BMJ Open. Acupuncture for acute migraine attacks in adults: a systematic review protocol

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1 Acupuncture for acute migraine attacks in adults: a systematic review protocol Journal: Manuscript ID: bmjopen-0-00 Article Type: Protocol Date Submitted by the Author: -Oct-0 Complete List of Authors: Du, Ruosang; Guang anmen Hospital, China Academy of Chinese Medical Sciences, Wang, Yang; Guang anmen Hospital, Acupuncture and Moxibustion Liu, Xiaoxu; Guang anmen Hospital, Acupuncture and Moxibustion LIU, Zhishun; Guang'anmen hospital, China Academy of Chinese Medical Sciences, Department of acupuncture <b>primary Subject Heading</b>: Neurology Secondary Subject Heading: Complementary medicine Keywords: Migraine < NEUROLOGY, COMPLEMENTARY MEDICINE, PAIN MANAGEMENT : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright. -

2 Page of Acupuncture for acute migraine attacks in adults: a systematic review protocol Ruosang Du, Yang Wang, Xiaoxu Liu,, Zhishun Liu * Department of Acupuncture, Guang anmen Hospital, China Academy of Chinese Medical Sciences, Beijing (000), China School of Graduates, Beijing University of Chinese Medicine, Beijing (000), China * Correspondence to: Professor Zhishun Liu Tel: liuzhishun@aliyun.com Key words Acupuncture; migraine; systematic review; protocol. Word count:, : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

3 Page of ABSTRACT Introduction This systematic review aims to assess the effectiveness and safety of acupuncture for acute migraine attacks in adults. Methods and analysis We will search the following databases from inception to October 0: MEDLINE (OVID), EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and four Chinese databases (Chinese Biomedical Database, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database and Wanfang Database). Any clinical randomized controlled trials (RCTs) in English or Chinese related to acupuncture for acute migraine attacks will be included. We will also try to find literature by searching relevant conference abstracts and reference lists. The study selection, data extraction, and quality assessment will be conducted independently by two reviewers. Meta-analysis will be performed using RevMan. statistical software. Dissemination The findings will be disseminated through peer-reviewed publication or conference presentations. Protocol registration: PROSPERO CRD : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

4 Page of Strength and limitations of this study For all we know, this systematic review will be the first one to assess the effectiveness and safety of acupuncture for acute migraine attacks in adults. The study selection, data extraction and quality assessment will be performed by two researchers independently. Studies not reported in the English or Chinese will not be included and some relevant studies might be missed. Other weaknesses may be the highly variable outcome measurement, insufficient reporting of results, publication bias and poor quality of the trials identified. - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

5 Page of INTRODUCTION Description of the condition Migraine is a prevalent neurovascular headache disorder, which is characterized by recurrent attacks of unilateral pulsating moderate to severe headache. It usually lasts h and has various concomitant symptoms, such as light and sound sensitivity, nausea and vomiting. It can be triggered by food, environment, mental factors and aggravated by routine physical activity. Migraine usually starts at puberty and has two major subtypes: migraine without aura and migraine with aura. Population-based surveys demonstrated that migraine occurred in at least adult in every of the world, affecting more women than men by a ratio :. In the Global Burden of Disease Survey 00, it was ranked as the third most prevalent disorder and seventh-highest specific cause of disability worldwide. Migraine brings a serious impact on the patients health and quality of life. When an attack happens, patients normal life will be interfered because migraine can be disabling. People with migraine may be unable to perform daily life activities. A study has founded that migraineurs normal activities were limited during % of migraine attacks. What is worse, the patients are afflicted not only during acute attacks but also in the period between episodes for worry and fear of the next headache attack. Meanwhile, the consequent economic burden of migraine is enormous. - The association between migraine and other diseases has also been revealed by numerous studies, especially with cardiovascular and cerebrovascular diseases. By a systematic review of studies, Schurks M et al found that the risk of ischemic stroke was doubled in migraine with aura and a two-fold increase was found among women. 0 Description of the intervention Acupuncture has been widely used to treat headache, including migraine. -.% of the people who accept acupuncture in the United States said that they had been treated with acupuncture for migraine or other headaches. In, acupuncture has been suggested as an adjunct or an alternative treatment for headache by the National - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

6 Page of Institutes of Health (NIH). How the intervention might work Various mechanisms about acupuncture relieving headache have been reported, but there is no consensus yet. Hemodynamic abnormalities have been found both in attack and interictal period of migraine, and were mainly manifested as an increase of baseline flow velocities in the basal cerebral. 0 Meanwhile, many studies demonstrated acupuncture can influence cerebral hemodynamic, thus existing an evidence of the analgesic effects of acupuncture on migraine. A study suggested that acupuncture could inhibit pain transmission to central nervous system by stimulating A delta fibres. Some others verified acupuncture facilitated the release of some pain suppressors--neurotransmitters and neurohormones (such as endorphins, opiate chemical substances) to relieve pain. Another explanation was that acupuncture may inhibit inflammatory reaction by impeding the release of calcitonin gene-related peptide, histamine and prostaglandins. - Why it is important to do this review Treatment of migraine includes two parts: the acute attacks treatment and the prophylaxis treatment. Acupuncture has been widely used in both parts. The large amounts of original studies have produced mixed evidence on the effectiveness of acupuncture treating migraine. A Cochrane systematic review published in 00 concluded that acupuncture was at least as effective as, or possibly more effective for migraine prophylaxis than preventive drug treatment, and with fewer adverse effects. However, to date no systematic review of acupuncture for acute migraine attacks has been performed, resulting in the lack of adequate evidence to assess the effectiveness and safety of acupuncture for treating acute migraine attacks. OBJECTIVES This systematic review aims to assess whether acupuncture is effective and safe in - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

7 Page of treating acute migraine attacks in adults. METHODS Criteria for considering studies for this review Types of studies Only randomized controlled trials (RCT) will be included. Quasi-randomized controlled trials will be excluded. We will include parallel group or cross-over designs. Types of participants Adults with the diagnosis of migraine (according to the definition of the Headache Classification Subcommittee of the International Headache Society) will be eligible for inclusion. Participants who are receiving migraine prophylactic treatment will be acceptable. There will be no restrictions on migraine type, course, frequency, headache intensity or duration. Types of intervention Conventional acupuncture therapy which can stimulate acupoints or other points (such as pain points, trigger points) will be included. Interventions can include manual acupuncture, electroacupuncture (EA), scalp acupuncture, auricular acupuncture, eye acupuncture, fire needling, warm needling, elongated needling. There won t be any duration restriction on the intervention. Comparison interventions will be sham acupuncture, placebo, no treatment, conventional intervention and non-specific treatment. We will include trials that compare acupuncture plus another treatment with that treatment alone. But trials aim to compare different forms of acupuncture or evaluate migraine prophylaxis effect of acupuncture will be excluded. - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

8 Page of Types of outcome measures Primary outcomes. Pain-free at hours after the treatment, without the use of rescue medication.. Headache relief (a decrease in headache from severe or moderate to none or mild or a reduction of 0% in headache intensity) at hours after the treatment, without the use of rescue medication.. Sustained pain freedom (pain-free at h with no use of rescue medication or relapse within the subsequent h). Secondary outcomes. Incidence of relapse (recurrence).. Adverse events.. Migraine-associated symptoms (such as nausea, photophobia, phonophobia, etc.) Search methods for the identification of studies Electronic searches We will search MEDLINE (OVID), EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and four Chinese databases (Chinese Biomedical Database, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database and Wanfang Database) from inception to October 0. Any relevant ongoing or unpublished trials will also be searched on the metaregister of Controlled Trials ( The US National Institutes of Health Ongoing Trials Register ( and the WHO International Clinical Trials Registry Platform ( We will only include trials reported in English and Chinese. The search strategy for MEDLINE is shown in table. Table Search strategy used in MEDLINE (OVID) database - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

9 Page of Number Search terms randomized controlled trial.pt. controlled clinical trial.pt. randomized. ab. randomised. ab. placebo. ab. randomly. ab. trial. ab. or/- exp migraine disorders 0 exp acupuncture therapy, or acupuncture acupuncture. ti, ab. {Including Related Terms} manual acupuncture. ti, ab. {Including Related Terms} electroacupuncture. ti, ab. {Including Related Terms} scalp acupuncture. ti, ab. {Including Related Terms} auricular acupuncture. ti, ab. {Including Related Terms} eye acupuncture. ti, ab. {Including Related Terms} fire needling. ti, ab. {Including Related Terms} warm needling, ti, ab. {Including Related Terms} elongated needling ti, ab. {Including Related Terms} 0 or/0-0 and and 0 This search strategy will be modified as required for other electronic databases. Other sources We will also check all reference lists of relevant articles and search relevant conference proceedings. Data collection and analysis Selection of studies Searches will be carried out by two reviewers (RD and XL) independently. Then we will view the titles and abstracts of the searched studies. Trials that clearly can t meet the inclusion criteria will be excluded. We will read full copies of the other studies to select those suitable for inclusion criteria. Disagreements will be resolved by discussion or decided by a third reviewer (ZL). The process of the study selection is - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

10 Page of shown in a PRISMA flow chart. (figure ). Data extraction and management Two reviewers (RD and XL) will independently assess the eligibility and quality of the trials. By using a specially designed form, reviewers will extract information on the author, year of publication, country, patient characteristics, methods, interventions and outcomes. If there are any disagreements, the consensus will be reached by discussion or judged by a third reviewer (ZL). We will seek additional information from the first or corresponding authors of the included studies, if necessary. Assessment of risk of bias in included studies Two independent reviewer (RD and XL) authors will assess the risk of bias using the Cochrane Collaboration s Risk of bias tool. Studies will be classified into three levels of bias: unclear, low or high risk of bias. The following items will be assessed: Random sequence generation. Allocation concealment. Blinding. Incomplete data. Selective outcome reporting. Other bias. We will resolve differences of opinions by discussion or consultation with a third reviewer (ZL). Measures of treatment effect For the dichotomous outcomes, data will be analyzed by using the risk ratio (RR) with % confidence intervals (CI).For continuous outcomes, the weighted mean difference (WMD) or the standard mean difference (SMD) with % CI will be used. If the same measurement scales are used, WMD analyses will be performed. On the contrary, SMD will be used. - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

11 Page 0 of Unit of analysis issues The unit of analysis will be the individual participant. Dealing with missing data If necessary data is missing, we will get the information by contacting the first or corresponding authors of the included studies. When possible, a sensitivity analysis will be conducted to address the potential impact of missing data. Assessment of heterogeneity Q statistic of Chi-square value test and I value will be used to quantify the statistical heterogeneity. According to the interpretation of Cochrane Handbook, Q is considered statistically significant at p<0.0. I value can be classified into four categories: 0 0% means little or no heterogeneity; 0 0% means moderate heterogeneity; 0 0% indicates substantial heterogeneity; and 00% indicates considerable heterogeneity. Assessment of reporting biases If there is a sufficient number of included trials (at least 0 trials), funnel plots will be generated to estimate reporting biases. Data synthesis Data synthesis will be conducted using Review Manager (V..) of the Cochrane Collaboration. If the test of heterogeneity shows little or no heterogeneity exists, the fixed effect model will be used for pooled data, otherwise the random effect model will be adopted. If excessive heterogeneity among included studies is found, meta-analysis will not be performed. Subgroup analysis Subgroup analysis can explore and assess the heterogeneity. If the data are available, - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

12 Page of we will plan to conduct subgroup analysis according to different types of comparison interventions (sham acupuncture, placebo, no treatment, conventional intervention or non-specific treatment). Sensitivity analysis Sensitivity analysis can assess the stability and reliability of the analysis results and restrict analysis to low risk of bias. The analysis will be repeated by remove the impact of lower quality studies, imputing missing data or choosing a different method of meta-analysis. DISCUSSION This systematic review will provide a detailed summary of the current evidence about the effectiveness of acupuncture in treating acute migraine attacks. In addition, it can help clinicians to manage migraineurs and benefit patients, or may be utilized to improve the application of acupuncture in treating migraine. But this comprehensive evaluation of effects of acupuncture on acute migraine attacks will still have some limitations. Because of the language barrier, trials not reported in English or Chinese will not be covered and some related trials might be missed. Some other relevant problems are the highly variable outcome measurement, insufficient reporting of results, publication bias and poor quality of the trials identified. These limitations all can make it more difficult for this systematic review to achieve a final conclusion. Contributors RD and ZL contributed to the conception of the study. The manuscript of the protocol was drafted by RD, and was revised by ZL and YW. The search strategy was developed by all authors and run by RD and XL, who will also independently screen the potential studies, extract data of included studies, assess the risk of bias and finish data synthesis. ZL will arbitrate the disagreements and ensure that no errors occur during the study. All authors have approved the publication of the - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

13 Page of protocol. Competing interests None. Provenance and peer review Not commissioned; externally peer reviewed REFERENCES. Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, rd edition (beta version).cephalalgia 0;(): 0.. World Health Organization(WHO). How common are eadaches? 0 Aug 0).. World Health Organization(WHO). Lifting the Burden: Atlas of headache disorders and resources in the world 0. essed 0 Aug 0).. Vos T, Flaxman AD, Naghavi M, Lozano R, et al. Years lived with disability (YLD) for 0 sequelae of diseases and injuries 0 00: A systematic analysis for the global burden of disease study 00. Lancet 0;0:.. Edmeads J, Findlay H, Tugwell P, et al. Impact of migraine and tension type headache on lifestyle, consulting behaviour, and medication use: a Canadian population survey. Can J Neurol Sci ;0:.. Freitag FG. The cycle of migraine: patients quality of life during and between migraine attacks. Clin Ther 00;:.. Stewart WF, Lipton RB. The economic and social impact of migraine. Eur Neurol - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

14 Page of ; :.. Goldberg L. The cost of migraine and its treatment. Am J of Manag Care 00;: S.. Simona S, Tobias K. Migraine and the risk for stroke and cardiovascular disease. Curr Cardiol Rep 0;:. 0. Schürks M, Rist PM, Bigal ME, et al. Migraine and cardiovascular disease: systematic review and meta analysis. BMJ 00;:.. Jerusa AA, Jayme M, Xavier C. Acupuncture in migraine prevention: a randomized sham controlled study with months posttreatment follow up. Clin J Pain 00; : 0.. Von PS, Ting W, Scrivani S, et al. Survey on the use of complementary and alternative medicine among patients with headache syndromes. Cephalalgia 00;: 00.. Baischer W. Acupuncture in migraine: long term outcome and predicting factor. Headache ;:.. Pintov S, Lahat E, Alstein M, et al. Acupuncture and the opioid system: implications in management of migraine. Pediatr Neurol ;:.. Allais G, Lorenzo C, Quirico PE, et al. Acupuncture in the prophylactic treatment of migraine without aura: a comparison with flunarizine. Headache 00;:.. Vickers A, Rees RW, Zollman CE, et al. Acupuncture for chronic headache in primary care: large, pragmatic, randomized trial. BMJ 00;: 0.. Burke A, Upchurch DM, Dye C, et al. Acupuncture use in the United States: findings from the National Health Interview Study. Journal of Alternative and Complementary Medicine 00;:.. National Institutes of Health (NIH) Consensus Conference. Acupuncture. JAMA ;0:.. Thomas MW, Thomas W, Britta M, et al. Cerebrovascular response in migraineurs during prophylactic treatment with acupuncture: a randomized controlled trial. Journal of Alternative and Complementary Medicine 0;:. - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

15 Page of Valikovics A, Olah L, Fulesdi B, et al. Cerebrovascular reactivity measured by transcranial doppler in migraine. Headache ;:.. Ming YL, Jaung GL, Ming WO, et al. Cerebral hemodynamic responses to acupuncture in migraine patients: a systematic review. Journal of Traditional and Complementary Medicine 0;: 0.. Zhao ZQ. Neural mechanism underlying acupuncture analgesia. Prog Neurobiol 00;:.. Griggs C, Jensen J. Effectiveness of acupuncture for migraine: critical literature review. J Adv Nurs 00;: 0.. Zijlstra FJ, van den Berg de Lange I, Huygen FJ, et al. Anti inflammatory actions of acupuncture. Mediators Inflamm 00;:.. Zhao CH, Stillman MJ, Rozen TD. Traditional and evidence based acupuncture in headache management: theory, mechanism, and practice. Headache 00;: 0.. Linde K, Streng A, Jurgens S, et al. Acupuncture for patients with migraine: a randomized controlled trial. JAMA 00;:.. Evers S, Afra J, Frese A, et al. European Federation of Neurological Societies. EFNS guideline on the drug treatment of migraine revised report of an EFNS task force. Eur J Neurol 00;:.. Linde K, Allais G, Brinkhaus B, et al. Acupuncture for migraine prophylaxis. Cochrane Database Syst Rev 00;:CD : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

16 Page of Figure Flow diagram of the trial selection process xmm (00 x 00 DPI) - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

17 Acupuncture for acute migraine attacks in adults: a systematic review protocol Journal: Manuscript ID: bmjopen-0-00.r Article Type: Protocol Date Submitted by the Author: -Dec-0 Complete List of Authors: Du, Ruosang; Guang anmen Hospital, China Academy of Chinese Medical Sciences, Wang, Yang; Guang anmen Hospital, Acupuncture and Moxibustion Liu, Xiaoxu; Guang anmen Hospital, Acupuncture and Moxibustion Liu, Zhishun; Guang'anmen hospital, China Academy of Chinese Medical Sciences, Department of acupuncture <b>primary Subject Heading</b>: Neurology Secondary Subject Heading: Complementary medicine Keywords: Migraine < NEUROLOGY, COMPLEMENTARY MEDICINE, PAIN MANAGEMENT : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright. -

18 Page of Acupuncture for acute migraine attacks in adults: a systematic review protocol Ruosang Du, Yang Wang, Xiaoxu Liu,, Zhishun Liu * Department of Acupuncture, Guang anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 000, China School of Graduates, Beijing University of Chinese Medicine, Beijing 000, China * Correspondence to: Professor Zhishun Liu Tel: liuzhishun@aliyun.com Keywords Acupuncture; migraine; systematic review; protocol. Word count: : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

19 Page of ABSTRACT Introduction: This systematic review aims to assess the effectiveness and safety of acupuncture for acute migraine attacks in adults. Methods and analysis: We will search the following seven databases from inception to October 0: MEDLINE (OVID), EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and four Chinese databases (Chinese Biomedical Database, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, and Wanfang Database). Any randomised controlled trials (RCTs) in English or Chinese related to acupuncture for acute migraine attacks will be included. We will also search relevant conference abstracts and reference lists. The study selection, data extraction, and quality assessment will be conducted independently by two reviewers. Meta-analysis will be performed using RevMan.. statistical software. Dissemination: The findings will be disseminated through peer-reviewed publication or conference presentations. Protocol registration: PROSPERO CRD : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

20 Page of Strength and limitations of this study Acupuncture has been used as a treatment for acute migraine attacks, but there is inadequate evidence on its effectiveness and safety. Study selection, data extraction, and quality assessment will be independently performed by two researchers. Studies not reported in English or Chinese will not be included, so some relevant studies might be missed. Other weaknesses include highly variable outcome measurements, insufficient reporting of results, publication bias, or poor trial quality. - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

21 Page of INTRODUCTION Description of the condition Migraine is a prevalent neurovascular headache disorder, which is characterised by recurrent attacks of unilateral pulsating moderate to severe headaches. The headaches usually last h and have concomitant symptoms such as light and sound sensitivity, nausea, and vomiting. Migraine can be triggered by food, environment, and mental factors, and may be aggravated by routine physical activity. Symptoms usually start at puberty and have two major subtypes: migraine with aura and migraine without aura. Population-based surveys have shown that migraine occurs in at least in every adults worldwide, and affects three-fold more women than men. In the Global Burden of Disease Survey 00, migraine was ranked as the third most prevalent disorder and seventh-highest specific cause of disability worldwide. Migraine seriously impacts patient health and quality of life, and often is a source of great disability. In fact, migraineurs normal activities can be limited during up to % of migraine attacks. Migraine patients are also afflicted in the period between episodes because of their fears of the next headache attack. Meanwhile, the consequent economic burden of migraine is enormous. An association between migraine and cardiovascular and cerebrovascular diseases has also been shown by numerous studies. One systematic review of studies found that the risk of ischemic stroke was doubled in migraine with aura and a two-fold increase was found among women. 0 Description of the intervention Acupuncture is widely used worldwide to treat headache, including migraine. Of patients in the United States who accept acupuncture as a valid treatment,.% said that they had been treated with acupuncture for migraine or other headaches. In, acupuncture was suggested as an adjunct or an alternative treatment for headache by the National Institutes of Health (NIH). - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

22 Page of How the intervention might work Various mechanisms have been reported to explain the mechanism of acupuncture in headache relief. Hemodynamic abnormalities have been found both in the attack and interictal period of migraine, 0 and mainly manifest as an increase in baseline flow velocity in the middle cerebral artery. Meanwhile, studies have demonstrated that acupuncture can influence cerebral hemodynamics, which could explain the analgesic effects of acupuncture on migraine. One study suggested that acupuncture could inhibit pain transmission to the central nervous system by stimulating A delta fibres. Another study found that acupuncture facilitated the release of some pain suppressors including endorphins, which are opiate chemical substances, among other neurotransmitters and neurohormones. Acupuncture may also inhibit inflammation by impeding the release of calcitonin gene-related peptide, histamine, and prostaglandins. Why it is important to do this review The treatment of migraine must include treatment for the acute attacks as well as prophylaxis. Acupuncture has been widely used in both the attacks and prevention, but studies have produced mixed results regarding actual efficacy. A Cochrane systematic review published in 00 concluded that acupuncture was at least as effective as, or possibly more effective, than preventive drug treatment for migraine prophylaxis. The review also found that acupuncture had fewer side effects than conventional treatment. Typical treatments for acute migraine include analgesics, nonsteroidal anti-inflammatory drugs, and triptans. Triptans account for almost 0% of antimigraine analgesics. 0 However, over one-third of migraine patients do not respond well to triptans, and over half were willing to try other treatments. There are unmet needs in acute migraine treatment. - In China, acupuncture has been suggested by the China Association for the Study Pain (CASP) as a complementary and alternative treatment for migraine. However, no systematic review on acupuncture for acute migraine attacks has been conducted, so there is a lack of - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

23 Page of adequate evidence to assess its effectiveness and safety. Objectives This systematic review aims to assess whether acupuncture is effective and safe in treating acute migraine attacks in adults, compared to sham acupuncture, placebo, no treatment or other interventions. METHODS AND ANALYSIS Types of studies Only randomised controlled trials (RCT) will be included. Quasi-randomised controlled trials will be excluded. The first period of randomised cross-over trials will be included. Types of participants Adults diagnosed with migraine (according to the definition of the Headache Classification Subcommittee of the International Headache Society) will be eligible for inclusion. Participants who are receiving migraine prophylactic treatment will be acceptable. There will be no restrictions on migraine type, course, frequency, headache intensity, or duration. Types of intervention Acupuncture therapy that can stimulate acupoints or other points (such as pain points or trigger points) will be included. Interventions can include manual acupuncture, electroacupuncture (EA), scalp acupuncture, auricular acupuncture, eye acupuncture, fire needling, warm needling, and elongated needling. There will be no duration restrictions on the intervention. Comparison interventions may include sham acupuncture, placebo, no treatment, conventional intervention, and non-specific treatment. We will include trials that compare acupuncture plus another treatment with the - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

24 Page of additional treatment alone. However, trials aiming to compare different forms of acupuncture, or those evaluating migraine prophylaxis effect will be excluded. Types of outcome measures Primary outcomes Pain-free at hours after the treatment, without the use of rescue medication. Secondary outcomes. Headache relief (a decrease in headache from severe or moderate to none or mild within h, before any rescue medication). Sustained pain freedom (pain-free at h with no use of rescue medication or relapse within the subsequent h).. Incidence of relapse (recurrence).. Adverse events.. Migraine-associated symptoms (such as nausea, photophobia, phonophobia, etc.) Search methods for identification of studies Electronic searches We will search MEDLINE (OVID), EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and four Chinese databases (Chinese Biomedical Database, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database and Wanfang Database) from inception to October 0. Any relevant ongoing or unpublished trials will also be searched on the metaregister of Controlled Trials ( The US National Institutes of Health Ongoing Trials Register ( and the WHO International Clinical Trials Registry Platform ( We will only include trials reported in English and Chinese. The search strategy for MEDLINE is shown in Table. - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

25 Page of Table Search strategy used in MEDLINE (OVID) database Number Search terms randomized controlled trial.pt. controlled clinical trial.pt. randomized. ab. randomised. ab. placebo. ab. randomly. ab. trial. ab. or/ exp migraine disorders 0 exp acupuncture therapy, or acupuncture acupuncture. ti, ab. {Including Related Terms} manual acupuncture. ti, ab. {Including Related Terms} electroacupuncture. ti, ab. {Including Related Terms} scalp acupuncture. ti, ab. {Including Related Terms} auricular acupuncture. ti, ab. {Including Related Terms} eye acupuncture. ti, ab. {Including Related Terms} fire needling. ti, ab. {Including Related Terms} warm needling, ti, ab. {Including Related Terms} elongated needling ti, ab. {Including Related Terms} 0 or/0 0 and and 0 This search strategy will be modified as required for other electronic databases. Other sources We will also check all reference lists of relevant articles and search relevant conference proceedings. Data collection and analysis Selection of studies Searches, data screening and selection process will be carried out by two independent reviewers (RD and XL). Reviewers will read the titles and abstracts of the searched studies. Those trials that clearly do not meet the inclusion criteria will be excluded. - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

26 Page of Reviewers will read full copies of the remaining studies to select those that are suitable for inclusion. Disagreements will be resolved by discussion or by a third reviewer (ZL). The process of the study selection is shown in a PRISMA flow chart (Figure ). Data extraction and management Two reviewers (RD and XL) will independently run the search strategy and assess the eligibility and quality of the trials. Using a form, reviewers will extract information on the author, year of publication, country, patient characteristics, methods, interventions, and outcomes. If there are any disagreements, the consensus will be reached by discussion or by a third reviewer (ZL). We will seek additional information from the first or corresponding authors of the included studies, if necessary. Assessment of risk of bias Two independent reviewers (RD and XL) will assess the risk of bias using the Cochrane Collaboration s Risk of bias tool. Studies will be classified into three levels of bias: unclear, low, or high risk of bias. The following items will be assessed for risk of bias: random sequence generation, allocation concealment, blinding, incomplete data, selective outcome reporting, and other bias. We will resolve differences of opinions by discussion or consultation with a third reviewer (ZL). Measures of treatment effect For dichotomous outcomes, data will be analysed using the risk ratio (RR) with % confidence intervals (CI). For continuous outcomes, the weighted mean difference (WMD) or the standard mean difference (SMD) with % CI will be used. If the same measurement scales are used, WMD analyses will be performed; otherwise, SMD will be used. Unit of analysis issues - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

27 Page 0 of The unit of analysis will be the individual participant. Dealing with missing data If necessary data is missing, we will try to get the information by contacting the first or corresponding authors of the included studies. When possible, a sensitivity analysis will be conducted to address the potential impact of missing data. Assessment of heterogeneity The Q statistic from the Chi-squared test and the I value will be used to quantify statistical heterogeneity. According to the Cochrane Handbook, Q is considered statistically significant if p<0.0. The I value is classified into four categories: 0 0% indicates little or no heterogeneity; 0 0% indicates moderate heterogeneity; 0 0% indicates substantial heterogeneity; and 00% indicates considerable heterogeneity. Assessment of reporting biases If there are at least ten included trials, funnel plots will be generated to estimate reporting biases. Data synthesis Data synthesis will be conducted using Review Manager (V...) from the Cochrane Collaboration. If the heterogeneity test shows little or no heterogeneity, the fixed effect model will be used for pooled data; otherwise the random effect model will be adopted. If there is considerable variation in results, and particularly if there is inconsistency in the direction of effect, then the meta-analysis will not be performed. Subgroup analysis Subgroup analysis can explore and assess the heterogeneity. If the data are available, we will conduct subgroup analysis according to different types of acupuncture - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

28 Page of therapies. Sensitivity analysis Sensitivity analysis can assess the stability and reliability of the analysis results and restrict analysis to low risk of bias. The analysis will be repeated by removing the impact of lower quality studies, inputting missing data, or choosing a different method of meta-analysis. DISCUSSION This systematic review will provide a detailed summary of the current evidence regarding acupuncture effectiveness in acute migraine treatment. In addition, it can help clinicians manage and benefit patients, and may be used to improve clinical acupuncture treatment for migraine. However, this comprehensive evaluation of acupuncture on acute migraine will have some limitations. Trials not reported in English or Chinese will not be included, so some related trials might be overlooked. Other relevant problems are the highly variable outcome measurement, insufficient reporting of results, publication bias, and poor trial quality. These limitations can make it difficult to achieve a conclusion on the effect of acupuncture on acute migraine attacks. Contributors RD and ZL contributed to the conception of the study. The manuscript of the protocol was drafted by RD and was revised by ZL and YW. The search strategy was developed by all authors and will be run by RD and XL, who will also independently screen the potential studies, extract data of included studies, assess the risk of bias and finish data synthesis. ZL will arbitrate the disagreements and ensure that no errors occur during the study. All authors have approved the publication of the protocol. Competing interests - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

29 Page of None. Provenance and peer review Not commissioned; externally peer reviewed REFERENCES. Headache Classification Committee of the International Headache Society (IHS): The international classification of headache disorders, rd edition (beta version). Cephalalgia 0;(): 0.. World Health Organization (WHO). How common are Headaches? (accessed 0 Aug 0).. World Health Organization (WHO). Lifting the Burden: Atlas of headache disorders and resources in the world 0. (accessed 0 Aug 0).. Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLD) for 0 sequelae of diseases and injuries 0 00: A systematic analysis for the global burden of disease study 00. Lancet 0;0:.. Edmeads J, Findlay H, Tugwell P, et al. Impact of migraine and tension type headache on lifestyle, consulting behaviour, and medication use: a Canadian population survey. Can J Neurol Sci ;0:.. Freitag FG. The cycle of migraine: patients quality of life during and between migraine attacks. Clin Ther 00;:.. Stewart WF, Lipton RB. The economic and social impact of migraine. Eur Neurol ;:.. Goldberg L. The cost of migraine and its treatment. Am J of Manag Care 00;: S.. Simona S, Tobias K. Migraine and the risk for stroke and cardiovascular disease. Curr Cardiol Rep 0;:. - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

30 Page of Schürks M, Rist PM, Bigal ME, et al. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ 00;:.. Jerusa AA, Jayme M, Xavier C. Acupuncture in migraine prevention: a randomized sham controlled study with -months posttreatment follow-up. Clin J Pain 00;: 0.. Von PS, Ting W, Scrivani S, et al. Survey on the use of complementary and alternative medicine among patients with headache syndromes. Cephalalgia 00;: 00.. Baischer W. Acupuncture in migraine: long-term outcome and predicting factor. Headache ;:.. Pintov S, Lahat E, Alstein M, et al. Acupuncture and the opioid system: implications in management of migraine. Pediatr Neurol ;:.. Allais G, Lorenzo C, Quirico PE, et al. Acupuncture in the prophylactic treatment of migraine without aura: a comparison with flunarizine. Headache 00;:.. Vickers A, Rees RW, Zollman CE, et al. Acupuncture for chronic headache in primary care: large, pragmatic, randomized trial. BMJ 00;: 0.. Linde K, Streng A, Jurgens S, et al. Acupuncture for patients with migraine: a randomized controlled trial. JAMA 00;:.. Burke A, Upchurch DM, Dye C, et al. Acupuncture use in the United States: findings from the National Health Interview Study. J Altern Complement Med 00;:.. National Institutes of Health (NIH) Consensus Conference. Acupuncture. JAMA ;0:. 0. Thomas MW, Thomas W, Britta M, et al. Cerebrovascular response in migraineurs during prophylactic treatment with acupuncture: a randomized controlled trial. J Altern Complement Med 0;:.. Valikovics A, Olah L, Fulesdi B, et al. Cerebrovascular reactivity measured by transcranial doppler in migraine. Headache ;:.. Ming YL, Jaung GL, Ming WO, et al. Cerebral hemodynamic responses to - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

31 Page of acupuncture in migraine patients: a systematic review. J Tradit Complement Med 0;: 0.. Zhao ZQ. Neural mechanism underlying acupuncture analgesia. Prog Neurobiol 00;:.. Griggs C, Jensen J. Effectiveness of acupuncture for migraine: critical literature review. J Adv Nurs 00;: 0.. Zijlstra FJ, van den Berg-de Lange I, Huygen FJ, et al. Anti-inflammatory actions of acupuncture. Mediators Inflamm 00;:.. Zhao CH, Stillman MJ, Rozen TD. Traditional and evidence-based acupuncture in headache management: theory, mechanism, and practice. Headache 00;: 0.. Evers S, Afra J, Frese A, et al. European Federation of Neurological Societies. EFNS guideline on the drug treatment of migraine revised report of an EFNS task force. Eur J Neurol 00;:.. Linde K, Allais G, Brinkhaus B, et al. Acupuncture for migraine prophylaxis. Cochrane Database Syst Rev 00;:CD00.. Rapoport AM. The therapeutic future in headache. Neurol Sci 0;(suppl ):S S. 0. Todd AS, Rebecca B, Huma S, et al. The prevalence, impact, and treatment of migraine and severe headaches in the United States: a review of statistics from national surveillance studies. Headache 0;:. Tfelt-Hansen P, Olesen J. Taking the negative view of current migraine treatments: the unmet needs. CNS Drugs 0;:.. Peer TH. What efficacy measures are clinically relevant and should be used in Cochrane reviews of acute migraine trials? a comment. Cephalalgia 0;0:.. China Association for the Study Pain (CASP). China diagnosis and management of migraine. Chinese Journal of Pain Medicine 0;:.. Higgins JPT, Green S. Cochrane handbook for systematic review of intervention version..0 [updated March 0]. The Cochrane Collaboration 0. (accessed Dec 0). - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

32 Page of Figure Flow diagram of the trial selection process xmm (00 x 00 DPI) - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

33 Acupuncture for acute migraine attacks in adults: a systematic review protocol Journal: Manuscript ID: bmjopen-0-00.r Article Type: Protocol Date Submitted by the Author: 0-Feb-0 Complete List of Authors: Du, Ruosang; Guang anmen Hospital, China Academy of Chinese Medical Sciences, Wang, Yang; Guang anmen Hospital, Acupuncture and Moxibustion Liu, Xiaoxu; Guang anmen Hospital, Acupuncture and Moxibustion Liu, Zhishun; Guang'anmen hospital, China Academy of Chinese Medical Sciences, Department of acupuncture <b>primary Subject Heading</b>: Neurology Secondary Subject Heading: Complementary medicine Keywords: Migraine < NEUROLOGY, COMPLEMENTARY MEDICINE, PAIN MANAGEMENT : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright. -

34 Page of Acupuncture for acute migraine attacks in adults: a systematic review protocol Ruosang Du, Yang Wang, Xiaoxu Liu,, Zhishun Liu * Department of Acupuncture, Guang anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 000, China School of Graduates, Beijing University of Chinese Medicine, Beijing 000, China * Correspondence to: Professor Zhishun Liu Tel: liuzhishun@aliyun.com Keywords Acupuncture; migraine; systematic review; protocol. Word count: - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

35 Page of ABSTRACT Introduction: This systematic review aims to determine whether acupuncture is effective and safe in relieving headache, preventing relapse and reducing migraine-associated symptoms in adults with acute migraine attacks. Methods and analysis: We will search the following seven databases from inception to October 0: MEDLINE (OVID), EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and four Chinese databases (Chinese Biomedical Database, China National Knowledge Infrastructure, Chinese Science and Technology Periodical Database, and Wanfang Database). Any randomised controlled trials (RCTs) in English or Chinese related to acupuncture for acute migraine attacks will be included. Conference abstracts and reference lists of included manuscripts will also be searched. The study inclusion, data extraction, and quality assessment will be conducted independently by two reviewers. Meta-analysis will be performed using RevMan.. statistical software. Dissemination: The findings will be disseminated through peer-reviewed publication and/or conference presentations. Protocol registration: PROSPERO CRD : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.

36 Page of Strength and limitations of this study Acupuncture has been used as a treatment for acute migraine attacks, yet evidence on its effectiveness and safety is inconclusive. Study selection, data extraction, and quality assessment will be independently performed by two researchers. Only studies reported in English or Chinese will be included. - : first published as 0./bmjopen-0-00 on April 0. Downloaded from on March 0 by guest. Protected by copyright.