# European headache federation consensus on the definition of resistant and refractory migraine

Simona Sacco, Mark Braschinsky, Anne Ducros, Christian Lampl, Patrick Little, Antoinette Maassen van den Brink, Patricia Pozo-Rosich, Uwe Reuter, Elena Ruiz de La Torre, Margarita Sanchez del Rio, et al.

► To cite this version:

Simona Sacco, Mark Braschinsky, Anne Ducros, Christian Lampl, Patrick Little, et al. European headache federation consensus on the definition of resistant and refractory migraine. Journal of Headache and Pain, 2020, 21 (1), pp.76. 10.1186/s10194-020-01130-5. hal-03611483

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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)

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Simona Sacco<sup>1,2*</sup>, Mark Braschinsky<sup>3</sup>, Anne Ducros<sup>4</sup>, Christian Lampl<sup>5</sup>, Patrick Little<sup>6</sup>, Antoinette Maassen van den Brink<sup>7</sup>, Patricia Pozo-Rosich<sup>8,9</sup>, Uwe Reuter<sup>10</sup>, Elena Ruiz de la Torre<sup>6</sup>, Margarita Sanchez Del Rio<sup>11</sup>, Alexandra J. Sinclair<sup>12,13</sup>, Zaza Katsarava<sup>14,15,16,17</sup> and Paolo Martelletti<sup>18,19</sup>

## 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)

<footnote>* Correspondence: simona.sacco@univaq.it</footnote>

<footnote n="1">¹Neuroscience section – Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy</footnote>

<footnote n="2">²Regional Referral Headache Center of the Abruzzo region, ASL
Avezzano-Sulmona-L’Aquila, L’Aquila, Italy</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
(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**

Despite advances in the management of headache disorders, some patients with migraine do not experience adequate pain relief with acute and preventive treatments. This correlates with higher burden and disability, as well as despair of patients who suffer from it. The terms “refractory” and “intractable” headache have been used to describe this particular condition and various definitions have been suggested over time [1–6] (Table 1). However, wide acceptance of the proposed definitions was not reached so far. Moreover, the International Classification of Headache Disorders (ICHD) neither includes a definition for refractory or resistant migraine nor for other primary headaches [7].

A previous consensus statement of the European Headache Federation (EHF) defined as refractory migraine those chronic migraine patients who do not show response to adequate dosages of at least 3 drugs from the following classes: beta-blockers, anticonvulsants, tri-cyclics, onabotulinumtoxinA and others (e.g., flunarizine, candesartan) for at least 3 months each, in absence of medication overuse [3]. The aim of the present Consensus paper is to critically revise the 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.

**Methods**

The Panel who developed this consensus statement consisted of the members of the Council of the EHF. Ten of the board members are physicians (with specialization in Neurology or Internal medicine) and one is a pharmacologist; all are experienced in headache. The Panel includes also two representatives (PL, ERDLT) of patients from the European Migraine and Headache Alliance (EMHA). Patients representatives were not involved in the consensus process to develop the definitions but had the opportunity to provide suggestions and comments.

This Consensus represents an update of a previous EHF consensus published in 2014 [3]. All the points of the

previous EHF consensus definition were reconsidered by the EHF Expert Consensus Group and revised if necessary.

As a first step, an in-person meeting was held to agree on the need of a new Consensus Statement, on the composition of the EHF Expert Consensus Group and on the mission of this updated Consensus Statement. Thereafter, the process proceeded via e-mails.

The Delphi method [8] was used to reach consensus. According to this method, the EHF Expert Consensus Group members were assigned to open or multiple-choice questions in several rounds. Participants were instructed not to discuss the responses amongst themselves. Feedback after each round was sent only to the facilitator (SS). The facilitator collected all the answers for each round and issued an anonymized report with comments and agreement rates. Participants were then encouraged to revise their earlier answers in light of the replies of other members. Questions were repeated until a clear majority (> 70% of agreement) was reached [9]. Each Panel member (with the exclusion of EHMA representatives) had the right to vote. A step by step approach was used to build the definitions, using the results of the Delphi questions. Seven rounds were needed to reach a consensus among all the different aspects of the definition (Table 2).

**Results**

Two categories of difficult to treat migraine were recognized, *resistant migraine* and *refractory migraine*. Criteria to define resistant and refractory migraine are reported in Table 3.

Definitions are based on fulfilling ICHD III criteria for migraine with or without aura or for chronic migraine [7] and having at least 8 debilitating headache days per month plus the failure of previous preventive treatments.

*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
<table><caption>**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</caption><thead><tr><th>Round</th><th>Task</th><th>Agree</th><th>Disagree</th><th>Unsure</th><th>Action</th></tr></thead><tbody><tr><td>1</td><td>Decide to work on two different definitions:<br/>- Resistant migraine which is a form of migraine that has not responded to some treatments but where there is room to try other available treatments;<br/>- Refractory migraine which is a form of migraine that cannot be managed with any of the available treatments.</td><td>73%</td><td>18%</td><td>9%</td><td>Work on two categories</td></tr><tr><td>2</td><td>Use in the definition of cut-off values of headache days per month instead of percent reduction from baseline after treatment.</td><td>73%</td><td>27%</td><td>-</td><td>Use cut-off values</td></tr><tr><td>3</td><td>Decide on preferable cut-off values for resistant and refractory migraine. Experts were asked for each category, resistant and refractory, to fill-in with numbers the following definition: "disabling headache being present for at least ( ) days per month for ( ) months in patients who have failed or have contraindication to at least ( ) drug categories".</td><td>Members provided values</td><td></td><td></td><td>Calculation of median values</td></tr><tr><td>4</td><td>Decide to add ± 2 days to the number of headache days selected as threshold (e.g. headache being present for at least 8 ± 2 days per month).</td><td>63%</td><td>37%</td><td>-</td><td>Rejected</td></tr><tr><td></td><td>Provide a list of the drug categories to have failed to meet definitions of resistant and refractory.</td><td>Members provided a list</td><td></td><td></td><td>-</td></tr><tr><td>5</td><td>Provide free comments on the first draft of the definition. Issues to be commented were:<br/>- Criteria to define resistant and refractory migraine<br/>- Drug classes to have failed to meet criteria<br/>- Definition of debilitating migraine<br/>- Definition of drug failure<br/>- Definition of contraindications<br/>- Assessment of patients<br/>- Medication overuse<br/>- Behavioral factors<br/>- Comorbidities</td><td>Members provided comments</td><td></td><td></td><td>Comments received and considered to improve the proposal</td></tr><tr><td>6</td><td>Provide comments on the second draft of the definition</td><td>Members provided comments</td><td></td><td></td><td>Comments received and considered to improve the proposal</td></tr><tr><td>7</td><td>Agree on the third draft of the definition</td><td>82%</td><td>18%*</td><td>-</td><td>Final definition agreed</td></tr></tbody></table>

debilitating headache days per month for at least 6 consecutive months. For refractory migraine, chart review alone is not sufficient and a minimum period of observation of 6 months is required together with completed diaries.

The drug classes considered for meeting the definitions include antidepressants, antiepileptics, beta-blockers, calcium channel blockers, drugs acting on the calcitonin-gene related peptide (CGRP) pathway, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, onabotulinumtoxinA, as well as any new developed drug with established efficacy in migraine prevention. Drug failure may include lack of efficacy or lack of tolerability. For lack of efficacy, appropriate dosing and duration of the considered preventatives is reported in Table 4.

A patient cannot be considered to try some drugs because of possible contraindications. Absolute, major and relative contraindications to drugs for migraine prevention are reported in Table 5.

The presence of medication overuse is compatible with the proposed definition of resistant and refractory migraine; however, in patients with refractory migraine documentation of failed attempts of withdrawal of medications is needed.

Both definitions of resistant and refractory migraine require the presence of at least 8 days of debilitating migraine. 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.

To validate the definitions, it is also recommended that patients with resistant migraine are evaluated by headache specialists and that patients with refractory migraine are evaluated in tertiary Headache Centers.

Triggers and comorbidities which may contribute to resistant or refractory migraine need to be identified and managed before assigning patients to those categories. Careful differential diagnosis with mimicking conditions must be done as suggested in Table 6.

## Discussion

### Resistant and refractory

It is necessary to distinguish between patients who easily respond to treatment and those who do not. The latter requires more attention and more persistence in the treatment. Moreover, patients who do not easily respond to treatment are at higher risk of developing chronic headache and therefore should be identified early and treated accordingly [10].

One of the major novelties of the updated EHF Consensus definition is the recognition that difficult-to-treat patients may be labelled into two major categories, *resistant migraine* and *refractory migraine*; the difference
<table><caption>**Table 3** Proposed updated definition of resistant and refractory migraine</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>Resistant migraine can be diagnosed if all the following criteria are met:<br>A. Established diagnosis of 1.1 Migraine without aura and/or 1.2 Migraine with aura or 1.3 Chronic migraine according to ICHD-III criteria;<br>B. Debilitating headache for at least 8 days per month for at least 3 months;<br>C. Failure and/or contraindication to 3 drug classes* with established evidence for migraine prevention, given at an appropriate dose for an appropriate duration.</td><td>Refractory migraine can be diagnosed if all the following criteria are met:<br>A. Established diagnosis of 1.1 Migraine without aura and/or 1.2 Migraine with aura or 1.3 Chronic migraine according to ICHD-III criteria;<br>B. Debilitating headache for at least 8 days per month for at least 6 months;<br>C. Failure and/or contraindication to all classes with established evidence for migraine prevention, given at an appropriate dose for an appropriate duration.</td></tr><tr><td colspan="2"><em>Specifies to the diagnosis</em></td></tr><tr><td colspan="2"><strong>Definition of debilitating headache</strong></td></tr><tr><td colspan="2">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 at the beginning of the attack; failure of at least two different triptans is required.</td></tr><tr><td colspan="2"><strong>Drug classes considered for the diagnosis</strong></td></tr><tr><td colspan="2">1. Antidepressant (Amitriptyline, Venlafaxine);<br>2. Antiepileptic (Topiramate or Valproate);<br>3. Beta-blocker (Atenol, Metoprolol, Propanolol, Timolol);<br>4. Calcium channel blocker (Flunarizine or Cinnarizine);<br>5. Drugs acting on the CGRP pathway (Monoclonal antibodies and Gepants);<br>6. Angiotensin-converting enzyme inhibitor (Lisinopril) or angiotensin II receptor blocker (Candesartan);<br>7. OnabotulinumtoxinA (for chronic migraine only);<br>8. Other pharmacologic preventive treatments with established efficacy in migraine (e.g. any new developed drug).</td></tr><tr><td colspan="2"><strong>Definition of drug failure</strong></td></tr><tr><td colspan="2">Failure, at any time, of migraine preventatives because of:<br>1. lack of efficacy due to persistence of headache with the required frequency for meeting criteria for resistant or refractory migraine, while the patient is on treatment with one of the recognized preventatives at an established dose and for an appropriate duration;<sup>5</sup><br>2. lack of tolerability due to side effects which are unbearable for the patient, cannot be effectively managed and require stopping the drug.</td></tr><tr><td colspan="2"><strong>Definition of contraindication</strong></td></tr><tr><td colspan="2">Contraindication is any specific situation in which the use of a given drug is inadvisable.<sup>*</sup></td></tr><tr><td colspan="2"><strong>Assessment of patients</strong></td></tr><tr><td colspan="2">To validate definitions, we suggest the following:<br>1. Resistant migraine, evaluation by a Headache specialist with review of medical charts;<br>2. Refractory migraine, evaluation in a tertiary level Headache Center with in-person follow-up for at least 6 months.</td></tr><tr><td colspan="2"><strong>Medication overuse</strong></td></tr><tr><td colspan="2">1. For resistant migraine presence of medication overuse does not exclude the diagnosis;<br>2. For refractory migraine presence of medication overuse does not exclude the diagnosis but attempts of unsuccessful medication withdrawal needs to be documented.</td></tr><tr><td colspan="2"><strong>Additional factors</strong></td></tr><tr><td colspan="2">Triggers and comorbidities need to be considered and managed; unsuccessful management of triggers and comorbidities is possible.<br>Careful differential diagnosis with mimicking conditions must be done.</td></tr></tbody></table>

<footnote><sup>a</sup>Trials with at least 3 drug classes is encouraged if allowed by contraindications</footnote>

<footnote><sup>b</sup>Established doses and duration as reported in Table 4</footnote>

<footnote><sup>c</sup>Absolute, major and relative contraindications as reported in Table 5</footnote>
<table><caption>**Table 4** Suggested doses and duration for assessment of lack of efficacy</caption><thead><tr><th>Drug</th><th>Usual dose</th><th>Minimum effective dose</th><th>Maximal effective dose</th><th>Minimum duration of treatment*</th></tr></thead><tbody><tr><td colspan="5">Monoclonal antibodies acting on the calcitonin-gene-related peptide pathway</td></tr><tr><td>Erenumab</td><td>70-140 mg monthly</td><td>70 mg</td><td>140 mg</td><td>3 months</td></tr><tr><td rowspan="2">Fremanezumab</td><td>225 mg monthly</td><td>225 mg/monthly</td><td>225 mg/monthly</td><td>3 months</td></tr><tr><td>675 mg quarterly</td><td>675 mg/quarterly</td><td>675 mg/quarterly</td><td>3 months</td></tr><tr><td>Galcanezumab</td><td>120 mg monthly (240 mg loading dose)</td><td>120 mg/monthly</td><td>120 mg/monthly</td><td>3 months</td></tr><tr><td colspan="5">Antidepressants</td></tr><tr><td>Amitriptyline</td><td>25 mg once a day</td><td>10 mg once a day</td><td>75 mg once a day</td><td>2 months</td></tr><tr><td>Venlafaxine</td><td>75-150 mg once a day</td><td>37.5 mg once a day</td><td>300 mg once a day</td><td>2 months</td></tr><tr><td colspan="5">Antiepileptics</td></tr><tr><td>Topiramate</td><td>50 mg twice a day</td><td>25 mg twice a day</td><td>100 mg twice a day</td><td>2 months</td></tr><tr><td>Valproate</td><td>300 mg twice a day</td><td>200 mg twice a day</td><td>1000 mg twice a day</td><td>2 months</td></tr><tr><td colspan="5">Antihypertensives</td></tr><tr><td>Candesartan</td><td>16 mg once a day</td><td>8 mg once a day</td><td>32 mg once a day</td><td>2 months</td></tr><tr><td>Lisinopril</td><td>20 mg once a day</td><td>5 mg once a day</td><td>40 mg once a day</td><td>2 months</td></tr><tr><td colspan="5">Calcium channel blockers</td></tr><tr><td>Cinnarizine</td><td>75 mg once a day</td><td>75 mg once a day</td><td>150 mg once a day</td><td>2 months</td></tr><tr><td>Flunarizine</td><td>5 mg once a day</td><td>5 mg once a day</td><td>10 mg once a day</td><td>2 months</td></tr><tr><td colspan="5">Beta-blockers</td></tr><tr><td>Atenolol</td><td>100 mg once a day</td><td>50 mg once a day</td><td>200 mg once a day</td><td>2 months</td></tr><tr><td>Metoprolol</td><td>100 mg once a day (extended release)</td><td>25 mg once a day</td><td>200 mg once a day (extended release)</td><td>2 months</td></tr><tr><td>Propranolol</td><td>40 mg twice a day</td><td>40 mg once a day</td><td>80 mg three times a day</td><td>2 months</td></tr><tr><td>Timolol</td><td>10 mg twice a day</td><td>5 mg twice a day</td><td>30 mg twice per day</td><td>2 months</td></tr><tr><td>Onabotulinumtoxin A</td><td>195 UI quarterly</td><td>155 UI quarterly</td><td>195 UI quarterly</td><td>2-3 cycles 9 months</td></tr></tbody></table>

between resistant and refractory migraine relies on the number of required previous treatment failures.

The two categories were identified in order to respond to different needs and to implement these needs in the clinical and research settings. In fact, the optimal definition of difficult to treat migraine depends on the

context and on the consequences of assigning the label. If the consequence of labeling is referral to a headache center or treatment escalation, the definition threshold should be lower than if the consequence is to develop new interventional treatments. Accordingly, resistant migraine is defined as migraine which remains significantly

<table><caption>**Table 5** Absolute, major and relative contraindications to drugs for migraine prevention</caption><thead><tr><th></th><th>Absolute</th><th>Major</th><th>Relative</th></tr></thead><tbody><tr><td colspan="4">Monoclonal antibodies acting on the calcitonin-gene-related peptide pathway</td></tr><tr><td>Eptinezumab</td><td></td><td></td><td>Myocardial infarction or angina, stroke or transient ischemic attack, uncontrolled vascular risk factors</td></tr><tr><td>Erenumab</td><td></td><td></td><td></td></tr><tr><td>Fremanezumab</td><td></td><td></td><td></td></tr><tr><td>Galcanezumab</td><td></td><td></td><td></td></tr><tr><td colspan="4">Antidepressants</td></tr><tr><td>Amitriptyline</td><td>Arrhythmias, congestive heart failure, coronary artery disease, heart block to any degree, mania, myocardial infarction, severe liver disease</td><td>Bipolar disorder, glaucoma, hepatic disease, monoamineoxidase inhibitors use, prostatic hypertrophy</td><td>Constipation, diabetes mellitus, driving or operating machinery, epilepsy, obesity, pheochromocytoma, seizure, thyroid disease</td></tr><tr><td>Venlafaxine</td><td>Mania</td><td>Bipolar disorder, close angle glaucoma, QT prolongation</td><td>Driving or operating machinery, epilepsy, hepatic disease, renal failure or renal impairment, uncontrolled hypertension</td></tr><tr><td colspan="4">Antiepileptics</td></tr><tr><td>Topiramate</td><td>Depression and suicidal ideation</td><td>Conditions predisposing to acidosis (ketogenic diet, severe pulmonary disease, metformin use), glaucoma, hepatic disease, nephrolithiasis, renal failure or renal impairment</td><td>Driving or operating machinery</td></tr><tr><td>Valproate</td><td>Liver disease, Mitochondrial disease; women of childbearing age not using precautions to avoid pregnancy</td><td>Depression and suicidal ideation</td><td>Driving or operating machinery, obesity</td></tr><tr><td colspan="4">Antihypertensives</td></tr><tr><td>Candesartan</td><td></td><td>Heart failure, hypotension, renal artery stenosis, renal impairment or failure</td><td>Hepatic disease, hyperkalemia</td></tr><tr><td>Lisinopril</td><td></td><td>Angioedema, renal artery stenosis, renal impairment or failure</td><td>Diabetes mellitus, hyperkalemia,</td></tr><tr><td colspan="4">Calcium channel blockers</td></tr><tr><td>Cinnarizine</td><td></td><td></td><td></td></tr><tr><td>Flunarizine</td><td></td><td></td><td></td></tr><tr><td colspan="4">Beta-blockers</td></tr><tr><td>Atenolol</td><td>Cardiogenic shock and hypotension, decompensated heart failure, heart block greater than first degree, Printzmetal angina, sick sinus syndrome (without a pacemaker), symptomatic bradycardia</td><td>Asthma and chronic pulmonary obstructive disease, calcium channel blockers (diltiazem o verapamil) use, hypotension, myasthenia gravis, peripheral artery occlusive disease, pheochromocytoma, psoriasis, Raynaud phenomenon</td><td>Diabetes mellitus, depression, hyperthyroidism or thyrotoxicosis, obesity, renal impairment or failure</td></tr><tr><td>Metoprolol</td><td></td><td></td><td></td></tr><tr><td>Propranolol</td><td></td><td></td><td></td></tr><tr><td>Timolol</td><td>Myasthenia gravis, amyotrophic lateral sclerosis</td><td>Peripheral nerve disease</td><td>Infection at injections side</td></tr></tbody></table>

<footnote>*after reaching the therapeutic dose for drugs which require titration</footnote>
<table><caption>**Table 6** Conditions to be excluded before diagnosis of resistant or refractory migraine</caption><thead><tr><td>Condition</td><td>Features</td></tr></thead><tbody><tr><td>Chronic cluster headache</td><td>Excessive use of analgesics may mask the condition. It should be suspected in patients with side-locked headache and prominent autonomic features.</td></tr><tr><td>Hemicrania continua</td><td>It should be suspected in patients with side-locked headache and prominent autonomic features and with net response to indomethacin</td></tr><tr><td>New daily persistent headache</td><td>It should be suspected in cases where the headache is daily since its onset</td></tr><tr><td>Headache attributed to idiopathic intracranial hypertension</td><td>It should be suspected especially in young women who are obese. Criteria which increase the likelihood of the condition are represented by the presence at brain magnetic resonance of empty sella, flattening of the posterior part of the ocular globe, distension of the periocular subarachnoid space, tortuous optic nerve, transverse sinus stenosis. Confirmed by cerebrospinal fluid pressure pressure >25 cm cerebrospinal fluid pressure at lumbar puncture</td></tr><tr><td>Headache attributed to spontaneous intracranial hypotension</td><td>It should be suspected in cases where the headache is orthostatic and associated with hearing symptoms and neck stiffness, but these features may not be obvious. Clues to the diagnosis are pachymeningeal gadolinium-enhancement, and subdural fluid collections on brain magnetic resonance and identification of a leak on spinal imaging.</td></tr></tbody></table>

debilitating despite some treatment attempts. In contrast, refractory migraine is defined as migraine which remains significantly debilitating after maximal or nearly maximal number of treatment attempts. It is important to note that resistance and refractoriness may just represent more or less treatable versions of migraine attacks, rather than a separate migraine entity. The same patient might be identified as refractory at one time, but treatment responsive at another. Therefore, it may be of crucial importance to evaluate acute and prophylactic treatment response, baseline headache severity, partial response versus an all-or-none response, and the possibility of any variability in the treatment response over time [11].

The categorization of difficult-to-treat patients might be helpful in the recognition of patients in need of more expensive treatments. Additionally, the definition could help patients to gain access to reimbursement policies, work-related disability benefits, and social security benefits.

Anyhow, we duly recognize that patients who also do not meet criteria for resistant migraine (e.g. 6 debilitating migraine days per month) may need access to dedicated headache care or treatment escalation.

## Cut-offs values

A further main novelty of the present definition is the use of cut-off values rather than percent reductions. The use of cut-off values is more in line with the ICHD III criteria while the use of percentage reductions is more in line with clinical trial criteria. Clinical trials for preventive treatment define responders as those achieving at least 50% reduction in monthly migraine/headache days with treatment as compared to baseline [12]. For chronic migraine a 30% reduction is accepted [13]. However, with the use of percent reduction, patients may be considered responders but still have a relevant number of debilitating

days with headache. To overcome this problem the EHF Expert Consensus Group opted to use 8 days per month as cut-off values. Eight days per month were chosen to consider evidence indicating that moderate disability starts after 4 migraine days per month [14–16]. Thus, the selected cut-off values allow us to consider both, episodic and chronic migraine as resistant or refractory. It is important to note that with the use of cut-off values, patients who have significant response to treatment (e.g a patient with 30 headache days per month and with > 50% reduction in headache days with treatment) may be labelled as resistant or refractory. With advancements in migraine treatment, goals of successful treatment may become more and more ambitious and cut-off values may need to be further reduced.

## Debilitating headache

The criteria proposed by the EHF Expert Consensus Group rely on the presence of a given number of days of debilitating headache attacks. The presence of a serious impairment in activities is a key feature of the proposed definitions. Debilitating headache was defined as headache causing serious impairment to the conduct of activities in daily living despite the use of pain-relief drugs with established efficacy at the recommended dose [17]. In order to assess the efficacy of acute headache medications, adequate timing of drug administration, dosage and formulations used, should be considered.

We opted for headache days rather than migraine days because overt migrainous features may be masked in complex patients especially in patients who overuse acute headache medication. We also voluntarily decided to use the term debilitating rather than disabling. The term disabling is more related to physical impairment caused by neurological disease such as stroke, multiple sclerosis, amyotrophic lateral sclerosis and others which cause permanent impairment in function of patients due
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
head pain but not to physical disability, a different ter-
minology may be more appropriate. However, we are
aware that patients who suffer from migraine live with
anticipatory anxiety as they do not know when the next
attack may occur. This fear conditions their life and that
of their families, social activities and work responsibil-
ities [18].

Ascertainment of debilitating attacks shall be done
with clinical interview or with the use of validated scales
in order to evaluate if headaches significantly interfere
with a patient's ability to work, attend school, or partici-
pate in family or social activities. The EHF Expert Con-
sensus Group did not choose to use cut scores at
common validated instruments to measure function or
disability such as the MIgraine Disability ASsessment
(MIDAS) tool [19], the Headache Impact Test (HIT-6)
scale [20], or the Headache-Attributed Lost Time
(HALT) Indices [21]. We considered the fact that there
is not one single Patient-Reported Outcome scale
(PROs) including the magnitude of the impairment that
a person with a migraine attack or frequent migraine
suffers. This is, in a large part, due to the impact of mi-
graine on cognition. When the brain can't function,
there is a wide impact on many different tasks which
need a wide range of instruments to capture the com-
plexity of the disability. Indeed, the recent randomized
controlled trials on migraine prevention used several
tools to capture the impact of both, the disease and the
treatment [22, 23]. Additionally, the choice of any cut-
off score might be controversial as there are no data re-
garding which threshold of score change in these instru-
ments should separate treatment failure from treatment
success. Moreover, the disability instruments may not be
translated or validated in certain countries. However,
when available, using PROs not only helps to translate
burden of disease but also tracks changes over time.

In the proposed definition, the efficacy of analgesics is
also considered. In fact, resistance or refractoriness to
acute or preventive treatment, are not to necessarily re-
lated. One patient may have a poor response to preven-
tatives but a good response to analgesics. Failure of at
least two triptans is required because there is evidence
that switching from a triptan that is ineffective to a sec-
ond one can result in positive treatment [24]. If the anal-
gesics are able to control adequately the pain allowing
patients to function normally, patients with migraine will
not qualify to be categorized as resistant or refractory. It
is worth mentioning that according to the proposed defi-
nitions of resistant and refractory migraine, patients who
overuse symptomatic drugs and who have pain relief
with them cannot be labelled as resistant or refractory.

Drug failure

Establishing drug failure or contraindication is pivotal to
identifying resistant or refractory migraine. This point
should carefully be addressed in order to avoid labelling
as resistant or refractory patients who are only pseudo-
resistant or pseudo-refractory.

One of the main criteria to define resistance and refrac-
toriness to treatment is the number of failed classes of
medications. The specific classes were picked because they
have shown clinical efficacy in randomized-controlled tri-
als and are supported by evidence-based guidelines for mi-
graine prevention [13, 22, 25, 26]. The Consensus group
agreed to select failure of drug classes, rather than single
medications, since a patient who fails a drug has a very
low probability of responding to another drug within the
same class based on expert opinion. However, it is import-
ant to note that different agents within a class may work
by different mechanisms [2, 27] and thus we support the
use of drugs in the same class, but with a different mech-
anism of action (e.g. topiramate and valproate). We ac-
knowledge that some agents may be not available or
accessible across all countries and that others require
technical expertise (e.g. OnabotulinumtoxinA), which may
limit the generalizability of the proposed definitions. Na-
tional adaptations of the EHF Consensus on the definition
of resistant and refractory migraine can be developed for
use at the country level.

The proposed definitions of resistant and refractory mi-
graine consider the appropriateness of doing trials with
preventive treatments. Identification of factors that con-
tribute to pseudo-resistance is important in preventing
costly and potentially risky diagnostic evaluations and in
avoiding inappropriate intensification of treatment. If
therapy was inadequate (low dose or incorrect duration)
the failure is to be reassessed. Suggested doses and dura-
tions for optimal treatment are specified in Table 4.
Minimal duration of drug trials was set at 2 months (after
reaching the therapeutic dose) for oral drugs in line with
previous definition of refractory migraine. For monoclonal
antibodies (mAbs) acting on the CGRP pathway a mini-
mum of 3 months is required and for Onabotulinumtox-
inA a minimum of 6 months, in line with available
guidelines and evidence from real-life studies [13, 22, 25,
28]. Longer trials would be preferable for some drugs, but
extending minimal time frame is not feasible in every case,
especially in those patients who do not have any kind of
improvement with the selected preventatives. On the
other hand, we may consider to extend the preventive
treatment if there was some improvement during the first
period of treatment. Undoubtedly, decisions will have to
be individualized. The EHF Expert Consensus Group de-
cided not to pose a time frame for previous trials of pre-
ventatives (e.g. failure within the 10 previous years) as any
choice would be arbitrary.
It is important to note that lack of adherence may con-
tribute to lack of success of medical treatment. Lack of ad-
herence is mostly due to side effects. Frequently, side
effects are too bothersome for patients and lead to drug
discontinuation. EHF criteria for resistant and refractory
migraine include lack of tolerability among the accepted
reasons of drug failure. Anyway, we want to point out that
side effects should always be addressed and if possible ad-
equately managed to promote drug adherence. A trusting
physician–patient relationship, setting reasonable goals
and expectations, and educating patients are key for a suc-
cessful patient management. Nocebo effect may lead pa-
tients to discontinue medications because of the fear of a
potential side effect [29, 30].

Some patients have medical contraindications to
specific preventive treatments (Table 5). Contraindicated drugs are considered in the criteria for resistant and refractory migraine. It is important to differentiate absolute contraindications that pose a risk for the patient if the drug is used, from a relative contraindication, which does not prohibit the use of the drug but may require stricter monitoring. One limit of the current definition is that a patient can be defined as resistant while not having tried any preventive medication because of hypothetical contraindications to at least three classes.

In the current EHF definitions of resistant and refrac-
tory migraine, we did not include in the criteria the pos-
sibility to combine different preventatives to achieve a
response to treatment in the criteria. Combinations of
suggested preventive treatments are recommended espe-
cially when one preventive treatment decreased the at-
tack frequency but did not control the situation
satisfactorily, upon the physician's decision [31]. Com-
bination therapy has the potential advantage to target
different aspects of the pain dysfunction, with potentially
better results due to the synergistic effects of different
treatments. However, there is insufficient evidence to
state definitively if combination therapy is clearly super-
ior to single therapy [32–34].

Medication overuse

It is well known that a variable proportion of patients
overusing acute headache medications may actually
benefit from withdrawal [35]. However, the ideal treat-
ment strategy for medication overuse is a matter of on-
going debate. Withdrawal cannot be achieved in every
patient and relapse or continued overuse has been re-
ported in many patients [36]. For those reasons we opted
to make the presence of medication overuse compatible
with the proposed definition of resistant and refractory
migraine. Up to know it is unclear if withdrawal of acute
medication may revert an apparent refractory headache
into a tractable one. Having a well-defined definition of

refractory and resistant headache will represent the basis
for research studies to establish this.

Triggers and comorbidities

In some cases, difficult-to-treat migraine is associated
with uncontrolled trigger factors (e.g. excessive use of
caffeine) and comorbidities. The role that those factors
have in drug resistance is not entirely clear. On one
hand, they may contribute to resistance or refractoriness
to prescribed pharmacological treatment but on the
other hand if medications are effective, triggers may not
be able to induce migraine attacks. Triggers and comor-
bidities should be addressed and managed before label-
ling patients as resistant or refractory, even if definite
removal is not always possible.

Trigger factors that can exaggerate migraine include al-
cohol consumption, caffeine overuse, diet, smoking and
vasodilating antihypertensives. Further triggers are repre-
sented by emotional stress [37], alterations in the sleep
cycle [38–40], and hormonal factors [41–43]. Manage-
ment of those factors is a staple of good clinical practice.
Additionally, patients suffering from migraine frequently
have comorbid disorders [44–48]. The identification and
management of all clinically significant comorbidities is
essential before declaring a treatment failure in migraine
patients. Psychiatric comorbidities and obesity may be
particularly relevant in the setting of resistance or refrac-
toriness to treatments [49, 50].

Differential diagnosis

A possible reason for treatment failure in patients with
headache is that the diagnosis is incomplete or incorrect.
When addressing patients with migraine who do not re-
spond to treatment it is always important to reconsider
the diagnosis and to rule out other primary or secondary
headaches, which may entirely account for the clinical
picture or which may coexist with migraine and contrib-
ute to the lack of response to treatments. Investigations
should be done where appropriate to exclude secondary
headaches [51]. A list of conditions mimicking resistant
or refractory migraine is reported in Table 6.

Particular attention should be paid to idiopathic intra-
cranial hypertension without papilledema (IIIWP). This
condition can be entirely responsible of difficult-to-treat
headache or can contribute to drug resistance or refrac-
toriness in patients who have concomitant migraine. Cri-
teria which increase the likelihood of IIIWP are
represented by the presence, at brain magnetic reson-
ance, of empty sella, flattening of the posterior part of
the ocular globe, distension of the perioptic subarach-
noid space, tortuous optic nerve, transverse sinus sten-
osis [52]. If this IIIWP is suspected, a lumbar puncture
with measurement of cerebrospinal fluid pressure should
be performed and patients treated according to available
guidelines [52].

## Other limitations to the definition

Migraine is a cyclic disorder which tends to fluctuate in frequency, severity and disability during life. Specifically, this has been investigated over the course of a year and for example, patients with chronic migraine can fluctuate into an episodic migraine phase [53]. This is why these new proposed criteria for the definition of resistant and refractory migraine have considered following also the International Classification for Headache Disorders, three consecutive months as a time frame to define at that time point in life, the presence of a resistant or refractory migraine. However, a diagnosis is not static in headache, and can change over time. If this should happen, it can always be revised.

It is also important to note that the present definition did not consider failure to devices or non-pharmacological therapies. A number of studies have shown that vagal nerve stimulation, biofeedback, relaxation, and cognitive behavior therapy are as efficacious for migraine as placebo, but still better than no improvement [54, 55]. However, behavioral treatments are less accessible, more professional-dependent and less standardized than pharmacological treatments, and in certain countries, not reimbursed by the Healthcare systems, than pharmacological treatments.

Moreover, physician-patient relationship, lifestyle
changes, and other qualitative variables can also influ-
ence the response to treatment.

## Assessment of patients

Migraine in general can be managed in the setting of primary care [56] or general neurology [57]. However, such settings cannot provide the necessary expertise to treat resistant and refractory patients. Patients with resistant migraine should be managed in special interest headache care settings (e.g. general practitioners with special interest in headache or neurologists, or first/second level headache clinics) and patients with refractory migraine must be managed in tertiary level headache clinics [58, 59]. In particular, refractory migraine patients must be offered the possibility of access to a multidisciplinary team.

Management by non-headache specialists often leads to perform-and-repeat exams which are not needed, thus raising the cost of migraine care [60, 61]. Additionally, incidental findings to unnecessary exams may lead to over-treatment of some conditions (e.g patent foramen closure) or additional unnecessary examinations (e.g. thrombophilia screening in unselected patients with white matter abnormalities).

Establishing previous treatment failures ideally should
be done by chart review. It is not reasonable to test

again preventive medications used in the past with no
efficacy or with intolerable side effects provided that in-
formation on duration, dose and adverse events is suffi-
cient and reliable. Unfortunately, not all patients provide
charts and headache diaries. In those cases, careful col-
lection of information from patient and relatives should
be looked for with the help of the general practitioner, if
available.

For patients with refractory migraine who were never
followed by a headache specialist, a minimum follow-up
of 6 months is suggested, to obtain reliable diaries and
allows the possibility to.

further improve headache management, as the diagno-
sis of refractory migraine is a very serious matter, which
should be carefully established.

## Implications to be defined as resistant or refractory
migraine patient

The diagnosis of resistant or refractory migraine may
contribute to stigmatizing the patient and therefore may
have profound psychological implications [62]. This is
especially true because the concept seems static and un-
resolvable. Education and effort will have to be put in
with both treating physicians and patients to help them
to understand the possible fluctuations of the disease.

There could also be legal and healthcare implications. It
may be possible that in certain countries only those patients
with a resistant or refractory migraine may have access to
newer treatments such as monoclonal Antibodies (mAbs)
acting on the Calcitonin-Gene-Related-Peptide (CGRP)
pathway; or in other countries, it might allow for temporary
or permanent social welfare [14, 63]. Even if revisable, it
does support a difficult-to-treat disorder and should facili-
tate access to more resources for its management.

## Future perspectives

The introduction of the concept of resistant and refrac-
tory migraine will have clinical and political implications.
We attempt to provide operational criteria of what intui-
tively has been used already. Introduction of expensive
migraine preventatives such as OnabotulinumtoxinA
and mAbs acting on the CGRP pathway and the expect-
ation of further preventatives raised the question of cost
effectiveness of these treatments. In many European
Countries use of these treatments is restricted to the
difficult-to-treat subpopulations of migraine patients.
These subpopulations were defined based on frequency
(e.g. in Spain more than 8 headache days per month) or
non-response (e.g. in Germany more than 5 preventa-
tives for episodic migraine and 6 preventatives including
OnabotulinumtoxinA for chronic migraine). This manu-
script aims to provide solid expert-opinion based criteria
for these subpopulations. It will be important to have
adequate field-testing of the proposed updated EHF
definition of resistant and refractory migraine in order to identify possible deficiencies and to make further improvements. Field-testing should be performed across different countries and different clinical settings. Adaptations at the country level may be needed to make the definition more usable.

Accepted and reliable criteria represents the basis of further research. At present, the exact pathophysiology of refractory migraine is unknown. It is important to reliably identify factors which may lead to refractoriness. We do not know whether genetic predisposition plays a role in resistance to treatment, whether resistance is accompanied over time by changes in the brain structure and function as assessed by neuroimaging, or which mechanisms play a pivotal role (e.g. central sensitization, peripheral sensitization).

There are several migraine preventive treatments in development; the proposed criteria will allow inclusion of these treatments when there is a good evidence basis for their use. Criteria will need to be changed when new treatments and significant advancements in the migraine field will happen.

## Conclusion

Crafting an operational definition of so called “difficult-to-treat migraine” is challenging. However, we all need to be aware that these patients exist and that a good definition represents a major need for clinical practice, for legal issues, and for research purposes. The proposed updated EHF definition identifies two subsets of difficult-to-treat migraine, resistant and refractory migraine, and considers both frequency and disability from single and frequent attacks. Although, in the previous literature formal and operational definitions for refractory or intractable headache were proposed, none was universally accepted. 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, underlying mechanisms can be identified, epidemiology can be characterized, and evidence-based treatments can be developed. Furthermore, the aim of this new definition is to increase the understanding of the impact of 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.

## Abbreviations

CGRP: Calcitonin-gene related peptide; EHF: European Headache Federation; EHMA: European Migraine & Headache Alliance; HALT: Headache-Attributed Lost Time; HIT-6: Headache Impact Test; ICHD: International Classification of Headache Disorders; IIWIP: Idiopathic intracranial hypertension without papilledema; mAbs: Monoclonal antibodies; MIDAS: Migraine Disability ASsessment; PROs: Patient-Reported Outcome scale

## Acknowledgements

Not applicable.

## Authors' contributions

SS conceived this consensus, acted as facilitator during the consensus process and drafted the paper; MB, AD, ZK, CL, PM, AMVDB, PPR, UR, MSDR, AJ S contributed to develop the consensus definition and revised the paper for important intellectual content; PL and ERDLT revised the paper for important intellectual content. All authors have approved the submitted version.

## Authors' information

European Headache Federation (EHF) Council: ZK (president), CL (1st vice-president), AMVDB (2nd vice-president), SS (treasurer), PM (past-president), MB (member), PPR (member), UR (member), MSDR (member), AS (member), AD (member).

European Migraine & Headache Alliance (EMHA): PL (president), ERDLT (Executive Director, Company Secretary and Immediate Past President).

## Funding

Publication fees for this publication were covered by the European Headache Federation.

## Availability of data and materials

Not applicable.

## Ethics approval and consent to participate

Not applicable.

## Consent for publication

Not applicable.

## Competing interests

Mark Braschinsky: Fees as a speaker or for participation to advisory boards from Abbott Laboratories, Allergan Inc., Berlin-Chemie AG (Menarini Group), Boehringer Ingelheim Pharma GmbH, Desitin Arzneimittel GmbH, EV3, Gedeon Richter Ltd, GlaxoSmithKline, KBM Pharma Ltd., H. Lundbeck A/S, Novartis Pharma Services Inc., Nycomed SEFA, Orion Pharma, Pfizer Inc., Sanofi-Aventis, Sandoz d.d., Scanmed Group, Solvay Pharmaceuticals, Teva Pharmaceutical Industries Ltd./Sicor Biotech UAB, Zentiva International.

Previously consultant for H. AbbePharma GmbH, Merz Pharmaceuticals.

Anne Ducros: Fees as speaker or participation to advisory boards from Eli-Lilly, Novartis, Teva.

Zaza Katsarava: Fees as speaker or participation to advisory boards from Novartis, Lilly, TEVA, Allergan, Merck and Daiichi.

Christian Lampf: Fees as speaker or for participation to advisory boards from Allergan, Eli-Lilly, Novartis, Pfizer, Teva.

Patrick Little: none.

Paolo Martelletti: Fees as speaker or for participation to advisory boards from Allergan, Eli-Lilly, Novartis, Teva.

Antoinette Massen van den Brink: Research grant and/or speaker/consultant fees from Amgen/Novartis, Eli-Lilly, Teva.

Patricia Pozo-Rosich: Fees as consultant and speaker for Allergan, Almirall, Biohaven, Chiesi, The Corpus, Eli Lilly, Medscape, Neurodiem, Novartis and Teva. Research funding from Allergan, AGAUR, la Caixa foundation, Migraine Research Foundation, Instituto Investigación Carlos III, MICINN, Novartis, PERIS, ERANet Neuron; funding for clinical trials from Alder, Electrocore, Eli Lilly, Novartis and Teva.

Uwe Reuter: Fees as consultant and speaker for Allergan, Biohaven, The Corpus, Eli Lilly, Medscape, Novartis, STREAMedUP and Teva. Research funding from BMBF and Novartis, Institutional funding for clinical trials from Alder, Amgen. Allergan, Eli Lilly, Novartis and Teva.

Elena Ruiz de la Torre: none.

Simona Sacco: Fees as speaker or for participation to advisory boards from Abbott, Allergan, Eli-Lilly, Medscape, Novartis, Teva.

Margarita Sanchez Del Rio: Fees as speaker or for participation to advisory boards from Allergan, Eli-Lilly, Novartis, Teva.

Alexandra J Sinclair: Fees as speaker from Novartis and Allergan.

## Author details

¹Neuroscience section – Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, Via Vetoio, 67100 L’Aquila, Italy.
²Regional Referral Headache Center of the Abruzzo region, ASL
Avezzano-Sulmona-L'Aquila, L'Aquila, Italy. ³Headache Clinic, Department of Neurology, Tartu University Clinics, Tartu, Estonia. ⁴Headache Unit, Neurology Department, Montpellier University Hospital and Montpellier University, Montpellier, France. ⁵Department of Neurology, Headache Medical Centre Linz, Hospital Barmherzige Brüder, Centre of Integrative Medicine (ZiAM) Ordensklinikum Linz, Linz, Austria. ⁶European Migraine & Headache Alliance (EMHA), Hendrik Ido Ambacht, The Netherlands. ⁷Division of Pharmacology, Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. ⁸Headache Unit, Neurology Department, Vall d'Hebron University Hospital, Barcelona, Spain. ⁹Headache and Neurological Pain Research Group, Vall d'Hebron Research Institute, Department de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain. ¹⁰Charité Universitätsmedizin Berlin, Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany. ¹¹Neurology department, Clínica Universidad de Navarra, Madrid, Spain. ¹²Metabolic Neurology, Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. ¹³Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK. ¹⁴Evangeli Hospital Unna, Unna, Germany. ¹⁵Departmentof Neurology, University of Duisburg-Essen, Essen, Germany. ¹⁶EVEX Medical Corporation, Tbilisi, Georgia. ¹⁷IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation. ¹⁸Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy. ¹⁹Regional Referral Headache Center of the Lazio region, Sant'Andrea Hospital, Rome, Italy.

Received: 28 February 2020 Accepted: 25 May 2020

Published online: 16 June 2020

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