Refractory chronic migraine: A Consensus Statement on clinical definition from the European Headache Federation

Abstract

The debate on the clinical definition of refractory Chronic Migraine (rCM) is still far to be concluded. The importance to create a clinical framing of these rCM patients resides in the complete disability they show, in the high risk of serious adverse events from acute and preventative drugs and in the uncontrolled application of therapeutic techniques not yet validated.
The European Headache Federation Expert Group on rCM presents hereby the updated definition criteria for this harmful subset of headache disorders. This attempt wants to be the first impulse towards the correct identification of these patients, the correct application of innovative therapeutic techniques and lastly aim to be acknowledged as clinical entity in the next definitive version of the International Classification of Headache Disorders 3 (ICHD-3 beta).

Full text

C O N S E N S U S A R T I C L E Open Access
Refractory chronic migraine: a Consensus
Statement on clinical definition from the
European Headache Federation
Paolo Martelletti
1,2*
, Zaza Katsarava
3,4
, Christian Lampl
5
, Delphine Magis
6
, Lars Bendtsen
7
, Andrea Negro
1
,
Michael Bjørn Russell
8,9
, Dimos-Dimitrios D Mitsikostas
10
and Rigmor Højland Jensen
7
Abstract
The debate on the clinical definition of refractory Chronic Migraine (rCM) is still far to be concluded. The
importance to create a clinical framing of these rCM patients resides in the complete disability they show, in
the high risk of serious adverse events from acute and preventative drugs and in the uncontrolled application
of therapeutic techniques not yet validated.
The European Headache Federation Expert Group on rCM presents hereby the updated definition criteria for
this harmful subset of headache disorders. This attempt wants to be the first impulse towards the correct
identification of these patients, the correct application of innovative therapeutic techniques and lastly aim to
be acknowledged as clinical entity in the next definitive version of the International Classification of Headache
Disorders 3 (ICHD-3 beta).
Keywords: Chronic migraine; Refractory chronic migraine; Disease progression; rCM classification
Introduction
Migraine is the most frequent neurological disease
observed in clinical practice. This primary headache is
associated with an important socioeconomic impact
[1,2] and the World Health Organization recognized the
disorder as a major public health problem, by ranking it at
7th place among all worldwide diseases causing ictal
disability [3,4].
Migraine is a paroxysmal disorder with a natural fluctu-
ation between a low and a high frequency pattern in part
influenced by modifiable and non-modifiable risk factors
[5]. Increased attack frequency can lead to the so-
called ‘chronic migraine’(CM), which then becomes less
responsive to acute as well as prophylactic migraine medi-
cations [6].
The understandable need to treat all the migraine attacks
combined with a reduced efficacy of rescue medications,
can determinate the occurrence of medication overuse [7].
All frequently used acute migraine medications, even
when effective, seem to make the migraineurs brain
more susceptible to migraine attack. In presence of CM
and medication overuse, a vicious circle is built up, and
the medication overuse becomes responsible of the per-
sistence of the high frequency of the attacks (Medication
Overuse Headache or MOH) and lack of responsiveness
to the abortive and to most preventive medications.
The treatment of choice for those patients is the with-
drawal of the overused drug either performed at home,
using some advice and patient coaching, or in hospital
settings exclusively for patients who failed ambulatory
detoxification or seem to have a real addictive behavior
[8-11]. This two-steps approach, education first and then
hospitalization, seems to be the more real and reliable if
we look at the 1 - 2% gross prevalence of MOH in the
total population [12].
The response to a preventive drug varies from person
to person and fluctuates over time. Moreover comorbidi-
ties like depression, insomnia, anxiety, hypertension and
obesity act as worsening factors in the chronification
process [13].
* Correspondence: paolo.martelletti@uniroma1.it
1
Department of Clinical and Molecular Medicine, Sapienza University of
Rome, Rome, Italy
2
Regional Referral Headache Centre, Sant’Andrea Hospital, Rome, Italy
Full list of author information is available at the end of the article
© 2014 Martelletti et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction
in any medium, provided the original work is properly credited.
Martelletti et al. The Journal of Headache and Pain 2014, 15:47
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Despite substantial advances in migraine therapy some
individuals with migraine are refractory to guideline-based
treatment [14]. Additionally recent studies revealed that
the majority of migraine patients are undertreated in terms
of use of prophylactic drugs [15], thus favouring the pro-
gression of migraine into chronicity.
In these past years the need to offer a rescue treatment
and a better prevention to the so-called medically intract-
able chronic headache patients has raised the possibilities
for neuromodulation and met the interest of device pro-
ducers willing to lend support to this complex clinical
situation.
The concept of refractory chronic migraine
The term CM is now well established in the clinical
practice as well as in RCTs. The International Classifi-
cation of Headache Disorders 3 beta (ICHD-3 beta)
amended the main criteria of ICHD-2R for chronic mi-
graine by adding the un-need to differentiate migraine
with or without aura in the calculation of the monthly
migraine days that must be 8 at least to the required cri-
teria with a total of 15 headache days or more per
month. Furthermore, the diagnosis can be ascertained
even though a medication overuse exists, but in that
case it is required that both CM and MOH diagnoses
are added. The diagnosis of CM should then be revised
after appropriate treatment of medication overuse as up
to 3/4 of CM patients reverts to an episodic form after
detoxification [8,10,11,16].
The term of refractory migraine has been used in the
literature for a long time. In 1952 Reisman reported the
first attempt to define refractory migraine by using a
new experimental drug, namely ergot-alkaloids [17], but
until recently, little attention has been paid to what it ac-
tually means to be refractory or how to define a patient
as refractory.
Intractable migraine [18,19] is another term that has
been used interchangeably for the headache types we
are addressing. If we go through the semantic of these
terms, it is easy to realize that they describe two differ-
ent conditions. While a refractory headache can improve
or worsen over time also in relation to events independ-
ent of the headache, an intractable headache carries in
itself the implication that the condition may never be
improved.
In our opinion the term “refractory”–which is more
frequently used in the literature –should be preferred
because it better emphasizes the lack of treatment re-
sponse. Although the term refractory migraine has been
used in the literature for decades, operational criteria
were not defined until recently.
Table 1 shows the first attempt to systematize this
controversial issue. The proposal of intractable headache
in migraine introduced the concept of failure of at least
four classes of preventative drugs for the first time [20].
Two years later, in 2008, the Refractory Headache Spe-
cial Interest Section (RHSIS) of the American Headache
Society (AHS) proposed the criteria for both refractory
episodic migraine and refractory chronic migraine
(rCM) (Table 1) [21]. According to this definition, rCM
must fulfill the ICHD-2R criteria for CM [22], and head-
aches have to cause significant interference with func-
tion or quality of life despite modification of triggers,
lifestyle factors, and adequate trials of acute and prevent-
ive medicines with established efficacy. This definition
requires that patients with migraine fail adequate trials
of preventive drugs, alone or in combination, from at
least 2 of 4 drug classes including: beta-blockers, anti-
convulsants, tricyclics, and calcium channel blockers,
whereas the term adequate is not further specified. Pa-
tients must also fail adequate trials of abortive medi-
cines, including both a triptan and dihydroergotamine
(DHE) intranasal or injectable formulation and either
nonsteroidal anti-inflammatory drugs (NSAIDs) or com-
bination analgesic, unless contraindicated. Since the
RHSIS criteria, other proposed definitions included a
rating scale to delineate the degree of intractability [23]
and defined certain issues of treatment failure more pre-
cisely [24]. One aspect before considering a CM patient
“refractory”to preventive therapy was the maximum
possible number of drugs that had to be tested and
found ineffective (Table 1) [25]. Likewise the beneficial
use of multidisciplinary team in these difficult to treat
patients is not further specified or requested despite
guidelines recommendations.
Some authors may argue that it wouldn’t be enough to
try one medication of each pharmacological class (e.g.,
one beta-blocker, one anticonvulsants, etc.) as the mem-
bers of a given class may work by various mechanisms
and a patient unresponsive to one molecule may im-
prove with another, and tolerability within a class varies
too [25]. However, since the 2008 RHSIS proposal some-
thing has changed in the treatment scenario for chronic
migraine patients. The results from the PREEMPT stud-
ies, published in 2010, have shown the efficacy and
safety of onabotulinumtoxinA for the preventive treat-
ment of CM [26] and it should also be added to the list
of preventive therapy to try before labeling a migraine
patient as refractory.
Despite the definitions provided by the current ICHD-
3 beta it does not include a definition of refractoriness
in migraine [27]. A growing need of a shared definition
of refractoriness has already been claimed from a multi-
disciplinary expert group [28].
It is not surprising that so far no consensus regarding
the definition of rCM has emerged. It is still being de-
bated what should be the key parameter of a definition
of refractoriness (e.g., unresponsiveness to treatment,
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high frequency, severe disability or all of these features)
and if refractory headache should be considered as a sin-
gle entity or rather a hard treatable version of different
headache disorders [23].
Our opinion is that the definition of rCM should be
based on the non-responsiveness to preventative treatment,
not on the non-responsiveness to acute treatment. In
fact the key for success is prevention: refractoriness is
the consequence of prophylaxis failure while medication
overuse headache can be both the cause and the con-
sequence of the refractoriness itself. Therefore it is
required that medication overuse headache should be
Table 1 Previous clinical definition of refractory chronic migraine
Intractable headache (Goadsby (2006) RHSIS criteria (AHS 2008) Refractory Migraine (after D’Amico 2008)
Failed an adequate trial of regulatory
approved and conventional treatments
according to local national guidelines
A. ICHD-II migraine or chronic migraine CM patients for whom adequate trials of
preventive therapies at adequate doses
have failed to reduce headache frequency
and improve headache-related disability.
In migraine, failure of at least 4 classes,
where 3 should come from 1 to 4
B. Headaches cause significant interference with
function or quality of life despite modification
of triggers, lifestyle factors, and adequate trials
of acute and preventive medicines with
established efficacy
MOH patients should also be considered
refractory when treatments fail to reduce
the consumption of symptomatic drugs.
1. Beta-blockers 1. Failed adequate trials of preventive medicines,
alone or in combination, from at least
2 of 4 drug classes:
Preventive drugs
2. Anticonvulsants a. Beta blockers The greatest possible number of drugs
should be tested and found ineffective
(or intolerable).
3. Calcium channel blockers b. Anticonvulsants It is not sufficient to try one medication
of each pharmacological class.
4. Tricylic antidepressants c. Tricyclics Adequate trial
5. Other treatments with at least 1
positive randomized controlled trial
d. Calcium channel blockers Adequate courses of all drugs considered
as first-line prophylactics for episodic
migraine by international guidelines,
and in addition adequate courses of
at least some of the drugs considered
second- or third-line prophylactic treatments.
6. Nonsteroidal anti-inflammatory drugs 2. Failed adequate trials of abortive medicines
from the following classes, unless
contraindicated:
Trial duration and dosage
7. Metabolic enhancers, such as vitamin B2
or coenzyme Q10
•Both a triptan and DHE intranasal or
injectable formulation
A 3-month treatment period is required
to assess efficacy but it may be useful to
continue for a further 3–6 months if there
was some improvement during the first 3 months.
Adequate trial •Either non-steroidal anti-inflammatory drugs
or combination analgesics
Treatment of medication overuse
Appropriate dose Adequate trial Acute medication overuse should be
curtailed before starting prophylaxis in
patients with chronic headaches.
Appropriate length of time Period of time during which an appropriate
dose of medicine is administered, typically
at least 2 months at optimal or maximum-tolerated
dose, unless terminated early due to adverse effects
Treatment of comorbidities
Consideration of medication overuse Modifiers Identification and appropriate treatment
of all clinically significant comorbidities
is essential before declaring a treatment
failure in CM patients.
Failed 1. With or without medication overuse, as
defined by ICHD-2
No therapeutic or unsatisfactory effect 2. With significant disability, as defined by
MIDAS ≥11
Intolerable side effects
Contraindications to use
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ruled out or be adequately treated before a patient can
be classified as refractory.
The attempt to define rCM has to keep in consideration
what are meant to be the operational purposes of that
classification as RCTs, referral from a primary care pro-
vider to a headache specialist, medical cost reimburse-
ment, screening tool for invasive treatment or implantable
devices. With the need of minimizing the risk of a mis-
diagnosis we have to exclude the possible causes of a false
refractoriness and to focus on the small group of
truly refractory patients.
A special attention should be paid to the very frequent
presence of comorbidities (psychiatric and/or somatic)
in this subset of rCM patients. Depression and anxiety
disorders represent undisputable co-factors in the progres-
sion of migraine chronification and must be adequately
treated [29-32].
Preventive medication should be preferably used as
monotherapy, since our knowledge of combining differ-
ent preventive medications is sparse. The combination
topiramate and propranolol did not have any synergy
effect and was not superior to either preventive medication
giveninmonotherapy[33].Ontheotherhand,additional
treatment of comorbidities is needed, either pharmaco-
logical or psychological, or even better a combination with
a multidisciplinary team when available.
Using the criteria proposed by RHSIS 5.1% of the
migraine patients evaluated in an US- headache clinic
is diagnosed as refractory [21]. However until a well-ac-
cepted definition is formulated evidence-based treatment
recommendations for rCM cannot be generated.
The clinical complexity of rCM moved the scientific
interest to new concepts by studying interesting but still
not sufficiently validated approaches, e.g. neuromodula-
tion [28,34].
The European Headache Federation (EHF) felt the
need to develop new consensus criteria that define rCM,
particularly for the purposes of controlled clinical trials
that involve experimental medication and neuromodula-
tion independently of the non-invasive therapies or the
implantable devices.
Considering rCM as an evolution of CM, we can
hypothesize the inclusion of rCM as a 3-digit diagnosis
of CM (1.3.1 Refractory chronic migraine) (see Table 2).
Conclusions
It is our opinion that exclusively headache experts should
conduct the management of this migraine population
particularly difficult to treat.
This EHF definition of rCM has to be considered as
a mandatory tool in any multidisciplinary or innovative
therapeutic approach.
The principal task of this EHF Expert Group Consensus
Statement is to bring the definition of rCM up to date. For
too long there has been a lot of utterance about it while
their nosography was not systemized. So far few innovative
neuromodulation practices have been widely applied to this
subset of headaches, numerically limited but with a severe
impact in terms of disability and social costs. Therapeutic
results are before our eyes, still too scanty and often with
weak scientific prerequisites. The lack of necessary evi-
dence and its validation has made possible that, in the re-
cent ICHD-3 β, refractoriness has found no room. It would
be very valuable to scotomize this subset of headache pa-
tients with clear universal definitions instead of entrusting
them only to striking case series without a scientific defin-
ition of refractoriness. This issue too must be investigated
further in the course of the explorative work on refrac-
toriness of headaches and its boundaries, by carefully field
testings and using updated clinical criteria for rCM.
Table 2 European Headache Federation proposed criteria
for refractory chronic migraine
EHF proposed criteria for refractory chronic migraine
A. ICHD-III βchronic migraine
No medication overuse
B. Prophylactic migraine medications in adequate dosages used
for at least 3 months each.
C. Contraindications or No effect of the following preventive
medication with at least 3 drugs from the following classes:
•Beta blockers
propranolol up to 240 mg/d
metoprolol up to200mg
atenolol up to100mg
bisoprolol up to10mg
•Anticonvulsants
Valproate acid up to 1,5 g/d
Topiramate up to 200 mg/d
•Tricyclics
amytriptyline up to 150 mg/d
•Others
Flunarizine up to 10 mg/d
Cardesartan 16 mg/d
•OnabotulinumtoxinA
155 - 195 U according to the PREEMPT protocol
D. Adequate treatment of psychiatric or other comorbidities
by multidisciplinary team, if available.
Notes:
-Secondary Headache must be excluded
- MRI provides no underlying cause
- Laboratory and CSF analyses within normal range, including
CSF pressure
- Meaning of efficacy: reduction on HA days >50%
- Detoxification procedure (in/out hospital setting): intravenous,
oral and advice only are all accepted.
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Competing interest
PM received travel grants, consulting fees or unrestricted grants from Nevro
Corporation, St Jude Medical, Allergan, Pfizer, ACRAF, is member of Advisory
Board in Allergan and St Jude Medical as well as director in LTB and EHF.
RHJ has given lectures for Pfizer, Berlin-Chemie, Allergan, Merck, ATI. Is also
member of advisory boards in: ATI, Medotech, Neurocore, and Linde Gas as
well as director in LTB, EHMTIC and President in EHF.
CL serves on scientific advisory boards for Allergan, Bayer HealthCare and
St. Jude Medical; has received funding for travel from Bayer Schering
Pharma, Pfizer, Allergan; served as a consultant to Bayer Schering Pharma,
Biogen Idec; received research support from Bayer Schering Pharma,
Allergan, Biogen Idec; has received personal compensation for consultations
or lectures from Bayer HealthCare, Sanofi Aventis, Biogen Idec, Teva
Pharmaceuticals, Pfizer.
DDM is member of advisory boards in Allergan, Astellas, Bayer-Schering,
Novartis, Genzyme-Sanofi, Merck-Serono, Genesis Pharma, Teva, and has
received honoraria for lecturing from Pfizer, Lilly, Menarini and UCB.
DM has received travel grants from Allergan and research funds from
Neurocore.
ZK, AN, DM and MBR declared no competing interests related to the
contents of this Consensus Statement.
In details they had not received any research funds, travel or unrestricted
grants, consulting fees, honoraria as speaker or consultant from the drug
companies of the medicines or devices mentioned above.
Furthermore, all authors declare to not own any stock option of the
manufacturers of drugs discussed in this review.
Finally, all the authors state they have received no direct or indirect payment
in preparation of this manuscript.
Authors’contributions
All Authors on behalf of European Headache Federation contributed equally
to the conception, design, drafting and critical revisions of the manuscript.
The final version has been approved by all Authors.
Acknowledgments
This article, as a Consensus Article from experts in the topic, has been
reviewed internally among Authors and the Editorial Office.
Author details
1
Department of Clinical and Molecular Medicine, Sapienza University of
Rome, Rome, Italy.
2
Regional Referral Headache Centre, Sant’Andrea Hospital,
Rome, Italy.
3
Department of Neurology, Evangelical Hospital, Unna, Germany.
4
Department of Neurology, University of Duisburg-Essen, Essen, Germany.
5
Headache Center Seilerstaette, Department of Neurogeriatric medicine and
Remobilisiation, Hospital Barmherzige Schwestern Linz, Linz, Austria.
6
Department of Neurology, Headache Research Unit, University of Liège,
Liège, Belgium.
7
Danish Headache Center, Department of Neurology,
University of Copenhagen, Glostrup Hospital, Copenhagen, Denmark.
8
Head
and Neck Research Group, Research Center, Akershus University Hospital,
Lørenskog, Norway.
9
Institute of Clinical Medicine, Campus Akershus
University Hospital, University of Oslo, Nordbyhagen, Norway.
10
Department
of Neurology, Naval Hospital, Athens, Greece.
Received: 15 July 2014 Accepted: 29 July 2014
Published: 28 August 2014
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Cite this article as: Martelletti et al.:Refractory chronic migraine: a
Consensus Statement on clinical definition from the European
Headache Federation. The Journal of Headache and Pain 2014 15:47.
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