Sacco et al. The Journal of Headache and Pain (2020) 21:76 https://doi.org/10.1186/s10194-020-01130-5 The Journal of Headache and Pain CONSENSUS ARTICLE Open Access European headache federation consensus on the definition of resistant and refractory migraine Developed with the endorsement of the European Migraine & Headache Alliance (EMHA) Simona Sacco1,2* , Mark Braschinsky3, Anne Ducros4, Christian Lampl5, Patrick Little6, Antoinette Maassen van den Brink7, Patricia Pozo-Rosich8,9, Uwe Reuter10, Elena Ruiz de la Torre6, Margarita Sanchez Del Rio11, Alexandra J. Sinclair12,13, Zaza Katsarava14,15,16,17 and Paolo Martelletti18,19 Abstract Introduction: Despite advances in the management of headache disorders, some patients with migraine do not experience adequate pain relief with acute and preventive treatments. It is the aim of the present document to provide a definition of those migraines which are difficult-to-treat, to create awareness of existence of this group of patients, to help Healthcare Authorities in understanding the implications, and to create a basis to develop a better pathophysiological understanding and to support further therapeutic advances. Main body: Definitions were established with a consensus process using the Delphi method. Patients with migraine with or without aura or with chronic migraine can be defined as having resistant migraine and refractory migraine according to previous preventative failures. Resistant migraine is defined by having failed at least 3 classes of migraine preventatives and suffer from at least 8 debilitating headache days per month for at least 3 consecutive months without improvement; definition can be based on review of medical charts. Refractory migraine is defined by having failed all of the available preventatives and suffer from at least 8 debilitating headache days per month for at least 6 consecutive months. Drug failure may include lack of efficacy or lack of tolerability. Debilitating headache is defined as headache causing serious impairment to conduct activities of daily living despite the use of pain-relief drugs with established efficacy at the recommended dose and taken early during the attack; failure of at least two different triptans is required. (Continued on next page) * Correspondence: simona.sacco@univaq.it 1 Neuroscience section – Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy 2 Regional Referral Headache Center of the Abruzzo region, ASL Avezzano-Sulmona-L’Aquila, L’Aquila, Italy Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sacco et al. The Journal of Headache and Pain (2020) 21:76 Page 2 of 12 (Continued from previous page) Conclusions: We hope, that the updated EHF definition will be able to solve the conflicts that have limited the use of definitions which have been put forward in the past. Only with a widely accepted definition, progresses in difficult-to-treat migraine can be achieved. This new definition has also the aim to increase the understanding of the impact of the migraine as a disease with all of its social, legal and healthcare implications. It is the hope of the EHF Expert Consensus Group that the proposed criteria will stimulate further clinical, scientific and social attention to patients who suffer from migraine which is difficult-to-treat. Keywords: Migraine, Chronic migraine, Resistant migraine, Refractory migraine, Intractable migraine Introduction Authorities in understanding the implications, and to Despite advances in the management of headache disor- create a basis to develop a better pathophysiological un- ders, some patients with migraine do not experience ad- derstanding and to support further therapeutic advances. equate pain relief with acute and preventive treatments. This correlates with higher burden and disability, as well Methods as despair of patients who suffer from it. The terms “re- The Panel who developed this consensus statement con- fractory” and “intractable” headache have been used to sisted of the members of the Council of the EHF. Ten of describe this particular condition and various definitions the board members are physicians (with specialization in have been suggested over time [1–6] (Table 1). However, Neurology or Internal medicine) and one is a pharma- wide acceptance of the proposed definitions was not cologist; all are experienced in headache. The Panel in- reached so far. Moreover, the International Classification cludes also two representatives (PL, ERDLT) of patients of Headache Disorders (ICHD) neither includes a defin- from the European Migraine and Headache Alliance ition for refractory or resistant migraine nor for other (EMHA). Patients representatives were not involved in primary headaches [7]. the consensus process to develop the definitions but had A previous consensus statement of the European the opportunity to provide suggestions and comments. Headache Federation (EHF) defined as refractory mi- This Consensus represents an update of a previous graine those chronic migraine patients who do not show EHF consensus published in 2014 [3]. All the points of response to adequate dosages of at least 3 drugs from the previous EHF consensus definition were reconsid- the following classes: beta-blockers, anticonvulsants, tri- ered by the EHF Expert Consensus Group and revised if cyclics, onabotulinumtoxinA and others (e.g., flunarizine, necessary. candesartan) for at least 3 months each, in absence of As a first step, an in-person meeting was held to agree medication overuse [3]. The aim of the present Consen- on the need of a new Consensus Statement, on the com- sus paper is to critically revise the definition of those mi- position of the EHF Expert Consensus Group and on graines which are difficult-to-treat, to create awareness the mission of this updated Consensus Statement. of existence of this group of patients, to help Healthcare Thereafter, the process proceeded via e-mails. Table 1 Available definitions for migraine which is difficult to treat Sacco et al. The Journal of Headache and Pain (2020) 21:76 Page 3 of 12 The Delphi method [8] was used to reach consensus. month plus the failure of previous preventive According to this method, the EHF Expert Consensus treatments. Group members were assigned to open or multiple- Resistant migraine is defined by having failed at least 3 choice questions in several rounds. Participants were classes of migraine preventatives and suffer from at least instructed not to discuss the responses amongst them- 8 debilitating headache days per month for at least 3 selves. Feedback after each round was sent only to the consecutive months without improvement; definition facilitator (SS). The facilitator collected all the answers can be based on review of medical charts. for each round and issued an anonymized report with Refractory migraine is defined by having failed all of comments and agreement rates. Participants were then the available preventatives and suffer from at least 8 de- encouraged to revise their earlier answers in light of the bilitating headache days per month for at least 6 consecu- replies of other members. Questions were repeated until tive months. For refractory migraine, chart review alone is a clear majority (> 70% of agreement) was reached [9]. not sufficient and a minimum period of observation of 6 Each Panel member (with the exclusion of EHMA repre- months is required together with completed diaries. sentatives) had the right to vote. A step by step approach The drug classes considered for meeting the definitions was used to build the definitions, using the results of the include antidepressants, antiepileptics, beta-blockers, cal- Delphi questions. Seven rounds were needed to reach a cium channel blockers, drugs acting on the calcitonin- consensus among all the different aspects of the defin- gene related peptide (CGRP) pathway, angiotensin- ition (Table 2). converting enzyme inhibitors or angiotensin II receptor blockers, onabotulinumtoxinA, as well as any new devel- oped drug with established efficacy in migraine preven- Results tion. Drug failure may include lack of efficacy or lack of Two categories of difficult to treat migraine were recog- tolerability. For lack of efficacy, appropriate dosing and nized, resistant migraine and refractory migraine. Cri- duration of the considered preventatives is reported in teria to define resistant and refractory migraine are Table 4. reported in Table 3. A patient cannot be considered to try some drugs be- Definitions are based on fulfilling ICHD III criteria for cause of possible contraindications. Absolute, major and migraine with or without aura or for chronic migraine relative contraindications to drugs for migraine preven- [7] and having at least 8 debilitating headache days per tion are reported in Table 5. Table 2 Rounds of the consensus process. After each round and before the next one, anonymized results and comments were shared. *Residual disagreement regarded 2 different issues from 2 different members of the group: 1. Threshold of headache days per month: 6 was the suggested alternative; 2 Assessment of patients: no need to be assessed by headache centers Sacco et al. The Journal of Headache and Pain (2020) 21:76 Page 4 of 12 Table 3 Proposed updated definition of resistant and refractory migraine a Trials with at least 3 drug classes is encouraged if allowed by contraindications b Established doses and duration as reported in Table 4 c Absolute, major and relative contraindications as reported in Table 5 The presence of medication overuse is compatible with Both definitions of resistant and refractory migraine the proposed definition of resistant and refractory migraine; require the presence of at least 8 days of debilitating mi- however, in patients with refractory migraine documentation graine. Debilitating headache is defined as headache of failed attempts of withdrawal of medications is needed. causing serious impairment to conduct activities of daily Sacco et al. The Journal of Headache and Pain (2020) 21:76 Page 5 of 12 Table 4 Suggested doses and duration for assessment of lack of efficacy living despite the use of pain-relief drugs with estab- by headache specialists and that patients with refrac- lished efficacy at the recommended dose and taken early tory migraine are evaluated in tertiary Headache during the attack; failure of at least two different triptans Centers. is required. Triggers and comorbidities which may contribute to To validate the definitions, it is also recommended resistant or refractory migraine need to be identified and that patients with resistant migraine are evaluated managed before assigning patients to those categories. Table 5 Absolute, major and relative contraindications to drugs for migraine prevention Sacco et al. The Journal of Headache and Pain (2020) 21:76 Page 6 of 12 Careful differential diagnosis with mimicking conditions treatment response, baseline headache severity, partial must be done as suggested in Table 6. response versus an all-or-none response, and the possi- bility of any variability in the treatment response over Discussion time [11]. Resistant and refractory The categorization of difficult-to-treat patients might It is necessary to distinguish between patients who easily be helpful in the recognition of patients in need of more respond to treatment and those who do not. The latter expensive treatments. Additionally, the definition could requires more attention and more persistence in the help patients to gain access to reimbursement policies, treatment. Moreover, patients who do not easily respond work-related disability benefits, and social security to treatment are at higher risk of developing chronic benefits. headache and therefore should be identified early and Anyhow, we duly recognize that patients who also do treated accordingly [10]. not meet criteria for resistant migraine (e.g. 6 debilitat- One of the major novelties of the updated EHF Con- ing migraine days per month) may need access to dedi- sensus definition is the recognition that difficult-to-treat cated headache care or treatment escalation. patients may be labelled into two major categories, re- sistant migraine and refractory migraine; the difference Cut-offs values between resistant and refractory migraine relies on the A further main novelty of the present definition is the use number of required previous treatment failures. of cut-off values rather than percent reductions. The use The two categories were identified in order to respond of cut-off values is more in line with the ICHD III criteria to different needs and to implement these needs in the while the use of percentage reductions is more in line with clinical and research settings. In fact, the optimal defin- clinical trial criteria. Clinical trials for preventive treat- ition of difficult to treat migraine depends on the con- ment define responders as those achieving at least 50% re- text and on the consequences of assigning the label. If duction in monthly migraine/headache days with the consequence of labeling is referral to a headache treatment as compared to baseline [12]. For chronic mi- center or treatment escalation, the definition threshold graine a 30% reduction is accepted [13]. However, with should be lower than if the consequence is to develop the use of percent reduction, patients may be considered new interventional treatments. Accordingly, resistant mi- responders but still have a relevant number of debilitating graine is defined as migraine which remains significantly days with headache. To overcome this problem the EHF debilitating despite some treatment attempts. In con- Expert Consensus Group opted to use 8 days per month trast, refractory migraine is defined as migraine which as cut-off values. Eight days per month were chosen to remains significantly debilitating after maximal or nearly consider evidence indicating that moderate disability starts maximal number of treatment attempts. It is important after 4 migraine days per month [14–16]. Thus, the se- to note that resistance and refractoriness may just repre- lected cut-off values allow us to consider both, episodic sent more or less treatable versions of migraine attacks, and chronic migraine as resistant or refractory. It is im- rather than a separate migraine entity. The same patient portant to note that with the use of cut-off values, patients might be identified as refractory at one time, but treat- who have significant response to treatment (e.g a patient ment responsive at another. Therefore, it may be of cru- with 30 headache days per month and with > 50% reduc- cial importance to evaluate acute and prophylactic tion in headache days with treatment) may be labelled as Table 6 Conditions to be excluded before diagnosis of resistant or refractory migraine Sacco et al. The Journal of Headache and Pain (2020) 21:76 Page 7 of 12 resistant or refractory. With advancements in migraine complexity of the disability. Indeed, the recent random- treatment, goals of successful treatment may become ized controlled trials on migraine prevention used sev- more and more ambitious and cut-off values may need to eral tools to capture the impact of both, the disease and be further reduced. the treatment [22, 23]. Additionally, the choice of any cut-off score might be controversial as there are no data Debilitating headache regarding which threshold of score change in these in- The criteria proposed by the EHF Expert Consensus struments should separate treatment failure from treat- Group rely on the presence of a given number of days of ment success. Moreover, the disability instruments may debilitating headache attacks. The presence of a serious not be translated or validated in certain countries. How- impairment in activities is a key feature of the proposed ever, when available, using PROs not only helps to trans- definitions. Debilitating headache was defined as head- late burden of disease but also tracks changes over time. ache causing serious impairment to the conduct of activ- In the proposed definition, the efficacy of analgesics is ities in daily living despite the use of pain-relief drugs also considered. In fact, resistance or refractoriness to with established efficacy at the recommended dose [17]. acute or preventive treatment, are not to necessarily re- In order to assess the efficacy of acute headache medica- lated. One patient may have a poor response to preven- tions, adequate timing of drug administration, dosage tatives but a good response to analgesics. Failure of at and formulations used, should be considered. least two triptans is required because there is evidence We opted for headache days rather than migraine days that switching from a triptan that is ineffective to a sec- because overt migrainous features may be masked in ond one can result in positive treatment [24]. If the anal- complex patients especially in patients who overuse gesics are able to control adequately the pain allowing acute headache medication. We also voluntarily decided patients to function normally, patients with migraine will to use the term debilitating rather than disabling. The not qualify to be categorized as resistant or refractory. It term disabling is more related to physical impairment is worth mentioning that according to the proposed defi- caused by neurological disease such as stroke, multiple nitions of resistant and refractory migraine, patients who sclerosis, amyotrophic lateral sclerosis and others which overuse symptomatic drugs and who have pain relief cause permanent impairment in function of patients due with them cannot be labelled as resistant or refractory. to physical disabilities. As the impairment related to mi- graine attacks is temporary if attacks are not frequent or not always severe and due to cognitive impairment and Drug failure head pain but not to physical disability, a different ter- Establishing drug failure or contraindication is pivotal to minology may be more appropriate. However, we are identifying resistant or refractory migraine. This point aware that patients who suffer from migraine live with should carefully be addressed in order to avoid labelling anticipatory anxiety as they do not know when the next as resistant or refractory patients who are only pseudo- attack may occur. This fear conditions their life and that resistant or pseudo-refractory. of their families, social activities and work responsibil- One of the main criteria to define resistance and re- ities [18]. fractoriness to treatment is the number of failed classes Ascertainment of debilitating attacks shall be done of medications. The specific classes were picked because with clinical interview or with the use of validated scales they have shown clinical efficacy in randomized- in order to evaluate if headaches significantly interfere controlled trials and are supported by evidence-based with a patient’s ability to work, attend school, or partici- guidelines for migraine prevention [13, 22, 25, 26]. The pate in family or social activities. The EHF Expert Con- Consensus group agreed to select failure of drug classes, sensus Group did not choose to use cut scores at rather than single medications, since a patient who fails common validated instruments to measure function or a drug has a very low probability of responding to an- disability such as the MIgraine Disability ASsessment other drug within the same class based on expert opin- (MIDAS) tool [19], the Headache Impact Test (HIT-6) ion. However, it is important to note that different scale [20], or the Headache-Attributed Lost Time agents within a class may work by different mechanisms (HALT) Indices [21]. We considered the fact that there [2, 27] and thus we support the use of drugs in the same is not one single Patient-Reported Outcome scale class, but with a different mechanism of action (e.g. (PROs) including the magnitude of the impairment that topiramate and valproate). We acknowledge that some a person with a migraine attack or frequent migraine agents may be not available or accessible across all coun- suffers. This is, in a large part, due to the impact of mi- tries and that others require technical expertise (e.g. graine on cognition. When the brain can’t function, OnabotulinumtoxinA), which may limit the there is a wide impact on many different tasks which generalizability of the proposed definitions. National ad- need a wide range of instruments to capture the aptations of the EHF Consensus on the definition of Sacco et al. The Journal of Headache and Pain (2020) 21:76 Page 8 of 12 resistant and refractory migraine can be developed for In the current EHF definitions of resistant and refrac- use at the country level. tory migraine, we did not include in the criteria the pos- The proposed definitions of resistant and refractory mi- sibility to combine different preventatives to achieve a graine consider the appropriateness of doing trials with pre- response to treatment in the criteria. Combinations of ventive treatments. Identification of factors that contribute suggested preventive treatments are recommended espe- to pseudo-resistance is important in preventing costly and cially when one preventive treatment decreased the at- potentially risky diagnostic evaluations and in avoiding in- tack frequency but did not control the situation appropriate intensification of treatment. If therapy was in- satisfactorily, upon the physician’s decision [31]. Com- adequate (low dose or incorrect duration) the failure is to bination therapy has the potential advantage to target be reassessed. Suggested doses and durations for optimal different aspects of the pain dysfunction, with potentially treatment are specified in Table 4. Minimal duration of better results due to the synergistic effects of different drug trials was set at 2 months (after reaching the thera- treatments. However, there is insufficient evidence to peutic dose) for oral drugs in line with previous definition state definitively if combination therapy is clearly super- of refractory migraine. For monoclonal antibodies (mAbs) ior to single therapy [32–34]. acting on the CGRP pathway a minimum of 3 months is re- quired and for OnabotulinumtoxinA a minimum of 6 Medication overuse months, in line with available guidelines and evidence from It is well known that a variable proportion of patients real-life studies [13, 22, 25, 28]. Longer trials would be pref- overusing acute headache medications may actually erable for some drugs, but extending minimal time frame is benefit from withdrawal [35]. However, the ideal treat- not feasible in every case, especially in those patients who ment strategy for medication overuse is a matter of on- do not have any kind of improvement with the selected going debate. Withdrawal cannot be achieved in every preventatives. On the other hand, we may consider to ex- patient and relapse or continued overuse has been re- tend the preventive treatment if there was some improve- ported in many patients [36]. For those reasons we opted ment during the first period of treatment. Undoubtedly, to make the presence of medication overuse compatible decisions will have to be individualized. The EHF Expert with the proposed definition of resistant and refractory Consensus Group decided not to pose a time frame for pre- migraine. Up to know it is unclear if withdrawal of acute vious trials of preventatives (e.g. failure within the 10 previ- medication may revert an apparent refractory headache ous years) as any choice would be arbitrary. into a tractable one. Having a well-defined definition of It is important to note that lack of adherence may con- refractory and resistant headache will represent the basis tribute to lack of success of medical treatment. Lack of ad- for research studies to establish this. herence is mostly due to side effects. Frequently, side effects are too bothersome for patients and lead to drug Triggers and comorbidities discontinuation. EHF criteria for resistant and refractory In some cases, difficult-to-treat migraine is associated migraine include lack of tolerability among the accepted with uncontrolled trigger factors (e.g. excessive use of reasons of drug failure. Anyway, we want to point out that caffeine) and comorbidities. The role that those factors side effects should always be addressed and if possible ad- have in drug resistance is not entirely clear. On one equately managed to promote drug adherence. A trusting hand, they may contribute to resistance or refractoriness physician–patient relationship, setting reasonable goals to prescribed pharmacological treatment but on the and expectations, and educating patients are key for a suc- other hand if medications are effective, triggers may not cessful patient management. Nocebo effect may lead pa- be able to induce migraine attacks. Triggers and comor- tients to discontinue medications because of the fear of a bidities should be addressed and managed before label- potential side effect [29, 30]. ling patients as resistant or refractory, even if definite Some patients have medical contraindications to removal is not always possible. specific preventive treatments (Table 5). Contraindi- Trigger factors that can exaggerate migraine include cated drugs are considered in the criteria for resistant alcohol consumption, caffeine overuse, diet, smoking and refractory migraine. It is important to differenti- and vasodilating antihypertensives. Further triggers are ate absolute contraindications that pose a risk for the represented by emotional stress [37], alterations in the patient if the drug is used, from a relative contraindi- sleep cycle [38–40], and hormonal factors [41–43]. Man- cation, which does not prohibit the use of the drug agement of those factors is a staple of good clinical prac- but may require stricter monitoring. One limit of the tice. Additionally, patients suffering from migraine current definition is that a patient can be defined as frequently have comorbid disorders [44–48]. The identi- resistant while not having tried any preventive medi- fication and management of all clinically significant co- cation because of hypothetical contraindications to at morbidities is essential before declaring a treatment least three classes. failure in migraine patients. Psychiatric comorbidities Sacco et al. The Journal of Headache and Pain (2020) 21:76 Page 9 of 12 and obesity may be particularly relevant in the setting of certain countries, not reimbursed by the Healthcare sys- resistance or refractoriness to treatments [49, 50]. tems, than pharmacological treatments. Moreover, physician-patient relationship, lifestyle changes, and other qualitative variables can also influ- Differential diagnosis ence the response to treatment. A possible reason for treatment failure in patients with headache is that the diagnosis is incomplete or incorrect. Assessment of patients When addressing patients with migraine who do not re- Migraine in general can be managed in the setting of spond to treatment it is always important to reconsider primary care [56] or general neurology [57]. However, the diagnosis and to rule out other primary or secondary such settings cannot provide the necessary expertise to headaches, which may entirely account for the clinical treat resistant and refractory patients. Patients with re- picture or which may coexist with migraine and contrib- sistant migraine should be managed in special interest ute to the lack of response to treatments. Investigations headache care settings (e.g. general practitioners with should be done where appropriate to exclude secondary special interest in headache or neurologists, or first/sec- headaches [51]. A list of conditions mimicking resistant ond level headache clinics) and patients with refractory or refractory migraine is reported in Table 6. migraine must be managed in tertiary level headache Particular attention should be paid to idiopathic intra- clinics [58, 59]. In particular, refractory migraine patients cranial hypertension without papilledema (IIIWP). This must be offered the possibility of access to a multidiscip- condition can be entirely responsible of difficult-to-treat linary team. headache or can contribute to drug resistance or refrac- Management by non-headache specialists often leads toriness in patients who have concomitant migraine. Cri- to perform-and-repeat exams which are not needed, thus teria which increase the likelihood of IIIWP are raising the cost of migraine care [60, 61]. Additionally, represented by the presence, at brain magnetic reson- incidental findings to unnecessary exams may lead to ance, of empty sella, flattening of the posterior part of over-treatment of some conditions (e.g patent foramen the ocular globe, distension of the perioptic subarach- closure) or additional unnecessary examinations (e.g. noid space, tortuous optic nerve, transverse sinus sten- thrombophilia screening in unselected patients with osis [52]. If this IIIWP is suspected, a lumbar puncture white matter abnormalities). with measurement of cerebrospinal fluid pressure should Establishing previous treatment failures ideally should be performed and patients treated according to available be done by chart review. It is not reasonable to test guidelines [52]. again preventive medications used in the past with no efficacy or with intolerable side effects provided that in- Other limitations to the definition formation on duration, dose and adverse events is suffi- Migraine is a cyclic disorder which tends to fluctuate in cient and reliable. Unfortunately, not all patients provide frequency, severity and disability during life. Specifically, charts and headache diaries. In those cases, careful col- this has been investigated over the course of a year and lection of information from patient and relatives should for example, patients with chronic migraine can fluctu- be looked for with the help of the general practitioner, if ate into an episodic migraine phase [53]. This is why available. these new proposed criteria for the definition of resistant For patients with refractory migraine who were never and refractory migraine have considered following also followed by a headache specialist, a minimum follow-up the International Classification for Headache Disorders, of 6 months is suggested, to obtain reliable diaries and three consecutive months as a time frame to define at allows the possibility to. that time point in life, the presence of a resistant or re- further improve headache management, as the diagno- fractory migraine. However, a diagnosis is not static in sis of refractory migraine is a very serious matter, which headache, and can change over time. If this should should be carefully established. happen, it can always be revised. It is also important to note that the present definition Implications to be defined as resistant or refractory did not consider failure to devices or non- migraine patient pharmacological therapies. A number of studies have The diagnosis of resistant or refractory migraine may shown that vagal nerve stimulation, biofeedback, relax- contribute to stigmatizing the patient and therefore may ation, and cognitive behavior therapy are as efficacious have profound psychological implications [62]. This is for migraine as placebo, but still better than no improve- especially true because the concept seems static and un- ment [54, 55]. However, behavioral treatments are less resolvable. Education and effort will have to be put in accessible, more professional-dependent and less stan- with both treating physicians and patients to help them dardized than pharmacological treatments, and in to understand the possible fluctuations of the disease. Sacco et al. The Journal of Headache and Pain (2020) 21:76 Page 10 of 12 There could also be legal and healthcare implications. It to be aware that these patients exist and that a good def- may be possible that in certain countries only those patients inition represents a major need for clinical practice, for with a resistant or refractory migraine may have access to legal issues, and for research purposes. The proposed newer treatments such as monoclonal Antibodies (mAbs) updated EHF definition identifies two subsets of acting on the Calcitonin-Gene-Related-Peptide (CGRP) difficult-to-treat migraine, resistant and refractory mi- pathway; or in other countries, it might allow for temporary graine, and considers both frequency and disability from or permanent social welfare [14, 63]. Even if revisable, it single and frequent attacks. Although, in the previous does support a difficult-to-treat disorder and should facili- literature formal and operational definitions for refrac- tate access to more resources for its management. tory or intractable headache were proposed, none was universally accepted. We hope, that the updated EHF Future perspectives definition will be able to solve the conflicts that have The introduction of the concept of resistant and refrac- limited the use of definitions which have been put for- tory migraine will have clinical and political implications. ward in the past. Only with a widely accepted definition, We attempt to provide operational criteria of what intui- progresses in difficult-to-treat migraine can be achieved, tively has been used already. Introduction of expensive underlying mechanisms can be identified, epidemiology migraine preventatives such as OnabotulinumtoxinA can be characterized, and evidence-based treatments can and mAbs acting on the CGRP pathway and the expect- be developed. Furthermore, the aim of this new defin- ation of further preventatives raised the question of cost ition is to increase the understanding of the impact of effectiveness of these treatments. In many European migraine as a disease with all of its social, legal and Countries use of these treatments is restricted to the healthcare implications. It is the hope of the EHF Expert difficult-to-treat subpopulations of migraine patients. Consensus Group that the proposed criteria will stimu- These subpopulations were defined based on frequency late further clinical, scientific and social attention to pa- (e.g. in Spain more than 8 headache days per month) or tients who suffer from migraine which is difficult-to- non-response (e.g. in Germany more than 5 preventa- treat. tives for episodic migraine and 6 preventatives including Abbreviations OnabotulinumtoxinA for chronic migraine). This manu- CGRP: Calcitonin-gene related peptide; EHF: European Headache Federation; script aims to provide solid expert-opinion based criteria EHMA: European Migraine & Headache Alliance; HALT: Headache-Attributed for these subpopulations. It will be important to have Lost Time; HIT-6: Headache Impact Test; ICHD: International Classification of Headache Disorders; IIIWP: Idiopathic intracranial hypertension without adequate field-testing of the proposed updated EHF def- papilledema; mAbs: Monoclonal antibodies; MIDAS: MIgraine Disability inition of resistant and refractory migraine in order to ASsessment; PROs: Patient-Reported Outcome scale identify possible deficiencies and to make further im- Acknowledgements provements. Field-testing should be performed across Not applicable. different countries and different clinical settings. Adap- tations at the country level may be needed to make the Authors’ contributions SS conceived this consensus, acted as facilitator during the consensus definition more usable. process and drafted the paper; MB, AD, ZK, CL, PM, AMVDB, PPR, UR, MSDR, Accepted and reliable criteria represents the basis of fur- AJ S contributed to develop the consensus definition and revised the paper ther research. At present, the exact pathophysiology of re- for important intellectual content; PL and ERDLT revised the paper for important intellectual content. All authors have approved the submitted fractory migraine is unknown. It is important to reliably version. identify factors which may lead to refractoriness. We do not know whether genetic predisposition plays a role in re- Authors’ information European Headache Federation (EHF) Council: ZK (president), CL (1st vice- sistance to treatment, whether resistance is accompanied president), AMVDB (2nd vice-president), SS (treasurer), PM (past-president), over time by changes in the brain structure and function as MB (member), PPR (member), UR (member), MSDR (member), AS (member), assessed by neuroimaging, or which mechanisms play a piv- AD (member). European Migraine & Headache Alliance (EMHA): PL (president), ERDLT otal role (e.g. central sensitization, peripheral sensitization). (Executive Director, Company Secretary and Immediate Past President). There are several migraine preventive treatments in development; the proposed criteria will allow inclusion Funding Publication fees for this publication were covered by the European of these treatments when there is a good evidence basis Headache Federation. for their use. Criteria will need to be changed when new treatments and significant advancements in the migraine Availability of data and materials Not applicable. field will happen. Ethics approval and consent to participate Conclusion Not applicable. Crafting an operational definition of so called “difficult- Consent for publication to-treat migraine” is challenging. However, we all need Not applicable. Sacco et al. The Journal of Headache and Pain (2020) 21:76 Page 11 of 12 Competing interests 2. Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick D (2006) Mark Braschinsky: Fees as a speaker or for participation to advisory boards Towards a definition of intractable headache for use in clinical practice and from Abbott Laboratories, Allergan Inc., Berlin-Chemie AG (Menarini Group), trials. Cephalalgia 26:1168–1170 Boehringer Ingelheim Pharma GmbH, Desitin Arzneimittel GmbH, EV3, 3. 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Headache 48:778–782 Zaza Katsarava: Fees as speaker or participation to advisory boards from 5. Silberstein SD, Dodick DW, Pearlman S (2010) Defining the Novartis, Lilly, TEVA, Allergan, Merck and Daiichi. pharmacologically intractable headache for clinical trials and clinical Christian Lampl: Fees as speaker or for participation to advisory boards from practice. Headache 50:1499–1406 Allergan, Eli-Lilly, Novartis, Pfizer, Teva. 6. Wöber C, Wessely P, Austrian Consensus Group on Refractory Chronic Patrick Little: none. Migraine (2014) Comment on: Martelletti et al. Refractory chronic migraine: Paolo Martelletti: Fees as speaker or for participation to advisory boards from a consensus statement on clinical definition from the European Headache Allergan, Eli-Lilly, Novartis, Teva. Federation. J Headache Pain 15:77 Antoinette Massen van den Brink: Research grant and/or speaker/consultant 7. Headache Classification Subcommittee of The International Headache fees from Amgen/Novartis, Eli-Lilly, Teva. Society (2018) The international classification of headache disorders 3rd Patricia Pozo-Rosich: Fees as consultant and speaker for Allergan, Almirall, Biohaven, edition. Cephalalgia 38:1–211 Chiesi, The Corpus, Eli Lilly, Medscape, Neurodiem, Novartis and Teva. Researchh 8. Dalkey NC, Helmer-Hirschberg O (1962) An experimental application of the funding from Allergan, AGAUR, la Caixa foundation, Migraine Research Foundation, Delphi method to the use of experts. Rand Corp, Santa Monica Instituto Investigación Carlos III, MICINN, Novartis, PERIS, ERANet Neuron; funding for 9. von der Gracht HA (2013) Consensus measurement in Delphi studies: clinical trials from Alder, Electrocore, Eli Lilly, Novartis and Teva. review and implications for future quality assurance. Technol Forecast Social Uwe Reuter: Fees as consultant and speaker for Allergan, Biohaven, The Change 79:1525–1536 Corpus, Eli Lilly, Medscape, Novartis, STREAMedUP and Teva. Research 10. Katsarava Z, Schneeweiss S, Kurth T, Kroener U, Fritsche G, Eikermann A, funding from BMBF and Novartis, Institutional funding for clinical trials from Diener HC, Limmroth V (2004) Incidence and predictors for chronicity of Alder, Amgen. Allergan, Eli Lilly, Novartis and Teva. headache in patients with episodic migraine. Neurology 62:788–790 Elena Ruiz de la Torre: none. 11. Lampl C, Jensen R, Martelletti P, Mitsikostas DD (2014) Refractory headache: Simona Sacco: Fees as speaker or for participation to advisory boards from one term does not cover all--a statement of the European headache Abbott, Allergan, Eli-Lilly, Medscape, Novartis, Teva. federation. J Headache Pain 15:50 Margarita Sanchez Del Rio: Fees as speaker or for participation to advisory 12. 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