{"Affiliation":[{"label":"Affiliation","value":"Medicine, Faculty of","attrs":{"lang":"en","ns":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","classmap":"vivo:EducationalProcess","property":"vivo:departmentOrSchool"},"iri":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","explain":"VIVO-ISF Ontology V1.6 Property; The department or school name within institution; Not intended to be an institution name."},{"label":"Affiliation","value":"Non UBC","attrs":{"lang":"en","ns":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","classmap":"vivo:EducationalProcess","property":"vivo:departmentOrSchool"},"iri":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","explain":"VIVO-ISF Ontology V1.6 Property; The department or school name within institution; Not intended to be an institution name."},{"label":"Affiliation","value":"Medicine, Department of","attrs":{"lang":"en","ns":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","classmap":"vivo:EducationalProcess","property":"vivo:departmentOrSchool"},"iri":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","explain":"VIVO-ISF Ontology V1.6 Property; The department or school name within institution; Not intended to be an institution name."},{"label":"Affiliation","value":"Population and Public Health (SPPH), School of","attrs":{"lang":"en","ns":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","classmap":"vivo:EducationalProcess","property":"vivo:departmentOrSchool"},"iri":"http:\/\/vivoweb.org\/ontology\/core#departmentOrSchool","explain":"VIVO-ISF Ontology V1.6 Property; The department or school name within institution; Not intended to be an institution name."}],"AggregatedSourceRepository":[{"label":"Aggregated Source Repository","value":"DSpace","attrs":{"lang":"en","ns":"http:\/\/www.europeana.eu\/schemas\/edm\/dataProvider","classmap":"ore:Aggregation","property":"edm:dataProvider"},"iri":"http:\/\/www.europeana.eu\/schemas\/edm\/dataProvider","explain":"A Europeana Data Model Property; The name or identifier of the organization who contributes data indirectly to an aggregation service (e.g. Europeana)"}],"Citation":[{"label":"Citation","value":"The Journal of Headache and Pain. 2016 Nov 24;17(1):107","attrs":{"lang":"en","ns":"https:\/\/open.library.ubc.ca\/terms#identifierCitation","classmap":"oc:PublicationDescription","property":"oc:identifierCitation"},"iri":"https:\/\/open.library.ubc.ca\/terms#identifierCitation","explain":"UBC Open Collections Metadata Components; Local Field; Indicates a bibliographic reference for the resource if it has been previously published."}],"CopyrightHolder":[{"label":"Copyright Holder","value":"The Author(s).","attrs":{"lang":"en","ns":"https:\/\/open.library.ubc.ca\/terms#rightsCopyright","classmap":"oc:PublicationDescription","property":"oc:rightsCopyright"},"iri":"https:\/\/open.library.ubc.ca\/terms#rightsCopyright","explain":"UBC Open Collections Metadata Components; Local Field; Refers to the publisher or author who holds the copyright."}],"Creator":[{"label":"Creator","value":"Thorlund, Kristian","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Sun-Edelstein, Christina","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Druyts, Eric","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Kanters, Steve","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Ebrahim, Shanil","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Bhambri, Rahul","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Ramos, Elodie","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Mills, Edward J","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Lanteri-Minet, Michel","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."},{"label":"Creator","value":"Tepper, Stewart","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/creator","classmap":"dpla:SourceResource","property":"dcterms:creator"},"iri":"http:\/\/purl.org\/dc\/terms\/creator","explain":"A Dublin Core Terms Property; An entity primarily responsible for making the resource.; Examples of a Contributor include a person, an organization, or a service."}],"DateAvailable":[{"label":"Date Available","value":"2018-05-14T17:34:59Z","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/issued","classmap":"edm:WebResource","property":"dcterms:issued"},"iri":"http:\/\/purl.org\/dc\/terms\/issued","explain":"A Dublin Core Terms Property; Date of formal issuance (e.g., publication) of the resource."}],"DateIssued":[{"label":"Date Issued","value":"2016-11-24","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/issued","classmap":"oc:SourceResource","property":"dcterms:issued"},"iri":"http:\/\/purl.org\/dc\/terms\/issued","explain":"A Dublin Core Terms Property; Date of formal issuance (e.g., publication) of the resource."}],"Description":[{"label":"Description","value":"Background:\r\n                The most commonly prescribed medications used to treat migraine acutely are single analgesics, ergots, opioids, and triptans. Due to varying mechanisms of action across drug classes, there is reason to believe that some classes may be less likely than others to elicit Medication Overuse Headache (MOH) than others. We therefore aimed to determine whether certain classes of acute migraine drugs are more likely to elicit MOH than others.\r\n              \r\n              \r\n                Methods:\r\n                A comprehensive systematic literature was conducted to identify studies of varying designs that reported on MOH within the considered treatment classes. Only studies that reported MOH according to the International Classification of Headache Disorders (ICHD) were considered. Since no causal comparative design studies were identified; data from prevalence studies and surveys were retrieved. Prevalence-based relative risks between treatment classes were calculated by integrating both medication overuse and medication use from published studies. For each pair wise comparison, pooled relative risks were calculated as the inverse variance weighted average.\r\n              \r\n              \r\n                Results:\r\n                A total of 29 studies informed the relative risk between treatment classes, all of which reported country-specific data. Five studies reported country-specific medication use data. For triptans versus analgesics the study relative risks generally favored triptans. The pooled relative risk was 0.65 (i.e., relative risk reduction of 35\u00a0%). For ergots versus analgesics, a similar trend was observed in favor of ergots with a relative risk of 0.41. For triptans versus ergots, the direction of effect was mixed, and the pooled relative risk was 1.07. Both triptans and ergots appeared favorable when compared to opioids, with pooled relative risks of 0.35 and 0.76, respectively. However, the evidence was limited for these comparisons. Analgesics and opioids also appeared to yield similar risk of MOH (pooled relative risk 1.09).\r\n              \r\n              \r\n                Conclusion:\r\n                Our study suggests that in patients receiving acute migraine treatment, analgesics and opioids are associated with a higher risk of developing MOH compared with other treatments. These findings provide incentive for better monitoring of use of analgesics and opioids for treating acute migraine, and suggest possible clinical preference for use of so-called \u201cmigraine-specific\u201d treatments, that is, triptans and ergots.","attrs":{"lang":"en","ns":"http:\/\/purl.org\/dc\/terms\/description","classmap":"dpla:SourceResource","property":"dcterms:description"},"iri":"http:\/\/purl.org\/dc\/terms\/description","explain":"A Dublin Core Terms Property; An account of the resource.; Description may include but is not limited to: an abstract, a table of contents, a graphical representation, or a free-text account of the resource."}],"DigitalResourceOriginalRecord":[{"label":"Digital Resource Original Record","value":"https:\/\/circle.library.ubc.ca\/rest\/handle\/2429\/65853?expand=metadata","attrs":{"lang":"en","ns":"http:\/\/www.europeana.eu\/schemas\/edm\/aggregatedCHO","classmap":"ore:Aggregation","property":"edm:aggregatedCHO"},"iri":"http:\/\/www.europeana.eu\/schemas\/edm\/aggregatedCHO","explain":"A Europeana Data Model Property; The identifier of the source object, e.g. the Mona Lisa itself. This could be a full linked open date URI or an internal identifier"}],"FullText":[{"label":"Full Text","value":"RESEARCH ARTICLE Open AccessRisk of medication overuse headacheacross classes of treatments for acutemigraineKristian Thorlund1,2*, Christina Sun-Edelstein3, Eric Druyts2,4, Steve Kanters2,5, Shanil Ebrahim1, Rahul Bhambri6,Elodie Ramos6, Edward J. Mills1,2, Michel Lanteri-Minet7,9 and Stewart Tepper8AbstractBackground: The most commonly prescribed medications used to treat migraine acutely are single analgesics,ergots, opioids, and triptans. Due to varying mechanisms of action across drug classes, there is reason to believethat some classes may be less likely than others to elicit Medication Overuse Headache (MOH) than others. Wetherefore aimed to determine whether certain classes of acute migraine drugs are more likely to elicit MOH thanothers.Methods: A comprehensive systematic literature was conducted to identify studies of varying designs that reportedon MOH within the considered treatment classes. Only studies that reported MOH according to the InternationalClassification of Headache Disorders (ICHD) were considered. Since no causal comparative design studies wereidentified; data from prevalence studies and surveys were retrieved. Prevalence-based relative risks between treatmentclasses were calculated by integrating both medication overuse and medication use from published studies. For eachpair wise comparison, pooled relative risks were calculated as the inverse variance weighted average.Results: A total of 29 studies informed the relative risk between treatment classes, all of which reported country-specificdata. Five studies reported country-specific medication use data. For triptans versus analgesics the study relative risksgenerally favored triptans. The pooled relative risk was 0.65 (i.e., relative risk reduction of 35 %). For ergots versusanalgesics, a similar trend was observed in favor of ergots with a relative risk of 0.41. For triptans versus ergots,the direction of effect was mixed, and the pooled relative risk was 1.07. Both triptans and ergots appeared favorablewhen compared to opioids, with pooled relative risks of 0.35 and 0.76, respectively. However, the evidence was limited forthese comparisons. Analgesics and opioids also appeared to yield similar risk of MOH (pooled relative risk 1.09).Conclusion: Our study suggests that in patients receiving acute migraine treatment, analgesics and opioids areassociated with a higher risk of developing MOH compared with other treatments. These findings provide incentive forbetter monitoring of use of analgesics and opioids for treating acute migraine, and suggest possible clinical preferencefor use of so-called \u201cmigraine-specific\u201d treatments, that is, triptans and ergots.BackgroundMedication-overuse headache (MOH) is caused by overuseof medications for migraines or other pain disorders.According to the International Classification of HeadacheDisorders, 3rd Edition, Beta (ICHD-3), MOH is defined asheadache occurring on 15 or more days per monthdeveloping as a consequence of regular overuse of acute orsymptomatic headache medication (on 10 or more, or 15or more days per month, depending on the medication) formore than 3 months [1].MOH manifests as increased frequency and intensityof headaches or migraine attacks and enhanced sensitivityto stimuli that elicit these episodes [2] Although themechanisms underlying MOH are not fully elucidated, itis hypothesized that repeated medication use could elicitincreased headache attacks as a consequence of neuronalplasticity that may increase responsiveness to triggers. The* Correspondence: kthorlund@redwoodoutcomes.com1Department of Clinical Epidemiology & Biostatistics, McMaster University,Hamilton, ON, Canada2Redwood Outcomes, 302-1505 2nd Ave. West, Vancouver, BC, CanadaFull list of author information is available at the end of the articleThe Journal of Headache                           and Pain\u00a9 The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http:\/\/creativecommons.org\/licenses\/by\/4.0\/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made.Thorlund et al. The Journal of Headache and Pain  (2016) 17:107 DOI 10.1186\/s10194-016-0696-8prevalence of MOH is 1\u20132 % in the general populationworldwide, and because of the estimated socio-economiccost, it is likely to be the most costly neurological disorderknown [3\u20136].Commonly prescribed medications for migraines mayinclude analgesics, ergots, opioids, and triptans. Due tovarying mechanisms of action across drug classes, thereis reason to believe that some classes may be less likelythan others to elicit MOH. Because of the estimatedsocio-economic burden of MOH, it is therefore import-ant to establish which drug class generally is least likelyto elicit MOH.The aim of this study was therefore to determine whethercertain classes of acute migraine drugs are more likely toelicit MOH than others. To achieve this, we performed acomprehensive systematic literature review of availableevidence and, to the extent data allowed, extrapolated thecomparative risks of MOH associated with available drugclasses.MethodsEligibility criteriaEligible studies could be either observational or clinical(randomized or non-randomized) in nature. Only studiesthat included adults 18 years of age and older who weresuffering from acute migraine were eligible. Eligible studiesmust have reported MOH by treatment class (i.e. analgesic,ergot, opioid, or triptan), and according to versions ofICHD-2 [1, 7\u20139].Search strategyIn consultation with an academic medical librarian, weconducted a systematic search of the medical literatureusing MEDLINE, EMBASE, and the Cochrane ControlledTrials Register (from inception to March 24, 2014). Thesearch strategy was sensitive and broad, consisting of thefollowing: \u2018medication overuse headache\u2019 and \u2018migraine\u2019.Conference abstracts provided through the EMBASEsearch were also reviewed to determine if there wererelevant studies recently completed. Additionally, handsearches of the bibliographies of published systematicreviews and health technology assessments were per-formed. All searches were performed independently, induplicate.Data extractionWe extracted data on the total number of patients, thenumber of patients with MOH by treatment class (i.e.analgesics, ergots, opioids, and triptans), MOH diagnosticcriteria, and the country\/region of each study. These datawere extracted from the baseline characteristics of thestudies. Two reviewers independently extracted and re-corded all data in a Microsoft Excel spreadsheet. All dataextraction were then checked by a third reviewer.MaterialsOut of 443 abstracts reviewed, a total of 29 studies wereeligible [10\u201339]. Additional file 1: Figure S1 shows theflow chart, and Additional file 1: Table S1 show the listof studies excluded following full-text review with ac-companying reason for exclusion. Table 1 presents thecharacteristics of the included studies. All included stud-ies had been published since the year 2004, when theICHD-2 was first released. Eleven of the included studiesadhered to the definition of MOH in version 1 of theICHD-2, whereas 9 studies adhered to the revision putforward in 2005, and 9 studies adhered to the appendixput forward in 2006. No studies made use of ICHD-3,released in beta in 2013. All studies took place in Europe(1 in Denmark, 3 in France, 2 in Germany, 19 in Italy, 2 inNorway, 1 in Spain, and 1 in Sweden). Two studies werepopulation based, the remaining were based out of a clinicalsetting (i.e., investigator headache centers, hospital depart-ments of neurology, of headache and pain clinics).In general, the included studies reported on use oftreatment classes, but did not distinguish which indi-vidual agent or agents (e.g., sumatriptan or eletriptanfor triptans) had been administered to patients. Thus,analysis by individual agents was not possible. However,since all eligible studies were published between 2006and 2013, it is reasonable to assume that most patientsreceiving ergots received dihydroergotamine (DHE) andnot the older ergotamine tartrate.All studies reported MOH as prevalence estimates withinincluded study population; no study reported MOH as anoutcome. All included studies were either observational(prospective or retrospective), clinical cohorts, or popula-tion surveys.Data considerationsAs indicated in section 3.4, no trials or observationalstudies looking at multiple migraine interventions re-ported development of MOH as an outcome. For thisreason, the comparison between interventions had tobe based on studies reporting prevalence estimates ofMOH. While relatively few available studies were specific-ally designed to estimate prevalence, several still provideddata on the proportion of patients using each of the inter-ventions that had developed MOH. For example, severalsurvey studies reported in their baseline table the numberand proportion of enrolled patients with MOH. Otherpublications described the characteristics of migraine pa-tients in one or more clinics, which included the numberand proportion of patients with MOH. To justify inclusionof studies not designed to estimate prevalence, we madethe assumption that prevalence estimates were not con-founded by the designs of these studies. We verified thatthe eligibility criteria in these studies did not include criteriarelated to MOH.Thorlund et al. The Journal of Headache and Pain  (2016) 17:107 Page 2 of 9Since the prevalence of MOH is highly correlated withthe prevalence of drug dispensing, prevalence estimatesdo not provide a good basis for comparison of risk ofMOH associated with the different interventions. Forexample, triptans are prescribed more frequently thanergots, and so we expect to see higher numbers of triptan-related MOH occurrences than ergot-related MOH occur-rences. To form a fair basis for comparisons of the relevantinterventions, it is therefore also necessary to know the fre-quency of treatment use. These were estimated post-hoc bya systematic review of the literature, and were incorporatedin the calculations of comparative risk of MOH. To thisend, we systematically searched MEDLINE and EMBASEfor population-based studies providing estimates of medica-tion use prevalence for the countries\/regions represented inthe eligible MOH prevalence studies.The prevalence of medication use for migraine wasderived from 5 studies identified in our literature review(See Table 2) [23, 40\u201343]. Because the data on medicationprevalence use was limited, some assumptions needed tobe made. For all countries, the prevalence of opioiduse among those with migraine was not available. Theclosest evidence of opioid use prevalence that we iden-tified was a Swedish study including chronic headachepatients. This study yielded an opioid use prevalenceof 4.1 %. Since use of opioids is known to be low inEurope (which is where all included studies camefrom) and since we believed it reasonable to assumeopioid use among chronic daily headache patientswould likely be higher than opioid use among acutemigraine patients, we assumed an opioid use preva-lence of 2 % for all included studies.Table 1 Summary of study characteristicsStudy Country DiagnosisclassificationStudysettingNo.patientsNo. medication overuse headacheAnalgesics Ergots Opioids TriptansAltieri et al. 2009 [11] Italy ICHD-2 [7] Clinic 27 11 NR NR 4Ayzenberg et al. 2008 [12] Germany ICHD-2 [7] Clinic 29 14 NR NR 15Biagianti et al. 2012 [13] Italy ICHD-2 Revised [8] Clinic 52 26 NR NR 20Boe et al. 2007 [14] Norway ICHD-2 Appendix [7] Clinic 100 20 1 NR 23Coppola et al. 2010 [15] Italy ICHD-2 Appendix [7] Clinic 29 10 NR NR 9Cupini et al. 2009 [16] Italy ICHD-2 Appendix [7] Clinic 33 NR 1 NR 4Di Lorenzo et al. 2009 [17] Italy ICHD-2 [7] Clinic 107 18 NR NR 29Donnet et al. 2009 [18] France ICHD-2 [7] Population 320 157 25 29 64Dousset et al. 2013 [19] France ICHD-2 Appendix [7] Clinic 42 8 1 0 9Galli et al. 2011 [20] Italy ICHD-2Appendix [7] Clinic 82 21 2 3 22Gambini et al. 2013 [21] Italy ICHD-2 Revised [8] Clinic 63 33 NR NR 21Gomez-Beldarrain et al. 2011 [22] Spain ICHD-2Revised [8] Clinic 42 25 NR NR 3Hagen et al. 2009 [23] Norway ICHD-2 Appendix [7] Clinic 56 18 NR 14 17Jonsson et al. 2011 [6] Sweden ICHD-2 Appendix [7] Population 799 517 7 33 66Lorenzo et al. 2012 [24] Italy ICHD-2 Appendix [7] Clinic 43 17 NR NR 8Pageler et al. 2008 [25] Germany ICHD-2 [7] Clinic 20 1 3 NR 5Perrotta et al. 2010 [26] Italy ICHD-2 [7] Clinic 31 11 NR NR 19Perrotta et al. 2012 [27] Italy ICHD-2 [7] Clinic 27 4 NR NR 6Radat et al. 2013 [28] France ICHD-2 [7] Clinic 17 2 NR 2 4Rainero et al. 2006 [29] Italy ICHD-2 [7] Clinic 18 NR 2 NR 3Relja et al. 2006 [30] Italy ICHD-2 [7] Clinic 101 38 9 0 12Rossi et al. 2006 [31] Italy ICHD-2 Revised [8] Clinic 118 63 3 NR 24Rossi et al. 2011 [32] Italy ICHD-2 Revised [8] Clinic 100 57 1 NR 23Sances et al. 2010 [33] Italy ICHD2 Revised [8] Clinic 172 42 5 5 50Sandrini et al. 2011 [34] Italy ICHD-2 Appendix [7] Clinic 56 23 2 NR 20Terrazzino et al. 2010 [35] Italy ICHD-2 Revised [8] Clinic 227 79 2 1 32Trucco et al. 2010 [36] Italy ICHD-2Revised [8] Clinic 70 18 0 NR 9Valguarnera et al. 2010 [37] Italy ICHD2 [7] Clinic 95 20 2 2 30Zeeberg et al. 2006 [38] Denmark ICHD2 Revised [8] Clinic 216 63 8 12 43Thorlund et al. The Journal of Headache and Pain  (2016) 17:107 Page 3 of 9AnalysisFor each study we first calculated the proportion of patientswith MOH in each treatment class, using the total numberof patients as the denominator for both proportions. Subse-quently the relative risk was calculated between each pairof treatment classes. As mentioned in the previous section,these relative risks are highly driven by the proportion ofpatients that received each treatment. For this reason, weapplied an adjustment to the relative risk estimates. In par-ticular, we first estimated the ratio with which treatmentsare being prescribed in clinical practice from prevalenceestimates of medication use, and multiplied the inverse ofthis ratio to the above-obtained relative risks (see Table 2).Further, sensitivity analysis assuming an 8 % medicationuse prevalence for opioids, was conducted.The adjusted study relative risks were pooled for eachcomparison in a fixed-effect meta-analysis. A fixed-effectmodel was used to provide a fair weighted average ofstudies. The meta function in R.v.3.0 was used to poolresults and produce forest plots. While this function byconvention produces 95 % credible intervals, one shouldonly focus on the relative risk estimates and the weighted(pooled) average relative risk, since confidence intervalsaddress sampling error and therefore are not valid underthe above adjustments.ResultsTriptans versus analgesicsTwenty-five studies informed MOH for both triptans andanalgesics in countries where medication use prevalenceTable 2 Prevalence of medication use for episodic migraine in Europe (column 2) and the applied adjustment factors in calculatingMOH prevalence and risk ratios (columns 3\u20136)Country\/Region Drug class (Prevalence, %) Analgesics Ergotamines Opioids TriptansDenmark [41] Analgesics (NA) \u2013 NA NA NAErgotamines (NA) NA \u2013 NA NAOpioids (2.0) NA NA \u2013 1:13 (0.08)Triptans (26.0) NA NA 13:1 (13.0) \u2013France [40, 42] Analgesics (12.0) \u2013 4:1 (4.00) 6:1 (6.0) 6:10 (0.58)Ergotamines (3.0) 1:4 (0.25) \u2013 3:2 (1.50) 1:7 (0.14)Opioids (2.0) 1:6 (0.17) 2:3 (0.67) \u2013 1:10 (0.10)Triptans (20.8) 10:6 (1.73) 7:1 (6.93) 10:1 (10.4) \u2013Germany [40, 42] Analgesics (31.0) \u2013 9:2 (4.43) 15:1 (15.0) 2:1 (2.14)Ergotamines (7.0) 2:9 (0.23) \u2013 7:2 (3.50) 1:2 (0.48)Opioids (2.0) 1:15 (0.06) 2:7 (0.29) \u2013 1:7 (0.14)Triptans (14.5) 1:2 (0.47) 2:1 (2.07) 7:1 (7.25) \u2013Italy [40, 42] Analgesics (12.0) \u2013 12:3 (3.75) 6:1 (6.00) 4:5 (0.79)Ergotamines (3.2) 3:12 (0.27) \u2013 8:5 (1.60) 1:5 (0.21)Opioids (2.0) 1:6 (0.17) 5:8 (0.63) \u2013 1:8 (0.13)Triptans (15.1) 5:4 (1.25) 5:1 (4.72) 8:1 (7.55) \u2013Norway [43] Analgesics (NA) \u2013 NA NA NAErgotamines (NA) NA \u2013 NA NAOpioids (2.0) NA NA \u2013 1:19 (0.05)Triptans (37.0) NA NA 19:1 (18.5) \u2013Spain [40] Analgesics (16.4) \u2013 4:5 (0.82) 8:1 (8.20) 1:2 (0.56)Ergotamines (20.0) 5:4 (1.22) \u2013 10:1 (10.0) 2:3 (0.69)Opioids (2.0) 1:8 (0.12) 1:10 (0.10) \u2013 1:15 (0.07)Triptans (29.1) 2:1 (1.77) 3:2 (1.46) 15:1 (14.6) \u2013Sweden [23] Analgesics (NA) \u2013 NA NA NAErgotamines (NA) NA \u2013 NA NAOpioids (2.0) NA NA \u2013 3:19 (0.16)Triptans (26.0) NA NA 19:3 (6.34) \u2013The medication use prevalence estimates presented in parenthesis next to treatment classes in column 2 are taken from included prevalence literature. The ratios(e.g. 3:1) presented in columns 3\u20136 are approximate ratios of prevalence of use of one medication over another. These ratios are also the adjustments factorsmultiplied to the unadjusted ratios of MOH for each study to account for the missing information about patients at risk on each medication within each studyThorlund et al. The Journal of Headache and Pain  (2016) 17:107 Page 4 of 9estimates were also available for both. Adjusted relativerisks from these studies are presented in Fig. 1a. Fourteenstudies yielded relative risks in favor of triptans, withadjusted relative risks varying from 0.12 to 0.94. In 9 ofthese 14 studies the relative risk was statistically signifi-cant. Eleven studies yielded adjusted relative risks in favorof analgesics, with adjusted relative risk estimates varyingfrom 1.05 to 5.00. The fixed-effect weighted average ad-justed relative risk was 0.65, thus suggesting an average35 % relative risk reduction of MOH associated with trip-tans compared with analgesics.Triptans versus ergotsFourteen studies informed MOH for both triptans andergots in countries where medication use prevalenceestimates were also available for both. Adjusted relativerisks from these studies are presented in Fig.1b. Fourstudies yielded adjusted relative risk estimates in favor oftriptans, two yielded no difference (i.e. relative risk of1.00), and eight studies yielded adjusted relative risk esti-mates in favor of ergots. The fixed-effect weighted aver-age relative risk was 1.07.Triptans versus opioidsEleven studies informed MOH for both triptans andopioids in countries where medication use prevalenceestimates were also available for both. Adjusted relativerisks from these studies are presented in Fig.1c. Fivestudies yielded adjusted relative risk estimates in favorof triptans, one study suggested no difference, and fivestudies yielded relative risk estimates in favor of opioids.The fixed-effect weighted average adjusted relative riskwas 0.35, suggesting an average 65 % relative risk reduc-tion of MOH with triptans compared with opioids.Ergots versus analgesicsTwelve studies informed MOH for both ergots andanalgesics in countries where medication use preva-lence estimates were also available for both. Adjustedrelative risks from these studies are presented in Fig.2a.Eleven of these yielded adjusted relative risk estimates infavor of ergots, and only one small study cell with a zerocell in the analgesics arm yielded a relative risk estimate infavor of analgesics. Among the former 11, adjusted relativerisks varied between 0.07 and 0.90. The fixed-effectweighted average adjusted relative risk was 0.41, suggestingan average 59 % relative risk reduction of MOH with ergotscompared with analgesics.Ergots versus opioidsSeven studies informed MOH for both ergots aminesand opioids. Adjusted relative risks from these studiesare presented in Fig.2b. Four of these studies yieldedadjusted relative risk estimates in favor of ergots (rangingfrom 0.33 to 0.60), one yielded an adjusted relative riskestimate of 1.00 (i.e., no difference), and two studies, bothwith zero cells in the opioids arm, yielded relative riskestimates in favor of opioids. The fixed-effect weightedaverage relative risk was 0.76, suggesting an average24 % relative risk reduction of MOH with ergots com-pared with opioids. As noted, this likely reflects mostlyDHE use rather than ergotamine tartrate.Analgesics versus OpioidsNine studies informed MOH for both analgesics andopioids. Adjusted relative risks from these studies arepresented in Fig.2c. Three studies yielded adjusted rela-tive risk estimates in favor of analgesics, and six studiesyielded relative adjusted risk estimates in favor of opioids.The fixed-effect weighted average adjusted relative riskwas 1.09, suggesting an average 9 % increased risk ofMOH with analgesics compared with opioids.DiscussionOur analysis aimed to evaluate rates of MOH dependingon the type of medication used. We found a considerablyhigher rate of MOH associated with analgesics in compari-son to triptans and ergots. Our findings also suggest thatopioids are either associated with a higher or similar risk ofMOH compared to triptans and ergots, but evidence wasmore limited for these comparisons. These findings shouldbe of interest to patients, clinicians, and policy-makers asmany patients may self-medicate, and the magnitude ofanalgesic use is potentially higher than what has generallybeen observed in population-based studies.There are strengths and limitations to our analysis thatshould be considered. Strengths of this study includeour extensive searching to complete the largest andfirst systematic review of MOH associated with mi-graine pharmacotherapies. We used an approach thatintegrated evidence on medication overuse and medi-cation use, the first such effort of which we are aware.The employed approach further strengthens compar-isons between interventions, since all studies providedata on at least two interventions, and so allows forthe analysis to retain within-study validity. Studies in-cluded had to use the ICHD-2 criteria or later, and thusremoved most uncertainty about the appropriateness ofthe MOH definition, which was particularly variable inolder studies. However, this eligibility criterion also camewith the limitation that the American Migraine Prevalenceand Prevention (AMPP) study was not eligible [35]. Infact, no US studies were eligible under the employed cri-teria. Therefore, generalizability of our findings to the USpopulation is somewhat limited.We relied instead on observational studies reportinga mix of pseudo-risk data and medication use data toapproximate the relative risk between interventions.Thorlund et al. The Journal of Headache and Pain  (2016) 17:107 Page 5 of 9Fig. 1 Forest plots and weighted average estimate for the relative risk of MOH for the three comparisons: a triptans versus analgesics; b triptansversus ergots; and c triptans versus opioidsThorlund et al. The Journal of Headache and Pain  (2016) 17:107 Page 6 of 9Fig. 2 Forest plots and weighted average estimate for the relative risk of MOH for the three comparisons: a ergots versus analgesics; b ergotsversus opioids; and c analgesics versus opioidsThorlund et al. The Journal of Headache and Pain  (2016) 17:107 Page 7 of 9The analytical approached employed to synthesize re-sults from these data relied on assumption that are ar-guably strong. There may therefore be controversy asto where the evidence fits in the evidence hierarchy.Recognizing the challenges of conducting these evalua-tions, and given the consistency of our study findings,the investigators believe this systematic review of obser-vational studies provides strong inferences about thecausative factors of MOH. The heterogeneity betweenstudies was generally low, in spite of the observationalnature of the included studies and the additional uncer-tainty one might expect from the employed medicationuse prevalence adjustments. Also, the findings of theindividual pair-wise meta-analysis added up \u2018indirectly\u2019.For example, the direct comparison of triptans andergots showed similar risk of MOH, and both drugclasses had similar relative risk estimates when com-pared with analgesics (0.65 and 0.41). These consisten-cies thus add considerable confidence to the findings ofthe analyses.There are several possible reasons for our finding in-creased MOH associated with analgesic and opioid useand less so with triptans and ergots. Analgesics and opi-oids typically work via targeting pain receptors. On theother hand, both triptans and ergots share serotonergicagonist activity and are vasoconstrictors. Furthermore,analgesics are frequently used in an over-the-countermanner whereby patients self-administer and may do sowithout the supervision of a clinician. Triptans are, forthe most part, prescription medications, and overusemay be better monitored than analgesics. In those coun-tries in which triptans are available without a prescription(e.g. UK, Germany), quantity limits may prevent tendencyto overuse.While our findings are in line with current clinicalguidelines and prejudice in favor of targeted migraine-specific pharmacotherapy, they should still only be inter-preted as exploratory due to their observational nature.Further, the inclusion of only European studies limits ourability to extrapolate the findings to other global regions.In summary, our study suggests that in patients withacute episodic migraine, the rate of MOH associated withanalgesics and opioids is considerably higher than the rateof MOH associated with triptans and ergots. These findingsshould be of interest to patients, clinicians, and policy-makers, as many patients self-medicate, and the magnitudeof analgesic use is potentially higher than what has gener-ally been observed in population-based studies.Additional fileAdditional file 1: Figure S1. Flow diagram for study selection. Table S1List of studies excluded after full text review and accompanying reason forexclusion. (DOCX 113 kb)Authors\u2019 contributionsKT prepared the first draft of the manuscript and contributed to all revisions,contributed to the concept and study design, contributed to the systematicliterature review, contributed to the statistical analyses, and contributed tothe interpretation of findings. CSE contributed to the writing of the manuscript,the concept and study design, the systematic literature review, as well as theinterpretation of findings. ED and SE contributed to the concept and studydesign, systematic literature review, and the writing of the manuscript. SKcontributed to concept and study design, the statistical analysis and the writingof the manuscript. RB and ER contributed to the concept and study design, thewriting of the manuscript and the interpretation of findings. EJM, MLM, and ST,contributed to the concept and study design, the writing of the manuscript,the systematic literature review, and the interpretation of findings. All authorsread and approved the final manuscript.Competing interestsThe study was funded by Pfizer Inc. Redwood Outcomes conducted thisstudy. Drs. Thorlund and Mills are founding partners of Redwood Outcomesand were paid consultants for conducting this study and for the developmentof this manuscript. Drs. Thorlund and Mills have previously consulted toBoehringer Ingleheim, Merck, Pfizer, Novartis, Janssen, Roche, Novo Nordisk,UCB, Sanofi, BTG, Bayer, Teva, Lundbeck, Lilly, and Gilead on systematic reviewsand network meta-analysis. In addition, Drs. Thorlund and Mills have receivedgrant funding from the Canadian Institutes of Health Research (CIHR) DrugSafety & Effectiveness Network to develop methods and educational materialson network meta-analysis. Eric Druyts, and Ping Wu are employees of RedwoodOutcomes. Drs Bhambri and Ramos are full-time employees of Pfizer Inc. Dr.Lanteri-Milnet has received compensation from Allergan, Almirall SAS, Amgen,Astellas, AstraZeneca Pharmaceuticals, ATI, BMS, Boehringer, Boston Scientific,CoLucid, Convergence, Glaxo-SmithKline, Grunenthal, Lilly, Johnson & Johnson,Medtronic, Menarini, MSD, Pierre Fabre, Pfizer, ReckittBenckiser, Saint-Jude,Sanofi-Aventis, UCB, Zambon. Dr. Sun-Edelstein has received lecture fees fromPfizer and MSD. Dr. Tepper has received grant funding from Alder, Allergan,Amgen, ATI, ElectroCore, eNeura, GSK, Teva, Pernix, Optinose\/Avanir\/Otsuka;served as a consultant to Acorda, Allergan, Amgen, ATI, Avanir, Depomed,Impax, Pfizer, Scion Neurostim, Teva, Zosana; participated in speakers bureauactivities for Allergan, Depomed, Impax, Pernix, Teva and Advisory activities forAllergan, Amgen, ATI, Avanir, Dr. Reddy\u2019s, Merck, Teva, Pfizer. Dr. Tepper furtherholds stock in ATI. Drs. Ebrahim and Kanters have nothing to disclose.Author details1Department of Clinical Epidemiology & Biostatistics, McMaster University,Hamilton, ON, Canada. 2Redwood Outcomes, 302-1505 2nd Ave. West,Vancouver, BC, Canada. 3Department of Medicine, St. Vincent\u2019s Hospital, TheUniversity of Melbourne, Melbourne, Australia. 4Department of Medicine,Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.5School of Population and Public Health, Faculty of Medicine, University ofBritish Columbia, Vancouver, BC, Canada. 6Pfizer Ltd, New York, NY, USA.7Pain Department, CHU Nice, France - FHU InovPain, Universit\u00e9 Nice C\u00f4ted\u2019Azur, Nice, France. 8Geisel School of Medicine at Dartmouth, Hanover, NH,USA. 9INSERM U1107, Neuo-Dol, Trigeminal Pain and Migraine Universit\u00e9Auvergne, Clermont-Ferrand, France.Received: 22 July 2016 Accepted: 22 October 2016References1. Headache Classification Committee of the International Headache Society(IHS). 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Zwart JA, Dyb G, Hagen K, Svebak S, Holmen J (2003) Analgesic use: a predictorof chronic pain and medication overuse headache: the Head-HUNT Study.Neurology 61:160\u20134Submit your manuscript to a journal and benefi t from:7 Convenient online submission7 Rigorous peer review7 Immediate publication on acceptance7 Open access: articles freely available online7 High visibility within the fi eld7 Retaining the copyright to your article    Submit your next manuscript at 7 springeropen.comThorlund et al. The Journal of Headache and Pain  (2016) 17:107 Page 9 of 9","attrs":{"lang":"en","ns":"http:\/\/www.w3.org\/2009\/08\/skos-reference\/skos.html#note","classmap":"oc:AnnotationContainer"},"iri":"http:\/\/www.w3.org\/2009\/08\/skos-reference\/skos.html#note","explain":"Simple Knowledge Organisation System; Notes are used to provide information relating to SKOS concepts. 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