LOW Sustained pain free at 24 hours 3 randomised trials very not serious not serious not serious none 236/976 serious 1 (24.2%) 135/949 (14.2%) RR 1.7 (1.41 to 2.06) 100 more per 1000 (from 58 more to 151 more) LOW Sustained headache relief at 24 hours 3 randomised trials very not serious not serious not serious none 447/976 serious 1 (45.8%) 314/949 (33.1%) RR 1.39 (1.24 to 1.55) 129 more per 1000 (from 79 more to 182 more) LOW Rescue medication use 3 randomised trials very not serious not serious not serious none 255/976 serious 1 (26.1%) 367/949 (38.7%) RR 0.66 (0.58 to 0.76) 131 fewer per 1000 (from 93 fewer to 162 few- LOW IMPORTANT

89 er) Relief of functional disability at 2 hours 2 randomised trials very not serious not serious not serious none 220/685 serious 1 (32.1%) 152/669 (22.7%) RR 1.41 (1.18 to 1.69) 93 more per 1000 (from 41 more to 157 more) LOW IMPORTANT Adverse events 4 randomised trials very not serious not serious serious 1 none 255/988 serious 1 (25.8%) 249/964 (25.8%) RR 1 (0.86 to 1.16) 0 fewer per 1000 (from 36 fewer to 41 more) VERY LOW IMPORTANT MD mean difference, RR relative risk 1. randomization, allocation concealment and investigator blinding unclear 2. confidence interval crosses a minimally important difference making effect uncertain Bibliography: 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: 1443-54. Landy S, DeRossett SE, Rapoport A, Rothrock J, AmesMH, McDonald SA, et al. Two double-blind, multicentre, randomized, placebo-controlled, single-dose studies of sumatriptan/naproxen sodium in the acute treatment of migraine: function, productivity and satisfaction outcomes. Medscape General Medicine 2007; 9: 53. Smith TR, Sunshine A, Stark SR, Littlefield DE, Spruill SE, Alexander WJ. Sumatriptan and naproxen sodium for the acute treatment of migraine. Headache 2005; 45: 983-91. Schoenen J, De KN, Giurgea S, Herroelen L, Jacquy J, Louis P et al. Almotriptan and its combination with aceclofenac for migraine attacks: a study of efficacy and the influence of auto-evaluated brush allodynia. Cephalalgia 2008; 28: 1095-1105.

90 07: Should beta-blockers versus no beta-blockers be used for prevention of recurrence of migraine? Population Intervention Comparison Those with episodic or chronic migraine headaches beta-blockers not using beta-blockers Outcomes of Interest Change in patient-reported headache days, frequency and intensity Functional health status and health-related quality of life Responder rate Headache specific quality of life Use of acute pharmacological treatment Incidence of serious adverse events Clinical background: Beta-blockers work to inhibit arterial dilation and have long been recognized as one of the preferred medication choices in migraine prophylaxis. 81,82 A 2003 systematic review by the Cochrane collaboration, summarized both randomized and quasi-randomized trials, that tested specifically propranolol for migraine prophylaxis in studies dated prior to the NICE 2012 systematic review literature search range. Many of these older trials were of very small sample size, of short duration of follow up and of poor methodological quality; however, they did conclude propranolol was more effective than placebo and at least as safe and effective as any other prophylactic medication in the short-term. 83 Evidence summary beta-blocker use in prevention of recurrence of migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014

91 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date Of potential sources, the available evidence was derived from the NICE 2012 systematic review. The available recent evidence is reflective of only patients with episodic migraine (15 or less per month) across 4 randomized controlled trials. 84-87 Trials were carried out on adults with primarily female (76-80%) participants. Dosing was similar in two trials with propranolol capsules 160 mg/day 84,86 and one trial used nadolol capsules 40-80 mg/day. 85 The final trial used bisoprolol capsules with either 5 mg/day or 10mg/day. 87 Outcomes for 5 mg/day are presented as they reported the best-case effect. There was an absolute benefit of responders showing a greater than 50% reduction in migraines in 146 per 1000 (number needed to treat = 7) more with 10 per 1000 (number needed to harm = 100) more ceasing medications due to adverse events (e.g. fatigue) with beta-blockers. The certainty of the evidence was quite variable, between low and high. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Frequency may differ.

92 Criteria Judgements Research evidence Additional considerations Benefits & harms of the options What is the overall certainty of this evidence? Is there important uncertainty about how much people value the main outcomes? Are the desirable anticipated effects large? included studies Very low Low Moderate High Important uncertainty or variability Possibly important uncertainty or variability Probably no important uncertainty of variability important uncertainty of variability known undesirable Uncertain The relative importance or values of the main outcomes of interest: Outcome Episodic: change in patientreported migraine days Episodic: responder rate Episodic: responder rate [>50% reduction] Episodic: change in reported migraine frequency Episodic: headache specific quality of life [MSQL score] Episodic: Adverse Events - ceasing medications due to side effects (e.g. fatigue) Summary of findings: Beta-blockers Outcome Without betablockers Relative importance IMPORTANT With beta-blockers Certainty of the evidence (GRADE) MODERATE LOW MODERATE LOW HIGH LOW Difference (95% CI) Episodic: change in The mean episodic: The mean episodic: MD 0.6 lower - Relative effect (RR) (95% CI) Some panel members thought that there is no important uncertainty of variability in values and preferences. Magnitude of benefits: some members were uncertain and some thought it is probably a large benefit.

93 Criteria Judgements Research evidence Additional considerations Yes patient-reported migraine days change in patientreported migraine days in the control group was -3.9 +/- 0.4 change in patient-reported migraine days in the intervention group was 0.6 lower (1.22 lower to 0.02 lower) (1.22 lower to 0.02 lower) Are the undesirable anticipated effects small? Probably yes Yes Episodic: responder rate Episodic: responder rate [>50% reduction] Episodic: change in reported migraine frequency 550 per 1000 154 per 1000 The mean episodic: change in migraine frequency in the control group was -0.8 +/- 0.21 517 per 1000 (336 to 787) 300 per 1000 (191 to 475) The mean episodic: change in reported migraine frequency in the intervention group was 1.37 lower (1.69 lower to 1.04 lower) 33 fewer per 1000 (from 215 fewer to 237 more) 146 more per 1000 (from 37 more to 322 more) MD 1.37 lower (1.69 lower to 1.04 lower) RR 0.94 (0.61 to 1.43) RR 1.95 (1.24 to 3.09) - Are the desirable effects large relative Episodic: headache specific quality of life [MSQL score] The mean episodic: headache specific quality of life [MSQL score] in the control group was -8.8 +/- 0.7 The mean episodic: headache specific quality of life [MSQL score] in the intervention group was 0.3 higher (0.84 higher to 1.44 higher) MD 0.3 higher (0.84 higher to 1.44 higher) -

94 Criteria Judgements Research evidence Additional considerations to undesirable effects? Uncertain Yes Episodic: Adverse Events - ceasing medications due to side effects (e.g. fatigue) 54 per 1000 63 per 1000 (21 to 181) 10 more per 1000 (from 33 fewer to 128 more) OR 1.19 (0.37 to 3.9) Resource use Are the resources required small? Is the incremental cost small relative to the net benefits? Yes Probably yes Yes Average monthly cost estimated at 50-100 SR by panel members. No evidence identified specific to KSA. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced No evidence identified specific to KSA.

95 Criteria Judgements Research evidence Additional considerations Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA

96 Recommendation Should beta-blockers vs. no beta-blockers be used for prevention of recurrence of migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel suggests that beta-blockers are used for prevention of migraine attacks. The panel thought that the potential benefits outweigh the undesirable effects. None In order to increase compliance and, when a decision to use beta-blockers is made, it may be beneficial to remind patients that this intervention does not eliminate migraine attacks but reduces their severity and frequency. None More well designed and performed RCTs are needed to establish both benefits and safety.

97 Evidence Profile: Should beta-blockers versus no beta-blockers be used for prevention of recurrence of migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations betablockers no betablockers Relative (95% CI) Absolute (95% CI) Quality Importance Episodic: change in patient-reported migraine days per month (follow up: 16 months) 1 randomised trials not serious not serious not serious serious 2 none 53 55 - MD 0.6 days per month lower (1.22 lower to 0.02 low- MODERATE er) Episodic: responder rate (follow up: 10 months) 1 randomised trials not serious not serious not serious very serious 3 none 18/35 (51.4%) 22/40 (55.0%) RR 0.94 (0.61 to 1.43) 33 fewer per 1000 (from 215 fewer to 237 more) LOW Episodic: responder rate [>50% reduction] (follow up: 26 weeks) 1 randomised trials not serious not serious not serious serious 2 none 43/143 (30.1%) 22/143 (15.4%) RR 1.95 (1.24 to 3.09) 146 more per 1000 (from 37 more to 322 more) MODERATE Episodic: change in reported migraine frequency per month (follow up: 26 weeks) 3 randomised trials serious 1 serious 4 not serious not serious none 334 252 - MD 1.37 episodes fewer (1.69 lower to 1.04 lower) LOW Episodic: headache specific quality of life [MSQL score; 100-point scale] (follow up: 16 months) 1 randomised trials not serious not serious not serious not serious none 53 55 - MD 0.3 higher (0.84 higher to 1.44 higher) HIGH

98 Episodic: Adverse Events - ceasing medications due to side effects (eg fatigue) (follow up: 16 months) 1 randomised trials not serious not serious not serious very serious 5 none 7/110 (6.4%) 5/93 (5.4%) OR 1.19 (0.37 to 3.9) 10 more per 1000 (from 33 fewer to 128 more) LOW IMPORTANT MD mean difference, RR relative risk 1. method of allocation concealment unclear 2. confidence interval crosses minimally important difference so effect is uncertain 3. confidence interval crosses minimally importance difference in both directions making effect very uncertain 4. significant heterogeneity between studies 5. had patients who received a co-intervention (behavioural therapy) Bibliography: Diener HC, Tfelt-Hansen P, Dahlof C, Lainez MJA, 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: 943-50. Holroyd KA, Cottrell CK, O'Donnell FJ, Cordingley GE, Drew JB, Carlson BW et al. Effect of preventive (beta blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial. BMJ 2010; 341: c4871. Pradalier A, Serratrice G, Collard M, Hirsch E, Feve J, Masson C et al. Long-acting propranolol in migraine prophylaxis: Results of a double-blind, placebo-controlled study. Cephalalgia 1989; 9: 247-53. Van De Ven LLM, Franke CL, Koehler PJ. Prophylactic treatment of migraine with bisoprolol: A placebo-controlled study. Cephalalgia 1997; 17: 596-9.

99 08: Should topiramate versus no antiepileptics be used for prevention of recurrence of migraine? Population Intervention Comparison Those with episodic or chronic migraine headaches Topiramate not using anti-epileptics Outcomes of Interest Change in patient-reported headache days, frequency and intensity Functional health status and health-related quality of life Responder rate Headache specific quality of life Use of acute pharmacological treatment Incidence of serious adverse events Clinical background: The theory that cortical hyperexcitability plays a role in migraine has led to the use of anti-epileptics. 88 As well, general modulation of pain appears to play a factor in their benefitial effects. 89 Currently, there are many preventative choices that are available, with such off-label prescribing practices commonplace with clinicians. 90,91 Anti-epileptic use may play a role in migraine prophylaxis. Evidence summary anti-epileptic use in prevention of recurrence of migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date

100 Of potential sources, the available evidence was combined from the NICE 2012 systematic review and 1 new Cochrane review from McMaster literature searches. The available recent evidence is reflective of adult patients with episodic migraine (less than 15 per month), across 1 Cochrane systematic review 92. Anti-epileptic medications outcomes were prioritized to those offered on the KSA 2012 formulary. On discussion with the panel, it was identified that the NICE 2012 systematic review did not capture specific comparisons looking at valproate and pregabalin against placebo. A search was of Medline was performed on March 15, 2015 that identified one Cochrane review on pregabalin. 93 The duration of the treatment phase was a mean of 12 weeks across trials. The pregabalin Cochrane review did not identify any trials. The certainty of the benefit and harms evidence was low to moderate. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the options What is the overall certainty of this evidence? included studies Very low Low Moderate The relative importance or values of the main outcomes of interest: Outcome Relative importance Certainty of the evidence (GRADE) Adverse effects were thought to be small for doses 50-100 mg of topiramate.

101 Criteria Judgements Research evidence Additional considerations Is there important uncertainty about how much people value the main outcomes? Are the desirable anticipated effects large? High Important uncertainty or variability Possibly important uncertainty or variability important uncertainty or variability No important uncertainty or variability known undesirable Probably yes Yes Topiramate: Responder Rate [>50% reduction in headache frequency] Topiramate: Headache frequency reduction per month Any Adverse event (50mg or 100mg dosages) Summary of findings: Anti-epileptics Outcome Topiramate: Responder Rate [>50% reduction in headache frequency] Topiramate: Headache frequency reduction per month Any adverse event Without antiepileptics 232 per 1000 With antiepileptics 469 per 1000 (364 to 603) MODERATE MODERATE Difference (95% CI) 237 more per 1000 (from 132 more to 371 more) MD 1.2 lower (1.59 lower to 0.8 lower) 47 more per 100 (23 fewer to 128 more) Relative effect (R) (95% CI) RR 2.02 (1.57 to 2.6) - RR 1.08 One panel member was uncertain whether benefits outweigh undesirable effects. Are the undesirable anticipated effects small? Probably yes Yes

102 Criteria Judgements Research evidence Additional considerations Are the desirable effects large relative to undesirable effects? Probably yes Yes Resource use Are the resources required small? Probably no Yes Anti-epileptics: average monthly cost estimated at 200-500 SR by panel members. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist component 500 SAR per month for 50 mg topiramate Is the incremental cost small relative to the net benefits? Probably yes Yes No evidence identified specific to KSA Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced No evidence identified specific to KSA Panel members determined that impact on health equity would depend on an income, insurance etc.

103 Criteria Judgements Research evidence Additional considerations Varies Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA

104 Recommendation Should topiramate vs. no anti-epileptics be used for prevention of recurrence of migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel suggests topiramate 50 or 100 mg per day for the prevention of migraine attacks. There is a benefit with some uncertainty about adverse effects. None Availability of resources will have important impact on this recommendation. None None

105 Evidence Profile: Should topiramate versus no antiepileptics be used for prevention of recurrence of migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations antiepileptics no antiepileptics Relative (95% CI) Absolute (95% CI) Quality Importance Topiramate: Responder Rate [>50% reduction in headache frequency] 9 randomised trials serious 1 not serious not serious not serious none 310/660 (47.0%) 136/586 (23.2%) RR 2.02 (1.57 to 2.6) 237 more per 1000 (from 132 more to 371 more) MODERATE Topiramate: Headache frequency reduction per month 9 randomised trials serious 1 not serious not serious not serious none 893 900 - MD 1.2 lower (1.59 lower to 0.8 lower) MODERATE Topiramate: Adverse effects using 50mg or 100mg 3 Randomized trials serious 1 not serious not serious serious 2 none 324/490 (66.1%) 293/503 (58.2%) RR 1.08 (0.96 to 1.22) 47 more per 1000 (from 23 fewer to 128 more) LOW MD mean difference, RR relative risk 1. selective outcome reporting in some trials 2. confidence interval crosses null value Bibliography: Linde M, Mulleners WM, Chronicle EP, McCrory DC. Topiramate for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev 2013; 6: CD010610.

106 09: Should valproate versus no antiepileptics be used for prevention of recurrence of migraine? Population Intervention Comparison Those with episodic or chronic migraine headaches Valproate not using anti-epileptics Outcomes of Interest Change in patient-reported headache days, frequency and intensity Functional health status and health-related quality of life Responder rate Headache specific quality of life Use of acute pharmacological treatment Incidence of serious adverse events Clinical background for anti-epileptic use in prevention of recurrence of migraine: The theory that cortical hyperexcitability plays a role in migraine has led to the use of anti-epileptics. 88 As well, general modulation of pain appears to play a factor in their benefitial effects. 89 Currently, there are many preventative choices that are available, with such off-label prescribing practices commonplace with clinicians. 90,91 Evidence summary anti-epileptic use in prevention of recurrence of migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date

107 Of potential sources, the available evidence was combined from the NICE 2012 systematic review and 1 new Cochrane review from McMaster literature searches. On discussion with the panel, it was identified that the NICE 2012 systematic review did not capture specific comparisons looking at valproate and pregabalin against placebo. A search was of Medline was performed on March 15, 2015 that identified two Cochrane systematic reviews in episodic migraine populations; one on valproate 94 and a second on pregabalin. 93 The doses of valproate investigated in the 5 included trials ranged from 500 to 1000 mg/day. The duration of the treatment phase was a mean of 12 weeks across trials. The pregabalin review did not identify any trials. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the options What is the overall certainty of this evidence? included studies Very low Low See Evidence profile below

108 Criteria Judgements Research evidence Additional considerations Moderate High Is there important uncertainty about how much people value the main outcomes? Are the desirable anticipated effects large? Are the undesirable anticipated effects small? Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable Yes Yes

109 Criteria Judgements Research evidence Additional considerations Are the desirable effects large relative to undesirable effects? Yes Resource use Are the resources required small? Is the incremental cost small relative to the net benefits? Yes Yes Anti-epileptics: average monthly cost estimated at 200-500 SR by panel members. No evidence identified specific to KSA -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist component 500 SAR per month for 50 mg tpiramate Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced No evidence identified specific to KSA Acceptability Is the option acceptable No evidence identified specific to KSA

110 Criteria Judgements Research evidence Additional considerations to key stakeholders? Yes Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA

111 Recommendation Should valproate vs. no anti-epileptics be used for prevention of recurrence of migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel suggests valproate 500 to 1000 mg daily for the prevention of migraine attacks. There is uncertainty in the effects because of low confidence in estimated effects, but panel felt that benefits outweigh harms. None None None None

112 Evidence Profile: Should valproate versus no antiepileptics be used for prevention of recurrence of migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations antiepileptics no antiepileptics Relative (95% CI) Absolute (95% CI) Quality Importance Episodic migraine: Valproate divalproex sodium: Responder Rate [>50% reduction in headache frequency] (12 week follow-up) 4 randomised trials serious 1 not serious not serious not serious none 147/349 (42.7%) 48/225 (21.3%) RR 2.18 (1.28 to 3.72) 252 more per 1000 (from 60 more to 580 more) MODERATE Episodic migraine: Valproate sodium valproate: Responder Rate (>50% reduction in headache frequency] (12 week follow-up) 1 randomised trials serious 4 not serious not serious serious 3 none 17/34 6/34 RR 2.83 (1.27 to 6.31) 390 more per 1000 (from 38 more to 1000 more) LOW Episodic migraine: Valproate sodium valproate: Headache frequency post treatment (12 week follow-up) 1 randomised trials serious 1 not serious not serious serious 3 none 63 63 - MD 4.31 lower (8.32 lower to 0.30 lower) LOW Episodic migraine: Valproate any adverse event (eg fatigue, dizziness, nausea, tremor, weight gain) (12 week follow-up) 2 randomised trials serious 4 not serious not serious serious 5 none 201/297 (67.6%) 123/202 (60.8%) RR 1.06 0.90 to 1.27 37 more per 1000 (from 61 fewer to164 more) LOW MD mean difference, RR relative risk 1. selective outcome reporting in some trials 2. withdrawals were excluded from analysis 3. very small sample size 4. no information on randomization 5. confidence interval crosses null value

113 Bibliography: Linde M, Mulleners WM, Chronicle EP, McCrory DC. Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev 2013; 6: CD010611.

114 10: Should topiramate versus valproate be used for prevention of recurrence of migraine? Population Intervention Comparison Those with episodic or chronic migraine headaches Topiramate Valproate Outcomes of Interest Change in patient-reported headache days, frequency and intensity Functional health status and health-related quality of life Responder rate Headache specific quality of life Use of acute pharmacological treatment Incidence of serious adverse events Clinical background: Topiramate is an effective and well-tolerated preventive treatment for episodic migraine. It also is one of the preventive treatments for chronic migraine that has been studied in placebo-controlled, randomized trials with statistically significant benefitial effects. 98-100 Sodium valproate, as a monotherapy, is also a common preventative medication used for migraine prophylaxis. 101 Therefore, the clinical decision between using topiramate or sodium valproate may arrise, in certain clinical situations, with migraine prophylactic medication approaches. Evidence summary for topiramate use versus sodium valproate in prevention of recurrence of migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014

115 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date Of potential sources, the available evidence was combined from the NICE 2012 systematic review and 1 new study from McMaster literature searches. The available recent evidence is reflective of two small randomized controlled trials which used low doses of topiramate. 102,103 Shaygannejad et al. (2006) and Afshari et al. (2012) evaluated, at 24 months, subject groups (n=64; n=56) using topiramate (50 mg/day) versus sodium valproate (400 mg/day) in adults with 43-79% female participants. 102,103 Migraine frequency as an absolute benefit was reported at a reduction of 1 migraine in the best case with 94 per 1000 (number needed to harm = 11) more having adverse events (e.g. weight change, paresthesia, somnolence, hair loss) with topiramate versus sodium valproate. No cost-effectiveness or values & preferences literature was identified, specific to KSA. The certainty of the evidence was low to very low. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the options What is the overall certainty of this evidence? included studies Very low The relative importance or values of the main outcomes of interest: Outcome Relative im- Certainty of the evidence Two panel members thought that anticipated undesirable effects are

116 Criteria Judgements Research evidence Additional considerations Low Moderate High Episodic: patient-reported migraine frequency for last 4 weeks portance (GRADE) LOW probably small and 3 were uncertain. Episodic: patient-reported migraine intensity for last 4 weeks LOW Patient-reported migraine frequency per month LOW Is there important uncertainty about how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable Patient-reported migraine intensity VA Adverse Events: (Weight change, paresthesia, somnolence, hairloss) Summary of findings: Topiramate Outcome Episodic: patientreported migraine frequency for4 last week With anti-convulsants (sodium valproate) The mean episodic: patient-reported migraine frequency for last 4 weeks in the control group was 3.6 +/- 1.8 With anti-epileptics (topiramate) The mean episodic: patient-reported migraine frequency for last 4 weeks in the intervention group was 0.6 lower (1.57 lower to 0.37 higher) VERY LOW LOW Difference (95% CI MD 0.6 lower (1.57 lower to 0.37 higher) Relative effect (R) (95% CI) -

117 Criteria Judgements Research evidence Additional considerations Are the desirable anticipated effects large? No Yes Episodic: patientreported migraine intensity for last weeks The mean episodic: patient-reported migraine intensity for last 4 weeks in the control group was 6.3 +/- 1.9 The mean episodic: patient-reported migraine intensity for last 4 weeks in the intervention group was 1.1 lower (0.2 lower to 2 lower) MD 1.1 lower (0.2 lower to 2 lower) - Are the undesirable anticipated effects small? Are the desirable effects large relative to undesirable effects? Uncertain Yes Uncertain Yes Patient-reported migraine frequency per month Patient-reported migraine intensity VAS Adverse Events: (Weight change, paresthesia, somnolence, hair loss) The mean patientreported migraine frequency per month in the control group was 3.6 +/- 2.1 The mean patientreported migraine intensity VAS in the control group was 4.0 +/- 2.1 438 per 1000 The mean patient-reported migraine frequency per month in the intervention group was 1.2 standard deviations higher (1.1 higher to 1.3 higher) The mean patient-reported migraine intensity VAS in the intervention group was 0.1 standard deviations lower (0 higher to 0.3 lower) 532 per 1000 (296 to 752) SMD 1.2 higher (1.1 higher to 1.3 higher) SMD 0.1 lower (0 higher to 0.3 lower) 94 more per 1000 (from 142 fewer to 315 more) - - OR 1.46 (0.54 to 3.9) Resource use Are the resources required small? Probably no Anti-epileptics: average monthly cost estimated at 200-500 SR by panel members. Anti-convulsants: average monthly cost estimated at 200-500 SR by panel members. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain

118 Criteria Judgements Research evidence Additional considerations Yes specialist, Psychologist, Psychiatrist Is the incremental cost small relative to the net benefits? Uncertain Yes No evidence identified specific to KSA Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced Varies No evidence identified specific to KSA Panel members thought that availability of resources will have impact on health equities in this context topiramate being more expensive. Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement?

119 Criteria Judgements Research evidence Additional considerations Yes

120 Recommendation Should topiramate vs. valproate be used for prevention of recurrence of migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel suggests that clinicians use either topiramate or valproate for the prevention of migraine attacks. Panel found not enough evidence to favor one over the other. There is low confidence in the estimated effects. Efficacy seems to be comparable, but there is higher cost associated with topiramate and more adverse effects associated with valproate. None When choosing between these two options one should weight the higher cost associated with topiramate vs. more adverse effects associated with valproate. None The panel suggests head to head comparison studies.

121 Evidence Profile: Should topiramate versus valproate be used for prevention of recurrence of migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations anti-epileptics (topiramate) anti-convulsants (sodium valproate) Relative (95% CI) Absolute (95% CI) Quality Importance Episodic: patient-reported migraine frequency for last weeks (follow up: 12 weeks) 1 randomised trials serious 2 not serious not serious serious 3 none 28 28 - MD 0.6 lower (1.57 lower to 0.37 higher) LOW Episodic: patient-reported migraine intensity for last weeks (follow up: 12 weeks) 1 randomised trials serious 2 not serious not serious serious 3 none 28 28 - MD 1.1 lower (0.2 lower to 2 lower) LOW Patient-reported migraine frequency per month (follow up: 8 weeks) 1 randomised trials serious 4 not serious not serious serious 6 none 32 32 - MD 1.2 higher (1.1 higher to 1.3 higher) LOW Patient-reported migraine intensity VAS (follow up: 8 weeks) 1 randomised trials serious 4 not serious 1 not serious very serious 5 6 none 32 32 - MD 0.1 lower (0 higher to 0.3 lower) VERY LOW Adverse Events: (Weight change, paresthesia, somnolence, hair loss) (follow up: 8 weeks) 1 randomised trials serious 4 not serious not serious serious 5 none 17/32 (53.1%) 14/32 (43.8%) OR 1.46 (0.54 to 3.9) 94 more per 1000 (from 142 fewer to 315 more) LOW 1. No explanation was provided 2. unclear method for allocation concealment 3. over 22% loss to follow up; confidence interval crosses a minimally important difference so effect estimate uncertain 4. unclear randomization or allocation concealment 5. confidence interval crosses null value making outcome uncertain 6. very small sample size

122 Bibliography: Shaygannejad V, Janghorbani M, Ghorbani A, Ashtary F, Za-kizade N, Nasr V. Comparison of the effect of topiramate and sodium valproate in migraine prevention: a randomized blinded crossover study. Headache 2006; 46: 642 8 Afshari D, Rafizadeh S, Rezaei M. A comparative study of the effects of low-dose topiramate versus sodium valproate in migraine prophylaxis. Int J Neurosci 2012; 122: 60-8.

123 11: Should antiepileptics other than topiramate or valproate versus no antiepileptics be used for prevention of recurrence of migraine? Population Intervention Comparison Those with episodic or chronic migraine headaches Antiepileptics other than topiramate or valproate not using antiepileptics Outcomes of Interest Change in patient-reported headache days, frequency and intensity Functional health status and health-related quality of life Responder rate Headache specific quality of life Use of acute pharmacological treatment Incidence of serious adverse events Clinical background for antiepileptic use in prevention of recurrence of migraine: The theory that cortical hyperexcitability plays a role in migraine has led to the use of anti-epileptics. 88 As well, general modulation of pain appears to play a factor in their benefitial effects. 89 Currently, there are many preventative choices that are available, with such off-label prescribing practices commonplace with clinicians. 90,91 Evidence summary anti-epileptic use in prevention of recurrence of migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date Of potential sources, the available evidence was combined from the NICE 2012 systematic review and new studies from McMaster literature searches. The available recent evidence is reflective of adult patients with episodic migraine (less than 15 per month), across 2 Cochrane systematic reviews 93,95 and 2 randomized controlled trials. 96,97 Systematic reviews identified outcomes related to various medications such as: carbamapezine and lamotrigine in various doses. For individual trials, gabapentin was dosed at

124 1200 mg/day 96 and levetiracetam was dosed at 1000 mg/day. 97 There was an absolute benefit of carbamapezine responders showing a greater than 50% reduction in migraine frequency in 474 per 1000 (number needed to treat = 2) more with 435 per 1000 (number needed to harm = 2) more adverse events with anti-epileptic use. Anti-epileptic medications outcomes were prioritized to those offered on the KSA 2012 formulary. The certainty of the evidence was low to moderate. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide crosssectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the options What is the overall certainty of this evidence? Is there important uncertainty about how much people value the main outcomes? included studies Very low Low Moderate High Important uncertainty or variability Possibly important uncertainty or variability The relative importance or values of the main outcomes of interest: Outcome Gabapentin: Change in patient-reported migraine frequency Carbamapezine: Responder Rate [>50% reduction in migraine frequency] Relative importance Certainty of the evidence (GRADE) LOW LOW

125 Criteria Judgements Research evidence Additional considerations Are the desirable anticipated effects large? Are the undesirable anticipated effects small? Are the desirable effects large relative to undesirable effects? important uncertainty of variability No important uncertainty of variability known undesirable Yes Yes Yes Lamotrigine: Responder Rate [>50% reduction in migraine frequency] Levetiracetam: Responder Rate [>%50 reduction inmigraine frequency] Carbamapezine: Adverse Events Levetiracetam: Change in migraine frequency Summary of findings: Antiepileptics Outcome Gabapentin: Change in patient-reported migraine frequency Carbamapezine: Responder Rate [>50% reduction in Without anti-epileptics With anti-epileptics The mean gabapentin: Change in patientreported migraine frequency in the control group was -4.7 migraines 104 per 1000 The mean gabapentin: Change in patientreported migraine frequency in the intervention group was 1.89 lower (2.37 lower to 1.41 lower) 578 per 1000 (313 to 804) LOW LOW LOW MODERATE Difference (95% CI) MD 1.89 lower (2.37 lower to 1.41 lower) 474 more per 1000 (from 209 more to Relative effect (R) (95% CI) - OR 11.77 (3.92 to 35.32)

126 Criteria Judgements Research evidence Additional considerations migraine frequency] 700 more) Lamotrigine: Responder Rate [>50% reduction in migraine frequency] 339 per 1000 456 per 1000 (281 to 642) 116 more per 1000 (from 59 fewer to 303 more) OR 1.63 (0.76 to 3.49) Levetiracetam: Responder Rate [>%50 reduction in migraine frequency] 91 per 1000 1000 per 1000 (74 to 1000) 17 fewer per 1000 (from 17 fewer to all) RR 12.75 (0.81 to 199.88) Carbamapezine: Adverse Events 229 per 1000 665 per 1000 (380 to 1166) 435 more per 1000 (from 151 more to 937 more) RR 2.9 (1.66 to 5.09) Levetiracetam: Change in migraine frequency The mean levetiracetam: Change in migraine frequency in the control group was -0.71 migraines The mean levetiracetam: Change in migraine frequency in the intervention group was 2.96 lower (1.63 fewer to 4.29 fewer) MD 2.96 lower (1.63 fewer to 4.29 fewer) - Resource use Are the resources required small? Yes Anti-epileptics: average monthly cost estimated at 200-500 SR by panel members. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist component

127 Criteria Judgements Research evidence Additional considerations 500 SAR per month for 50 mg tpiramate Is the incremental cost small relative to the net benefits? Yes No evidence identified specific to KSA Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced No evidence identified specific to KSA Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA

128 Recommendation Should antiepileptics other than topiramate or valproate vs. no antiepileptics be used for prevention of recurrence of migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation The panel suggests that clinicians do not use antiepileptics other than topiramate or valproate for the prevention of migraine attacks until more research about their efficacy and safety is available. Antiepileptics other than topiramate or valproate are sometimes used off label for the prevention of migraine attacks despite there are no experimental studies that investigated their effects. Given the availability of other options for the prevention of migraine attacks the panel considered it prudent not to use other antiepileptics until evidence for their effectiveness in this setting is available. None None None Research possibilities RCTs of anti-emetics for prevention of migraine attacks that properly measure and report patient-important outcomes. Evidence Profile: Should antiepileptics other than topiramate or valproate versus no antiepileptics be used for prevention of recurrence of migraine?

129 Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations antiepileptics no antiepileptics Relative (95% CI) Absolute (95% CI) Quality Importance Gabapentin: Change in patient-reported migraine frequency 1 randomised trials serious 4 not serious not serious serious 3 none 35 28 - MD 1.89 lower (2.37 lower to 1.41 lower) LOW Gabapentin: Change in patient-reported migraine intensity 1 randomised trials serious 4 not serious not serious serious 3 none 35 28 - MD 0.62 lower (0.91 lower to 0.33 lower) LOW Carbamapezine: Responder Rate [>50% reduction in migraine frequency] 1 randomised trials serious 2 not serious not serious serious 3 none 26/45 (57.8%) 5/48 (10.4%) OR 11.77 (3.92 to 35.32) 474 more per 1000 (from 209 more to 700 more) LOW Carbamapezine: Adverse Events 1 randomised trials serious 2 not serious not serious serious 3 none 30/45 (66.7%) 11/48 (22.9%) RR 2.9 (1.66 to 5.09) 435 more per 1000 (from 151 more to 937 more) LOW Lamotrigine: Responder Rate [>50% reduction in migraine frequency] 1 randomised trials serious 4 not serious not serious serious 3 none 26/57 (45.6%) 19/56 (33.9%) OR 1.63 (0.76 to 3.49) 116 more per 1000 (from 59 fewer to 303 more) LOW Levetiracetam: Responder Rate [>%50 reduction in migraine frequency] 1 randomised trials serious 4 not serious not serious serious 3 none 8/15 (53.3%) 0/11 (0.0%) RR 12.75 (0.81 to 199.88) 0 fewer per 1000 (from 0 fewer to 0 fewer) LOW Levetiracetam: Change in migraine frequency (follow up: 4 months)

130 1 randomised trials serious 4 not serious not serious not serious none 32 33 - MD 2.25 lower (3.65 lower to 0.85 lower) MODERATE Levetiracetam: Change in symptomatic medications taken (follow up: 4 months) 1 randomised trials serious 4 not serious not serious not serious none 32 33 - MD 3.98 lower (0 higher to 0 higher) MODERATE MD mean difference, RR relative risk 1. selective outcome reporting in some trials 2. withdrawals were excluded from analysis 3. very small sample size 4. no information on randomization 5. confidence interval crosses null value Bibliography: Linde M, Mulleners WM, Chronicle EP, McCrory DC. Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev 2013; 6: CD010609. Linde M, Mulleners WM, Chronicle EP, McCrory DC. Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev 2013; 6: CD010608. Di Trapani G, Mei D, Marra C, Mazza S, Capuano A. Gabapentin in the prophylaxis of migraine: a double-blind randomized placebo-controlled study. Clinica Terapeutica 2000; 151: 145-8. Verma A, Srivastava D, Kumar A, Singh V. Levetiracetam in migraine prophylaxis: a randomized placebo-controlled study in a rural medical institute in northern India. Clin Neuropharmacol 2013; 36: 193-7.

131 12: Should topiramate versus beta-blockers be used for prevention of recurrence of migraine? Population Intervention Comparison Those with episodic or chronic migraine headaches Topiramate beta-blockers Outcomes of Interest Change in patient-reported headache days, frequency and intensity Functional health status and health-related quality of life Clinical background: Responder rate Headache specific quality of life Use of acute pharmacological treatment Incidence of serious adverse events Topiramate is an effective and well-tolerated preventive treatment for episodic migraine. It also is one of the preventive treatments for chronic migraine that has been studied in placebo-controlled, randomized trials with statistically significant effects. 98-100 Beta-blockers, as a monotherapy, are a standard preventative medication used for episodic migraine. 104 However, when tested in combination with topiramate failures, in chronic migraine populations, beta-blockers did not offer benefit. 105 Therefore, the clinical decision between using topiramate or a beta-blocker, in certain clinical situatios, may arrise with migraine prophylactic medication approaches. Evidence summary anti-epileptic (topiramate) use versus beta-blockers in prevention of recurrence of migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014

132 KSA Panel input to date Of potential sources, the available evidence was derived from from the NICE 2012 systematic review. The available recent evidence is reflective of adults (mean age 40), with episodic (less than 15 per month) migraine, in one randomized controlled trial evaluating topiramate either with 100 mg/day or 200 mg/day doses versus propranolol 160 mg/day. 106 Outcomes for 100 mg topiramate were presented as they represented the best case. There was no apparent absolute benefit using topiramate with 45 per 1000 fewer experiencing a responder outcome of 50% reduction in migraines when compared to propranolol use. The certainty of the evidence was low to moderate. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the options What is the overall certainty of this evidence? included studies Very low Low Moderate High The relative importance or values of the main outcomes of interest: Outcome Episodic: change in patient-reported migraine days Relative importance Certainty of the evidence (GRADE) MODERATE

133 Criteria Judgements Research evidence Additional considerations Is there important uncertainty about how much people value the main outcomes? Are the desirable anticipated effects large? Are the undesirable anticipated effects small? Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable No Yes Probably yes Episodic: responder rate [>50% reduction] Episodic: change in patient-reported migraine frequency Episodic: use of acute pharmacological treatment Summary of findings: Topiramate Outcome Episodic: change in patient-reported migraine days Episodic: responder rate [>50% reduction] With beta blockers The mean episodic: change in patientreported migraine days in the control group was -1.1 +/- 0.24 301 per 1000 With anti-epileptics (topiramate) LOW The mean episodic: change in patient-reported migraine days in the intervention group was 0.35 higher (0.25 higher to 0.95 higher) 256 per 1000 (186 to 352) MODERATE MODERATE Difference (95% CI) MD 0.35 higher (0.25 higher to 0.95 higher) 45 fewer per 1000 (from 51 more to 114 fewer) Episodic: change in The mean episodic: The mean episodic: change MD 0.25 - Relative effect (RR) (95% CI) - RR 0.85 (0.62 to 1.17)

134 Criteria Judgements Research evidence Additional considerations Are the desirable effects large relative to undesirable effects? Yes No Yes patient-reported migraine frequency Episodic: use of acute pharmacological treatment change in patientreported migraine frequency in the control group was -0.8 +/- 0.21 The mean episodic: use of acute pharmacological treatment in the control group was -0.8 +/- 0.20 in patient-reported migraine frequency in the intervention group was 0.25 higher (0.26 higher to 0.76 higher) The mean episodic: use of acute pharmacological treatment in the intervention group was 0.4 higher (0.1 higher to 0.9 higher) higher (0.26 higher to 0.76 higher) MD 0.4 higher (0.1 higher to 0.9 higher) - Resource use Are the resources required small? Is the incremental cost small relative to the net benefits? Probably no Yes Probably no Yes Anti-epileptics: average monthly cost estimated at 200-500 SR by panel members. Beta-blockers: average monthly cost estimated at 50-100 SR by panel members. No evidence identified specific to KSA. An original cost-effectiveness analysis by the NICE systematic review in 2012 showed that topiramate is more cost-effective than beta-blockers (propranolol). Topiramate is more costly but more effective than betablockers and the ICER is below the 20,000/QALY threshold for the UK. When compared to other available strategies (no treatment, telmisartan, and acupuncture), topiramate is the most cost-effective option, followed by propranolol. When the model was run probabilistically, topiramate was the most cost-effective strategy in 45.2% of the simulations while propranolol in 25.5% of the simulations. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist Equity What would be the impact on health Increased Probably No evidence identified specific to KSA

135 Criteria Judgements Research evidence Additional considerations inequities? increased Probably reduced Reduced Varies Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA

136 Recommendation Should topiramate vs. beta-blockers be used for prevention of recurrence of migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel suggests that clinicians use either topiramate or beta-blockers for the prevention of migraine attacks. Panel found not enough evidence to favor one over the other. No difference in effectiveness was found in 1 study with serious limitations; use of topiramate would require larger resources. Availability of resources will have important impact on this choice. None None None More head-to-head studies.

137 Evidence Profile: Should topiramate versus beta-blockers be used for prevention of recurrence of migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision topiramate Other considerations betablockers Relative (95% CI) Absolute (95% CI) Quality Importance Episodic: change in patient-reported migraine days (follow up: 26 weeks) 1 randomised trials serious 1 not serious not serious not serious none 282 143 - MD 0.35 higher (0.25 higher to 0.95 higher) MODERATE Episodic: responder rate [>50% reduction] (follow up: 26 weeks) 1 randomised trials serious 1 not serious not serious serious 2 none 72/282 (25.5%) 43/143 (30.1%) RR 0.85 (0.62 to 1.17) 45 fewer per 1000 (from 51 more to 114 fewer) LOW Episodic: change in patient-reported migraine frequency (follow up: 26 weeks) 1 randomised trials serious 1 not serious not serious not serious none 282 143 - MD 0.25 higher (0.26 higher to 0.76 higher) MODERATE Episodic: use of acute pharmacological treatment (follow up: 26 weeks) 1 randomised trials MD mean difference, RR relative risk 1. method of allocation concealment not reported 2. confidence interval crosses minimally important difference making effect size uncertain Bibliography: serious 1 not serious not serious not serious none 282 143 - MD 0.4 higher (0.1 higher to 0.9 higher) MODERATE Diener HC, Tfelt-Hansen P, Dahlof C, Lainez MJA, Sandrini G, Wang SJ et al. Topiramate in migraine prophylaxis: Results from a placebo-controlled trial with propranolol as an active control. J Neurol 2004; 251: 943-50.

138 13: Should triptans versus no triptans be used for prevention of recurrence of menstrual-related migraine? Population Intervention Comparison Those women with menstrual-related migraine headaches triptans no triptans Outcomes of Interest Change in patient-reported headache days, frequency and intensity Clinical background: Functional health status and health-related quality of life Responder rate Headache specific quality of life Use of acute pharmacological treatment Incidence of serious adverse events Migraine is frequently associated with menstruation, with up to a 50% increase in likelihood of experiencing a migraine in the premenstrual phase due to decreasing estrogen levels. 107 During an acute migraine attack in menstruation, sumatriptan is known to have a benefitial effect. 108,109 It is uncertain if triptans should also be a considered as well as a method of prophylaxis. A narrative review, comparing different triptan medications and dosing approaches, suggested that mini-prophylaxis only in the pre-menstrual period rather than ongoing daily preventive treatment is effective and when considering the choice of triptan use of short-term miniprophylaxis, sumatriptan, zolmitriptan, naratriptan, and frovatriptan were described to have shown efficacy; however, frovatriptan was concluded to be the triptan of best choice based on overall efficacy. 110 Evidence summary for triptan use in menstrual-related migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014

139 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date Of potential sources, the available evidence was derived from the NICE 2012 systematic review. The available evidence, specifically in menstrually-related migraine prophylaxis, relates to 3 randomized controlled trials. 111-113 For the outcomes of 50% reduction in migraine frequency, reduction in patient need for acute medication and resource reduction in number of breakthrough attacks requiring acute treatment, absolute benefits ranged from 188 per 1000 (number need to treat = 5) to 126 per 1000 (number needed to treat = 8) with no significant adverse events reported. Generally, the certainty of the benefits and harms evidence was low. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. One panel member was uncertain if the desirable anticipated effects were large. Benefits & harms of the options What is the overall certainty of this evidence? included studies Very low Low The relative importance or values of the main outcomes of interest: Outcome Relative importance Certainty of the evidence (GRADE)

140 Moderate High Responder rate [>50% reduction in migraine frequency] IMPORTANT LOW Is there important uncertainty about how much people value the main outcomes? Are the desirable anticipated effects large? Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable Probably yes Yes Use of acute pharmacological treatment [% of patients treated] Use of acute pharmacological treatment [% of breakthrough attacks treated] Adverse Events Frovatriptan BID: free from menstrual-migraine per menstrual period Summary of findings: Triptans Outcome Without triptans With triptans Responder rate [>50% reduction in migraine frequency] 383 per 1000 570 per 1000 (421 to 777) IMPORTANT IMPORTANT IMPORTANT IMPORTANT LOW LOW LOW LOW Difference (95% CI) 188 more per 1000 (from 38 moreto 394 more) Relative effect (RR) (95% CI) RR 1.49 (1.1 to 2.03) Are the undesirable anticipated effects small? Use of acute pharmacological treatment [% of patients treated] 856 per 1000 668 per 1000 (599 to 745) 188 fewer per 1000 (from 111 fewer to 257 fewer) RR 0.78 (0.7 to 0.87)

141 Yes Use of acute pharmacological treatment [% of breakthrough attacks treated] 741 per 1000 615 per 1000 (511 to 733) 126 fewer per 1000 (from 7 fewer to 230 fewer) RR 0.83 (0.69 to 0.99) Are the desirable effects large relative to undesirable effects? Probably yes Yes Adverse Events 4 per 1000 Frovatriptan BID: free from menstrualmigraine per menstrual period The mean frovatriptan BID: free from menstrual-migraine per menstrual period in the control group was 0.42 +/- 0.78 2 per 1000 (0 to 37) The mean frovatriptan BID: free from menstrual-migraine per menstrual period in the intervention group was 0.92 higher (0.11 lower to 1.95 higher) 2 fewer per 1000 (from 4 fewer to 33 more) mean 0.92 higher (0.11 lower to 1.95 higher) OR 0.58 (0.04 to 9.35) - Resource use Are the resources required small? Probably yes Yes Average monthly cost was estimated at 67-133 SAR by panel members. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist From health system perspective may be small, from individual perspective, out of the pocket cost may not be small. Is the incremental No evidence identified specific to KSA.

142 cost small relative to the net benefits? Probably yes Yes Equity What would be the impact on health inequities? Increased X Probably increased Probably reduced Reduced No evidence identified specific to KSA Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA

143 Recommendation Should triptans vs. no triptans be used in menstrual-related migraine for prevention of recurrence? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation The panel suggests triptans for the prevention of menstrual-related migraine attacks. Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities In women with irregular menstrual period it is uncertain if this will be effective because of feasibility of determining when to start treatment. Treatment is used only during the menstrual period but needs to be timed to start treatment before period starts. None None

144 Evidence Profile: Should triptans versus no triptans be used for prevention of recurrence of menstrual-related migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations triptans no triptans Relative (95% CI) Absolute (95% CI) Quality Importance Responder rate [>50% reduction in migraine frequency] 1 randomised trials serious 1 not serious not serious serious 3 none 93/163 (57.1%) 31/81 (38.3%) RR 1.49 (1.1 to 2.03) 188 more per 1000 (from 38 more to 394 more) LOW IMPORTANT Use of acute pharmacological treatment [% of patients treated] 1 randomised trials not serious not serious serious 2 serious 3 none 167/250 (66.8%) 137/160 (85.6%) RR 0.78 (0.7 to 0.87) 188 fewer per 1000 (from 111 fewer to 257 fewer) LOW IMPORTANT Use of acute pharmacological treatment [% of breakthrough attacks treated] 1 randomised trials serious 1 not serious not serious serious 3 none 100/163 (61.3%) 60/81 (74.1%) RR 0.83 (0.69 to 0.99) 126 fewer per 1000 (from 7 fewer to 230 fewer) LOW IMPORTANT Adverse Events 2 randomised trials serious 1 not serious not serious serious 4 none 1/413 (0.2%) 1/241 (0.4%) OR 0.58 (0.04 to 9.35) 2 fewer per 1000 (from 4 fewer to 33 more) LOW IMPORTANT Frovatriptan BID: free from menstrual-migraine per menstrual period (follow up: 6 days) 1 randomised trials serious 1 not serious not serious serious 3 none 104 168 - mean 0.92 higher (0.11 lower to 1.95 higher) MD mean difference, RR relative risk 1. allocation concealment and randomization unclear 2. tension-type headache patients 3. confidence interval crosses minimally important difference 4. no meta-analysis LOW IMPORTANT

145 Bibliography: Brandes J, Poole A, Kallela M, Schreiber C, MacGregor E, Silberstein S et al. Short-term frovatriptan for the prevention of difficult-to-treat menstrual migraine attacks. Cephalalgia 2009; 29: 1133-48. 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, doubleblind, placebo- controlled study. Headache 2001; 41: 248-56. Tuchman MM, Hee A, Emeribe U, Silberstein S. Oral zolmitriptan in the short-term prevention of menstrual migraine: a randomized, placebo-controlled study. CNS Drugs 2008; 22: 877-86.

146 14: Should botulinum toxin A injections versus no injections be used for prevention of recurrence of episodic migraine? Population Intervention Comparison Those with episodic migraine headaches botulinum toxin A injections no injections Outcomes of Interest Change in patient-reported headache days, frequency and intensity Functional health status and health-related quality of life Clinical background: Responder rate Headache specific quality of life Use of acute pharmacological treatment Incidence of serious adverse events Botulinum toxin A injections were first proposed for headaches when it was found that those with chronic headaches receiving cosmetic botulinum injection had headache improvement. 114,115 Botulinum toxin is a neuro-muscular blocking agent that has been used to treat various conditions autonomic dysfunction or chronic pain. 116,117 These injection are often used to auguement typical prophylactic approaches. In 2011, botulinum toxin A was approved for use in both the United Kingdom and United States for headache prophylaxis. Evidence summary for botulinum toxin A injection use in prevention of recurrence of migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014

147 KSA Panel input to date The main NICE 2012 systematic review did not address this topic. Of potential sources, the available evidence available relates to studies identified McMaster literature searches. The available evidence is reflective of both episodic and chronic migraine adult (mean age 42.1; 76% female) participants across 18 randomized controlled trials, 118-135 with pooled effects from trials summarized in one systematic review and meta-analysis. 136 The outcome of adverse events was a pooled outcome across a mixed group of episodic and chronic migraine populations across 25 trials. 136 Most trials (85%) allowed participants to continue with any stable prophylactic medication use. There were a variety of injection protocols used with most using a fixed site injection plan and only some trials used a follow-the-pain approach where targeted painful elicited points were injected. The majority of trials did injections at a single time point with the range of between 4 and 58 individual injections per intervention. Outcomes in episodic patients showed little effect Two cost-effectiveness studies were identified in European populations. 137,138 Also, some studies have identified appropriate dosing and reconfirmed effectiveness of botulinum toxin A in those chronic migrainers already with medication overuse headache from other prophylactic approaches. 139,140 Generally, the certainty of the benefits and harms evidence for episodic populations was moderate. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the What is the overall certainty of this evi- included studies The relative importance or values of the main outcomes of interest:

148 Criteria Judgements Research evidence Additional considerations options dence? Very low Low Moderate High Outcome Episodic:Number of monthly headaches Relative importance Certainty of the evidence (GRADE) LOW Episodic: 50% reduction in number of monthly headaches MODERATE Is there important uncertainty about how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable Adverse events (e.g. blepharoptosis, dizziness, muscle weakness, nausea, neck pain, parasthesia) Summary of findings: Botulinum toxin A injection Outcome Episodic: Number of monthly headaches Episodic: 50% reduction in number of monthly headaches Without botulinum toxin A injection The mean episodic: Number of monthly headaches in the control group was 3.74 579 per 1000 IMPORTANT With botulinum toxin A injection The mean episodic: Number of monthly headaches in the intervention group was 0.05 higher (0.26 lower to 0.36 higher) 579 per 1000 (492 to 683) MODERATE Difference (95% CI) MD 0.05 higher (0.26 lower to 0.36 higher) 0 fewer per 1000 (from 87 fewer to 104 Relative effect (RR) (95% CI) - RR 1 (0.85 to 1.18)

149 Criteria Judgements Research evidence Additional considerations Are the desirable anticipated effects large? Are the undesirable anticipated effects small? No Yes Probably yes Yes Adverse events (e.g. blepharoptosis, dizziness, muscle weakness, nausea, neck pain, parasthesia) 460 per 1000 575 per 1000 (524 to 626) more) 115 more per 1000 (from 64 more to 166 more) RR 1.25 (1.14 to 1.36) Are the desirable effects large relative to undesirable effects? No Yes Resource use Are the resources required small? No Yes Average monthly cost was estimated at 1000-1500 SR by panel members. -Pain specialist visits -Hospital: ER/urgent care visit, inpatient hospital stay per day -Injection component

150 Criteria Judgements Research evidence Additional considerations No evidence identified specific to KSA. Is the incremental cost small relative to the net benefits? No Yes In chronic migraine in the UK, at 2 years, treatment with onabotulinumtoxina was associated with an increase in costs of 1367 and an increase in QALYs of 0.1 compared to placebo, resulting in an incremental costeffectiveness ratio (ICER) of 15,028. Treatment with onabotulinumtoxina reduced headache days by an estimated 38 days per year at a cost of 18 per headache day avoided. The ICER remained cost-effective at a willingness to pay threshold of 20,000 30,000/QALY. The incremental cost-effectiveness ratio, in the Italian sector was also favorable compared to the value usually considered by other groups (eg. NICE 2012) as a threshold limit for reimbursement which ranges between 20,000 and 40,000/QALY. Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced No evidence identified specific to KSA Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement? No evidence identified specific to KSA irrelevant

151 Criteria Judgements Research evidence Additional considerations Yes

152 Recommendation Should botulinum toxin A injection vs. no injection be used for prevention of recurrence of migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel recommends that clinicians do not use botulinum toxin A for the prevention of migraine attacks in patients with episodic migraine. There is no evidence of benefit and there is a potential harm and large cost. None None None None Evidence Profile: Should botulinum toxin A injections versus no injections be used for prevention of recurrence of episodic migraine?

153 Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations botulinum toxin A injection no injection Relative (95% CI) Absolute (95% CI) Quality Importance Episodic: Number of headache episodes per month (follow up: range 84-270 days) 9 randomised trials not serious none 1261 577 - MD 0.05 higher serious 1 not serious no serious imprecision 2 (0.26 lower to 0.36 higher) MODERATE Episodic: 50% reduction in number of monthly headaches (follow up: range 84-270 days) 2 randomised trials not serious not serious not serious serious 2 none 121/224 (54.0%) 114/197 (57.9%) RR 1.00 (0.85 to 1.18) 0 fewer per 1000 (from 87 fewer to 104 more) MODERATE Adverse events (eg. blepharoptosis, dizziness, muscle weakness, nausea, neck pain, parasthesia) 25 randomised trials not serious not serious serious 3 not serious 4 none 1672/2955 (56.6%) 1268/2756 (46.0%) RR 1.25 (1.14 to 1.36) 115 more per 1000 (from 64 more to 166 more) MODERATE IMPORTANT MD mean difference, RR relative risk 1. significant heterogeneity between trials 2. confidence interval crosses null value 3. mix of populations (episodic / chronic) 4. wide range of events; the decision would not differ irrespective of CI Bibliography: Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA 2012; 307: 1736-45.

154 15: Should botulinum toxin A injections versus no injections be used for prevention of recurrence of chronic migraine? Population Intervention Comparison Those with chronic migraine headaches botulinum toxin A injections no injections Outcomes of Interest Change in patient-reported headache days, frequency and intensity Functional health status and health-related quality of life Clinical background: Responder rate Headache specific quality of life Use of acute pharmacological treatment Incidence of serious adverse events Botulinum toxin A injections were first proposed for headaches when it was found that those with chronic headaches receiving cosmetic botulinum injection had headache improvement. 114,115 Botulinum toxin is a neuro-muscular blocking agent that has been used to treat various conditions autonomic dysfunction or chronic pain. 116,117 These injection are often used to augment typical prophylactic approaches. In 2011, botulinum toxin A was approved for use in both the United Kingdom and United States for headache prophylaxis. Evidence summary for botulinum toxin A injection use in prevention of recurrence of migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014

155 KSA Panel input to date The main NICE 2012 systematic review did not address this topic. Of potential sources, the available evidence available relates to studies identified McMaster literature searches. The available evidence is reflective of both episodic and chronic migraine adult (mean age 42.1; 76% female) participants across 18 randomized controlled trials, 118-135 with pooled effects from trials summarized in one systematic review and meta-analysis. 136 The outcome of adverse events was a pooled outcome across a mixed group of episodic and chronic migraine populations across 25 trials. 136 Most trials (85%) allowed participants to continue with any stable prophylactic medication use. There were a variety of injection protocols used with most using a fixed site injection plan and only some trials used a follow-the-pain approach where targeted painful elicited points were injected. The majority of trials did injections at a single time point with the range of between 4 and 58 individual injections per intervention. While outcomes in episodic patients showed little effect, in chronic migrainers, responders reporting 50% reduction in the number of monthly headaches was found to have an absolute benefit in 309 per 1000 (number needed to treat = 3) more with 115 per 1000 (number needed harm = 9) more adverse events (e.g. blepharoptosis, dizziness, muscle weakness) when using botulinum toxin A injections. Two cost-effectiveness studies were identified in European populations. 137,138 Also, some studies have identified appropriate dosing and reconfirmed effectiveness of botulinum toxin A in those chronic migrainers already with medication overuse headache from other prophylactic approaches. 139,140 Generally, the certainty of the benefits and harms evidence for episodic populations was moderate. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1- year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death.

156 Criteria Judgements Research evidence Additional considerations What is the overall certainty of this evidence? included studies Very low Low Moderate High The relative importance or values of the main outcomes of interest: Outcome Chronic Number of monthly headaches Chronic: 50% reduction in number of monthly headaches Relative importance Certainty of the evidence (GRADE) LOW LOW Two of 5 panel members were uncertain whether the anticipated desirable effects were large and whether they were large relative to undesirable effects. Chronic: functioningand health related quality oflife clinically important improvement MODERATE Benefits & harms of the options Is there important uncertainty about how much people value the main outcomes? Are the desirable anticipated effects Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable Chronic: Responders (>5% reduction in moderate/severe headache days) Adverse events (e.g. blepharoptosis, dizziness, muscle weakness, nausea, neck pain, parasthesia) Summary of findings: Botulinum toxin A injection Outcome Chronic: Number of monthly headaches Without botulinum toxin A injection The mean chronic: Number IMPORTANT With botulinum toxin A injection The mean chronic: Number of monthly MODERATE LOW Difference (95% CI) MD 2.3 lower (3.66 lower to Relative effect (RR) (95% CI) -

157 Criteria Judgements Research evidence Additional considerations large? Probably yes Yes of monthly headaches in the control group was 14.74 headaches in the intervention group was 2.3 lower (3.66 lower to 0.94 lower) 0.94 lower) Are the undesirable anticipated effects small? Probably yes Yes Chronic: 50% reduction in number of monthly headaches Chronic: functioning and health related quality of life clinically important improvement 255 per 1000 254 per 1000 564 per 1000 (332 to 965) 440 per 1000 (366 to 526) 309 more per 1000 (from 77 more to 710 more) 185 more per 1000 (from 112 more to 272 more) RR 2.21 (1.3 to 3.78) RR 1.73 (1.44 to 2.07) Are the desirable effects large relative to undesirable effects? Probably yes Yes Chronic: Responders (>50% reduction in moderate/severe headache days) Adverse events (e.g. blepharoptosis, dizziness, muscle weakness, nausea, neck pain, parasthesia) 359 per 1000 460 per 1000 485 per 1000 (417 to 568) 575 per 1000 (524 to 626) 126 more per 1000 (from 58 more to 208 more) 115 more per 1000 (from 64 more to 166 more) RR 1.35 (1.16 to 1.58) RR 1.25 (1.14 to 1.36) Resource use Are the resources required small? No Average monthly cost was estimated at 1000-1500 SR by panel members. -Pain specialist visits -Hospital: ER/urgent care visit, inpatient hospital stay per day -Injection component 2000 SAR

158 Criteria Judgements Research evidence Additional considerations Yes No evidence identified specific to KSA. Is the incremental cost small relative to the net benefits? Uncertain Yes In chronic migraine in the UK, at 2 years, treatment with onabotulinumtoxina was associated with an increase in costs of 1367 and an increase in QALYs of 0.1 compared to placebo, resulting in an incremental cost-effectiveness ratio (ICER) of 15,028. Treatment with onabotulinumtoxina reduced headache days by an estimated 38 days per year at a cost of 18 per headache day avoided. The ICER remained cost-effective at a willingness to pay threshold of 20,000 30,000/QALY. The incremental cost-effectiveness ratio, in the Italian sector was also favorable compared to the value usually considered by other groups (eg. NICE 2012) as a threshold limit for reimbursement which ranges between 20,000 and 40,000/QALY. Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced No evidence identified specific to KSA Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA

159 Criteria Judgements Research evidence Additional considerations Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA Barriers to implementation include large cost and required experience to perform the procedure.

160 Recommendation Should botulinum toxin A injection vs. no injection be used for prevention of recurrence of migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings 3 2 Type of recommendation Recommendation Justification Subgroup considerations We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option The panel suggests botulinum toxin A injections for prevention or recurrence of chronic migraine in patients who have not responded to other prophylactic treatments. There is possibly a benefit but cost is large resulting in possible increase in inequity in access to health care. There is also requirement for special training of clinicians who would perform the procedure. Two of the 5 panel members thought that desirable consequences probably outweigh undesirable consequences in most settings. None Implementation considerations Injections of botulinum toxin A require specific skills and following specific protocol. If the procedure is done, clinicians performing it need specific training. Monitoring and evaluation Optimum duration of treatment and indications for discontinuation in patients with no response are not known. Research possibilities Additional research is needed to clarify the required duration of treatment and criteria for its discontinuation. Comparative studies of different botulinum toxin preparations may be beneficial.

161 Evidence Profile: Should botulinum toxin A injections versus no injections be used for prevention of recurrence of chronic migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations botulinum toxin A injection no injection Relative (95% CI) Absolute (95% CI) Quality Importance Chronic: Number of monthly headaches (follow up: range 84-168 days) 5 randomised trials serious 1 serious 2 not serious serious 1 none 748 760 - MD 2.3 lower (3.66 lower to 0.94 lower) LOW Chronic: 50% reduction in number of monthly headaches (follow up: range 84-112 days) 2 randomised trials serious 1 not serious not serious serious 1 none 25/45 (55.6%) 12/47 (25.5%) RR 2.21 (1.3 to 3.78) 309 more per 1000 (from 77 more to 710 more) LOW Chronic: functioning and health related quality of life clinically important improvement (follow up: 24 weeks) 1 randomised trials serious 1 not serious not serious not serious none 226/513 (44.1%) 125/492 (25.4%) RR 1.73 (1.44 to 2.07) 185 more per 1000 (from 112 more to 272 more) MODERATE Chronic: Responders (>50% reduction in moderate/severe headache days) (follow up: 24 weeks) 1 randomised trials serious 1 not serious not serious not serious none 216/445 (48.5%) 165/459 (35.9%) RR 1.35 (1.16 to 1.58) 126 more per 1000 (from 58 more to 208 more) MODERATE Adverse events (eg. blepharoptosis, dizziness, muscle weakness, nausea, neck pain, parasthesia) 25 randomised trials not serious not serious serious 5 serious 4 none 1672/2955 (56.6%) 1268/2756 (46.0%) RR 1.25 (1.14 to 1.36) 115 more per 1000 (from 64 more to 166 more) LOW IMPORTANT MD mean difference, RR relative risk 1. No possibility of blinding and likely overestimation of effects due to cosmetic effects 2. No explanation was provided 3. Very small number of events 4. wide range of events - none were serious 5. mix of populations (episodic / chronic)

162 Bibliography: Jackson JL, Kuriyama A, Hayashino Y. Botulinum toxin A for prophylactic treatment of migraine and tension headaches in adults: a meta-analysis. JAMA 2012; 307: 1736-45.

163 16: Should tricyclic antidepressants versus no antidepressants be used for prevention of recurrence of migraine? Population Intervention Comparison Those with episodic or chronic migraine headaches Tricyclic anti-depressants (TCAs) not using Antidepressants Outcomes of Interest Change in patient-reported headache days, frequency and intensity Clinical background: Functional health status and health-related quality of life Responder rate Headache specific quality of life Use of acute pharmacological treatment Incidence of serious adverse events Trycyclic anti-depressants (TCAs) have long been used in migraine prophylaxis. 141 Some have suggested a direct analgesic effect unrelated to depression which has prompted their use over 30 years ago. 142,143 Whether antidepressants can improve pain is often a controversial subject and historically has been a challenge in clinical research. 144 Evidence summary for anti-depressant use in migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date

164 The NICE 2012 systematic review focused on tension-type headache and did not address this topic in specifically migraine populations. Of potential sources, the available evidence relates to 1 systematic review identified McMaster literature searches. The outcome of resource use did not rate as critical to decision-making by KSA panel members and was excluded. 145 For TCAs, there was an absolute benefit in responders having 50% reduction in migraines in 181 per 1000 (number needed to treat = 6) with 442 per 1000 (number needed to harm = 2) more adverse events (e.g. anxiety, blurred vision, constipation, weight gain). Generally, the certainty of the benefits and harms evidence was low for TCAs. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the options What is the overall certainty of this evidence? included studies Very low Low Moderate High The relative importance or values of the main outcomes of interest: Outcome TCAs: Burden of headache Relative importance Certainty of the evidence(grade) 0 LOW

165 Criteria Judgements Research evidence Additional considerations TCAs Responder Rate(50% reduction) TCAs: Adverse events (e.g. anxiety, blurred vision, constipation, weight gain, nausea, dry mouth) IMPORTANT LOW HIGH Is there important uncertainty about how much people value the main outcomes? Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable Summary of findings: Anti-depressants (TCAs) Outcome TCAs: Burden of headache TCAs: Responder Rate (50% reduction) Without antidepressants (TCAs) The mean TCAs: Burden of headache in the control group was 206 226 per 1000 With anti-depressants (TCAs) The mean TCAs: Burden of headache in the intervention group was 0.96 standard deviations lower (1.39 lower to 0.53 lower) 406 per 1000 (280 to 592) Difference (95% CI) SMD 0.96 lower (1.39 lower to 0.53 lower) 181 more per 1000 (from 54 more to 366 more) Relative effect (RR) (95% CI) - RR 1.8 (1.24 to 2.62) Are the desirable anticipated effects large? Probably yes TCAs: Adverse events (e.g. anxiety, blurred vision, constipation, weight gain, nausea, 497 per 1000 939 per 1000 (586 to 1501) 442 more per 1000 (from 89 more to 1004 more) RR 1.89 (1.18 to 3.02)

166 Criteria Judgements Research evidence Additional considerations Yes dry mouth) Are the undesirable anticipated effects small? Probably yes Yes Are the desirable effects large relative to undesirable effects? Probably yes Yes Resource use Are the resources required small? Yes Average cost per month was estimated at 50-100 SR by panel members. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist -Hospital: ER/urgent care visit, inpatient hospital stay per day Probably yes but varies based by drug: newer are more expensive.

167 Criteria Judgements Research evidence Additional considerations Is the incremental cost small relative to the net benefits? Probably yes Yes No evidence identified specific to KSA Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced No evidence identified specific to KSA Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA

168 Recommendation Should TCAs vs. no anti-depressants be used for prevention of recurrence of migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation The panel suggests tricyclic antidepressants for the prevention of migraine attacks. Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities None Most evidence is available for amitriptyline. None None

169 Evidence Profile: Should tricyclic antidepressants versus no antidepressants be used for prevention of recurrence of migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations antidepressants (TCAs, SSRIs) no antidepressants Relative (95% CI) Absolute (95% CI) Quality Importance TCAs: Burden of headache (follow up: range 4-26 weeks) 9 randomised trials not serious not serious serious 4 serious 2 none 245 250 - SMD 0.96 lower (1.39 lower to 0.53 lower) LOW TCAs: Responder Rate (50% reduction) (follow up: range 4-12 weeks) 4 randomised trials not serious not serious 1 not serious very serious 3 none 102/232 (44.0%) 56/248 (22.6%) RR 1.8 (1.24 to 2.62) 181 more per 1000 (from 54 more to 366 more) LOW TCAs: Adverse events (eg anxiety, blurred vision, constipation, weight gain, nausea, dry mouth) 7 randomised trials not serious not serious not serious not serious none 265/366 (72.4%) 161/324 (49.7%) RR 1.89 (1.18 to 3.02) 442 more per 1000 (from 89 more to 1004 more) HIGH IMPORTANT MD mean difference, RR relative risk 1. No explanation was provided 2. confidence interval crosses null value making estimate uncertain; small sample size 3. high lost to follow up in trials 4. high variability in follow up with the majority of trials having 12 week or less endpoint Bibliography: Jackson JL, Shimeall W, Sessums L, Dezee KJ, Becher D, Diemer M, Berbano E, O'Malley PG. Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ. 2010 Oct 20;341:c5222. doi: 10.1136/bmj.c5222.

170 17: Should SSRIs versus no antidepressants be used for prevention of recurrence of migraine? Population Intervention Comparison Those with episodic or chronic migraine headaches anti-depressants (SSRIs) not using Antidepressants Outcomes of Interest Change in patient-reported headache days, frequency and intensity Functional health status and health-related quality of life Clinical background: Responder rate Headache specific quality of life Use of acute pharmacological treatment Incidence of serious adverse events Trycyclic anti-depressants (TCAs) have long been used in migraine prophylaxis. 141 Some have suggested a direct analgesic effect unrelated to depression which has prompted their use over 30 years ago. 142,143 Likewise, selective serotonin re-uptake inhibitors (SSRIs) have been reported to act as an active central modulator of pain which has similarly prompted their use. 146 Whether antidepressants can improve pain is often a controversial subject and historically has been a challenge in clinical research. 144 Evidence summary for anti-depressant use in migraine: Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date

171 The NICE 2012 systematic review focused on tension-type headache and did not address this topic in specifically migraine populations. Of potential sources, the available evidence relates to 1 systematic review identified McMaster literature searches. 147 The outcome of resource use did not rate as critical to decision-making by KSA panel members and was excluded. Although few outcomes of interest were identified for SSRIs, there was a negligible benefit in the outcome of headache index score changes with 15 per 1000 (number needed to harm = 67) more adverse events. Generally, the certainty of the benefits and harms evidence was low for SSRIs. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95% CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the options What is the overall certainty of this evidence? included studies Very low Low Moderate High The relative importance or values of the main outcomes of interest: Outcome Relative importance Certainty of the evidence(grade) SSRIs: Headache Index change IMPORTANT LOW

172 Criteria Judgements Research evidence Additional considerations Is there important uncertainty about how much people value the main outcomes? Are the desirable anticipated effects large? Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable Uncertain Yes SSRIs: Adverse events IMPORTANT Summary of findings: Anti-depressants (SSRIs) Outcome SSRIs: Headache Index change SSRIs: Adverse events Without antidepressants (SSRIs) The mean SSRIs: Headache Index change in the control group was -39 67 per 1000 With anti-depressants (SSRIs) LOW The mean SSRIs: Headache Index change in the intervention group was 0.14 standard deviations higher (0.57 lower to 0.3 higher) 82 per 1000 (89 to 237) Difference (95% CI) SMD 0.14 higher (0.57 lower to 0.3 higher) 15 more per 1000 (from 22 more to 170 more) Relative effect (RR) (95% CI) - OR 1.25 (1.36 to 4.35) Are the undesirable anticipated effects small? Probably yes

173 Criteria Judgements Research evidence Additional considerations Yes Are the desirable effects large relative to undesirable effects? Uncertain Yes Resource use Are the resources required small? Yes Average cost per month was estimated at 50-100 SR by panel members. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist -Hospital: ER/urgent care visit, inpatient hospital stay per day Probably yes but varies based by drug: newer are more expensive. Is the incremental cost small relative to the net benefits? Uncertain Yes No evidence identified specific to KSA Panel members were uncertain whether the incremental cost is small relative to benefits for SSRIs.

174 Criteria Judgements Research evidence Additional considerations Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced No evidence identified specific to KSA Acceptability Is the option acceptable to key stakeholders? Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement? Yes No evidence identified specific to KSA

175 Recommendation Should SSRIs vs. no anti-depressants be used for prevention of recurrence of migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings o Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option o Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities The panel suggests that clinicians do not use SSRIs for the prevention of migraine attacks until more evidence is available. The panel was uncertain about the balance between desirable and undesirable consequences. None None None More studies with adequate follow-up reporting all patient-important outcomes.

176 Evidence Profile: Should SSRIs versus no antidepressants be used for prevention of recurrence of migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations anti-depressants ( SSRIs) no antidepressants Relative (95% CI) Absolute (95% CI) Quality Importance SSRIs: Headache Index change (follow up: 8 weeks) 3 randomised trials not serious not serious serious 1 serious 2,3 none 43 43 - SMD 0.14 higher (0.57 lower to 0.3 higher) LOW IMPORTANT SSRIs: Adverse events 4 randomised trials not serious not serious serious 1 serious none 86 75 OR 1.25 (0.36 to 4.35) 15 more per 1000 (from 22 more to 170 more) LOW MD mean difference, RR relative risk 1. Too short a follow up 2. confidence interval crosses null value making estimate uncertain; small sample size 3. high lost to follow up in trials Bibliography: Moja PL, Cusi C, Sterzi RR, Canepari C. Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches. Cochrane Database Syst Rev 2005; (3): CD002919

177 18: Should education and self-management programs versus no such programs (usual care only) be used for prevention of recurrence of migraine? Population Intervention Comparison Those with episodic or chronic migraine headaches Education & self-management programs No such programs (usual care only) Outcomes of Interest Change in patient-reported headache days, frequency & intensity Responder rate Functional health status and health-related quality of life Headache specific quality of life Resource use Use of acute pharmacological treatment Patient s perception of the usefulness of programs Clinical background: Ongoing migraine pain negatively influences daily function, emotions and social roles, 148 especially during an individual s most productive years. 149 Patients are often in need of education on self-management and appropriate medication use. 150 For many migrainers, prophylactic medications are not always effective, leading to poor compliance. Barriers also exist for patients with respect to their migraine-specific knowledge, self-management skills, coping emotionally, communicating their pain to others and general understanding of medication overuse and safety. Lastly, surveys to patients have found that up to half of migraine sufferers typically have not even discussed approaches to prophlyaxis with their primary health care provider. 151 As example, fasting for approximately one month is a customary practice for Muslims during the month of Ramadan, where patients could benefit from education of the potential for Ramadan month headache exacerbation along with the effects of dehydration and caffeine withdrawal. 152 As well, with driving, up to 4.7% of traffic accidents were associated with migraine headaches in a survey of 1985 drivers in the United Arab Emirates. 153 Education and self-management programs may be an option for highly motivated patients to augment, often ignored, medication approaches to prophylaxis, 154 as well as to improve medication compliance. 155 However, the main limitations of self-help interventions are the lack of opportunity for corrective feedback, motivational assistance, optimal medical screening and monitoring. 156 Evidence summary for education & self-management programs:

178 Potential Sources: NICE 2012 systematic review McMaster randomized controlled trial literature search (Medline, Embase, CINAHL, Cochrane) from 2012 to September 2014 McMaster cost-effectiveness search (Medline, Embase) from 2012 to September 2014 McMaster values & preferences search (Medine, Embase, PsychInfo) from database inception to September 2014 KSA Panel input to date Of potential sources, the available evidence was combined from the NICE 2012 systematic review and 2 new studies from McMaster literature searches. Additional background information on fasting withdrawal headaches during Ramadan was provided by the KSA panel. There were 3 trials identified, all in adults with the majority (over 80%) female being participants, that measured outcomes of interest using interventions such as educational materials provided directly to patients or through websites. 157-159 Kohlenberg & Cahn (1981) 157 used a self-help program as their intervention, reporting a substantial 62% reduction in patient reported migraine frequency versus 14% using a basic information control, but the trial was very small (n=51) and the loss-to-follow up exceeded 60% of those completing the program. Bromberg et al. (2012) 158 used a web based intervention (n=185) where participants completed a minimum of eight 20-minute sessions online with migraine-specific content such as: self-assessments; headache diary taking lessons; use of interactive education tools on the phrases of migraine; readings on topics (e.g. caffeine intake); and study outcome tracking tasks. At 6-month follow up the patient global rating of much improvement as an absolute measure was 54 of 1000 (number needed to treat = 18). However, the very wide confidence interval adds to a very low certainty of this outcome. Similarly, Kleiboer et al. (2014), 159 provided participants (n=368) a password protected web-portal (www.mymigraine.nl) with a voiceover training text, videos, interactive exercises, homework, e-mail support. The certainty of the benefits and harms evidence was overall low to very low. Criteria Judgements Research evidence Additional considerations Problem Is there a problem priority? Yes Prevalence of migraine headache in Saudi Arabia was originally reported from a survey of 22,630 individuals in 1997 at 5% (95% CI: 4.7-5.3) with authors suggesting that the low figure relative to other population-based surveys possibly being affected by a skew towards younger age of the sample, traditional lifestyles and cultural differences in the Kingdom. More recently, country wide cross-sectional survey with 2421 respondents found migraine headache to have 1-year prevalence of 32% with an odds ratio (OR) = 1.9 for female gender. The disutility in US populations of within-attack mild migraine pain was estimated to be 0.140 (95%

179 Criteria Judgements Research evidence Additional considerations CI: 0.0848, 0.1940), with a disutility for moderate migraine pain of 0.186 (95% CI: 0.1645, 0.2053) and for severe migraine pain of 0.493 (95% CI: 0.4100, 0.5654). Results in the UK population indicate that all levels of migraine pain are associated with significantly reduced utility values. As severity worsened, utility decreased and severe migraine pain was considered a health state worse than death. Benefits & harms of the options What is the overall certainty of this evidence? Is there important uncertainty about how much people value the main outcomes? Are the desirable anticipated effects included studies Very low Low Moderate High Important uncertainty or variability Possibly important uncertainty or variability important uncertainty of variability No important uncertainty of variability known undesirable No The relative importance or values of the main outcomes of interest: Outcome Change in patient-reported migraine frequency Use of acute pharmacological treatment mean doses per week ] Intervention Responder [ >50% clinically significant improvement ) Migraine attack frequency Migraine-specific quality of life Headache Days per month Patient Global Rating of Improvement (much improved) Relative importance CITICAL IMPORTANT Certainty of he evidence (GRADE) LOW VERY LOW LOW LOW LOW LOW VERY LOW

180 Criteria Judgements Research evidence Additional considerations large? Are the undesirable anticipated effects small? Yes Yes Summary of findings: Education and self-management programs Outcome Change in patientreported migraine frequency Without education and self-management program 138 per 1000 With education and self-management programs (usual care only) 636 per 1000 (243 to 1668) Difference (95% CI) 498 more per 1000 (from 105 more to 1530 more) Relative effect (RR) (95%CI) RR 4.61 (1.76 to 12.09) Are the desirable effects large relative to undesirable effects? No Yes Use of acute pharmacological treatment [ mean doses per week ] Intervention Responder [ >50% clinically significant improvement ) The mean use of acute pharmacological treatment [ mean doses per week ] in the control group was 2.2 doses 387 per 1000 The mean use of acute pharmacological treatment [ mean doses per week ] in the intervention group was 2.5 lower 442 per 1000 (337 to 573) mean 2.5 lower 6-54 more per 1000 (from 50 fewer to 186 more) RR 1.14 (0.87 to 1.48) Migraine attack frequency The mean migraine attack frequency in the control group was 2.7 +/- 1.7 The mean migraine attack frequency in the intervention group was 0.7 lower (2.33 lower to 0.95 higher) mean 0.7 lower (2.33 lower to 0.95 higher) -

181 Criteria Judgements Research evidence Additional considerations Migraine-specific quality of life The mean migrainespecific quality of life in the control group was 53.9 +/- 8.3 The mean migrainespecific quality of life in the intervention group was 0.8 higher (7.55 lower to 9.15 higher) mean 0.8 higher (7.55 lower to 9.15 higher) - Headache Days per month The mean headache Days per month in the control group was 7.6 +/- 4.1 The mean headache Days per month in the intervention group was 2.3 lower (6.1 lower to 1.5 higher) mean 2.3 lower (6.1 lower to 1.5 higher) - Patient Global Rating of Improvement (much improved) 126 per 1000 181 per 1000 (91 to 357) 54 more per 1000 (from 35 fewer to 231 more) RR 1.43 (0.72 to 2.83) Resource use Are the resources required small? Yes Average cost per month of such programs was estimated between 100-500 SAR by panel members. -Outpatient Provider visits: Primary care physician, Neurologist, OB/GYN, Pain specialist, Psychologist, Psychiatrist Is the incremental cost small relative No No evidence identified specific to KSA

182 Criteria Judgements Research evidence Additional considerations to the net benefits? Yes Equity What would be the impact on health inequities? Increased Probably increased Probably reduced Reduced No evidence identified specific to KSA Acceptability Is the option acceptable to key stakeholders? Probably yes Yes No evidence identified specific to KSA Feasibility Is the option feasible to implement? Probably no Yes No evidence identified specific to KSA Implementation would require setting up websites, creating educational materials, training psychologists etc.

183 Recommendation Should education and self-management programs vs. no such programs (or usual care) be used for prevention of recurrence of migraine? Balance of consequences Undesirable consequences clearly outweigh desirable consequences in most settings Undesirable consequences probably outweigh desirable consequences in most settings The balance between desirable and undesirable consequences is closely balanced or uncertain Desirable consequences probably outweigh undesirable consequences in most settings Desirable consequences clearly outweigh undesirable consequences in most settings Type of recommendation We recommend against offering this option We suggest not offering this option We suggest offering this option We recommend offering this option Recommendation Justification Subgroup considerations Implementation considerations Monitoring and evaluation Research possibilities We suggest that more research of effectiveness and cost-effectiveness is done. The panel thought that desirable and undesirable consequences were closely balanced. The panel found no evidence of effectiveness but also no evidence of ineffectiveness and it is possible that there is a benefit from those educational programs. However, possibly substantial resources would be required in order to implement such programs. None None None None

184 Evidence Profile: Should education and self-management programs versus no such programs (usual care only) be used for prevention of recurrence of migraine? Quality assessment of patients Effect of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations education and self-management programs no such programs (usual care only) Relative (95% CI) Absolute (95% CI) Quality Importance Change in patient-reported migraine frequency (follow up: 3 months) 1 randomised trials very serious not serious not serious very seri- 1 ous 3 strong association 14/22 (63.6%) 4/29 (13.8%) RR 4.61 (1.76 to 12.09) 498 more per 1000 (from 105 more to 1530 more) VERY LOW Use of acute pharmacological treatment [ mean doses per week ] (follow up: 3 months) 1 randomised trials very serious not serious not serious serious 3 none 22 29 - mean 2.5 lower 6 1 VERY LOW Intervention Responder [ >50% clinically significant improvement ) (follow up: 3 months) 1 randomised trials serious 2 not serious not serious serious 5 none 80/195 (41.0%) 67/173 (38.7%) RR 1.14 (0.87 to 1.48) 54 more per 1000 (from 50 fewer to 186 more) LOW Migraine attack frequency (follow up: mean 3 months) 1 randomised trials serious 2 not serious not serious serious 5 none 195 173 - mean 0.7 lower (2.33 lower to 0.95 higher) LOW Migraine-specific quality of life [80-point scale] (follow up: 3 months) 1 randomised trials serious 2 not serious not serious serious 5 none 195 173 - mean 0.8 higher (7.55 lower to 9.15 higher) LOW Headache Days per month (follow up: 3 months) 1 randomised serious 2 not serious not serious serious 5 none 195 173 - mean 2.3 lower

185 trials (6.1 lower to 1.5 higher) LOW Patient Global Rating of Improvement (much improved) (follow up: 6 months) 1 randomised trials very serious not serious not serious serious 5 none 17/94 (18.1%) 12/95 4 (12.6%) RR 1.43 (0.72 to 2.83) 54 more per 1000 (from 35 fewer to 231 more) VERY LOW IMPORTANT MD mean difference, RR relative risk 1. unclear blinding and allocation; patient perceived outcome; 50% loss to followup; 2. 22% lost to followup 3. very small sample size 4. 45% loss to followup in intervention arm 5. confidence interval crosses null making effect uncertain Bibliography: Kohlenberg RJ, Cahn T. Self-help treatment for migraine headaches: A controlled outcome study. Headache 1981; 21: 196-200. Bromberg J, Wood ME, Black RA, Surette DA, Zacharoff KL, Chiauzzi EJ. A randomized trial of a web-based intervention to improve migraine self-management and coping. Headache 2012; 52: 244-61. Kleiboer A, Sorbi M, van Silfhout M, Kooistra L, Passchier J. Short-term effectiveness of an online behavioral training in migraine self-management: a randomized controlled trial. Behav Res Ther 2014; 61: 61-9.

186 Appendix 2: Search Strategies and Results Benefits and Harms Searches Migraine GL Questions and Strategies Diagnosis 1- Should head MRI with or without contrast rather than no imaging be done in patients with suspected migraine headache? 2- Should head CT with or without contrast rather than no imaging be done in patients with suspected migraine headache? population Intervention Comparison Study filter date database results Headaches, All Imaging n/a RCTs & SRs 2012+ MEDLINE 117 2014/09/12 RCTs& SRs, Dx senstitive 2012+ 2014/09/16 EMBASE 220 Dx sensitive 2012+ 2014/09/16 Cochrane 217 subtotal 554 -duplicates 54 total 500 MEDLINE Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present> Search Strategy: -------------------------------------------------------------------------------- 1 Headache/ (22675) 2 exp Headache Disorders/ (26950) 3 (headache* or migraine*).ti,ab. (73612) 4 or/1-3 (84534) 5 Letter/ (857837) 6 Editorial/ (366078) 7 exp Historical Article/ (327187) 8 Anecdotes as Topic/ (4608) 9 Comment/ (603211) 10 Case Reports/ (1713319) 11 animals/ not humans/ (3916923) 12 exp Animals, Laboratory/ (739097) 13 exp Animal Experimentation/ (6492) 14 exp Models, Animal/ (427510) 15 exp Rodentia/ (2718645) 16 or/5-15 (7699591) 17 4 not 16 (58414) 18 exp Tomography, X-Ray Computed/ (308764) 19 exp Magnetic Resonance Imaging/ (321847) 20 (neuroimag* or neuro-imag*).ti,ab. (29761)

187 21 (compute* adj2 tomograph*).ti,ab. (195513) 22 (ct or cat).ti,ab. (302862) 23 ((MR or magnetic resonance or NMR) adj2 (imag* or tomograph* or angiograph*)).ti,ab. (197791) 24 MRI.ti,ab. (147460) 25 or/18-24 (873078) 26 17 and 25 (5997) 27 "review"/ or review.pt. or review.ti. (2042474) 28 (systematic or evidence* or methodol* or quantitativ*).ti,ab. (1983763) 29 27 and 28 (334602) 30 Meta-Analysis/ (51733) 31 Meta-Analysis as Topic/ (14114) 32 (meta-analy* or metanaly* or metaanaly* or meta analy*).ti,ab. (69971) 33 ((systematic* or evidence* or methodol* or quantitativ*) adj3 (review* or overview*)).ti,ab. (96242) 34 ((pool* or combined or combining) adj2 (data or trials or studies or results)).ti,ab. (40939) 35 or/29-34 (440031) 36 randomized controlled trial.pt. (388657) 37 controlled clinical trial.pt. (89832) 38 randomi#ed.ab. (370035) 39 placebo.ab. (159634) 40 randomly.ab. (222530) 41 Clinical Trials as topic.sh. (173067) 42 trial.ti. (133717) 43 or/36-42 (959543) 44 35 or 43 (1323370) 45 26 and 44 (466) 46 limit 45 to yr="2012 -Current" (117) EMBASE Database: Embase <1974 to 2014 September 15> Search Strategy: -------------------------------------------------------------------------------- 1 exp "headache and facial pain"/ (209065) 2 (headache* or migraine*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] (211712) 3 1 or 2 (228018) 4 letter.pt. or letter/ (859278) 5 note.pt. (569101) 6 editorial.pt. (456329) 7 case report/ or case study/ (1962642) 8 animal/ not human/ (1196719) 9 nonhuman/ (4373472) 10 animals, laboratory/ (17700) 11 exp experimental animal/ (416671) 12 exp animal experiment/ (1802957) 13 animals, laboratory/ (17700) 14 exp animal model/ (787035) 15 exp rodent/ (2912527) 16 or/4-15 (9876963)

188 17 3 not 16 (154702) 18 neuroimaging/ (63556) 19 exp computer assisted tomography/ (615592) 20 exp nuclear magnetic resonance imaging/ (550220) 21 (neuroimag* or neuro-imag*).ti,ab. (38728) 22 (compute* adj2 tomograph*).ti,ab. (227877) 23 (ct or cat).ti,ab. (408672) 24 ((MR or magnetic resonance or NMR) adj2 (imag* or tomograph* or angiograph*)).ti,ab. (230050) 25 MRI.ti,ab. (218413) 26 or/18-25 (1279571) 27 17 and 26 (15037) 28 "review"/ or review.pt. or review.ti. (2235771) 29 (systematic or evidence* or methodol* or quantitativ* or analys* or assessment*).ti,sh,ab. (7291552) 30 28 and 29 (653798) 31 Meta-Analysis/ (82731) 32 "systematic review"/ (79634) 33 (meta-analy* or metanaly* or metaanaly* or meta analy*).mp. (128371) 34 ((systematic* or evidence* or methodol* or quantitativ*) adj5 (review* or survey* or overview*)).ti,ab,sh. (312206) 35 ((pool* or combined or combining) adj (data or trials or studies or results)).ti,ab. (18085) 36 or/30-35 (797629) 37 randomized controlled trial/ (352287) 38 crossover procedure/ (40203) 39 single blind procedure/ (18818) 40 double blind procedure/ (117867) 41 random*.ti,ab. (912334) 42 factorial*.ti,ab. (23860) 43 (crossover* or cross over* or cross-over*).ti,ab. (72264) 44 ((doubl* or singl*) adj blind*).ti,ab. (163247) 45 (assign* or allocat* or volunteer*).ti,ab. (507549) 46 or/37-45 (1420615) 47 36 or 46 (2109599) 48 27 and 47 (2204) 49 limit 48 to yr="2012 -Current" (672) 50 limit 49 to "diagnosis (maximizes sensitivity)" (220) 51 di.fs. or predict:.tw. or specificity.tw. (3864137) 52 49 and 51 (220) Cochrane Search Name: Diagnosis Migraine Date Run: 16/09/14 20:22:36.782 Description: ID Search Hits #1 headache* or migraine*:ti,ab,kw (Word variations have been searched) 13390 #2 MeSH descriptor: [Tomography, X-Ray Computed] explode all trees 4023 #3 MeSH descriptor: [Magnetic Resonance Imaging] explode all trees 5666 #4 neuroimag* or neuro-imag*:ti,ab,kw (Word variations have been searched) 780

189 #5 compute* near/2 tomograph*:ti,ab,kw (Word variations have been searched) 7246 #6 ct or cat:ti,ab,kw (Word variations have been searched) 34569 #7 (MR or magnetic resonance or NMR) near/2 (imag* or tomograph* or angiograph*):ti,ab,kw (Word variations have been searched) 8350 #8 MRI:ti,ab,kw (Word variations have been searched) 3849 #9 #2 or #3 or #4 or #5 or #6 or #7 or #8 47594 #10 #1 and #9 Publication Year from 2012 to 2014 1799 #11 diagnos* or predict* or specificity:ti,ab,kw (Word variations have been searched) 94783 #12 #10 and #11 217 Antiemetics 3- Should antiemetics versus NSAIDs be used for acute migraine? Population Intervention comparator Study filter Date database results Migraine NOT exclusion filter Pharmacological terms for: antiemetics n/a RCTs&SRs Medline, Embase & Cinahl 2012+ 2014/09/12 MEDLINE 37 2012+ 2014/09/16 2012+ 2014/09/17 2012+ 2014/09/1 EMBASE 464 CINAHL 46 Cochrane 15 subtotal 562 -duplicates 85 total 477 MEDLINE Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present> Search Strategy: -------------------------------------------------------------------------------- 1 exp Migraine Disorders/ (21829) 2 migraine*.ti,ab. (25104) 3 1 or 2 (29328) 4 Letter/ (857837) 5 Editorial/ (366078) 6 exp Historical Article/ (327187) 7 Anecdotes as Topic/ (4608) 8 Comment/ (603211) 9 Case Reports/ (1713319) 10 animals/ not humans/ (3916923) 11 exp Animals, Laboratory/ (739097) 12 exp Animal Experimentation/ (6492)

190 13 exp Models, Animal/ (427510) 14 exp Rodentia/ (2718645) 15 or/4-14 (7699591) 16 3 not 15 (21920) 17 antiemetics/ or domperidone/ or metoclopramide/ or cinnarizine/ or cyclizine/ (13185) 18 antiemetic*.mp. (10105) 19 Domperidone.mp. (2334) 20 Metoclopramide.mp. (6450) 21 Cinnarizine.mp. (959) 22 Cyclizine.mp. (321) 23 Phenothiazines/ or prochlorperazine/ or perphenazine/ or trifluoperazine/ or promethazine/ (16282) 24 Phenothiazine*.mp. (11474) 25 Prochlorperazine.mp. (1284) 26 Perphenazine.mp. (1895) 27 Trifluoperazine.mp. (5002) 28 Promethazine.mp. (3565) 29 exp Histamine Antagonists/ (55858) 30 antihistamine*.mp. (8750) 31 Cyproheptadine.mp. (2987) 32 migraleve.mp. (8) 33 migramax.mp. (0) 34 paramax.mp. (24) 35 or/17-34 (92516) 36 16 and 35 (856) 37 "review"/ or review.pt. or review.ti. (2042474) 38 (systematic or evidence* or methodol* or quantitativ*).ti,ab. (1983763) 39 37 and 38 (334602) 40 Meta-Analysis/ (51733) 41 Meta-Analysis as Topic/ (14114) 42 (meta-analy* or metanaly* or metaanaly* or meta analy*).ti,ab. (69971) 43 ((systematic* or evidence* or methodol* or quantitativ*) adj3 (review* or overview*)).ti,ab. (96242) 44 ((pool* or combined or combining) adj2 (data or trials or studies or results)).ti,ab. (40939) 45 or/39-44 (440031) 46 randomized controlled trial.pt. (388657) 47 controlled clinical trial.pt. (89832) 48 randomi#ed.ab. (370035) 49 placebo.ab. (159634) 50 randomly.ab. (222530) 51 Clinical Trials as topic.sh. (173067) 52 trial.ti. (133717) 53 or/46-52 (959543) 54 45 or 53 (1323370) 55 36 and 54 (367) 56 limit 55 to yr="2012 -Current" (37) EMBASE Database: Embase <1974 to 2014 September 15> Search Strategy:

191 -------------------------------------------------------------------------------- 1 exp migraine/ (44420) 2 migraine*.ti,ab. (35137) 3 1 or 2 (48545) 4 letter.pt. or letter/ (859278) 5 note.pt. (569101) 6 editorial.pt. (456329) 7 case report/ or case study/ (1962642) 8 animal/ not human/ (1196719) 9 nonhuman/ (4373472) 10 animals, laboratory/ (17700) 11 exp experimental animal/ (416671) 12 exp animal experiment/ (1802957) 13 animals, laboratory/ (17700) 14 exp animal model/ (787035) 15 exp rodent/ (2912527) 16 or/4-15 (9876963) 17 "review"/ or review.pt. or review.ti. (2235771) 18 (systematic or evidence* or methodol* or quantitativ* or analys* or assessment*).ti,sh,ab. (7291552) 19 17 and 18 (653798) 20 Meta-Analysis/ (82731) 21 "systematic review"/ (79634) 22 (meta-analy* or metanaly* or metaanaly* or meta analy*).mp. (128371) 23 ((systematic* or evidence* or methodol* or quantitativ*) adj5 (review* or survey* or overview*)).ti,ab,sh. (312206) 24 ((pool* or combined or combining) adj (data or trials or studies or results)).ti,ab. (18085) 25 or/19-24 (797629) 26 randomized controlled trial/ (352287) 27 crossover procedure/ (40203) 28 single blind procedure/ (18818) 29 double blind procedure/ (117867) 30 random*.ti,ab. (912334) 31 factorial*.ti,ab. (23860) 32 (crossover* or cross over* or cross-over*).ti,ab. (72264) 33 ((doubl* or singl*) adj blind*).ti,ab. (163247) 34 (assign* or allocat* or volunteer*).ti,ab. (507549) 35 or/26-34 (1420615) 36 25 or 35 (2109599) 37 3 not 16 (34198) 38 36 and 37 (7314) 39 exp antimigraine agent/ (251772) 40 antiemetics/ or domperidone/ or metoclopramide/ or cinnarizine/ or cyclizine/ (38678) 41 antiemetic*.mp. (16935) 42 Domperidone.mp. (7679) 43 Metoclopramide.mp. (22311) 44 Cinnarizine.mp. (2326) 45 Cyclizine.mp. (1394) 46 phenothiazine derivative/ or prochlorperazine/ or perphenazine/ or trifluoperazine/ or promethazine/ (39579)

192 47 Phenothiazine*.mp. (17048) 48 Prochlorperazine.mp. (6046) 49 Perphenazine.mp. (7135) 50 Trifluoperazine.mp. (10479) 51 Promethazine.mp. (12907) 52 exp antihistaminic agent/ (172011) 53 antihistamine*.mp. (12863) 54 Cyproheptadine.mp. (7699) 55 migraleve.mp. (37) 56 migramax.mp. (7) 57 paramax.mp. (54) 58 or/39-57 (443090) 59 38 and 58 (3056) 60 limit 59 to yr="2012 -Current" (464) CINAHL S12 S11Limiters - Published Date: 20120101-20141231; English Language; Clinical Queries: Therapy - Best Balance, Review - Best Balance Search modes - Boolean/Phrase 46 S11 S3 AND S10 275 S10 S4 OR S5 OR S6 OR S7 OR S8 OR S9 10,380 S9 antiemetic* or cyclizine or domperidone or metoclopramide or cinnarizine 2,123 S8 phenothiazine* or prochlorperazine or perphenazine or trifluoperazine or promethazine 593 S7 (MH "Histamine Antagonists+") 3,208 S6 antihistamine* or cyproheptadine 895 S5 migraleve or migramax or paramax 1 S4 (MH "Antiemetics+") 6,867 S3 S1 OR S2 8,512 S2 "migraine*" 8,512 S1 (MH "Migraine") 7,095 Cochrane Search Name: Migraine antiemetics Date Run: 17/09/14 16:16:59.56 Description: ID Search Hits #1 migraine:ti,ab,kw (Word variations have been searched) 3039 #2 MeSH descriptor: [Migraine Disorders] explode all trees 1698 #3 #1 or #2 3039 #4 (antiemetic* or cyclizine or domperidone or metoclopramide or cinnarizine):ti,ab,kw (Word variations have been searched) 5103 #5 (phenothiazine* or prochlorperazine or perphenazine or trifluoperazine or promethazine):ti,ab,kw (Word variations have been searched) 1629 #6 MeSH descriptor: [Histamine Antagonists] explode all trees 2648 #7 (antihistamine* or cyproheptadine):ti,ab,kw (Word variations have been searched) 1761 #8 (migraleve or migramax or paramax):ti,ab,kw (Word variations have been searched) 7 #9 #4 or #5 or #6 or #7 or #8 9982 #10 #3 and #9 Publication Year from 2012 to 2014 15

193 Triptans 4- Should triptans versus antiemetics be used for acute migraine? 5- Should triptans versus paracetamol be used for acute migraine? 6- Should triptans, in combination with NSAIDs, versus NSAIDs be used for acute migraine? 7- Should triptans, in combination with NSAIDs, versus triptans be used for acute migraine? 12- Should triptans versus no triptans be used for prevention of recurrence of menstrual-related migraine? Population Intervention comparator Study filter Migraine Pharmacological n/a RCTs&SRs NOT exclusion terms for: Trip- Medline, filter tans Embase & Cinahl Date database results 2012+ 2014/09/17 MEDLINE 141 2012+ 2014/09/17 EMBASE 292 CINAHL 168 Cochrane 87 subtotal 684 -duplicatees 257 total 427 MEDLINE Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present> Search Strategy: -------------------------------------------------------------------------------- 1 exp Migraine Disorders/ (21834) 2 migraine*.ti,ab. (25125) 3 1 or 2 (29349) 4 Letter/ (858890) 5 Editorial/ (366730) 6 exp Historical Article/ (327344) 7 Anecdotes as Topic/ (4608) 8 Comment/ (604207) 9 Case Reports/ (1714101) 10 animals/ not humans/ (3918587) 11 exp Animals, Laboratory/ (739371) 12 exp Animal Experimentation/ (6497) 13 exp Models, Animal/ (427801) 14 exp Rodentia/ (2719652) 15 or/4-14 (7704363) 16 3 not 15 (21935) 17 Tryptamines/ (4694) 18 Sumatriptan/ (2029)

194 19 (triptan* or Almotriptan or Eletriptan or Frovatriptan or Naratriptan or Rizatriptan or Sumatriptan or Zolmitriptan).mp. (4403) 20 (almogran or relpax or migard or naramig or maxalt or imigran or zomig).mp. (85) 21 or/17-20 (7740) 22 16 and 21 (2511) 23 "review"/ or review.pt. or review.ti. (2044159) 24 (systematic or evidence* or methodol* or quantitativ*).ti,ab. (1987197) 25 23 and 24 (335122) 26 Meta-Analysis/ (51846) 27 Meta-Analysis as Topic/ (14118) 28 (meta-analy* or metanaly* or metaanaly* or meta analy*).ti,ab. (70243) 29 ((systematic* or evidence* or methodol* or quantitativ*) adj3 (review* or overview*)).ti,ab. (96592) 30 ((pool* or combined or combining) adj2 (data or trials or studies or results)).ti,ab. (41011) 31 or/25-30 (440836) 32 randomized controlled trial.pt. (389021) 33 controlled clinical trial.pt. (89864) 34 randomi#ed.ab. (370769) 35 placebo.ab. (159833) 36 randomly.ab. (223013) 37 Clinical Trials as topic.sh. (173122) 38 trial.ti. (133979) 39 or/32-38 (960928) 40 31 or 39 (1325418) 41 22 and 40 (1101) 42 limit 41 to (yr="2012-2015" and english) (141) EMBASE Database: Embase <1974 to 2014 September 16> Search Strategy: -------------------------------------------------------------------------------- 1 exp migraine/ (44424) 2 migraine*.ti,ab. (35141) 3 1 or 2 (48549) 4 letter.pt. or letter/ (859329) 5 note.pt. (569153) 6 editorial.pt. (456358) 7 case report/ or case study/ (1962730) 8 animal/ not human/ (1196721) 9 nonhuman/ (4373839) 10 animals, laboratory/ (17700) 11 exp experimental animal/ (416689) 12 exp animal experiment/ (1803096) 13 animals, laboratory/ (17700) 14 exp animal model/ (787129) 15 exp rodent/ (2912687) 16 or/4-15 (9877523) 17 "review"/ or review.pt. or review.ti. (2235967) 18 (systematic or evidence* or methodol* or quantitativ* or analys* or assessment*).ti,sh,ab. (7292011)

195 19 17 and 18 (653872) 20 Meta-Analysis/ (82741) 21 "systematic review"/ (79661) 22 (meta-analy* or metanaly* or metaanaly* or meta analy*).mp. (128392) 23 ((systematic* or evidence* or methodol* or quantitativ*) adj5 (review* or survey* or overview*)).ti,ab,sh. (312248) 24 ((pool* or combined or combining) adj (data or trials or studies or results)).ti,ab. (18086) 25 or/19-24 (797722) 26 randomized controlled trial/ (352320) 27 crossover procedure/ (40208) 28 single blind procedure/ (18819) 29 double blind procedure/ (117875) 30 random*.ti,ab. (912439) 31 factorial*.ti,ab. (23860) 32 (crossover* or cross over* or cross-over*).ti,ab. (72271) 33 ((doubl* or singl*) adj blind*).ti,ab. (163257) 34 (assign* or allocat* or volunteer*).ti,ab. (507585) 35 or/26-34 (1420743) 36 25 or 35 (2109803) 37 3 not 16 (34201) 38 36 and 37 (7314) 39 exp triptan derivative/ (2297) 40 (triptan* or Almotriptan or Eletriptan or Frovatriptan or Naratriptan or Rizatriptan or Sumatriptan or Zolmitriptan).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] (11405) 41 (almogran or relpax or migard or naramig or maxalt or imigran or zomig).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] (990) 42 or/39-41 (11407) 43 38 and 42 (1689) 44 limit 43 to yr="2012 -Current" (292) CINAHL S9 S8 Limiters - Published Date: 20120101-20141231; English Language; Clinical Queries: Therapy - Best Balance, Review - Best Balance Search modes - Boolean/Phrase 168 S8 S3 AND S7 168 S7 S4 OR S5 OR S6 314 S6 almogran or relpax or migard or naramig or maxalt or imigran or zomig 0 S5 triptan* or Almotriptan or Eletriptan or Frovatriptan or Naratriptan or Rizatriptan or Sumatriptan or Zolmitriptan 168 S4 (MH "Tryptamines+") 171 S3 S1 OR S2 8,512 S2 "migraine*" 8,512 S1 (MH "Migraine") 7,095 Search Name: Migraine triptans Date Run: 17/09/14 16:54:54.196 Description:

196 ID Search Hits #1 migraine:ti,ab,kw (Word variations have been searched) 3039 #2 MeSH descriptor: [Migraine Disorders] explode all trees 1698 #3 #1 or #2 3039 #4 MeSH descriptor: [Tryptamines] explode all trees 2201 #5 (triptan* or Almotriptan or Eletriptan or Frovatriptan or Naratriptan or Rizatriptan or Sumatriptan or Zolmitriptan):ti,ab,kw (Word variations have been searched) 926 #6 (almogran or relpax or migard or naramig or maxalt or imigran or zomig):ti,ab,kw (Word variations have been searched) 33 #7 #4 or #5 or #6 2540 #8 #3 and #7 Publication Year from 2012 to 2014 87 Topiramate, antiepileptics betablockers 8- Should beta-blockers versus no beta-blockers be used for prevention of recurrence 9- Should antiepileptics versus no antiepileptics be used for prevention of recurrence 10- Should topiramate versus sodium valproate be used for prevention of recurrence 11- Should topiramate versus beta-blockers be used for prevention of recurrence Population Intervention comparator Study filter Migraine n/a NOT exclusion filter Pharmacological terms for: Antiepileptics, BetaBlockers OR Topiramate RCTs&SRs Medline, Embase & Cinahl Date database results 2012+ 2014/09/18 2012+ 2014/09/18 MEDLINE 96 EMBASE 243 CINAHL 107 Cochrane 64 subtotal 510 -duplicatees 148 total 362 Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present> Search Strategy: -------------------------------------------------------------------------------- 1 exp Migraine Disorders/ (21840) 2 migraine*.ti,ab. (25117) 3 1 or 2 (29342) 4 Letter/ (858437) 5 Editorial/ (366451) 6 exp Historical Article/ (327360) 7 Anecdotes as Topic/ (4608) 8 Comment/ (603798) 9 Case Reports/ (1714551) 10 animals/ not humans/ (3919036) 11 exp Animals, Laboratory/ (739473) 12 exp Animal Experimentation/ (6501)

197 13 exp Models, Animal/ (427914) 14 exp Rodentia/ (2719940) 15 or/4-14 (7704511) 16 3 not 15 (21926) 17 Metoclopramide.mp. (6451) 18 "review"/ or review.pt. or review.ti. (2044157) 19 (systematic or evidence* or methodol* or quantitativ*).ti,ab. (1985878) 20 18 and 19 (335046) 21 Meta-Analysis/ (51872) 22 Meta-Analysis as Topic/ (14119) 23 (meta-analy* or metanaly* or metaanaly* or meta analy*).ti,ab. (70144) 24 ((systematic* or evidence* or methodol* or quantitativ*) adj3 (review* or overview*)).ti,ab. (96467) 25 ((pool* or combined or combining) adj2 (data or trials or studies or results)).ti,ab. (40987) 26 or/20-25 (440650) 27 randomized controlled trial.pt. (389067) 28 controlled clinical trial.pt. (89866) 29 randomi#ed.ab. (370410) 30 placebo.ab. (159740) 31 randomly.ab. (222828) 32 Clinical Trials as topic.sh. (173132) 33 trial.ti. (133839) 34 or/27-33 (960408) 35 26 or 34 (1324753) 36 16 and 35 (4502) 37 exp Adrenergic beta-antagonists/ (77818) 38 (beta-blocker* or beta?blocker*).ti,ab. (24649) 39 (propranolol or metoprolol or nadolol or timolol or atenolol).ti,ab. (43177) 40 methysergide/ (2858) 41 pizotyline/ (246) 42 Ergotamine/ (2116) 43 Cyproheptadine/ (2087) 44 (serotonergic adj2 modulator*).ti,ab. (53) 45 (methysergide or pizotifen or pizotyline or ergotamine or cyproheptadine).ti,ab. (6747) 46 exp Anticonvulsants/ (120235) 47 (anticonvulsant* or antiepileptic or anti-epileptic*).ti,ab. (35406) 48 (sodium valproate or valproic acid or topiramate or gabapentin).ti,ab. (14885) 49 or/37-48 (242153) 50 36 and 49 (855) 51 limit 50 to yr="2012 -Current" (96) Database: Embase <1974 to 2014 September 17> Search Strategy: -------------------------------------------------------------------------------- 1 exp migraine/ (44426) 2 migraine*.ti,ab. (35144) 3 1 or 2 (48552) 4 letter.pt. or letter/ (859361) 5 note.pt. (569289) 6 editorial.pt. (456394)

198 7 case report/ or case study/ (1962868) 8 animal/ not human/ (1196942) 9 nonhuman/ (4374065) 10 animals, laboratory/ (17700) 11 exp experimental animal/ (416738) 12 exp animal experiment/ (1803231) 13 animals, laboratory/ (17700) 14 exp animal model/ (787218) 15 exp rodent/ (2912875) 16 or/4-15 (9878291) 17 "review"/ or review.pt. or review.ti. (2236112) 18 (systematic or evidence* or methodol* or quantitativ* or analys* or assessment*).ti,sh,ab. (7292827) 19 17 and 18 (653942) 20 Meta-Analysis/ (82758) 21 "systematic review"/ (79673) 22 (meta-analy* or metanaly* or metaanaly* or meta analy*).mp. (128416) 23 ((systematic* or evidence* or methodol* or quantitativ*) adj5 (review* or survey* or overview*)).ti,ab,sh. (312306) 24 ((pool* or combined or combining) adj (data or trials or studies or results)).ti,ab. (18088) 25 or/19-24 (797812) 26 randomized controlled trial/ (352340) 27 crossover procedure/ (40217) 28 single blind procedure/ (18821) 29 double blind procedure/ (117878) 30 random*.ti,ab. (912555) 31 factorial*.ti,ab. (23863) 32 (crossover* or cross over* or cross-over*).ti,ab. (72281) 33 ((doubl* or singl*) adj blind*).ti,ab. (163262) 34 (assign* or allocat* or volunteer*).ti,ab. (507643) 35 or/26-34 (1420910) 36 25 or 35 (2110046) 37 3 not 16 (34202) 38 36 and 37 (7314) 39 exp *beta adrenergic receptor blocking agent/ (103915) 40 (beta-blocker* or beta?blocker*).ti,ab. (35217) 41 (propranolol or metoprolol or nadolol or timolol or atenolol).ti,ab. (52309) 42 (serotonergic adj2 modulator*).ti,ab. (67) 43 (methysergide or pizotifen or pizotyline or ergotamine or cyproheptadine).ti,ab. (7650) 44 methysergide/ or methysergide maleate/ (9119) 45 pizotifen/ or pizotifen maleate/ (1829) 46 ergotamine/ or ergotamine tartrate/ (6152) 47 cyproheptadine/ (7450) 48 exp anticonvulsive agent/ (294186) 49 (anticonvulsant* or antiepileptic or anti-epileptic*).ti,ab. (50143) 50 (sodium valproate or valproic acid or topiramate or gabapentin).ti,ab. (21139) 51 or/39-50 (447439) 52 38 and 51 (1592) 53 limit 52 to (english language and yr="2012 -Current") (243)

199 CINAHL S10 S9 Limiters - Published Date: 20120101-20141231; English Language; Clinical Queries: Therapy - Best Balance, Review - Best Balance 107 S9 S3 AND S8 801 S8 S4 OR S5 OR S6 OR S7 16,901 S7 (propranolol or metoprolol or nadolol or timodol or atenolol or methysergide or pizotyline or pizotifen or ergotamine or cyproheptadine or "sodium valproate" or "valproic acid" or topiramate or gabapentin or anticonvulsant* or antiepileptic* or anti-epileptic*) 8,903 S6 beta-blocker* OR beta blocker* 2,561 S5 (MH "Anticonvulsants+") 8,503 S4 (MH "Adrenergic Beta-Antagonists+") 5,674 S3 S1 OR S2 8,513 S2 "migraine*" 8,513 S1 (MH "Migraine") 7,095 Cochrane Search Name: MigraineAntiEps BBs Date Run: 18/09/14 18:56:49.26 Description: ID Search Hits #1 migraine:ti,ab,kw (Word variations have been searched) 3039 #2 MeSH descriptor: [Migraine Disorders] explode all trees 1698 #3 #1 or #2 3039 #4 MeSH descriptor: [Adrenergic beta-antagonists] explode all trees 4195 #5 MeSH descriptor: [Anticonvulsants] explode all trees 2083 #6 (propranolol or metoprolol or nadolol or timodol or atenolol or methysergide or pizotyline or pizotifen or ergotamine or cyproheptadine or "sodium valproate" or "valproic acid" or topiramate or gabapentin or anticonvulsant* or antiepileptic* or anti-epileptic*) 14715 #7 #4 or #5 or #6 16967 #8 #3 and #7 Publication Year from 2012 to 2014 64 Botox 13. Should botox injections versus no botox injections be used for prevention of recurrence of migraine? Population Intervention comparator Study filter Migraine Botox n/a RCTs&SRs NOT exclusion Medline, filter Embase & Cinahl Date database results 2012+ 2014/09/24 MEDLINE 22 2012+ 2014/09/24 EMBASE 72 CINAHL 40 Cochrane 21 subtotal 155

200 -duplicates 31 total 124 MEDLINE Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present> Search Strategy: -------------------------------------------------------------------------------- 1 exp Migraine Disorders/ (21851) 2 migraine*.ti,ab. (25162) 3 1 or 2 (29388) 4 Letter/ (859569) 5 Editorial/ (367186) 6 exp Historical Article/ (327464) 7 Anecdotes as Topic/ (4612) 8 Comment/ (605107) 9 Case Reports/ (1715202) 10 animals/ not humans/ (3920844) 11 exp Animals, Laboratory/ (739877) 12 exp Animal Experimentation/ (6506) 13 exp Models, Animal/ (428244) 14 exp Rodentia/ (2721365) 15 or/4-14 (7709774) 16 3 not 15 (21964) 17 Metoclopramide.mp. (6455) 18 "review"/ or review.pt. or review.ti. (2046329) 19 (systematic or evidence* or methodol* or quantitativ*).ti,ab. (1990036) 20 18 and 19 (335746) 21 Meta-Analysis/ (52013) 22 Meta-Analysis as Topic/ (14144) 23 (meta-analy* or metanaly* or metaanaly* or meta analy*).ti,ab. (70473) 24 ((systematic* or evidence* or methodol* or quantitativ*) adj3 (review* or overview*)).ti,ab. (96923) 25 ((pool* or combined or combining) adj2 (data or trials or studies or results)).ti,ab. (41104) 26 or/20-25 (441703) 27 randomized controlled trial.pt. (389365) 28 controlled clinical trial.pt. (89884) 29 randomi#ed.ab. (371282) 30 placebo.ab. (159975) 31 randomly.ab. (223296) 32 Clinical Trials as topic.sh. (173203) 33 trial.ti. (134164) 34 or/27-33 (961910) 35 26 or 34 (1327057) 36 16 and 35 (4511) 37 exp Botulinum Toxins/ (12676) 38 botox*.mp. (1406) 39 botulinum.mp. (17346) 40 or/37-39 (17483) 41 36 and 40 (144)

201 42 limit 41 to yr="2012 -Current" (22) EMBASE Database: Embase <1974 to 2014 September 23> Search Strategy: -------------------------------------------------------------------------------- 1 exp migraine/ (44446) 2 migraine*.ti,ab. (35167) 3 1 or 2 (48576) 4 letter.pt. or letter/ (859575) 5 note.pt. (569978) 6 editorial.pt. (456589) 7 case report/ or case study/ (1963805) 8 animal/ not human/ (1197646) 9 nonhuman/ (4376086) 10 animals, laboratory/ (17710) 11 exp experimental animal/ (417172) 12 exp animal experiment/ (1804116) 13 animals, laboratory/ (17710) 14 exp animal model/ (787945) 15 exp rodent/ (2914319) 16 or/4-15 (9883280) 17 "review"/ or review.pt. or review.ti. (2237354) 18 (systematic or evidence* or methodol* or quantitativ* or analys* or assessment*).ti,sh,ab. (7299892) 19 17 and 18 (654488) 20 Meta-Analysis/ (82910) 21 "systematic review"/ (79910) 22 (meta-analy* or metanaly* or metaanaly* or meta analy*).mp. (128674) 23 ((systematic* or evidence* or methodol* or quantitativ*) adj5 (review* or survey* or overview*)).ti,ab,sh. (312740) 24 ((pool* or combined or combining) adj (data or trials or studies or results)).ti,ab. (18105) 25 or/19-24 (798662) 26 randomized controlled trial/ (352660) 27 crossover procedure/ (40250) 28 single blind procedure/ (18841) 29 double blind procedure/ (117955) 30 random*.ti,ab. (913941) 31 factorial*.ti,ab. (23885) 32 (crossover* or cross over* or cross-over*).ti,ab. (72327) 33 ((doubl* or singl*) adj blind*).ti,ab. (163403) 34 (assign* or allocat* or volunteer*).ti,ab. (508162) 35 or/26-34 (1422691) 36 25 or 35 (2112509) 37 3 not 16 (34224) 38 36 and 37 (7320) 39 botulinum toxin A/ (13900) 40 botulinum toxin/ (11811) 41 botulinum.mp. (28241) 42 botox*.mp. (5295)

202 43 or/39-42 (28320) 44 38 and 43 (289) 45 limit 44 to (english language and yr="2012 -Current") (72) Cochrane Search Name: Date Run: 24/09/14 18:47:38.715 Description: ID Search Hits #1 MeSH descriptor: [Botulinum Toxins] explode all trees 916 #2 "Botox":ti,ab,kw (Word variations have been searched) 264 #3 "botulinum":ti,ab,kw (Word variations have been searched) 1560 #4 #1 or #2 or #3 1592 #5 MeSH descriptor: [Migraine Disorders] explode all trees 1698 #6 headache* or migraine*:ti,ab,kw (Word variations have been searched) 13391 #7 #5 or #6 13391 #8 #4 and #7 Publication Year from 2012 to 2014 21 CINAHLS6 S5 Limiters - Published Date: 20120101-20141231; Clinical Queries: Therapy - Best Balance, Review - Best Balance 40 S5 S3 AND S4 217 S4 (MH "Botulinum Toxins") OR "botox" 2,500 S3 S1 OR S2 8,509 S2 "migraine*" 8,509 S1 (MH "Migraine") 7,087 Antidepressants for all headaches 14. Should antidepressants versus no antidepressants be used for prevention of recurrence of migraine? Population Intervention comparator Study filter Headaches antidepressants n/a RCTs&SRs NOT exclusion Medline, filter Embase & Cinahl Date database results 2012+ 2014/09/23 MEDLINE 25 2012+ 2014/09/23 EMBASE 27 CINAHL 21 Cochrane 3 subtotal 76 -duplicates 14 total 62

203 MEDLINE Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present> Search Strategy: -------------------------------------------------------------------------------- 1 Headache/ (22690) 2 exp Headache Disorders/ (26979) 3 (headache* or migraine*).ti,ab. (73760) 4 or/1-3 (84687) 5 Letter/ (859295) 6 Editorial/ (366964) 7 exp Historical Article/ (327438) 8 Anecdotes as Topic/ (4612) 9 Comment/ (604638) 10 Case Reports/ (1714972) 11 animals/ not humans/ (3920331) 12 exp Animals, Laboratory/ (739759) 13 exp Animal Experimentation/ (6503) 14 exp Models, Animal/ (428163) 15 exp Rodentia/ (2720991) 16 or/5-15 (7708283) 17 4 not 16 (58526) 18 "review"/ or review.pt. or review.ti. (2045712) 19 (systematic or evidence* or methodol* or quantitativ*).ti,ab. (1989115) 20 18 and 19 (335570) 21 Meta-Analysis/ (51985) 22 Meta-Analysis as Topic/ (14139) 23 (meta-analy* or metanaly* or metaanaly* or meta analy*).ti,ab. (70421) 24 ((systematic* or evidence* or methodol* or quantitativ*) adj3 (review* or overview*)).ti,ab. (96823) 25 ((pool* or combined or combining) adj2 (data or trials or studies or results)).ti,ab. (41080) 26 or/20-25 (441463) 27 randomized controlled trial.pt. (389260) 28 controlled clinical trial.pt. (89874) 29 randomi#ed.ab. (371068) 30 placebo.ab. (159930) 31 randomly.ab. (223175) 32 Clinical Trials as topic.sh. (173170) 33 trial.ti. (134063) 34 or/27-33 (961502) 35 26 or 34 (1326454) 36 exp Antidepressive Agents, Tricyclic/ (29383) 37 tricyclic*.ti,ab. (13706) 38 (amitryptyline or amitriptiline or imipramine or nortriptyline or desipramine or dosulepin).ti,ab. (14743) 39 36 or 37 or 38 (40583) 40 17 and 35 and 39 (260) 41 limit 40 to yr="2012 -Current" (25)

204 EMBASE Database: Embase <1974 to 2014 September 22> Search Strategy: -------------------------------------------------------------------------------- 1 exp tension headache/ (5575) 2 (headache* adj3 (tension or tension type or muscle contraction or psychomyogenic or stress or ordinary or essential or idiopathic or psychogenic)).tw. (5397) 3 ((chronic adj2 daily adj2 headache) or (daily adj2 persistent adj2 headache*)).ti,ab. (1180) 4 or/1-3 (8109) 5 letter.pt. or letter/ (859506) 6 note.pt. (569792) 7 editorial.pt. (456536) 8 case report/ or case study/ (1963634) 9 animal/ not human/ (1197434) 10 nonhuman/ (4375246) 11 animals, laboratory/ (17707) 12 exp experimental animal/ (417030) 13 exp animal experiment/ (1803698) 14 animals, laboratory/ (17707) 15 exp animal model/ (787650) 16 exp rodent/ (2913839) 17 or/5-16 (9881778) 18 "review"/ or review.pt. or review.ti. (2236964) 19 (systematic or evidence* or methodol* or quantitativ* or analys* or assessment*).ti,sh,ab. (7298427) 20 18 and 19 (654325) 21 Meta-Analysis/ (82872) 22 "systematic review"/ (79817) 23 (meta-analy* or metanaly* or metaanaly* or meta analy*).mp. (128590) 24 ((systematic* or evidence* or methodol* or quantitativ*) adj5 (review* or survey* or overview*)).ti,ab,sh. (312624) 25 ((pool* or combined or combining) adj (data or trials or studies or results)).ti,ab. (18104) 26 or/20-25 (798395) 27 randomized controlled trial/ (352605) 28 crossover procedure/ (40246) 29 single blind procedure/ (18839) 30 double blind procedure/ (117940) 31 random*.ti,ab. (913584) 32 factorial*.ti,ab. (23879) 33 (crossover* or cross over* or cross-over*).ti,ab. (72322) 34 ((doubl* or singl*) adj blind*).ti,ab. (163383) 35 (assign* or allocat* or volunteer*).ti,ab. (508063) 36 or/27-35 (1422255) 37 26 or 36 (2111845) 38 4 not 17 (6823) 39 37 and 38 (1553) 40 exp tricyclic antidepressant agent/ (99646) 41 tricyclic*.ti,ab. (18669)

205 42 (amitryptyline or amitriptiline or imipramine or nortriptyline or desipramine or dosulepin).ti,ab. (17032) 43 40 or 41 or 42 (107842) 44 39 and 43 (230) 45 limit 44 to (english language and yr="2012 -Current") (27) Cochrane Search Name: Date Run: 23/09/14 17:09:13.380 Description: ID Search Hits #1 headache* or migraine*:ti,ab,kw (Word variations have been searched) 13391 #2 MeSH descriptor: [Antidepressive Agents, Tricyclic] explode all trees 1005 #3 (tricyclic* or amitryptyline or amitriptiline or imipramine or nortriptyline or desipramine or dosulepin):ti,ab,kw (Word variations have been searched) 4240 #4 #2 or #3 4240 #5 #1 and #2 Publication Year from 2012 to 2014 3 CINAHLS8 S7 Limiters - Published Date: 20120101-20141231; Clinical Queries: Therapy - Best Balance, Review - Best Balance 21 S7 S3 AND S6 183 S6 S4 OR S5 2,363 S5 (tricyclic* or amitryptyline or amitriptiline or imipramine or nortriptyline or desipramine or dosulepin) 1,955 S4 (MH "Antidepressive Agents, Tricyclic+") 1,765 S3 S1 or S2 17,681 S2 headache* or migraine* 17,673 S1 (MH "Headache+") 13,383 Education and self-management programmes 15- Should education and self-management programs versus no such programs (or usual care) be used for the prevention of recurrence of migraine? Population Intervention comparator Study filter Migraine n/a NOT exclusion filter Education and selfmanagement programmes RCTs&SRs Medline, Embase & Cinahl Date database results 2012+ 2014/09/12 MEDLINE 26 2012+ 2014/09/16 EMBASE 93 PsycInfo 16 CINAHL 73 Cochrane 8 subtotal 216 -duplicates 28

206 total 188 Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present> Search Strategy: -------------------------------------------------------------------------------- 1 exp Migraine Disorders/ (21843) 2 migraine*.ti,ab. (25138) 3 1 or 2 (29363) 4 Letter/ (858942) 5 Editorial/ (366743) 6 exp Historical Article/ (327410) 7 Anecdotes as Topic/ (4612) 8 Comment/ (604306) 9 Case Reports/ (1714747) 10 animals/ not humans/ (3919722) 11 exp Animals, Laboratory/ (739599) 12 exp Animal Experimentation/ (6502) 13 exp Models, Animal/ (428031) 14 exp Rodentia/ (2720416) 15 or/4-14 (7706544) 16 3 not 15 (21944) 17 Metoclopramide.mp. (6452) 18 "review"/ or review.pt. or review.ti. (2044949) 19 (systematic or evidence* or methodol* or quantitativ*).ti,ab. (1987525) 20 18 and 19 (335286) 21 Meta-Analysis/ (51913) 22 Meta-Analysis as Topic/ (14126) 23 (meta-analy* or metanaly* or metaanaly* or meta analy*).ti,ab. (70288) 24 ((systematic* or evidence* or methodol* or quantitativ*) adj3 (review* or overview*)).ti,ab. (96634) 25 ((pool* or combined or combining) adj2 (data or trials or studies or results)).ti,ab. (41028) 26 or/20-25 (441051) 27 randomized controlled trial.pt. (389176) 28 controlled clinical trial.pt. (89873) 29 randomi#ed.ab. (370731) 30 placebo.ab. (159836) 31 randomly.ab. (223025) 32 Clinical Trials as topic.sh. (173150) 33 trial.ti. (133957) 34 or/27-33 (960980) 35 26 or 34 (1325657) 36 16 and 35 (4506) 37 Self Care/ or Social Support/ or Counseling/ (102051) 38 Self-Help Groups/ or exp Patient participation/ (26350) 39 health education/ or exp consumer health information/ or patient education as topic/ or Communication/ or Health Communication/ (184660) 40 patient education handout/ (4038) 41 teaching/ or exp Programmed Instruction as Topic/ (53182) 42 exp communications media/ or Hotlines/ or exp Internet/ (279071)

207 43 information centers/ or information services/ or learning/ (63717) 44 Information Dissemination/ or Health Knowledge, Attitudes, Practice/ (84914) 45 (self care or self-care or selfcare or selfhelp or self-help or self help or self-management or self management).ti,ab. (23503) 46 (social support or support group*).ti,ab. (27202) 47 ((education* or learn* or training or teach*) adj2 (program* or patient* or consumer* or material* or resource* or aid*)).ti,ab. (97244) 48 (information adj2 (resource* or leaflet* or pamphlet* or handout*)).ti,ab. (4120) 49 (patient adj (information or knowledge or website*)).ti,ab. (6042) 50 (workshop* or counse?ling or seminar* or discussion group*).ti,ab. (96380) 51 (factsheet* or advice line* or advice-line* or help line* or help-line* or helpline*).ti,ab. (648) 52 or/37-51 (839917) 53 36 and 52 (125) 54 limit 53 to yr="2012 -Current" (26) EMBASE Database: Embase <1974 to 2014 September 19> Search Strategy: -------------------------------------------------------------------------------- 1 exp migraine/ (44436) 2 migraine*.ti,ab. (35157) 3 1 or 2 (48565) 4 letter.pt. or letter/ (859478) 5 note.pt. (569644) 6 editorial.pt. (456493) 7 case report/ or case study/ (1963238) 8 animal/ not human/ (1197330) 9 nonhuman/ (4374920) 10 animals, laboratory/ (17700) 11 exp experimental animal/ (416806) 12 exp animal experiment/ (1803552) 13 animals, laboratory/ (17700) 14 exp animal model/ (787430) 15 exp rodent/ (2913318) 16 or/4-15 (9880354) 17 "review"/ or review.pt. or review.ti. (2236617) 18 (systematic or evidence* or methodol* or quantitativ* or analys* or assessment*).ti,sh,ab. (7294846) 19 17 and 18 (654134) 20 Meta-Analysis/ (82799) 21 "systematic review"/ (79728) 22 (meta-analy* or metanaly* or metaanaly* or meta analy*).mp. (128495) 23 ((systematic* or evidence* or methodol* or quantitativ*) adj5 (review* or survey* or overview*)).ti,ab,sh. (312441) 24 ((pool* or combined or combining) adj (data or trials or studies or results)).ti,ab. (18091) 25 or/19-24 (798078) 26 randomized controlled trial/ (352502) 27 crossover procedure/ (40233) 28 single blind procedure/ (18833) 29 double blind procedure/ (117924)

208 30 random*.ti,ab. (912999) 31 factorial*.ti,ab. (23869) 32 (crossover* or cross over* or cross-over*).ti,ab. (72297) 33 ((doubl* or singl*) adj blind*).ti,ab. (163307) 34 (assign* or allocat* or volunteer*).ti,ab. (507808) 35 or/26-34 (1421472) 36 25 or 35 (2110826) 37 3 not 16 (34215) 38 36 and 37 (7317) 39 self care/ or self help/ or social support/ (98102) 40 health education/ or patient education/ or patient participation/ (178761) 41 consumer health information/ or patient information/ (21781) 42 teaching/ or counseling/ or patient counseling/ (139603) 43 exp mass communication/ or interpersonal communication/ (472675) 44 information center/ or information dissemination/ or information service/ (36013) 45 learning/ or lifelong learning/ or self-directed learning/ (131251) 46 (self care or selfcare or self-care or selfhelp or self-help or self help or self-management or self management).ti,ab. (30748) 47 (support group* or social support).ti,ab. (33081) 48 ((education* or learn* or training or teach*) adj2 (program* or patient* or consumer* or material* or resource* or aid*)).ti,ab. (127368) 49 (information adj2 (resource* or leaflet* or pamphlet* or handout*)).ti,ab. (5532) 50 (patient adj (information or knowledge or website*)).ti,ab. (8729) 51 or/39-50 (1057344) 52 38 and 51 (398) 53 limit 52 to (english language and yr="2012 -Current") (93) PsycInfo Database: PsycINFO <1987 to September Week 3 2014> Search Strategy: -------------------------------------------------------------------------------- 1 migraine headache/ (6158) 2 migraine*.ti,ab. (7602) 3 1 or 2 (7901) 4 exp Self Help Techniques/ (6763) 5 Social Support/ (23171) 6 Counseling/ (12952) 7 Support Groups/ (3389) 8 Client Participation/ (1260) 9 health education/ or client education/ or health knowledge/ (14957) 10 communication/ or information dissemination/ (13604) 11 computer assisted instruction/ or individualized instruction/ or programmed instruction/ (12024) 12 exp Communications Media/ (36410) 13 Teaching/ (22372) 14 hot line services/ (602) 15 exp communication systems/ (24007) 16 information services/ (527) 17 learning/ (33223)

209 18 (self care or selfcare or self-care or selfhelp or self-help or self help or self-management or self management).ti,ab. (13788) 19 (support group$ or social support).ti,ab. (32298) 20 ((education$ or learn$ or training or teach$) adj2 (program$ or patient$ or consumer$ or material$ or resource$ or aid$)).ti,ab. (48416) 21 (information adj2 (resource$ or leaflet$ or pamphlet$ or handout$)).ti,ab. (1429) 22 (patient adj2 (information or knowledge or website$)).ti,ab. (1387) 23 (workshop$ or counselling or seminar$ or discussion group$).ti,ab. (20279) 24 (factsheet$ or advice line$ or advice-line$ or help line$ or help-line$ or helpline$).ti,ab. (352) 25 or/4-24 (256102) 26 3 and 25 (180) 27 limit 26 to (english language and yr="2012 -Current") (16) Cochrane Search Name: MigraineSelfHelp Date Run: 22/09/14 15:51:40.242 Description: ID Search Hits #1 migraine:ti,ab,kw (Word variations have been searched) 3039 #2 MeSH descriptor: [Migraine Disorders] explode all trees 1698 #3 #1 or #2 3039 #4 MeSH descriptor: [Self Care] this term only 2766 #5 MeSH descriptor: [Social Support] explode all trees 2387 #6 MeSH descriptor: [Counseling] this term only 2911 #7 MeSH descriptor: [Self-Help Groups] this term only 597 #8 MeSH descriptor: [Health Education] this term only 2969 #9 MeSH descriptor: [Consumer Health Information] explode all trees 168 #10 MeSH descriptor: [Consumer Health Information] explode all trees 168 #11 MeSH descriptor: [Patient Education as Topic] this term only 6572 #12 MeSH descriptor: [Communication] this term only 1423 #13 MeSH descriptor: [Teaching] this term only 1335 #14 MeSH descriptor: [Programmed Instruction as Topic] explode all trees 1018 #15 MeSH descriptor: [Communications Media] explode all trees 7072 #16 MeSH descriptor: [Hotlines] this term only 130 #17 MeSH descriptor: [Internet] explode all trees 1812 #18 MeSH descriptor: [Information Centers] this term only 2 #19 MeSH descriptor: [Information Services] this term only 101 #20 MeSH descriptor: [Learning] this term only 1349 #21 MeSH descriptor: [Information Dissemination] explode all trees 178 #22 MeSH descriptor: [Health Knowledge, Attitudes, Practice] explode all trees 3747 #23 (selfcare or "self care" or self-care or selfhelp or self-help or "self help" or self-management or "self management"):ti,ab,kw (Word variations have been searched) 5961 #24 ("social support" or "support group*"):ti,ab,kw (Word variations have been searched) 3893 #25 ((education* or training or teach* or learn*) near/2 (program* or consumer* or material* or aid* or resource* or patient*)):ti,ab,kw (Word variations have been searched) 18247 #26 (information next (resource* or leaflet* or pamphlet* or handout*)):ti,ab,kw (Word variations have been searched) 307

210 #27 (patient next (information or knowledge or website*)):ti,ab,kw (Word variations have been searched) 756 #28 (workshop* or counseling or counselling or seminar* or "discussion group*"):ti,ab,kw (Word variations have been searched) 9370 #29 (factsheet* or "advice line*" or advice-line* or help-line* or helpline* or "help line*"):ti,ab,kw (Word variations have been searched) 66 #30 #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 43290 #31 #3 and #30 Publication Year from 2012 to 2014 8 CINAHL # Query Results S13 S12 Limiters - Published Date: 20120101-20141231; Clinical Queries: Therapy - Best Balance, Review - Best Balance 73 S12 S8 AND S11 728 S11 S9 OR S10 8,513 S10 "migraine*" 8,513 S9 (MH "Migraine") 7,095 S8 S1 OR S2 OR S3 OR S4 OR S5 OR S6 OR S7 505,986 S7 information n2 resource* or information n2 leaflet* or information N2 pamphlet* or information N2 handout* or patient N2 information or patient n2 knowledge or patient N2 website* 59,613 S6 (education N2 program* or patient n2 education or consumer N2 education ) or (learn* N2 program* or training n2 program* or consumer n2 program* or patient N2 program* ) or (training N2 program* or patient n2 train* or consumer n2 train* ) 69,136 S5 (education N2 material* or education N2 resource* or education N2 aid* ) or (learn* N2 material* or learn* n2 resource* or learn N2 aid* ) or (training N2 resource* or training n2 aid* or training n2 material* or teach* N2 aid*or teach n2 resource* or teach N2 material* ) 5,403 S4 (self-care or selfcare or self care or selfhelp or self-help or self help or self-management or self management ) or (social support or support group* or workshop* or counseling or counselling or seminar* or discussion group* ) or (factsheet* or advice line* or advice-line* or help line* or helpline* or helpline* ) 85,975 S3 (MH "Learning") or (MH "Lifelong Learning") or (MH "Health Knowledge") or (MH "Information Needs") 31,783 S2 (MH "Teaching") or (MH "Self Directed Learning") or (MH "Teaching Materials") or (MH "Programmed Instruction+") or (MH "Seminars and Workshops") or (MH "Communications Media+") or (MH "Information Centers") or (MH "Telephone Information Services") or (MH "Library Services") or (MH "Information Services") or (MH "Pamphlets") 312,570 S1 (MH "Self Care") or (MH "Support, Psychosocial") or (MH "Counseling") or (MH "Support Groups") or (MH "Consumer Participation") or (MH "Health Education") or (MH "Health Information") or (MH "Consumer Health Information") or (MH "Libraries, Consumer Health") or (MH "Patient Education") or (MH "Communication") Cost effectiveness all Migraine Interventions Population Intervention comparator Study filter Date database results Migraine terms for: cost effectiveness n/a 2012+ 2014/10/01 MEDLINE 111

211 2012+ 2014/10/01 EMBASE 531 subtotal 642 -duplicates 104 total 538 MEDLINE Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present> Search Strategy: -------------------------------------------------------------------------------- 1 economics/ or exp economics, hospital/ or exp economics, medical/ or economics, nursing/ or economics, pharmaceutical/ (66164) 2 exp "Costs and Cost Analysis"/ (185533) 3 Value-Based Purchasing/ (210) 4 exp "Fees and Charges"/ (27365) 5 budget$.mp. or Budgets/ (25530) 6 (low adj cost).mp. (26862) 7 (high adj cost).mp. (8502) 8 (health?care adj cost$).mp. (4948) 9 (cost adj estimate$).mp. (1513) 10 (cost adj variable$).mp. (110) 11 (unit adj cost$).mp. (1669) 12 (fiscal or funding or financial or finance).tw. (88002) 13 (economic$ or pharmacoeconomic$ or price$ or pricing).tw. (185535) 14 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 (497725) 15 exp Migraine Disorders/ (21872) 16 migraine*.ti,ab. (25192) 17 15 or 16 (29419) 18 14 and 17 (709) 19 limit 18 to yr="2012 -Current" (118) 20 remove duplicates from 19 (111) Database: Embase <1974 to 2014 September 30> Search Strategy: -------------------------------------------------------------------------------- 1 economic evaluation$.mp. or exp economic evaluation/ (217851) 2 fee$.mp. or exp fee/ (603101) 3 health care cost$.mp. or exp "health care cost"/ (213071) 4 hospital cost$.mp. or exp "hospital cost"/ (29319) 5 pharmacoeconomics.mp. or exp pharmacoeconomics/ (170740) 6 health economics.mp. or health economics/ (35964) 7 budget$.mp. or budget/ (36207) 8 socioeconomics.mp. or socioeconomics/ (110593) 9 1 or 2 or 3 or 4 or 5 or 6 (1073330) 10 7 or 9 (1095858) 11 8 or 10 (1189433)

212 12 (low adj cost).mp. (30307) 13 (high adj cost).mp. (9670) 14 (health?care adj cost$).mp. (13873) 15 (cost adj estimate$).mp. (2057) 16 (cost adj variable$).mp. (164) 17 (unit adj cost$).mp. (2513) 18 (fiscal or funding or financial or finance).tw. (108348) 19 (economic$ or pharmacoeconomic$ or price$ or pricing).tw. (233392) 20 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 (375471) 21 11 or 20 (1424838) 22 10 or 20 (1349041) 23 9 or 20 (1330847) 24 exp migraine/ (44479) 25 migraine*.ti,ab. (35197) 26 24 or 25 (48612) 27 letter.pt. or letter/ (859916) 28 note.pt. (570602) 29 editorial.pt. (456957) 30 case report/ or case study/ (1964936) 31 animal/ not human/ (1198334) 32 nonhuman/ (4379022) 33 animals, laboratory/ (17730) 34 exp experimental animal/ (418037) 35 exp animal experiment/ (1805317) 36 animals, laboratory/ (17730) 37 exp animal model/ (789164) 38 exp rodent/ (2916953) 39 or/27-38 (9890313) 40 26 not 39 (34252) 41 23 and 40 (2736) 42 limit 41 to yr="2012 -Current" (531) Database: Embase <1974 to 2014 September 30> Search Strategy: -------------------------------------------------------------------------------- 1 economic evaluation$.mp. or exp economic evaluation/ (217851) 2 fee$.mp. or exp fee/ (603101) 3 health care cost$.mp. or exp "health care cost"/ (213071) 4 hospital cost$.mp. or exp "hospital cost"/ (29319) 5 pharmacoeconomics.mp. or exp pharmacoeconomics/ (170740) 6 health economics.mp. or health economics/ (35964) 7 budget$.mp. or budget/ (36207) 8 socioeconomics.mp. or socioeconomics/ (110593) 9 1 or 2 or 3 or 4 or 5 or 6 (1073330) 10 7 or 9 (1095858) 11 8 or 10 (1189433) 12 (low adj cost).mp. (30307) 13 (high adj cost).mp. (9670) 14 (health?care adj cost$).mp. (13873) 15 (cost adj estimate$).mp. (2057)

213 16 (cost adj variable$).mp. (164) 17 (unit adj cost$).mp. (2513) 18 (fiscal or funding or financial or finance).tw. (108348) 19 (economic$ or pharmacoeconomic$ or price$ or pricing).tw. (233392) 20 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 (375471) 21 11 or 20 (1424838) 22 10 or 20 (1349041) 23 9 or 20 (1330847) 24 exp migraine/ (44479) 25 migraine*.ti,ab. (35197) 26 24 or 25 (48612) 27 letter.pt. or letter/ (859916) 28 note.pt. (570602) 29 editorial.pt. (456957) 30 case report/ or case study/ (1964936) 31 animal/ not human/ (1198334) 32 nonhuman/ (4379022) 33 animals, laboratory/ (17730) 34 exp experimental animal/ (418037) 35 exp animal experiment/ (1805317) 36 animals, laboratory/ (17730) 37 exp animal model/ (789164) 38 exp rodent/ (2916953) 39 or/27-38 (9890313) 40 26 not 39 (34252) 41 23 and 40 (2736) 42 limit 41 to yr="2012 -Current" (531) 43 Saudi Arab$.mp,in. or Saudi Arabia/ (48689) 44 Riyadh.mp,in. (26427) 45 Jeddah.mp,in. (6785) 46 Kh*bar.mp,in. (1254) 47 Dammam.mp,in. (1960) 48 43 or 44 or 45 or 46 or 47 (48984) 49 Kuwait$.mp,in. or Kuwait/ (11065) 50 United Arab Emirates.mp,in. or United Arab Emirates/ (9876) 51 Qatar$.mp,in. or Qatar/ (4795) 52 Oman$.mp,in. or Oman/ (5602) 53 Yemen$.mp,in. or Yemen/ (2584) 54 Bahr*in$.mp,in. or Bahrain/ (3085) 55 49 or 50 or 51 or 52 or 53 or 54 (34946) 56 Middle East$.mp,in. or Middle East/ (15243) 57 Jordan$.mp,in. or Jordan/ (30670) 58 Libya$.mp,in. or Libya/ (3000) 59 Egypt$.mp,in. or Egypt/ (69182) 60 Syria$.mp,in. or Syria/ (16147) 61 Iraq$/ or Iraq.mp,in. (10458) 62 Morocc$.mp,in. or Morocco/ (18551) 63 Tunisia$.mp,in. or Tunisia/ (25075) 64 Leban$.mp,in. or Lebanon/ (27058) 65 West Bank.mp,in. (1105)

214 66 Iran$.mp,in. or Iran/ (110991) 67 Turkey/ or (Turkey or Turkish).mp,in. (254703) 68 Algeria$.mp,in. or Algeria/ (7977) 69 Arab$.mp,in. or Arabs/ (156922) 70 56 or 57 or 58 or 59 or 60 or 61 or 62 or 63 or 64 or 65 or 66 or 67 or 68 (571964) 71 69 or 70 (707414) 72 48 or 55 or 71 (726622) 73 42 and 72 (28) KSA Values and Preferences on Migraine Population Intervention comparator Study Date database results filter Migraine Saudi filter n/a MEDLINE 701 EMBASE 1662 PsycInfo 712 subtotal 3075 -duplicates 738 total 2337 Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to Present> Search Strategy: -------------------------------------------------------------------------------- 1 Saudi Arab$.mp,in. or Saudi Arabia/ (30941) 2 Riyadh.mp,in. (16227) 3 Jeddah.mp,in. (3725) 4 Kh*bar.mp,in. (759) 5 Dammam.mp,in. (1353) 6 1 or 2 or 3 or 4 or 5 (31362) 7 Kuwait$.mp,in. or Kuwait/ (6930) 8 United Arab Emirates.mp,in. or United Arab Emirates/ (4474) 9 Qatar$.mp,in. or Qatar/ (2462) 10 Oman$.mp,in. or Oman/ (3880) 11 Yemen$.mp,in. or Yemen/ (1913) 12 Bahr*in$.mp,in. or Bahrain/ (1248) 13 7 or 8 or 9 or 10 or 11 or 12 (20065) 14 Middle East$.mp,in. or Middle East/ (11877) 15 Jordan$.mp,in. or Jordan/ (10272) 16 Libya$.mp,in. or Libya/ (1847) 17 Egypt$.mp,in. or Egypt/ (38722) 18 Syria$.mp,in. or Syria/ (10742) 19 Iraq$/ or Iraq.mp,in. (8082) 20 Morocc$.mp,in. or Morocco/ (8640) 21 Tunisia$.mp,in. or Tunisia/ (12806) 22 Leban$.mp,in. or Lebanon/ (14834) 23 West Bank.mp,in. (762) 24 Iran$.mp,in. or Iran/ (65783)

215 25 Turkey/ or (Turkey or Turkish).mp,in. (153205) 26 Algeria$.mp,in. or Algeria/ (4307) 27 Arab$.mp,in. or Arabs/ (122911) 28 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 (331320) 29 27 or 28 (445517) 30 6 or 13 or 29 (457962) 31 exp Migraine Disorders/ (21872) 32 migraine*.ti,ab. (25192) 33 31 or 32 (29419) 34 30 and 33 (701) Database: Embase <1974 to 2014 September 30> Search Strategy: -------------------------------------------------------------------------------- 1 Saudi Arab$.mp,in. or Saudi Arabia/ (48689) 2 Riyadh.mp,in. (26427) 3 Jeddah.mp,in. (6785) 4 Kh*bar.mp,in. (1254) 5 Dammam.mp,in. (1960) 6 1 or 2 or 3 or 4 or 5 (48984) 7 Kuwait$.mp,in. or Kuwait/ (11065) 8 United Arab Emirates.mp,in. or United Arab Emirates/ (9876) 9 Qatar$.mp,in. or Qatar/ (4795) 10 Oman$.mp,in. or Oman/ (5602) 11 Yemen$.mp,in. or Yemen/ (2584) 12 Bahr*in$.mp,in. or Bahrain/ (3085) 13 7 or 8 or 9 or 10 or 11 or 12 (34946) 14 Middle East$.mp,in. or Middle East/ (15243) 15 Jordan$.mp,in. or Jordan/ (30670) 16 Libya$.mp,in. or Libya/ (3000) 17 Egypt$.mp,in. or Egypt/ (69182) 18 Syria$.mp,in. or Syria/ (16147) 19 Iraq$/ or Iraq.mp,in. (10458) 20 Morocc$.mp,in. or Morocco/ (18551) 21 Tunisia$.mp,in. or Tunisia/ (25075) 22 Leban$.mp,in. or Lebanon/ (27058) 23 West Bank.mp,in. (1105) 24 Iran$.mp,in. or Iran/ (110991) 25 Turkey/ or (Turkey or Turkish).mp,in. (254703) 26 Algeria$.mp,in. or Algeria/ (7977) 27 Arab$.mp,in. or Arabs/ (156922) 28 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 (571964) 29 27 or 28 (707414) 30 6 or 13 or 29 (726622) 31 exp migraine/ (44479) 32 migraine*.ti,ab. (35197) 33 31 or 32 (48612) 34 30 and 33 (1662)

216 Database: PsycINFO <1987 to October Week 1 2014> Search Strategy: -------------------------------------------------------------------------------- 1 client$ participation.mp. or exp client participation/ (1533) 2 client$ satisfaction.mp. or exp client satisfaction/ (5022) 3 exp Health Attitudes/ (7993) 4 (patient$ preference$ or patient$ perception$ or patient$ decision$ or patient$ perspective$ or user$ view$ or patient$ view$ or patient$ value$ or patient$ attitude$).mp. (8296) 5 (patient$ utilit$ or health utilit$).mp. (527) 6 health related quality of life.mp. or exp "quality of life"/ (29337) 7 (health stat$ utilit$ or health stat$ indicator$ or (health stat$ adj 2 valu$)).mp. (142) 8 (standard gambl$ or time trade off or willingness to pay or visual analog scale or (VAS or "visual analog$ adj 2 scal$")).mp. (4704) 9 or/1-8 (54515) 10 exp Headache/ (11193) 11 (headache* or migraine*).ti,ab. (15774) 12 10 or 11 (15973) 13 9 and 12 (712) Final Summary Benefits and Harms Medline, Embase, Cochrane, CINAHL, PsycINFO 2757 Duplicates 617 Total Abstracts Screened 2140 Full Text Retrieved 60 Included 13 Cost-Effectiveness Medline, Embase 642 Duplicates 104 Total Abstracts Screened 538 Full Text Retrieved 12 Included 7 Patient Values & Preferences Medline, Embase, PsycINFO 3075 Duplicates 738 Total Abstracts Screened 2337 Full Text Retrieved 49 Included 2