CONSENSUS Statement OPEN Diagnosis and management of migraine in ten steps Anna K. Eigenbrodt 1,36, Håkan Ashina1,36, Sabrina Khan 1, Hans-​Christoph Diener 2, Dimos D. Mitsikostas3, Alexandra J. Sinclair 4,5,6,7, Patricia Pozo-​Rosich 8,9, Paolo Martelletti 10,11, Anne Ducros 12, Michel Lantéri-​Minet13, Mark Braschinsky 14, Margarita Sanchez del Rio15, Oved Daniel 16, Aynur Özge 17, Ayten Mammadbayli18, Mihails Arons 19, Kirill Skorobogatykh 20, Vladimir Romanenko21, Gisela M. Terwindt22, Koen Paemeleire 23, Simona Sacco 24, Uwe Reuter 25, Christian Lampl26,27, Henrik W. Schytz 1, Zaza Katsarava 28,29,30,31, Timothy J. Steiner 32,33 and Messoud Ashina1,31,34,35 ✉ Abstract | Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-​diagnosed and under-​treated. To support clinical decision-​making, we convened a European panel of experts to develop a ten-​step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-​term follow-​up. Migraine is a highly disabling primary headache dis- processes and few mechanism-​based treatment options order with a 1-​year prevalence of ~15% in the gen- currently exist10. eral population1,2. According to the Global Burden of Treatments for migraine include acute and preven- Disease Study, migraine is the second most prevalent tive medications and a range of non-​pharmacological neurological disorder worldwide and is responsible for therapies10. Despite these treatment options and the more disability than all other neurological disorders comprehensive diagnostic criteria, clinical care remains combined2,3. suboptimal — misdiagnosis and under-​treatment of Migraine manifests clinically as recurrent attacks of migraine are substantial public health challenges11,12. headache with a range of accompanying symptoms4. Population-​based data from Europe indicate that pre- In approximately one third of individuals with migraine, ventive medication for migraine is used by only 2–14% headache is sometimes or always preceded or accom- of eligible individuals11, an alarming finding that calls panied by transient neurological disturbances, referred for global action12. A comprehensive approach is needed to as migraine aura5,6. Furthermore, a minority of those to facilitate accurate diagnosis and evidence-​b ased affected develop chronic migraine, in which attacks management. become highly frequent7. The pathogenesis of migraine In this Consensus Statement, we provide a ten-​step is widely believed to involve peripheral and central acti- approach to the diagnosis and management of migraine vation of the trigeminovascular system8, and cortical (Fig. 1). Development of this approach was initiated by the ✉e-​mail: ashina@dadlnet.dk spreading depression is thought to be the underlying Danish Headache Society, and the Consensus Statement https://doi.org/10.1038/ neurophysiological substrate of migraine aura9. However, is endorsed by the European Headache Federation s41582-021-00509-5 much remains unknown about specific pathogenic (EHF) and the European Academy of Neurology NAtuRe RevIews | NeUROlOgy volume 17 | August 2021 | 501 0123456789();: C o n S e n S u S S tat e m e n t (EAN). The aim of the approach is to support care and Statement. Three authors (H.A., T.J.S. and M.Ashina) clinical decision-​making by primary care practitioners, identified the ten most important steps in diagno- neurologists and headache specialists alike. sis and management of migraine through email cor- respondence. Once these steps were agreed, seven Methods authors (A.K.E., H.A., S.K., H.-​C.D., H.W.S., T.J.S. and The Danish Headache Society and its representatives M.Ashina) wrote the initial draft. (A.K.E., H.A., H.W.S. and M.Ashina) conceived a For each of the ten steps, a structured literature search European Consensus Statement on the diagnosis and was performed in April 2021 using the PubMed database. clinical management of migraine. A formal proposal, We searched for “migraine” in combination with the including a suggested list of authors, was prepared terms “diagnosis”, “treatment”, “therapies”, “treatment out- and submitted to the Board of Directors of the EHF, come” or “prognosis”. We excluded publi­cations written the Chairs of the EAN Headache Panel and the Chair in a language other than English. We also selected addi- of the EAN Scientific Committee. The proposal was tional articles deemed relevant from a search of the refer- approved by unanimous decision and a European ence lists of the originally identified articles. The content expert panel was convened to develop this Consensus was targeted towards a broad readership of primary care practitioners, neurologists and headache specialists. In continuous email correspondence, all authors Author addresses reviewed the initial draft and contributed to all subse- 1 Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty quent drafts. Whenever possible, recommendations of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. were based on interpretation of findings from systematic 2 Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty, reviews and meta-​analyses, relying on expert opinion University Duisburg-​Essen, Essen, Germany. only when scientific evidence was limited or unavailable. 3 First Department of Neurology, Aeginition Hospital, National and Kapodistrian The views of each author were taken fully into con- University of Athens, Athens, Greece. sideration and revisions were made until unani­mous 4 Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical consensus was reached. Four rounds of review were and Dental Sciences, University of Birmingham, Birmingham, UK. required to establish consensus. 5 Birmingham Neuro-​Ophthalmology, Queen Elizabeth Hospital, Birmingham, UK. 6 Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK. Step 1: When to suspect migraine 7 Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, In the third edition of the International Classification Queen Elizabeth Hospital, Birmingham, UK. of Headache Disorders (ICHD-3), migraine is classified 8 Headache Unit, Neurology Department, Vall d’Hebron University Hospital, into three main types4: migraine without aura, migraine Barcelona, Spain. with aura, and chronic migraine. The clinical character- 9 Headache and Neurological Pain Research Group, Vall d’Hebron Research Institute, istics of each must be considered to ensure an accurate Universitat Autònoma de Barcelona, Barcelona, Spain. diagnosis. 10 Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy. 11 Regional Referral Headache Centre, Sant’Andrea Hospital, Rome, Italy. Migraine without aura. Migraine without aura is char- 12 Neurology Department, Montpellier University Hospital, Montpellier, France. acterized by recurrent headache attacks that last 4–72 h4. 13 Departement d’Evaluation et Traitement de la Douleur, Centre Hospitalo-​Universitaire de Nice, Nice, France. Typical features of an attack include a unilateral location, 14 Neurology Clinic, Tartu University Hospital, Tartu, Estonia. pulsating quality, moderate or severe pain intensity, and 15 Department of Neurology, Clínica Universidad de Navarra, Madrid, Spain. aggravation by routine physical activity4,13. However, 16 Headache & Facial Pain Clinic, Laniado Medical Center, Netanya, Israel. bilateral pain is not uncommon; population-​based data 17 Department of Neurology, Mersin University Medical Faculty, Mersin, Turkey. indicate that ~40% of individuals with migraine report 18 Department of Neurology, Azerbaijan State Medical University, Baku, Azerbaijan. bilateral pain during attacks5. The most common asso- 19 Department of Anesthesiology and Intensive Care, P. Stradins University, Riga, Latvia. ciated symptoms are photophobia, phonophobia, nau- 20 University Headache Clinic, Moscow, Russia. sea and vomiting4,13. Before the onset of pain, prodromal 21 Ukrainian Institute of Family Medicine, Kiev, Ukraine. symptoms can include a depressed mood, yawning, 22 Department of Neurology, Leiden University Medical Center, Leiden, Netherlands. fatigue and cravings for specific foods14. After resolu- 23 Department of Neurology, Ghent University Hospital, Ghent, Belgium. 24 Neuroscience Section, Department of Applied Clinical Sciences and Biotechnology, tion of the headache, postdromal symptoms can last University of L’Aquila, L’Aquila, Italy. up to 48 h and often include tiredness, concentration 25 Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany. difficulties and neck stiffness15. 26 Headache Medical Center, Seilerstaette Linz, Linz, Austria. 27 Department of Geriatric Medicine, Ordensklinikum Linz, Linz, Austria. Migraine with aura. Approximately one third of indivi­ 28 Department of Neurology, University of Duisburg-​Essen, Essen, Germany. duals with migraine experience aura5, either with every 29 Department of Neurology, Evangelical Hospital Unna, Unna, Germany. attack or with some attacks. Aura is defined as transient 30 EVEX Medical Corporation, Tbilisi, Georgia. focal neurological symptoms that usually precede, but 31 Department of Nervous Diseases of the Institute of Professional Education, sometimes accompany, the headache phase of a migraine IM Sechenov First Moscow State Medical University, Moscow, Russia. attack4. In >90% of affected individuals, aura manifests 32 Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, NTNU Norwegian University of Science and Technology, Trondheim, Norway. visually4,16, classically as fortification spectra4. Sensory 33 Division of Brain Sciences, Imperial College London, London, UK. symptoms occur in ~31% of affected individuals and are 34 Danish Knowledge Center on Headache Disorders, Glostrup, Denmark. usually experienced as predominantly unilateral paraes- 35 Department of Neurology, Azerbaijan Medical University, Baku, Azerbaijan. thesia (pins and needles and/or numbness) that spreads 36 These authors contributed equally: Anna K. Eigenbrodt, Håkan Ashina. gradually in the face or arm16. 502 | August 2021 | volume 17 www.nature.com/nrneurol 0123456789();: C o n S e n S u S S tat e m e n t Diagnosis 1 When to suspect migraine 2 Diagnosis of migraine 3 Patient centricity and education • Recurrent headache of moderate • Record medical history • Provide appropriate reassurance to severe intensity • Apply diagnostic criteria • Agree on realistic objectives • Visual aura • Consider differential diagnoses • Identify predisposing and/or trigger • Family history of migraine • Examine patient to exclude other factors • Onset of symptoms at or around causes • Follow strategy to individualize puberty • Use neuroimaging only when a therapy according to symptoms and secondary headache disorder is needs suspected Acute and preventative treatment 4 Acute treatment 5 Preventative treatment 6 Managing migraine in special populations First-line medication • Recommended for patients Older people • NSAIDs (acetylsalicylic acid, adversely affected on ≥2 days • Secondary headache, comorbidities and ibuprofen or diclofenac per month despite optimized adverse events are all more likely potassium) acute therapy • Poor evidence base for all drugs in this age Second-line medication First-line medication group • Triptans • Beta blockers (propranolol, Children and adolescents • When triptans provide metoprolol, atenolol, • Be aware that presentation can differ from insufficient pain relief, bisoprolol) migraine in adults combine with fast-acting • Topiramate • Parents and schools have important roles in the NSAIDs • Candesartan management of young children Third-line medication Second-line medication • Bed rest alone can be sufficient • Ditans • Flunarizine • Use ibuprofen for acute treatment and • Gepants • Amitriptyline propranolol, amitriptyline or topiramate for Adjunct medications for • Sodium valproatea prevention nausea and/or vomiting Third-line medication Women who are pregnant or breastfeeding • Prokinetic antiemetics • CGRP monoclonal • Use paracetamol for acute treatment (domperidone or antibodiesb • Avoid preventive treatment if possible metoclopramide) Women with menstrual migraine • Perimenstrual preventive therapy with long-acting NSAID or triptan Clinical management and follow-up 7 Evaluation of treatment 8 Managing complications 9 Recognizing 10 Planning long-term response and • Discourage medication and managing follow-up management of failure overuse and recognize comorbidities • Manage migraine • Use headache calendars and stop established • Identify comorbid long-term in primary • Assess effectiveness and medication overuse to conditions care adverse events prevent MOH • Select drugs and • Repatriate patients • When outcomes are • For MOH, withdraw adjust their use from specialist care in a suboptimal, review overused medication, according to timely manner and with diagnosis, treatment preferably abruptly comorbidities a comprehensive strategy, dosing and • Specialist referral is present treatment plan adherence indicated for patients • Alleviate • Maintain stability of • When treatment fails, with chronic migraine comborbidities effective treatment in re-evaluate before changing • Use preventive treatment if possible to primary care and react • Referral to specialist care for chronic migraine: improve outcome to change should be reserved for topiramate, patients whose condition is onabotulinumtoxinA or diagnostically challenging, CGRP monoclonal difficult to treat or antibodiesb complicated by comorbidities Fig. 1 | Ten-step approach to the diagnosis and management of migraine. CGRP, calcitonin gene-​related peptide; MOH, medication overuse headache; NSAID, non-​steroidal anti-​inflammatory drug. aSodium valproate is absolutely contraindicated in women of childbearing potential. bCGRP monoclonal antibodies target CGRP or its receptor. Less common aura symptoms include aphasic be similar to those of transient ischaemic attacks (TIA), speech disturbance, brainstem symptoms (such as dys- but can be differentiated on the basis that aura symp- arthria and vertigo), motor weakness (in hemiplegic toms often spread gradually (over ≥5 min) and occur in migraine) and retinal symptoms (for example, repeated succession, whereas symptoms of a TIA have a sudden, monocular visual disturbances)4. Aura symptoms can simultaneous onset4. NAtuRe RevIews | NeUROlOgy volume 17 | August 2021 | 503 0123456789();: C o n S e n S u S S tat e m e n t Notably, migraine with aura and migraine with- retransformation to chronic migraine can subsequently out aura can coexist. Many individuals with migraine occur17. with aura also experience attacks that are not preceded by aura4. In such cases, migraine with aura and migraine Family history of migraine. Migraine has a strong genetic without aura should both be diagnosed. component and its prevalence is higher among people with directly affected first-​degree relatives than among Chronic migraine. Chronic migraine is defined as ≥15 the general population18,19. Family history is, therefore, headache days per month for >3 months and fulfil- an important part of the medical history and is often ment of ICHD-3 criteria for migraine on ≥8 days per positive in patients with migraine, although it might be month4. Chronic migraine is not a static entity and under-​reported by patients20. reversion to episodic migraine is not unusual. Similarly, Recommendations. Box 1 | ICHD-3 diagnostic criteria for primary headache disorders4 • Suspect migraine without aura in a person with recurrent moderate to severe headache, particu- Migraine without aura 1. At least five attacks that fulfil criteria 2–5 larly if pain is unilateral and/or pulsating, and when the person has accompanying symptoms such as 2. Headache attacks that last 4–72 h when untreated or unsuccessfully treated photophobia, phonophobia, nausea and/or vomiting. 3. Headache has at least two of the following four characteristics: • Suspect migraine with aura in a person with the -- unilateral location -- pulsating quality symptoms above and recurrent, short-​lasting visual -- moderate or severe pain intensity and/or hemisensory disturbances. -- aggravation by, or causing avoidance of, routine physical activity (for example, • Suspect chronic migraine in a person with ≥15 walking or climbing stairs) headache days per month. 4. At least one of the following during the headache: • Suspicion of migraine should be strengthened by a -- nausea and/or vomiting family history of migraine and if onset of symptoms -- photophobia and phonophobia is at or around puberty. 5. Not better accounted for by another ICHD-3 diagnosis Migraine with aura Step 2: Diagnosis of migraine 1. At least two attacks that fulfil criteria 2 and 3 The medical history is the mainstay of migraine diag- nosis; with the assistance of a range of published aids 2. One or more of the following fully reversible aura symptoms: -- visual (see the section Diagnostic aids), a full history should -- sensory enable systematic application of the criteria set out in the -- speech and/or language ICHD-3. Physical examination is most often confirma- -- motor tory and further investigations (for example, neuroimag- -- brainstem ing, blood samples or lumbar puncture) are occasionally -- retinal required to confirm or reject suspicions of secondary 3. At least three of the following six characteristics: causes for headache. -- at least one aura symptom spreads gradually over ≥5 min -- two or more aura symptoms occur in succession Medical history. An adequate medical history must -- each individual aura symptom lasts 5–60 min include at least the following: age at onset of headache; -- at least one aura symptom is unilateral duration of headache episodes; frequency of head- -- at least one aura symptom is positive ache episodes; pain characteristics (for example, loca- -- the aura is accompanied with or followed by headache within 60 min tion, quality, severity, aggravating factors and relieving 4. Not better accounted for by another ICHD-3 diagnosis factors); accompanying symptoms (for example, photo­ Chronic migraine phobia, phonophobia, nausea and vomiting); aura 1. Headache (migraine-​like or tension-​type-​like) on ≥15 days/month for >3 months symptoms (if any); and history of acute and preventive that fulfil criteria 2 and 3 medication use. All are essential for the application of 2. Attacks occur in an individual who has had at least five attacks that fulfil the criteria the ICHD-3 criteria. for migraine without aura and/or for migraine with aura 3. On ≥8 days/month for >3 months, any of the following criteria are met: Diagnostic criteria. The ICHD-3 criteria4 (Box 1), which -- criteria 3 and 4 for migraine without aura were developed by the International Headache Society, -- criteria 2 and 3 for migraine with aura set out the clinical features that establish the diagnosis -- believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative of migraine and its types and subtypes. These criteria prioritize specificity over sensitivity, so an additional set 4. Not better accounted for by another ICHD-3 diagnosis of criteria are given for a diagnosis of probable migraine, Medication-​overuse headache which is defined as “migraine-​like attacks missing one 1. Headache on ≥15 days/month in an individual with a pre-​existing headache of the features required to fulfil all criteria for a type or disorder subtype of migraine”4. Probable migraine is a diagnosis 2. Regular overuse for >3 months of one or more drugs that can be taken for acute pending confirmation during early follow-​up. and/or symptomatic treatment of headache (regular intake of one or more non-​opioid analgesics on ≥15 days/month for ≥3 months or any other acute Diagnostic aids. Headache diaries are useful diagnostic medication or combination of medications on ≥10 days/month for ≥3 months) aids that can also be used to re-​evaluate the diagnosis 3. Not better accounted for by another ICHD-3 diagnosis whenever needed (Box 2). Daily diary entries record 504 | August 2021 | volume 17 www.nature.com/nrneurol 0123456789();: C o n S e n S u S S tat e m e n t because some of these disorders are serious and poten- Box 2 | Diagnostic aids and screening tools tially life-​t hreatening (for example, meningitis and Headache diary subarachnoid haemorrhage) (Table 2). Headache diaries are useful diagnostic aids and can also, if needed, assist with Tension-​type headache (TTH) is the only other paroxy­ re-​evaluation of diagnosis at follow-​ups (see Related links for an example smal headache disorder that is prevalent in the general headache diary). population28. TTH lacks the symptoms that accompany Headache calendar migraine and usually involves bilateral, mild to moder- Headache calendars are useful in follow-​ups for recording the temporal occurrence ate pain with a pressing or tightening quality that is not of headaches and related events, such as menstruation (see Related links for an aggravated by routine physical activity4,28 (Table 1). example headache calendar). Cluster headache is a much less prevalent primary Three-​item Identify Migraine questionnaire headache disorder that affects ~0.1% of the general The three-​item Identify Migraine (ID-​Migraine) questionnaire identifies individuals who population29. Its features are highly characteristic and are likely to have migraine on the basis of their answers to three questions regarding include frequently recurrent but short-​lasting attacks headache-​associated nausea, photophobia and disability22. (15–180 min) of strictly unilateral headache of severe Migraine Screen Questionnaire or very severe intensity4. The head pain is accompanied The Migraine Screen Questionnaire (MS-​Q), like ID-​Migraine, is designed to screen by ipsilateral cranial autonomic symptoms, such as con- patients for migraine but includes five questions regarding headache frequency, junctival injection, lacrimation and nasal congestion4 intensity and length, headache associated nausea, photophobia and phonophobia, (Table 1). and disability23. Medication-​overuse headache (MOH) is a secondary headache disorder that is an important differential information on the pattern and frequency of headaches diagnosis for chronic migraine30 (Box 1). This disorder and its accompanying symptoms (for example, nausea, commonly develops from overuse of acute medication photophobia and phonophobia), as well as use of acute to treat migraine attacks, so the two disorders are often medications (Box 2). Diaries should not be conflated with conflated (see Step 8 for more on MOH). headache calendars, which typically include less infor- Some other secondary headache disorders can present mation but are useful in the follow-​up assessment of with features that suggest migraine, but specific red flags patients. Headache calendars should be used to record, should create suspicion (Table 2). Red flags in the medi- at minimum, the frequency of migraine, the frequency cal history include thunderclap headache, atypical aura and intensity of headaches, and headache-​related and head trauma. Red flags in the physical examination events, such as acute and preventive medication use and include unexplained fever, impaired memory and focal menstruation (Box 2). neurological symptoms (Table 2). These red flags are indi- The emergence and refinement of electronic head- cations for further investigation, such as neuroimaging, ache diaries and calendars are important developments, blood samples or lumbar puncture31. as these are likely to facilitate acquisition of more detailed information without markedly compromising Need for neuroimaging. The only role for neuroimaging compliance. Compliance with headache diaries can be in the diagnosis of headache is to confirm or exclude an issue, particularly in primary care; for example, in causes of secondary headache that are suspected on the one population-​based study of patients who reported basis of red flags in the medical history and/or physical frequent headaches, only 46% of participants completed examination32,33. Otherwise, neuroimaging is not only the study21. rarely necessary in the diagnostic work-​up of migraine Diagnosis of migraine can also be facilitated by use of but can be harmful, as it can involve exposure to ion- screening instruments that evaluate whether a patient’s izing radiation33,34. When needed for investigation of clinical features suggest migraine (Box 2). After use of such possible secondary headache disorders, MRI is pre- screening instruments, diagnosis should be confirmed by ferred to CT, as it offers a higher resolution and does a review of the medical history and/or use of a diagnostic not involve exposure to ionizing radiation35,36. However, headache diary. Validated screening instruments include MRI can reveal clinically insignificant abnormalities the three-​item ID-​Migraine questionnaire22 and the (for example, white matter lesions, arachnoid cysts and five-​item Migraine Screen Questionnaire (MS-​Q)23. meningiomas), which can alarm the patient and lead to The ID-​Migraine questionnaire has a sensitivity of 0.81, further unnecessary testing33,37,38. a specificity of 0.75 and a positive predictive value of 0.93 when compared with ICHD-​based diagnosis by a Recommendations. headache specialist22. The MS-​Q instrument has a sen- • Take a careful medical history, applying the ICHD-3 sitivity of 0.93, a specificity of 0.81 and a positive pre- criteria. dictive value of 0.83 (ref.23). Both instruments have been • Use validated diagnostic aids and screening tools, translated and validated for use in several languages24–27. such as headache diaries, the three-​item ID-​Migraine questionnaire and the five-​item Migraine Screen Differential diagnoses. Differential diagnoses for migraine Questionnaire. include other primary headache disorders (Table 1) • Consider differential diagnoses, including other pri- and some secondary headache disorders (Table 2) . mary headache disorders and secondary headache Distinction from other primary headache disorders is disorders. a prerequisite for successful management, whereas dis- • Use neuroimaging only when a secondary headache tinction from secondary headache disorders is crucial disorder is suspected. NAtuRe RevIews | NeUROlOgy volume 17 | August 2021 | 505 0123456789();: C o n S e n S u S S tat e m e n t Table 1 | Characteristics of primary headache disorders Headache Headache Headache Pain intensity Pain Accompanying symptoms Routine physical disorder duration location characteristics activity Migraine 4–72 h Usually unilateral Usually moderate Usually Photophobia, phonophobia, Often aggravated or severe pulsating nausea, vomiting by routine physical activity Tension-​type Hours to Usually bilateral or Usually mild or Usually pressing Often none; sometimes Not aggravated by headache days or circumferential moderate or tightening photophobia or phonophobia routine physical unremitting (but not both); sometimes mild activity nausea in chronic tension-​type headache Cluster 15–180 min Strictly unilateral Severe or very Overwhelming Ipsilateral to the headache: Restlessness or headache and orbital, severe cranial autonomic symptoms, agitation supraorbital, such as conjunctival injection, and/or temporal lacrimation, and nasal congestion Step 3: Education and patient centricity (which is often not possible), some headache control Patient centricity and education have important roles in might be achievable without further intervention43. For the management of migraine. Indeed, optimal outcomes instance, lifestyle changes can benefit patients with poor are unlikely when these aspects are not given sufficient sleep quality or physical fitness, though any changes attention. should not result in unnecessary avoidance behaviour, which can itself damage quality of life. Explanation, reassurance and objectives. Patient satis- faction is a key management outcome and treatment Individualized therapy. Multiple effective acute and success depends on it but most people with migraine preventive therapies are available for migraine. When report at least one perceived unmet treatment need39. selecting from these therapies, the objective is that Unrealistic expectations constitute a major obstacle to each patient receives the therapy that provides the best achieving patient satisfaction — a common misconcep- personal outcome. Unfortunately, no a priori basis for tion among patients is that effective treatment means selection currently exists, at least for acute therapy. cure of their migraine32,40. Clinicians must therefore disa- Optimal individualized therapy is therefore currently buse patients of this belief without being overly negative. best achieved with a stepped care approach, set out in A realistic objective is a return of control from the dis- detail in Step 4. ease to the patient with treatment that mitigates attack-​ related disability (by reducing attack frequency, attack Recommendations. duration and/or pain intensity) to an extent that the • Provide every patient with a full explanation of migraine patient can continue with life with as little hindrance as a disease and of the principles of its management. as possible. • Consider predisposing and trigger factors, but keep Non-​adherence is also an obstacle to effective treat- in mind that true trigger factors are often self-​evident. ment41 and requires management. Education is the • Adhere to the principles of stepped care to achieve solution — clinicians must explain to the patient both optimal individualized therapy (see Step 4). the disease and the principles of managing it effectively, including instruction on the correct use of medication, Step 4: Acute treatment potential adverse effects and what to do about them, and Acute treatments can be classified as first-​line, second-​line, the importance of avoiding medication overuse. Such third-​line and adjunct (Table 3), and should be used in education can require time that is not available, but a stepped care approach32 (Fig. 2). Our recommenda- freely available patient information leaflets can support tions for each line of treatment are outlined below. The patient education32. medi­cations at each stage were selected on the basis of efficacy, tolerability, safety, cost and availability. Predisposing factors and triggers. Contrary to popular belief, predisposing and trigger factors are of limited impor- First-​line medication. Over-​t he-​counter analgesics tance in migraine, and their role is often overemphasized42. are used worldwide for acute migraine treatment44. An important exception is menstruation, as some Those with proven efficacy include non-​steroidal women’s migraine attacks are exclusively or frequently anti-​inflammatory drugs (NSAIDs), and the strongest menstruation-​related. True trigger factors are often self-​ evidence supports use of acetylsalicylic acid, ibuprofen evident. Moreover, aggravating factors should not be and diclofenac potassium as first-​line medications45–47. conflated with predisposing factors. The former worsen Paracetamol has less efficacy48 and should be used only headache during migraine attacks (for example, physical in those who are intolerant of NSAIDs. activity), whereas predisposing factors increase suscepti- bility to the development of a migraine attack (for example, Second-​line medication. Patients for whom over-​the-​ poor sleep quality, poor physical fitness or stress). counter analgesics provide inadequate headache relief Nevertheless, if predisposing and trigger factors should be offered a triptan. All triptans have well-​ can be correctly identified and subsequently avoided documented effectiveness, but availability of and access 506 | August 2021 | volume 17 www.nature.com/nrneurol 0123456789();: C o n S e n S u S S tat e m e n t to each vary between countries. Triptans are most effec- lasmiditan might be unable to self-​assess their driving tive when taken early in an attack, when the headache is competence and should not operate machinery for at still mild49,50. However, no evidence supports the use of least 8 h after intake. triptans during the aura phase of a migraine attack. If one triptan is ineffective, others might still provide relief51,52. Adjunct medication. For patients who experience nau- When all other triptans have failed or in patients who sea and/or vomiting during migraine attacks, prokinetic rapidly reach peak headache intensity or cannot take antiemetics such as domperidone and metoclopramide oral triptans because of vomiting, sumatriptan by are useful oral adjuncts. subcutaneous injection can be useful53. Some patients can experience relapses, which are Medications to avoid. Oral ergot alkaloids are poorly defined as a return of symptoms within 48 h after effective and potentially toxic, and should not be used apparently successful treatment. Upon relapse, patients as a substitute for triptans59. The efficacy of opioids can repeat their triptan treatment or combine the and barbiturates is questionable, and both are associ- triptan with simultaneous intake of fast-​acting for- ated with considerable adverse effects and the risk of mulations of naproxen sodium, ibuprofen lysine or dependency60. All of these medications should, therefore, diclofenac potassium54,55. However, patients should be be avoided for the acute treatment of migraine. informed that repeating the treatment does not pre- clude further relapses and ultimately increases the risk Recommendations. of developing MOH. • Offer acute medication to everyone who experiences migraine attacks. Third-​line medication. If all available triptans fail after • Advise use of acute medications early in the head- an adequate trial period (no or insufficient therapeutic ache phase of the attack, as effectiveness depends on response in at least three consecutive attacks) or their timely use with the correct dose. use is contraindicated, alternatives are currently limited. • Advise patients that frequent, repeated use of acute Ditans or gepants could be used, but their availability medication risks development of MOH. is currently very limited. Lasmiditan is the only ditan • Use NSAIDs (acetylsalicylic acid, ibuprofen or approved for acute treatment of migraine, and ubroge- diclofenac potassium) as first-​line medication. pant and rimegepant are the only gepants approved. • Use triptans as second-​line medication. Indirect comparison of data from randomized con- • Consider combining triptans with fast-​acting NSAIDs trolled trials suggests that the efficacy of lasmiditan is to avert recurrent relapse. comparable to that of triptans56–58, but its use is associ- • Consider ditans and gepants as third-​line medications. ated with temporary driving impairment, which is likely • Use prokinetic antiemetics (domperidone or meto- to discourage widespread use. Individuals who take clopramide) as adjunct oral medications for nausea and/or vomiting. • Avoid oral ergot alkaloids, opioids and barbiturates. Table 2 | Red flags associated with secondary headaches31,32 When to look Red flag Indication Step 5: Preventive treatment Patient history Thunderclap headache Subarachnoid haemorrhage Initiation and termination. In patients whose migraine continues to impair their quality of life despite optimized Atypical aura Transient ischaemic attack, stroke, epilepsy, arteriovenous acute therapy, additional preventive therapy should malformations be considered (Table 4). In practice, patients who are Head trauma Subdural haematoma considered for preventive treatment remain adversely affected on at least 2 days per month32, although this Progressive headache Intracranial space-​occupying lesion should not be regarded as an absolute rule32. Aside from Headache aggravated by Intracranial hypertension or migraine frequency, clinicians should always consider postures or manoeuvres that hypotension factors such as the severity of attacks, the duration of raise intracranial pressure attacks (for example, menstruation-​related attacks tend Headache brought on by Intracranial space-​occupying lesion to last longer) and migraine-​related disability. A further sneezing, coughing or exercise indication for preventive therapy is overuse of acute Headache associated with Suggests secondary headache medication. weight loss and/or change Efficacy of preventive therapy is rarely observed in memory or personality immediately. Only after several weeks or months can Headache onset at >50 years Suggests secondary headache; efficacy be ascertained, so patients should be discour- of age consider temporal arteritis aged from abandoning the treatment in these early stages Physical Unexplained fever Meningitis on the grounds of apparent inefficacy32. If a therapeu- examination tic dose of an oral preventive medication is ineffective Neck stiffness Meningitis, subarachnoid haemorrhage after 2–3 months, an alternative should be tried32,61,62. Focal neurological symptoms Suggests secondary headache For monoclonal antibody treatments that target cal- citonin gene-​related peptide (CGRP) or its receptor, Weight loss Suggests secondary headache efficacy should be assessed only after 3–6 months. For Impaired memory and/or altered Suggests secondary headache onabotulinumtoxinA, efficacy should be assessed after consciousness or personality 6–9 months. NAtuRe RevIews | NeUROlOgy volume 17 | August 2021 | 507 0123456789();: C o n S e n S u S S tat e m e n t Failure of one preventive treatment does not pre- days or monthly headache days of moderate-​to-​severe dict failure of treatment with other drug classes, except intensity. However, a pragmatic approach is needed and when failure is due to poor adherence. Treatment adher- clini­cians should decide to pause preventive therapy on ence is often very poor but can be improved by simpli- a case-​by-​case basis. fied dosing schedules (once daily or less)32. For most preventive medications, clinical experience suggests that Current standard of care. As for acute medications, pausing can be considered when treatment has been suc- preventive treatments can be classified as first-​line, cessful for 6–12 months32. The purpose of pausing is to second-​line and third-​line options (Table 4). However, ascertain whether preventive treatment can be stopped, choice of medication and the order of use depend on which minimizes the risk of unnecessary drug exposure local practice guidelines and local availability, costs and and allows some patients to manage their migraine with reimbursement policies. acute medications only. A useful measure to quantify First-​line medications are beta blockers without the degree of preventive treatment success is to cal- intrinsic sympathomimetic activity (atenolol, bisopr- culate the percentage reduction in monthly migraine olol, metoprolol or propranolol)63, topiramate64 and candesartan65,66. If these fail, second-​line medications include flunarizine 67, amitriptyline 68 and sodium Table 3 | Acute migraine treatment valproate69, although valproate is strictly contraindicated Drug class Drug Dosage and route Contraindications in women of childbearing potential, which greatly limits First-​line medication its utility in migraine70–72. Third-​line medications are the four CGRP monoclonal antibodies erenumab, fremane- NSAIDs Acetylsalicylic 900–1,000 mg oral Gastrointestinal acid bleeding, heart failure zumab, galcanezumab and eptinezumab. These antibod- ies have been approved for the preventive treatment of Ibuprofen 400–600 mg oral migraine in the past few years61. In Europe, regulatory Diclofenac 50 mg oral (soluble) restrictions limit their use to patients in whom other potassium preventive drugs have failed or are contraindicated61. Other simple Paracetamol 1,000 mg oral Hepatic disease, renal analgesics failure Non-​pharmacological therapies. A range of non-​ (if NSAIDs are contraindicated) pharmacological preventive therapies can be used either as adjuncts to acute and preventive medications Antiemetics Domperidone 10 mg oral or Gastrointestinal or instead of them if medication use is contraindicated. (when necessary) suppository bleeding, epilepsy, renal failure, cardiac Some evidence supports the use of non-​invasive neu- arrhythmia romodulatory devices73, biobehavioural therapy74 and Metoclopramide 10 mg oral Parkinson disease, acupuncture75, although a study of acupuncture indi- epilepsy, mechanical cated that it is not superior to sham acupuncture76. ileus Contrary to popular belief, little to no evidence exists Second-​line medication for physical therapy77, spinal manipulation and dietary approaches78. We make no recommendations about Triptans Sumatriptan 50 or 100 mg oral or Cardiovascular or 6 mg subcutaneous cerebrovascular other therapeutic options, such as melatonin, magne- or 10 or 20 mg disease, uncontrolled sium and riboflavin, as limited evidence for their efficacy intranasal hypertension, is available and their use in clinical practice is limited. hemiplegic migraine, Zolmitriptan 2.5 or 5 mg oral or migraine with 5 mg intranasal Recommendations. brainstem aura Almotriptan 12.5 mg oral • Consider preventive treatment in patients who are adversely affected by migraine on ≥2 days per month Eletriptan 20, 40 or 80 mg oral despite optimized acute treatment. Frovatriptan 2.5 mg oral • Use beta blockers (atenolol, bisoprolol, metoprolol or Naratriptan 2.5 mg oral propranolol), topiramate or candesartan as first-​line Rizatriptan 10 mg oral tablet medications. (5 mg if treated with • Use flunarizine, amitriptyline or (in men) sodium propranolol) or 10 mg valproate as second-​line medications. mouth-​dispersible • Consider CGRP monoclonal antibodies as third-​line wafers medications. Third-​line medication • Consider neuromodulatory devices, biobehavioural Gepants Ubrogepant 50, 100 mg oral Co-​administration therapy and acupuncture as adjuncts to acute and with strong CYP3A4 preventive medication or as stand-​alone preventive inhibitors treatment when medication is contraindicated. Rimegepant 75 mg oral Hypersensitivity, hepatic impairment Step 6: Managing migraine in special populations Ditans Lasmiditan 50, 100 or 200 mg Pregnancy, concomitant Older people. Migraine often remits with older age oral use with drugs that whereas the incidence of many secondary headaches are P-​glycoprotein increases79–81. Onset of apparent migraine after the age substrates of 50 years should, therefore, arouse suspicion of an 508 | August 2021 | volume 17 www.nature.com/nrneurol 0123456789();: C o n S e n S u S S tat e m e n t First-line Second-line Third-line medications medications medications Three Three NSAIDs + consecutive Triptans (when consecutive Switch to a Treatment Ditan or antiemetic if attacks without suboptimal attacks without different failure of all gepants necessary treatment effect, consider treatment triptan available success combining with a success triptans fast-acting NSAID Fig. 2 | Stepped care across migraine attacks. Preventive therapy, in addition, may be indicated at any stage. In general, initiation of preventive therapy is indicated in patients who are adversely affected on ≥2 days per month despite acute treatment optimized according to the stepped care approach. NSAID, non-​steroidal anti-​inflammatory drug. underlying cause. In individuals whose migraine persists acute treatment of migraine90,91, and some evidence indi- from earlier life into later years, clinical management cates that nasal spray formulations of sumatriptan and often remains unchanged in practice. Little formal evi- zolmitriptan are the most effective92. If acute medication dence is available with respect to therapeutic approaches provides insufficient pain relief, referral to specialist care in older people with migraine. is indicated32. In practice, propranolol, amitriptyline and Nonetheless, known and possible unknown comor- topiramate are used for preventive treatment, although bidities need to be considered, as well as harm that their effectiveness in children and adolescents has not might be caused by drug-​specific adverse effects82, to been proven in clinical trials88,89. which older people are generally more susceptible. For instance, use of triptans in older people is often advised Pregnant and breastfeeding women. Migraine often against owing to the relatively high likelihood that remits during pregnancy, but if treatment is continued, these patients have cardiovascular disease and/or car- the potential for harm to the fetus demands special diovascular risk factors. However, no robust evidence consideration93. Despite relatively poor efficacy, par- supports an increased risk of cerebrovascular or cardi- acetamol should be used as the first-​line medication for ovascular events in older people owing to triptan use acute treatment of migraine in pregnancy48; NSAIDs can per se83. Nonetheless, clinicians are advised to regularly be used only during the second trimester93,94. Triptans monitor blood pressure in older patients with migraine should be used only under the strict supervision of a spe- who use triptans, in addition to periodical assessment of cialist, as the safety data available are limited and origi- cardiovascular risk factors84. nate from post-​marketing surveillance; most data relate to the use of sumatriptan32. For nausea associated with Children and adolescents. Migraine is common among migraine in pregnancy, metoclopramide can be used94,95. children and its prevalence increases in adolescence85. Preventive migraine medications are best avoided As in adults, diagnosis is primarily based on the medical during pregnancy owing to the potential for fetal harm. history, although the criteria are slightly different — the However, if preventive therapy is considered clinically duration of migraine attacks can be 2 to 72 h4. The clini- indicated because of frequent and disabling migraine cal features of migraine in children and adolescents also attacks, the best available safety data support the use differ somewhat from those in adults — the attacks are of propranolol or, if propranolol is contraindicated, often shorter4, the headache is more often bilateral and amitriptyline. Both should be used under specialist less often pulsating, and gastrointestinal disturbances are supervision to adequately monitor any potential fetal commonly prominent32. Descriptions of these features harm32. Topiramate, candesartan and sodium valproate might be more reliably provided by parents than chil- are contraindicated; sodium valproate is known to be dren, and parents will also provide a better account of teratogenic, so must not be used70,94, and the use of lifestyle factors that might need to be addressed86. topiramate and candesartan is associated with adverse In children and young adolescents, clinical manage- effects on the fetus. ment usually requires active help from family mem- Migraine medication therapy in the post-​partum bers and teachers86, so education of both is necessary. period also requires caution because of potential risks Bed-​rest alone might suffice in children with attacks to the infant. Paracetamol is the preferred acute med- that have a short duration. When needed, ibuprofen is ication, although ibuprofen and sumatriptan are also recommended as first-​line medication, at a dose appro- considered safe94. If preventive medication is required, priate for body weight32. Domperidone can be used for propranolol is the recommended first choice as it has nausea in adolescents aged 12–17 years87, although oral the best safety profile94. Pharmacological treatments for administration is unlikely to prevent vomiting. migraine during pregnancy and breastfeeding have been The evidence base for medication therapy in chil- reviewed in more detail elsewhere94. dren and adolescents is confounded by a high placebo response in clinical trials88,89. As a consequence, the Women with menstrual migraine. Approximately 8% of apparent therapeutic gain is low, and this effect probably women with migraine experience migraine attacks that explains why a benefit of triptans has not been demon- are exclusively related to their menstruation, referred strated in children. For adolescents aged 12–17 years, to as pure menstrual migraine96,97. If optimized acute multiple NSAIDs and triptans have been approved for medication therapy does not suffice for these patients, NAtuRe RevIews | NeUROlOgy volume 17 | August 2021 | 509 0123456789();: C o n S e n S u S S tat e m e n t Table 4 | Preventive migraine treatment Drug class Drug Dosage and route Contraindications First-​line medication Beta blockers Atenolol 25–100 mg oral twice daily Asthma, cardiac failure, Raynaud disease, atrioventricular block, Bisoprolol 5–10 mg oral once daily depression Metoprolol 50–100 mg oral twice daily or 200 mg modified-​release oral once daily Propranolol 80–160 mg oral once or twice daily in long-​acting formulations Angiotensin Candesartan 16–32 mg oral per day Co-​administration of aliskiren II-​receptor blocker Anticonvulsant Topiramate 50–100 mg oral daily Nephrolithiasis, pregnancy, lactation, glaucoma Second-​line medication Tricyclic Amitriptyline 10–100 mg oral at night Age <6 years, heart failure, antidepressant co-​administration with monoamine oxidase inhibitors and SSRIs, glaucoma Calcium antagonist Flunarizine 5–10 mg oral once daily Parkinsonism, depression Anticonvulsant Sodium valproate a 600–1,500 mg oral once daily Liver disease, thrombocytopenia, female and of childbearing potential Third-​line medication Botulinum toxin OnabotulinumtoxinA 155–195 units to 31–39 sites every Infection at injection site 12 weeks Calcitonin Erenumab 70 or 140 mg subcutaneous once Hypersensitivity gene-​related monthly Not recommended in patients peptide monoclonal Fremanezumab 225 mg subcutaneous once with a history of stroke, antibodies monthly or 675 mg subcutaneous subarachnoid haemorrhage, once quarterly coronary heart disease, inflammatory bowel disease, Galcanezumab 240 mg subcutaneous, then 120 mg chronic obstructive pulmonary subcutaneous once monthly disease or impaired wound healing Eptinezumab 100 or 300 mg intravenous quarterly SSRI, selective serotonin reuptake inhibitor. aSodium valproate is absolutely contraindicated in women of childbearing potential. initiation of perimenstrual preventive treatment should • In pregnant or breastfeeding women, use paracetamol be considered. This approach typically involves daily for acute treatment and avoid preventive medication intake of a long-​acting NSAID (for example, naproxen) whenever possible. or triptan (for example, frovatriptan or naratriptan) for • In women with menstrual migraine, consider per- 5 days, beginning 2 days before the expected first day of imenstrual preventive therapy with a long-​acting menstruation98–101. Some women with pure menstrual NSAID or triptan. migraine without aura benefit from continuous use (that is, without a break) of combined hormonal contracep- Step 7: Follow-​up, treatment response and failure tives. By contrast, combined hormonal contraceptives Active follow-​up is the only appropriate means of deter- are contraindicated in women with migraine with aura mining outcome and provides the opportunity to review regardless of any association with their menstrual cycle, both diagnosis and treatment strategies. The response to owing to an associated increase in the risk of stroke32. treatment should be evaluated within 2–3 months after initiation or a change in treatment, and regularly there- Recommendations. after, though not necessarily at short intervals (for exam- • In patients with apparent late-​onset migraine, suspect ple, 6–12 months). Evaluation of treatment responses an underlying cause. should include a review of effectiveness, adverse events • In older people, consider the higher risks of second- and adherence. ary headache, comorbidities and adverse events with Key outcome measures for effectiveness are attack fre- older age. quency, attack severity and migraine-​related disability32. • In children and adolescents with migraine, bed Attack frequency is usually measured in headache or rest alone might suffice; if not, use ibuprofen for migraine days per month. Severity is usually expressed acute treatment and propranolol, amitriptyline or as pain intensity rather than functional consequence, topiramate for prevention. which should be separately assessed. Headache calendars 510 | August 2021 | volume 17 www.nature.com/nrneurol 0123456789();: C o n S e n S u S S tat e m e n t are extremely useful for capturing these measures and Step 8: Managing complications require little time commitment if completed only on Medication overuse headache. MOH is a chronic head- symptomatic days32. In addition, headache calendars ache disorder characterized by headache on ≥15 days are valuable for monitoring acute medication use. At per month. It develops over a variable period of time follow-​up assessments, the self-​administered Migraine in patients with a pre-​existing headache disorder as a Treatment Optimization Questionnaire (mTOQ-4) result of regular overuse of acute or symptomatic head- can be used to evaluate the effectiveness of acute ache medication4. Patients with migraine account for medications102, whereas the self-​completed eight-​item approximately two thirds of all cases of MOH, although HURT questionnaire (Headache Under-​Response to this estimate is based on limited evidence and might be Treatment) can be used to assess the effectiveness of an too low106. intervention and generates suggestions for changes to Withdrawal of the overused medication is the nec- improve effectiveness103 (Box 3). essary and only remedy for MOH107. Expert consensus is that abrupt withdrawal is preferable to slow with- When treatment fails. A conclusion that treatment has drawal, except for opioids30. This process can be man- failed should be made with caution and must always aged in primary care unless addictive drugs, such as be preceded by a thorough review of the underlying opioids, are involved108,109. Patient education is a key reasons. In some cases, apparent failures might be reme- component of the clinical management of MOH, as diable, such as when failure is due to poor adherence withdrawal is usually followed by worsening before or suboptimal dosing32. Whereas some patients bene- recovery30,110. Preventive therapy (pharmacological fit from higher doses, others might benefit from lower and/or non-​pharmacological) appropriate to the ante- doses that have fewer adverse effects and therefore cedent headache can be started in parallel with acute improve adherence. Alternatives when first-​line medi- medication withdrawal or upon re-​emergence of the cations fail are outlined above (see Step 4 and Step 5). headache disorder30, although this topic remains a If all treatments fail, the diagnosis should be questioned subject of debate111,112. and specialist referral is indicated32. Transformation to chronic migraine. Some estimates When specialist referral is needed. Approximately 90% suggest that up to 3% of patients with episodic migraine of people who seek professional care for migraine should experience transformation to chronic migraine each be treated in primary care104. Referral to specialist care year 113. The reliability of such estimates is uncer- should be reserved for the minority of patients whose tain because chronic migraine is often conflated with condition is diagnostically challenging, difficult to MOH114, but transformation to chronic migraine does treat or complicated by comorbidities32. Specialist care occur. Recognized risk factors include female sex, a high provides access to greater expertise maintained by expe- headache frequency, inadequate treatment, overuse of rience and to multidisciplinary care. However, specialist acute medications and a range of comorbidities, includ- capacity is limited and the cost is much higher105. ing depression, anxiety and obesity115–118. Recognition of these risk factors is part of good clinical management, as Recommendations. their modification can prevent transformation. • Evaluate treatment responses shortly after initiation Once chronic migraine has developed, its manage- (after 2–3 months) or a change of treatment and ment is challenging and referral to specialist care is regularly thereafter (every 6–12 months). usually necessary32. If MOH, which frequently causes • Evaluate the effectiveness of treatment by assessing symptoms that suggest chronic migraine, can be ruled attack frequency, attack severity and migraine-​related out, then a preventive treatment should be established114. disability. Individuals with chronic migraine should also be • When outcomes are suboptimal, review the diagnosis, educated on the modifiable risk factors for chronic treatment strategy, dosing and adherence. migraine so that they can make lifestyle changes that • If all treatment fails, question the diagnosis and might help. consider specialist referral. Preventive medications for which evidence supports effectiveness in chronic migraine include topiramate119, onabotulinumtoxinA 120 and CGRP monoclonal Box 3 | Tools for evaluation of treatment response antibodies121. Topiramate is the drug of first choice HURT questionnaire owing to its much lower cost. Regulatory restrictions The Headache Under-​Response to Treatment (HURT) questionnaire is an eight-​item, generally limit the use of onabotulinumtoxinA and self-​administered questionnaire developed specifically to guide follow-​up in primary CGRP antibodies to patients in whom two or three other care103. The questionnaire assesses treatment outcome in several domains, and responses preventive medications have failed, despite the fact that are coupled to suggested changes in management. It has been validated for clinical use topiramate is the only other treatment with evidence in English and Arabic133,134 and is available online in 12 languages (see Related links for supporting its use. Three CGRP antibodies (erenumab, where to access the HURT questionnaire). fremanezumab and galcanezumab) have been proven mTOQ-4 to be beneficial for patients in whom at least two other The Migraine Treatment Optimization Questionnaire (mTOQ-4) is a self-​administered preventive medications have failed122–124. As in episodic questionnaire that can be used to assess acute treatment, including treatment efficacy102. migraine, the choice of preventive medication and their This questionnaire has been validated for use in primary care and used in several studies order of use depends on local practice guidelines, avail- to assess treatment outcomes102,118,135. ability, cost and reimbursement policies. No robust data NAtuRe RevIews | NeUROlOgy volume 17 | August 2021 | 511 0123456789();: C o n S e n S u S S tat e m e n t from random controlled trials support the use of beta Step 10: Long-​term follow-​up blockers, candesartan or amitriptyline for the preven- Long-​term management of migraine should be the respon- tive treatment of chronic migraine, although they are sibility of primary care. Referral from specialist care back commonly used in clinical practice. to primary care should be timely, coordinated with the general practitioner and accompanied by a comprehensive Recommendations. treatment plan that includes recommendations for • Educate patients with migraine about the risk of re-​evaluation and steps to be taken for each of the likely MOH with frequent overuse of acute medication. outcomes. In general, timely return to primary care can be • Manage established MOH by explanation and with- made once the patient experiences sustained efficacy with drawal of the overused medication; abrupt withdrawal preventive therapy for up to 6 months with no substantial is preferred, except for opioids. treatment-​related adverse effects. • Recognize and, when possible, modify risk factors for In primary care, the main goal of follow-​up is to main- the transformation of episodic migraine to chronic tain stability of adequate outcomes, whether achieved in migraine. primary or specialist care, and to react appropriately to • Refer patients with chronic migraine to specialist care. any change that might call for review. Neither purpose • Once MOH is ruled out, initiate preventive medication requires regular routine contact, which should, there- therapy for chronic migraine; evidence-​based treat- fore, be avoided unless necessary in the context of repeat ment options are topiramate, onabotulinumtoxinA prescriptions. Instead, primary care physicians should and CGRP monoclonal antibodies. emphasize patient education and self-​efficacy with respect to judging when a return visit is necessary. Step 9: Recognizing and managing comorbidities Migraine is associated with anxiety, depression, sleep Recommendations. disturbances and chronic pain conditions (for example, • Primary care should be responsible for the long-​term neck and lower back pain)125–129. These associations are management of patients with migraine, maintaining more pronounced in people with chronic migraine than stability and reacting to change. in those with episodic migraine130. Obesity is also an • Referral from specialist back to primary care should important risk factor for transformation from episodic be timely and accompanied by a comprehensive migraine to chronic migraine and should be accounted treatment plan. for in the clinical evaluation131. Furthermore, migraine • The patient can be referred back to primary care with aura has been associated with cardiovascular events once sustained efficacy with preventive therapy in women132. for up to 6 months is obtained with no substantial Recognition of comorbid conditions in migraine treatment-​related adverse effects. is important because they can influence drug choice. For example, topiramate is the preferred treatment for Conclusions patients with obesity owing to its association with weight Migraine is a ubiquitous neurological disorder that adds loss. For patients with depression or sleep disturbances, substantially to the global burden of disease. Despite amitriptyline is most likely to be of benefit. Recognition the existence of comprehensive diagnostic criteria and a of comorbidities is also important because their allevia- multitude of therapeutic options, diagnosis and clinical tion can improve treatment outcomes for migraine, and management of migraine remain suboptimal worldwide. vice versa. This Consensus Statement was developed by experts from Europe to provide generally applicable recommen- Recommendations. dations for the diagnosis and management of migraine • Ensure that comorbidities are identified in patients and to promote best clinical practices. The recommen- with migraine, as they can affect treatment choice dations are based on published evidence and expert and outcomes. opinion, and will be updated when new information • Adjust treatments accordingly and consider possible and treatments emerge. interactions between drug-​related adverse effects and the patient’s comorbidity profile. Published online 18 June 2021 1. Ashina, M. Migraine. N. Engl. J. Med. 383, 6. 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Newman, L. et al. Naratriptan as short-​term prophylaxis in patients with episodic migraine in whom two-​to-four ber of the Council of the European Headache Federation. She of menstrually associated migraine: a randomized, previous preventive treatments were unsuccessful: is on the editorial board of Revista de Neurologia, an associate double-​blind, placebo-​controlled study. Headache 41, a randomised, double-​blind, placebo-​controlled, editor for Cephalalgia, Frontiers of Neurology and Journal of 248–256 (2001). phase 3b study. Lancet 392, 2280–2287 (2018). Headache and Pain. She is also a member of the Clinical Trials 99. Silberstein, S. & Patel, S. Menstrual migraine: an 123. Ferrari, M. D. et al. Fremanezumab versus placebo Guidelines Committee of the International Headache Society updated review on hormonal causes, prophylaxis for migraine prevention in patients with documented and has edited the Guidelines for the Diagnosis and Treatment and treatment. Expert Opin. Pharmacother. 15, failure to up to four migraine preventive medication of Headache of the Spanish Neurological Society. P.M. has 2063–2070 (2014). classes (FOCUS): a randomised, double-​blind, placebo-​ served on advisory boards for Allergan, Lilly, Novartis and Teva. 100. van Dijkman, S. C., de Jager, N. C. B., Rauwé, W. M., controlled, phase 3b trial. Lancet 394, 1030–1040 He has received royalties from Springer Nature and travel Danhof, M. & Della Pasqua, O. Effect of age-​related (2019). support from the European Medicines Agency, and serves factors on the pharmacokinetics of lamotrigine and 124. Ruff, D. D. et al. Efficacy of galcanezumab in patients as Editor-​in-​Chief for Journal of Headache and Pain. A.D. potential implications for maintenance dose with episodic migraine and a history of preventive reports consultant fees from Eli Lilly, Novartis and Teva. She optimisation in future clinical trials. Clin. treatment failure: results from two global randomized also serves as President of the French Headache Society. Pharmacokinet. 57, 1039–1053 (2018). clinical trials. Eur. J. Neurol. 27, 609–618 (2020). M.L.-​M. reports personal fees for advisory boards, speaker 101. Silberstein, S. D. et al. Evidence-​based guideline 125. Dresler, T. et al. Understanding the nature of panels or investigation studies from Allergan, Amgen, Astellas, update: pharmacologic treatment for episodic migraine psychiatric comorbidity in migraine: a systematic ATI, BMS, Boehringer, Boston Scientific, CoLucid, Convergence, prevention in adults. Neurology 78, 1337–1345 review focused on interactions and treatment GlaxoSmithKline, Grunenthal, Lilly, Medtronic, Menarini, MSD, (2012). implications. J. Headache Pain 20, 51 (2019). Novartis, Pfizer, ReckittBenckiser, Saint-​Jude, Sanofi-​Aventis, 102. Lipton, R. B. et al. Validity and reliability of the 126. Lampl, C. et al. Headache, depression and anxiety: Teva, UCB and Zambon. M.S.d.R. reports consultant fees as a migraine-​treatment optimization questionnaire. associations in the Eurolight project. J. Headache Pain speaker or participation on advisory boards from Allergan, Cephalalgia 29, 751–759 (2009). 17, 59 (2016). Eli-​Lilly, Novartis and Teva. G.M.T. reports consultant fees from 103. Steiner, T. J. et al. The headache under-​response to 127. Buse, D. C. et al. Sleep disorders among people Amgen, Eli Lilly, Novartis and Teva, and has received grant sup- treatment (HURT) questionnaire, an outcome measure with migraine: results from the chronic migraine port from the Dutch Brain Foundation, Dutch Heart Foundation, to guide follow-​up in primary care: development, epidemiology and outcomes (CaMEO) study. Headache NIH, NOW and ZonMW. K.P. has received honoraria as a psychometric evaluation and assessment of utility. 59, 32–45 (2019). speaker and/or consultant, and/or received research support J. Headache Pain 19, 15 (2018). 128. Ashina, S. et al. Increased pain sensitivity in migraine from Allergan, Amgen/Novartis, Autonomic Technologies, 104. Steiner, T. J. et al. Recommendations for headache and tension-​type headache coexistent with low back Eli-​Lilly and Teva. S.S. reports fees as a speaker or consultant service organisation and delivery in Europe. pain: A cross-​sectional population study. Eur. J. Pain for Allergan, Abbott, Eli-​Lilly, Novartis and Teva. She is also an J. Headache Pain 12, 419–426 (2011). 22, 904–914 (2018). associate editor for Stroke and serves as co-​editor for Journal 105. World Health Organization. Building the economic 129. Ashina, S. et al. Prevalence of neck pain in migraine of Headache and Pain. U.R. has received consulting fees, speak- case for primary health care: a scoping review. and tension-​type headache: a population study. ing or teaching fees and/or research grants from Allergan, Technical series on primary health care (WHO, 2018). Cephalalgia 35, 211–219 (2015). Amgen, Autonomic Technologies, CoLucid, ElectroCore and 106. GBD 2016 Disease and Injury Incidence and 130. Buse, D. C., Manack, A., Serrano, D., Turkel, C. Novartis. H.W.S. has received consultant fees for lectures from Prevalence Collaborators. Global, regional, and & Lipton, R. B. Sociodemographic and comorbidity Eli-​Lilly, Novartis and TEVA. He has received consultant fees for national incidence, prevalence, and years lived with profiles of chronic migraine and episodic migraine advisory board participation from Balancair and Eli Lilly, and disability for 328 diseases and injuries for 195 sufferers. J. Neurol. Neurosurg. Psychiatry 81, has received funding from Novartis. Z.K. has been a speaker countries, 1990-2016: a systematic analysis for the 428–432 (2010). and/or consultant, and/or received research support from Global Burden of Disease Study 2016. Lancet 390, 131. Bigal, M. E. & Lipton, R. B. Obesity is a risk factor for Allergan, Amgen/Novartis, Ely-​Lilly, Merck and Teva. T.J.S. 1211–1259 (2017). transformed migraine but not chronic tension-​type reports personal fees from Eli Lilly. M.A. has received personal 107. Diener, H. C. et al. European Academy of Neurology headache. Neurology 67, 252–257 (2006). fees from Alder BioPharmaceuticals, Allergan, Amgen, Eli-​Lilly, guideline on the management of medication-​overuse 132. Kurth, T., Schürks, M., Logroscino, G. & Buring, J. E. Novartis and Teva. He has been or is currently a principal inves- headache. Eur. J. Neurol. 27, 1102–1116 (2020). Migraine frequency and risk of cardiovascular disease tigator on clinical trials for Alder, Amgen, ElectroCore, Novartis 108. Kristoffersen, E. S. et al. Brief intervention for in women. Neurology 73, 581–588 (2009). and Teva. He serves as Associate Editor of Cephalalgia, medication-​overuse headache in primary care. 133. Westergaard, M. L. S. et al. The headache under-​ Headache and Journal of Headache and Pain. He also reports The BIMOH study: a double-​blind pragmatic cluster response to treatment (HURT) questionnaire: research grants from Lundbeck Foundation, Novo Nordisk randomised parallel controlled trial. J. Neurol. assessment of utility in headache specialist care. Foundation, and Research Foundation of the Capital Region of Neurosurg. Psychiatry 86, 505–512 (2015). Cephalalgia 33, 245–255 (2013). Denmark. The other authors report no competing interests. 109. Kristoffersen, E. S. et al. Brief intervention by general 134. Al Jumah, M. et al. HURT (Headache Under-​Response practitioners for medication-​overuse headache, follow- to Treatment) questionnaire in the management of Peer review information up after 6 months: a pragmatic cluster-​randomised primary headache disorders: reliability, validity and Nature Reviews Neurology thanks J. Rothrock, A. Tinsley and controlled trial. J. Neurol. 263, 344–353 (2016). clinical utility of the Arabic version. J. Headache Pain the other, anonymous, reviewer(s) for their contribution to the 110. Lai, J. T. F. et al. Should we educate about the risks of 14, 16 (2013). peer review of this work. medication overuse headache? J. Headache Pain 15, 135. Lipton, R., Manack, A., Serrano, D. & Buse, D. Publisher’s note 10 (2014). Acute treatment optimization for migraine: results Springer Nature remains neutral with regard to jurisdictional 111. Pijpers, J. A. et al. Acute withdrawal and botulinum of the American Migraine Prevalence and Prevention claims in published maps and institutional affiliations. toxin A in chronic migraine with medication overuse: (AMPP) study. J. Headache Pain 14, P201 (2013). a double-​blind randomized controlled trial. Brain 142, Open Access This article is licensed under Author contributions 1203–1214 (2019). a Creative Commons Attribution 4.0 A.K.E., H.A. and M.A. researched data for the article. All 112. Carlsen, L. N. et al. Comparison of 3 treatment International License, which permits use, authors made substantial contributions to discussion of the strategies for medication overuse headache: sharing, adaptation, distribution and reproduction in any content, contributed to writing and reviewed and edited the a randomized clinical trial. JAMA Neurol. 77, medium or format, as long as you give appropriate credit to manuscript before submission. 1069–1078 (2020). the original author(s) and the source, provide a link to the 113. Buse, D. C. et al. Chronic migraine prevalence, Competing interests Creative Commons license, and indicate if changes were disability, and sociodemographic factors: results from S.K. has been an invited speaker for Novartis. H.-​C.D. has made. The images or other third party material in this article the American Migraine Prevalence and Prevention received honoraria for participation in clinical trials, contribu- are included in the article’s Creative Commons license, unless Study. Headache 52, 1456–1470 (2012). tion to advisory boards or oral presentations from Alder, indicated otherwise in a credit line to the material. If material 114. Diener, H.-C. et al. Chronic migraine — classification, Allergan, Amgen, Electrocore, Ipsen, Lilly, Medtronic, Novartis, is not included in the article’s Creative Commons license and characteristics and treatment. Nat. Rev. Neurol. 8, Pfizer, Teva and Weber & Weber. Electrocore has provided finan- your intended use is not permitted by statutory regulation or 162–171 (2012). cial support for his research projects. The German research exceeds the permitted use, you will need to obtain permission 115. Buse, D. C., Greisman, J. D., Baigi, K. & Lipton, R. B. council (DFG), the German ministry of Education and Rese­ directly from the copyright holder. To view a copy of this Migraine progression: a systematic review. Headache arch (BMBF) and the European Union support his headache license, visit http://creativecommons.org/licenses/by/4.0/. 59, 306–338 (2019). research. He also serves on the editorial boards of Cephalalgia 116. Probyn, K. et al. Prognostic factors for chronic headache: and Lancet Neurology, chairs the clinical guidelines committee a systematic review. Neurology 89, 291–301 (2017). of the German Society of Neurology and is a member of the 117. Xu, J., Kong, F. & Buse, D. C. Predictors of episodic Clinical Trials Committee of the International Headache Society. Related links migraine transformation to chronic migraine: a example headache calendar: https://static-​content.springer. D.D.M. has received honoraria, research and travel grants from systematic review and meta-​analysis of observational com/esm/art%3A10.1186%2Fs10194-018-0899-2/ Allergan, Amgen, Biogen, Cefaly, Eli Lilly, Electrocore, Mertz, cohort studies. Cephalalgia 40, 503–516 (2019). MediaObjects/10194_2018_899_MOESM17_ESM.pdf Novartis, Roche, Sanofi, Specifar and Teva. A.J.S. reports per- 118. Lipton, R. B. et al. Ineffective acute treatment example headache diary: https://static-​content.springer. sonal fees from Allergan and Novartis, grants from Novartis, of episodic migraine is associated with new-​onset com/esm/art%3A10.1186%2Fs10194-018-0899-2/ and grants and personal fees from Invex Therapeutics. He is a chronic migraine. Neurology 84, 688–695 (2015). MediaObjects/10194_2018_899_MOESM16_ESM.pdf trustee of the board of the International Headache Society and 119. Silberstein, S. et al. Topiramate treatment of chronic HuRt questionnaire: https://migraine-​acute-​treatment.ime. a member of the Council of the European Headache Federation. migraine: a randomized, placebo-​controlled trial of springerhealthcare.com/wp-​content/uploads/EN-​HURT.pdf P.P.-​R. has received honoraria as a consultant and speaker for quality of life and other efficacy measures. Headache Patient information leaflets: https://static-​content.springer. Allergan, Almirall, Biohaven, Chiesi, Eli Lilly, Medlink, 49, 1153–1162 (2009). com/esm/art%3A10.1186%2Fs10194-018-0899-2/ Medscape, Neurodiem, Novartis and Teva. Her research group 120. Herd, C. P. et al. Botulinum toxins for the prevention MediaObjects/10194_2018_899_MOESM21_ESM.pdf has received research grants from Allergan, AGAUR, la Caixa of migraine in adults. Cochrane Database Syst. Rev. 6, foundation, EraNET Neuron, FEDER RISC3CAT, Migraine CD011616 (2018). 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