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Arquivos de Neuro-Psiquiatria

Print version ISSN 0004-282XOn-line version ISSN 1678-4227

Arq. Neuro-Psiquiatr. vol.77 no.7 São Paulo July 2019  Epub July 29, 2019

http://dx.doi.org/10.1590/0004-282x20190078 

CONSENSUS

Consensus of the Brazilian Headache Society on the treatment of chronic migraine

Consenso da Sociedade Brasileira de Cefaleia sobre o tratamento da migrânea crônica

Fernando KOWACS1  2  3 
http://orcid.org/0000-0002-0407-407X

Célia Aparecida de Paula ROESLER1  4 
http://orcid.org/0000-0001-5557-6056

Élcio Juliato PIOVESAN5 
http://orcid.org/0000-0002-0915-0430

Elder Machado SARMENTO6  7 
http://orcid.org/0000-0003-4500-1376

Henrique Carneiro de CAMPOS8 
http://orcid.org/0000-0002-0144-0687

Jayme Antunes MACIEL JR9 
http://orcid.org/0000-0001-7086-9623

Leandro Cortoni CALIA10 
http://orcid.org/0000-0002-5758-5789

Liselotte Menke BAREA2 
http://orcid.org/0000-0002-9531-9115

Marcelo Cedrinho CICIARELLI11 
http://orcid.org/0000-0002-3682-1228

Marcelo Moraes VALENÇA12 
http://orcid.org/0000-0003-0678-3782

Maria Eduarda Nobre de Magalhães COSTA13 
http://orcid.org/0000-0002-0052-5566

Mário Fernando Prieto PERES10  14 
http://orcid.org/0000-0002-0068-1905

Pedro André KOWACS5  15 
http://orcid.org/0000-0001-7770-7475

Pedro Augusto Sampaio ROCHA-FILHO12  16 
http://orcid.org/0000-0001-5725-2637

Raimundo Pereira da SILVA-NÉTO1  17 
http://orcid.org/0000-0002-2343-9679

Thais Rodrigues VILLA18  19 
http://orcid.org/0000-0001-8448-4935

Mauro Eduardo JURNO20  21 
http://orcid.org/0000-0002-8743-9395

1Departamento Científico de Cefaleia da Academia Brasileira de Neurologia, São Paulo SP, Brasil;

2Universidade Federal de Ciências da Saúde de Porto Alegre, Irmandade Santa Casa de Misericórdia, Serviço de Neurologia, Porto Alegre RS, Brasil;

3Hospital Moinhos de Vento, Serviço de Neurologia e Neurocirurgia, Porto Alegre RS, Brasil;

4Clínica de Cefaleia e Neurologia Dr. Edgard Raffaelli, São Paulo SP, Brasil;

5Universidade Federal do Paraná, Hospital das Clínicas, Departamento de Clínica Médica, Serviço de Neurologia, Curitiba PR, Brasil;

6Centro Universitário de Volta Redonda, Volta Redonda RJ, Brasil;

7Fundação Educacional Dom André Arcoverde, Centro de Ensino Superior de Valença, Valença RJ, Brasil;

8Santa Casa de Belo Horizonte, Belo Horizonte MG, Brasil;

9Universidade de Campinas, Faculdade de Ciências Médicas, Campinas SP, Brasil;

10Hospital Israelita Albert Einstein, São Paulo SP, Brasil;

11Centro Universitário Barão de Mauá , Faculdade de Medicina, Ribeirão Preto SP, Brasil;

12Universidade Federal de Pernambuco, Recife PE, Brasil;

13Clínica Neurológica Dra. Maria Eduarda Nobre, Rio de Janeiro RJ, Brasil;

14Universidade de São Paulo, Faculdade de Medicina, Hospital das Clínicas Instituto de Psiquiatria, São Paulo SP, Brasil;

15Instituto de Neurologia de Curitiba, Curitiba PR, Brasil;

16Universidade de Pernambuco, Hospital Universitário Oswaldo Cruz, Ambulatório de Cefaleias, Recife PE, Brasil;

17Universidade Federal do Piauí, Teresina PI, Brasil;

18Universidade Federal de São Paulo, Setor de Cefaleias, São Paulo SP, Brasil;

19Headache Center Brasil, São Paulo SP, Brasil;

20Faculdade de Medicina de Barbacena, Barbacena MG, Brasil;

21Fundação Hospital do Estado de Minas Gerais, Hospital Regional de Barbacena Dr. José Américo, São Paulo SP, Brasil.

ABSTRACT

Chronic migraine poses a significant personal, social and economic burden and is characterized by headache present on 15 or more days per month for at least three months, with at least eight days of migrainous headache per month. It is frequently associated with analgesic or acute migraine medication overuse and this should not be overlooked. The present consensus was elaborated upon by a group of members of the Brazilian Headache Society in order to describe current evidence and to provide recommendations related to chronic migraine pharmacological and nonpharmacological treatment. Withdrawal strategies in medication overuse headache are also described, as well as treatment risks during pregnancy and breastfeeding. Oral topiramate and onabotulinum toxin A injections are the only treatments granted Class A recommendation, while valproate, gabapentin, and tizanidine received Class B recommendation, along with acupuncture, biofeedback, and mindfulness. The anti-CGRP or anti-CGRPr monoclonal antibodies, still unavailable in Brazil, are promising new drugs already approved elsewhere for migraine prophylactic treatment, the efficacy of which in chronic migraine is still to be definitively proven.

Key words: Migraine disorders; headache; headache disorders

RESUMO

A migrânea (enxaqueca) crônica determina uma carga pessoal, social e econômica significativa e é caracterizada por dor de cabeça presente em quinze ou mais dias por mês por ao menos três meses, com no mínimo oito dias de cefaleia migranosa a cada mês. É frequentemente associada ao uso excessivo de medicação analgésica ou antimigranosa aguda e isso não deve ser negligenciado. Este consenso foi elaborado por um grupo de membros da Sociedade Brasileira de Cefaleia, para descrever as evidências atualmente disponíveis e fornecer recomendações relacionadas ao tratamento farmacológico e não farmacológico da migrânea crônica. Estratégias de retirada na cefaleia por uso excessivo de medicamentos também são descritas, assim como os riscos dos tratamentos durante a gravidez e a amamentação. O topiramato oral e as injeções de toxina onabotulínica A são os únicos tratamentos que receberam a recomendação classe A, enquanto que o valproato, a gabapentina e a tizanidina receberam recomendação classe B, juntamente com acupuntura, biofeedback e mindfulness. Os anticorpos monoclonais anti-CGRP ou anti-CGRPr, ainda não disponíveis no Brasil, são novos fármacos promissores, já aprovados em outros países para o tratamento profilático da migrânea, cuja eficácia na migrânea crônica ainda está por ser definitivamente comprovada.

Palavras-Chave: Transtornos de enxaqueca; cefaleia; transtornos da cefaleia

Chronic migraine is a widespread disorder that poses a significant personal, social and economic burden. Although less prevalent than episodic migraine, chronic migraine patients present with more comorbidities and are more refractory to treatment1,2,3. After the publication of the third edition of the International Classification of Headaches Disorders (ICHD-3)4and considering new evidence published since the Latin American Consensus on Guidelines for the Treatment of Chronic Migraine was reached in 20125,6, the Brazilian Headache Society (Sociedade Brasileira de Cefaleia) recognized the need to elaborate on a new consensus on this subject.

METHODS

A group of 17 members of the Brazilian Headache Society met on September 29–30, 2018, after a process of literature searches made by five subgroup coordinators. The first day was dedicated to discussion of the relevant literature and to the drafting, by five independent subgroups, of the text sections. On the second day, the full text was read, discussed and modified in a plenary session. The text was then reviewed by one of the members (FK) and submitted for translation into English, which was approved by all members before being submitted for publication. Classes of evidence and levels of recommendation were described according to the American Academy of Neurology Classification for the Rating of a Therapeutic Study and Classification of Recommendations whenever possible7,8,9. According to the latter, studies vary from class I (high quality well-designed randomized double- or triple-blind controlled trials) to class IV (uncontrolled studies, consensus and expert opinions). Levels of recommendation are described in Table 1. The Brazilian Headache Society received a grant from Allergan Specialty Care designated specifically to the logistics and editorial expenses. The authors did not receive any fee. Allergan Specialty Care staff did not interfere in the authors’ selection process, nor took part in any step of the manuscript elaboration.

Table 1 Levels of recommendation (adapted from AAN9). 

Levels of recommendation Requirements Recommendation
Level A At least two consistent Class I studies Established as effective, ineffective or harmful for the given condition in the specified population
Level B At least one Class I study or two consistent Class II studies Probably effective, ineffective or harmful for the given condition in the specified population
Level C At least one Class II study or two consistent Class III studies Possibly effective, ineffective or harmful for the given condition in the specified population
Level U Inadequate or conflicting data Given current knowledge, treatment is unproven

CONCEPTUALIZATION

The ICHD-3 classifies headaches into three groups. The first group comprises the primary headaches, conditions whose mechanisms are eminently neurochemical – in other words, the tendency to develop headache attacks is the disorder itself. The secondary headaches, which compose the second group, are caused by some underlying disorder, e.g. intracranial structural lesions, whereas the third group includes the painful cranial neuropathies, other facial pains, and unspecified or nonspecific headache4.

DIAGNOSTIC CRITERIA, EPIDEMIOLOGY AND IMPACT

According to ICHD-3, chronic migraine belongs to the primary headache group and is defined by the diagnostic criteria listed in Table 2.

Table 2 ICHD-3 chronic migraine diagnostic criteria4

A. Headache (migraine-like or tension-type-like) on ≥ 15 days/month for more than three months, and fulfilling criteria B and C
B. Occurring in a patient who has had at least five attacks fulfilling criteria B–D for 1.1 Migraine without aura* and/or criteria B and C for 1.2 Migraine with aura*
C. On ≥ 8 days/month for > 3 months, fulfilling any of the following:
1. Criteria C and D for 1.1 Migraine without aura*
2. Criteria B and C for 1.2 Migraine with aura*
3. Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative
D. Not better accounted for by another ICHD-3 diagnosis.

*For migraine without aura and migraine with aura diagnostic criteria, see reference 4. ICHD: International Classification of Headaches Disorders

It is estimated that up to 5% of patients with migraine meet the criteria for the chronic form of the disease1. In systematic reviews of population studies, the prevalence of chronic migraine ranges from 0.9% to 5.1%1,10, while in the Brazilian infant population it is around 1.7%11. Since the publication of the last report by the World Health Organization’s Global Burden of Disease, migraine has come to be considered the second major cause of disability among all diseases, behind only mental disorders, led by depression12. Over the period of a year, 25% of the patients with chronic migraine return to the episodic form of the disease and another 40% oscillate between the episodic and chronic forms13.

Nearly 50% of individuals with headache self-medicate5. Overuse of symptomatic drugs is believed to cause headache in individuals previously affected by a primary headache. This headache is classified in the ICHD-3 among secondary headaches, as item 8.2 Medication-overuse headache. From 55% to 70% of the patients seen at specialized centers in Latin America receive this diagnosis14. The term chronic migraine was first mentioned in ICHD-2, in 200415, and its diagnostic criteria were reviewed in 200616. In previously-proposed classifications, these diagnoses were grouped, and the terms transformed migraine and chronic daily headache were used17. Currently, a patient who meets the criteria for chronic migraine (Table 2) and for medication-overuse headache (triptans, ergot drugs, common analgesics alone or in combination and/or nonsteroidal anti-inflammatory drugs) should initially receive both diagnoses. It should be emphasized that patients who present with headache on 15 or more days per month may have primary headaches other than chronic migraine, such as chronic tension-type headache, new daily persistent headache and hemicrania continua15,18.

Pathophysiological mechanisms probably involved in migraine include cortical hyperexcitability (or deficient inhibition), dysmodulation in areas of the brainstem and hypothalamus, and central and peripheral trigeminal sensitization, with release of vasoactive/neuroactive peptides, such as calcitonin gene-related peptide (CGRP). Episodic trigeminovascular system activation, faulty filtering of sensorial stimuli and heredity are characteristics that point to the neural basis of this disorder19,20.

ADDITIONAL INVESTIGATION

Additional investigation, such as neuroimaging, cerebrospinal fluid analysis and blood tests, should be employed judiciously and parsimoniously in chronic headache patients, considering the inherent risks and costs. Patients who meet the ICHD-3 criteria for chronic migraine and have a normal neurological examination do not require, in most cases, additional tests21. On the other hand, these tests may become necessary to rule out alternative diagnoses in the presence of various secondary headache red flags, listed in Table 3.

Table 3 Warning signs for secondary headache (“red flags”). 

1. Headache of sudden onset (thunderclap*)
2. New headache or progressive worsening of a pre-existing headache
3. Change in the pattern of a previously stable headache
4. Headache that is aggravated or alleviated by postural changes
5. Headache that awakens the patient
6. Headache precipitated by physical activity and/or Valsalva maneuver
7. Onset ≥ 50 years of age
8. Symptoms and/or focal neurologic signs, altered level of consciousness, seizures
9. History of cranial and/or cervical trauma
10. Neck stiffness and/or history of fever
11. Neoplasia, HIV, immunosuppression, active infection

*reaching maximum intensity in < 1 minute.

In the presence of tinnitus, visual changes, headache aggravated by Valsalva-like maneuver and/or morning headache with improvement throughout the day, lumbar puncture with cerebrospinal fluid manometry (plus cerebral venous angioresonance, when appropriate) is recommended even in the absence of papilledema, to rule out idiopathic intracranial hypertension (pseudotumor cerebri) without papilledema (class of evidence IV, level of recommendation U). On the other hand, lumbar puncture is not necessary when the clinical picture is typical and these symptoms are absent21. Although epidemiological data do not correlate chronic migraine with obstructive sleep apnea headache22, this differential diagnosis may be difficult, especially in patients with headache attributed to medication overuse. In the presence of strictly morning headaches, polysomnography may be indicated21.

MANAGEMENT OF HEADACHE ATTRIBUTED TO MEDICATION OVERUSE ASSOCIATED WITH CHRONIC MIGRAINE

The concept of medication-overuse headache has evolved since the first edition of the ICHD, e.g. the inclusion of triptan-overuse headache, elimination of the need for a specific headache pattern and the establishment of different thresholds for each type of analgesic/antimigrainous agents. Medication-overuse headache, present in ICHD-3 as item 8.2, is defined as a secondary headache that occurs in ≥ 15 days per month, in a patient with a pre-existing primary headache, that develops as a consequence of the regular overuse of symptomatic medication for the treatment of headache (ergotamine, triptans, opioid analgesics or combined analgesics: ≥ 10 days/month; common analgesics or NSAIDS: ≥ 15 days/month)4. Smoking, sedentary lifestyle, metabolic syndrome, obesity, musculoskeletal diseases, psychiatric comorbidities and excessive use of caffeine increase the risk of developing medication-overuse headache23,24,25,26.

Treatment of patients with medication-overuse headache is often difficult, specific guidelines are lacking and the available evidence does not establish the superiority of a strategy. The treatment modalities proposed in the literature are summarized in Table 4. The main poor prognosis risk factors are the amounts of overused drugs, the association of drugs from multiple classes, use of opioids, recurrence of a previous episode and psychiatric comorbidities27,28,29.

Table 4 Management of medication-overuse headache. 

Management strategies Evidence Recommendation References
Counseling (explain the role of medication-overuse in pain chronification and the risk of serious adverse effects; emphasize the importance of withdrawing these drugs for successful treatment; inform the possibility of headache worsening at the beginning of withdrawal with later gradual improvement 2 class II trials B 30, 31
Discourage the anticipatory use of symptomatic medications (cephalalgiophobia 1 class III trial U 27
Guidance to complete the pain diary 3 class III trials C 27, 28, 32
Full abrupt withdrawal of analgesic, ergotamine, triptans or anti-inflammatory drugs and gradual suspension of opioid analgesics 4 class III trials C 28, 32-34
Starting prophylactic treatment simultaneously with suspension of analgesics 19 class III trials C 27, 28, 33-51
Management in the withdrawal of overuse drugs
Outpatient
Suspension not associated with transitional treatment 3 class III trials C 52-54
Suspension associated with transitional treatment, with individual or combined strategies
Corticosteroids 1 class I trial, 4 class II trials, with conflicting results U 29, 55-58
Neuroleptics 2 class III trials C 27, 34
Antiemetics (metoclopramide, ondansetron, dimenhydrinate 2 class III trials C 27, 34
Switching acute drugs between different classes, limiting amount, frequency and duration of use (except for opioid prescription 2 class III trials C 27, 34
Greater occipital nerve blocks 1 class III trial U 59
Inpatient
This approach is indicated for patients who overuse opioids and/or barbiturates or patients with serious psychiatric and clinical comorbidities (metabolic disorders, dehydration, refractory vomiting, decompensated systemic arterial hypertension, unstable cardiovascular diseases, severe allergic reactions and others and/or failure in previous attempts to withdraw overuse drugs. 1 class II trial C 31

PROPHYLACTIC PHARMACOLOGICAL MANAGEMENT OF CHRONIC MIGRAINE: SYSTEMIC TREATMENTS

General aspects of the pharmacological management of chronic migraine

Drugs included in this section were tested in randomized controlled trials (RCTs) with well-defined inclusion criteria, double-blind or open, involving chronic migraine patients. Uncontrolled or poor-quality trials, with small samples and/or published in periodicals considered to be unreliable (“predatory journals”) were discarded. Papers published prior to the International Headache Society’s adoption of diagnostic criteria for chronic migraine15,16 were included, provided that they had enrolled participants presenting with “chronic daily headache” and that the methods section made clear that the majority of the study population suffered from chronic migraine if the current criteria were applied4.

Table 5 lists oral drugs used in the treatment of chronic migraine in adults, along with levels of evidence and recommendation, doses used in daily practice and risk categories regarding use during pregnancy or breastfeeding60,61.

Table 5 Oral drugs evaluated in the treatment of chronic migraine in adults: evidence of efficacy, class of recommendation, recommended doses and risk categories regarding use during pregnancy and lactation. 

Drug Evidence Recommendation Dose (mg/day) Risk during pregnancy* Risk during lactation** References
Neuromodulators
Topiramate I A 50-200 D L3 62, 64-66, 70
Valproate II B 500-2000 X L2 71
Gabapentin II B 900-1800 C L2 72
Pregabalin III C 125-450 C L2 73
Zonisamide III C 50-200 D L5 74
Beta-blockers
Atenolol III C 50-200 C L3 75
Tricyclics
Amitriptyline II C 50-100 C L2 76
Calcium channel blockers
Flunarizine III C 10 C L5 77
Miscellaneous
Tizanidine II B fev/24 C L3 78

*FDA classic classification of drug risk during pregnancy, adapted from reference79: A – the possibility of fetal harm appears remote (adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters)); B – the possibility of fetal harm is remote. Nevertheless, because the studies in humans cannot rule out the possibility of harm, it should be used during pregnancy only if clearly needed; C – animal reproduction studies have shown an adverse effect on the fetus, there are no adequate and well-controlled studies in humans, the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks or there are no animal reproduction studies and no adequate and well-controlled studies in humans. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. D – there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks. X – studies in animals or humans have demonstrated fetal abnormalities or there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing experience (or both). It is contraindicated in women who are or may become pregnant.

**Risk of use during breastfeeding is described using the WHO scheme80: L1 - Compatible with breastfeeding; L2 - Compatible with breastfeeding. Infant should be monitored for side-effects; L3 – Should be avoided if possible. Infant should be monitored for side-effects; L4 – Should be avoided if possible. May inhibit lactation; L5 – Must be avoided.

Topiramate is the only oral drug with class I evidence and level A recommendation for preventive treatment in chronic migraine. Its efficacy was initially demonstrated in a small single-center double-blind RCT published in 200362, involving patients with the diagnosis of “chronic daily headache” and past migraine without aura (classified as chronic migraine), overuse of acute medication and at least four previous preventive treatment failures. Topiramate (50 mg/day) caused a significant reduction in headache frequency and was well tolerated. This was followed by another positive single-center double-blind RCT63 and two larger multicenter double-blind placebo-controlled trials64,65. These two to three-month duration trials showed significant reduction in monthly migraine days with topiramate (slow titration, mean final dose around 100 mg/day). The most important adverse events were paresthesias, fatigue, difficulties with memory, concentration and/or attention, taste perversion. When analyzing the results of both studies together, the authors concluded that topiramate was safe and effective in chronic migraine patients with or without concomitant medication overuse66.

As of January 2019, three subcutaneous-administered monoclonal antibodies against CGRP67 or its receptor68, were not yet available in Brazil but have already been approved by the Food and Drug Administration (FDA) for the preventive treatment of migraine (without specification of the type or frequency of attacks): erenumab, fremanezumab and galcanezumab (eptinezumab, an intravenous-administered CGRP antagonist, is awaiting approval). Positive results from phase III (fremanezumab, galcanezumab) and phase IIb (erenumab) RCTs, specifically addressing chronic migraine patients, were recently published67-69.

Practical aspects of the pharmacological management of chronic migraine

The choice of prophylactic drugs should favor those with greater evidence of efficacy, considering the individual patient preferences, associated clinical conditions and absolute and relative contraindications.

Drugs acting on the central nervous system and/or with marked systemic effects should be started with low initial doses followed by gradual increments. The final therapeutic dose should be the lowest effective dose, considering the maximum dose used in each clinical trial or, eventually, at the discretion and under the responsibility of the prescriber, the maximum tolerated dose. A drug should not be considered ineffective before two to three months after the recommended dose or maximum tolerated dose has been achieved. Laboratory tests must be ordered in a predetermined manner or on demand, looking for potential hydro-electrolytic disturbances, hematological, metabolic and/or intoxication imbalances, according to the prescribed drug or drug combinations.

The strategy of associating different prophylactic drugs is not supported by high level evidence. A class II trial did not show superiority of the association of topiramate with long-acting propranolol versus topiramate alone81. However, the so-called rational polytherapy—the association of effective drugs with different mechanisms—can be used in monotherapy refractory patients82. Regarding comparative efficacy, one single-center double-blind RCT showed equivalence between onabotulinum toxin A (100 units at fixed points plus 100 units at “follow the pain” points) and topiramate (maximum dose of 200 mg), with better tolerability and adherence in the onabotulinum toxin A group83, while one single-center open-label study showed comparable efficacy between amitriptyline (25-50 mg/day) and onabotulinum toxin A (250 U/15 sites), also with better tolerability and compliance in the group treated with onabotulinum toxin A84. On the other hand, and acupuncture performed better than topiramate in two small single-center open-label RCTs77,85. Although there is no evidence of response consistency in long term, it is usually recommended that individuals who have undergone reversal of chronic migraine for episodic migraine should be maintained on prophylactic treatment for at least one to two years86(class of evidence IV, level of recommendation U).

Pharmacological management of chronic migraine during pregnancy and breastfeeding

Pharmacological treatment of pregnant and breastfeeding women should be avoided, whenever possible, in favor of nonpharmacological methods. Considering the lack of RCTs specifically dedicated to the treatment of chronic migraine in pregnant women, the following recommendations (Table 5) are based on evidence from trials involving nonpregnant women in the light of current knowledge about potential consequences to the fetus. Atenolol and flunarizine may be considered as first-choice migraine prophylactic drugs in pregnancy, if atenolol is discontinued in the third trimester to prevent bradycardia and intrauterine growth retardation. Amitriptyline (despite its classification as category C) and gabapentin, which must be discontinued early due to possible interference with fetal bone development, may also be used87,88. On the other hand, topiramate and valproate should be avoided during pregnancy. Some authors consider that all prophylactic migraine drugs are poorly excreted in breast milk, but others contraindicate the use of atenolol and flunarizine in high doses. There is a consensus that topiramate may be poorly metabolized by premature infants, therefore, in these cases, discontinuation or close monitoring of the infant is necessary89,90.

Pharmacological management of chronic migraine in the elderly

In the pharmacological management of chronic migraine in the elderly, the presence of other clinical conditions, potential adverse effects of medications and possible drug interactions should be considered. Some drugs, such as beta-blockers, amitriptyline and flunarizine require special attention in this age group91,92,93.

Pharmacological management of chronic migraine in children

The only RCT involving drug treatment of chronic migraine in children and adolescents points towards the efficacy of the combination of amitriptyline and cognitive-behavioral therapy in the treatment of this condition94. Despite the lack of trials, drugs with proven efficacy in episodic migraine, such as flunarizine, have been used in clinical practice.

PROPHYLACTIC PHARMACOLOGICAL TREATMENT: ONABOTULINUM TOXIN A AND PERIPHERAL NERVE BLOCKS

Onabotulinum toxin A (class I evidence, level A recommendation)

Onabotulinum toxin A is a purified neurotoxin derived from the Clostridium botulinum bacteria. It has been approved since 2011 by Anvisa (Agência Nacional de Vigilância Sanitária: the Brazilian government agency equivalent to the FDA) for use in the prophylactic treatment of chronic migraine in adults. This approval was based on a pooled analysis of two large double-blind clinical trials (PREEMPT 1 and 2), which demonstrated significant reduction in headache days and improvement in the patients’ quality of life during the trial period, effects also observed in those patients with medication overuse (class of evidence I, level of recommendation A)95-97. In a 56-week treatment period, 1,384 patients were assigned into two groups: active and control treatment (onabotulinum toxin A and placebo, respectively). In the first, double-blind, 24-weeks phase of the trial, the patients received 31 to 39 injections of onabotulinum toxin A (active treatment) or saline (control) at predetermined points of the head and shoulders, every 12 weeks. In the second phase (open), all participants received onabotulinum toxin A injections, according to the same protocol, every 12 weeks, for 32 weeks. As each injection of 0.1 ml contained 5 units of the toxin and the injections were performed on 31 fixed sites and up to eight random (“follow-the-pain”) sites, each participant received 155 U to 195 U per session (Table 6).

Table 6 PREEMPT95-97 protocol: Dose of onabotulinum toxin A (Botox®) per application site. 

Muscle area Units of onabotulinum toxin A per application site *,**,***
Mandatory sites Optional sites Total
(“follow the pain”)
Left Right Left Right
Frontal 10U 10U Do not use 20U
Corrugators 5U 5U Do not use 10U
Procerus 5U Do not use 5U
Temporal 20U 20U 5U 5U 40U to 50U
Occipital 15U 15U 5U 5U 30U to 40U
Cervical 10U 10U Do not use 20U
paraspinal
Trapezius 15U 15U 10U 10U 30U to 50U
All areas 155U to 195U

*recommended dilution is 200 units per 4 mL of saline solution; **each application site is injected with 0.1 mL (5 units); ***application is subcutaneous, except in the corrugator and procerus muscles, where it must be intramuscular.

Open-label prospective long term and observational studies conducted in different centers, according to the same injection paradigm, have corroborated the efficacy, tolerability and safety of onabotulinum toxin A98,99,100,101,102,103,104,105. The Chronic Migraine Onabotulinum Toxin A Prolonged Efficacy Open Label trial, for example, evidenced that onabotulinum toxin A had its efficacy sustained for as long as 108 weeks, without further safety or tolerability problems101. Increase in productivity and a reduction of about 60% in expenses with medical visits and hospitalizations were suggested by pharmacoeconomics studies106,107.

There is no consensus in the literature regarding the number of onabotulinum toxin A cycles required for the management of chronic migraine. Some trials suggest an increasing efficacy with regular cycle repetition for more than one year, including in patients that overuse symptomatic drugs (three class II trials, level B recommendation)104,108,109. To date, no clinical features predicting responses to onabotulinum toxin A (recommendation level B) have been identified100,101.

An onabotulinum toxin A trial including children110 showed a significant reduction in pain days, but without improvement in quality of life or reduction of pain intensity during the attacks. It should be noted that onabotulinum toxin A has its use in chronic migraine approved in Brazil for patients ≥ 18 years old.

The adverse effects caused by this treatment are rare, transient and mild. The most frequently reported were neck and shoulder muscle weakness, post-application headache, palpebral pseudoptosis and other facial mimics asymmetries, in addition to pain at injection sites95-98,101,102(class of evidence I).

Peripheral nerve blocks

Not many trials have been conducted to investigate the efficacy of cephalic segment peripheral nerve blocks in the management of chronic migraine. The heterogeneity of study cohorts, designs and techniques do not allow consistent conclusions111,112,113,114. However, it is worth mentioning a double-blind RCT in which 44 participants were submitted to weekly bilateral greater occipital nerve blockades for one month, with 0.5% bupivacaine or saline solution (1.5 mL). The active group showed a significant reduction in headache days, which lasted for three weeks after the end of treatment111 (evidence class I, recommendation level B.)

NONPHARMACOLOGICAL TREATMENT AND COMPLEMENTARY THERAPIES

The number of trials contemplating nonpharmacological treatments in patients with chronic migraine is limited, but some of these showed promising results, especially when these methods were used in association with conventional treatment with prophylactic drugs.

Psychological and behavioral therapies

Positive results were seen in some trials addressing cognitive behavioral therapy, biofeedback and meditation techniques such as mindfulness. In one RCT, cognitive behavioral therapy, combined with amitriptyline, was more effective than amitriptyline alone in reducing days of headache in children and adolescents with chronic migraine115. Two RCTs showed biofeedback efficacy in adult patients with chronic migraine and medication-overuse headache when combined with pharmacological treatment116,117, with higher reduction of analgesic use and number of headache days in the long run. These results are supported by an RCT that demonstrated a reduction of oxidative stress indexes in women with chronic migraine who were submitted to biofeedback118. The mindfulness meditation technique has been tested in prophylactic management of chronic migraine and medication-overuse headache in a one-year follow-up RCT comparing prophylactic medication versus six weeks of mindfulness training. There was a comparable reduction in headache frequency and in the use of analgesic medication in both groups119. Two other trials with similar design demonstrated reduction of inflammation biomarkers120and catecholamine production121 in both groups.

Physical activity

One RCT comparing isolated amitriptyline versus amitriptyline associated with aerobic exercise three times a week in the management of chronic migraine showed a greater reduction in the frequency of headache days in the combined approach group122.

Physiotherapeutic measures

One RCT evaluated patients with chronic migraine using prophylactic drugs (amitriptyline or topiramate). They were allocated into two groups, one of which was submitted to physiotherapy sessions (diaphragmatic breathing exercises, cervical traction and mobilization, massage therapy, myofascial release, manual compression of muscle trigger points and passive stretching of cervical muscles). A greater reduction of days of headache was observed in patients with chronic migraine and associated neck pain with the combined approach in comparison with drug treatment alone123.

Acupuncture

A multicenter RCT involving 205 chronic migraine patients showed acupuncture’s superiority (one session per week for 12 weeks) compared with sham acupuncture, regarding the reduction in number of headache days124. Two subsequent class II trials comparing acupuncture with onabotulinum toxin A and topiramate demonstrated a similar or superior efficacy of acupuncture85,125.

Nutraceuticals

Individuals with chronic migraine using amitriptyline were enrolled in a double-blind RCT that demonstrated a greater reduction in headache days in the group that received the polyunsaturated long-chain fatty acid eicosapentaenoic acid 400mg/day and the polyunsaturated very long-chain fatty acid docosahexaenoic acid 350mg/day126.

Neuromodulation

Transcutaneous supraorbital stimulation

Although daily transcutaneous supraorbital stimulation using the Cefaly® device is approved both by ANVISA and the FDA as a prophylactic treatment for episodic migraine, a single preliminary open prospective trial was performed in patients with chronic migraine, in which the goal of 50% reduction on headache days was achieved by only 30% of participants127.

Transcutaneous electrical vagus nerve stimulation

In a double-blind RCT including patients with chronic migraine receiving a 1 Hz or 25 Hz stimulation in the auricular branch of the vagus nerve, only patients who underwent 1 Hz stimulation achieved a reduction greater than or equal to 50% on headache days128. Another multicenter double-blind RCT did not show a reduction in the number of attacks compared with a sham procedure control group, except in the open phase, after eight months of treatment129.

Invasive electrical stimulation of the occipital nerves

The results obtained with invasive occipital electrical stimulation of patients with chronic migraine considered refractory are controversial. A multicenter RCT with 110 participants showed that only 39% of them achieved a reduction of 50% or more in the number of headache attacks per month130. Another RCT compared effective stimulation with sham stimulation and no stimulation. In this trial, participants who underwent effective stimulation showed a reduction of pain severity131. On the other hand, a third double-blind multicenter RCT found no difference between the active stimulation and sham stimulation groups in relation to the primary endpoint of 50% or more reduction of headache days after twelve weeks132.

Transcranial magnetic stimulation

Two transcranial magnetic stimulation trials have shown opposite results in the management of chronic migraine. A first double-blind RCT showed a reduction of more than 50% in the frequency and intensity of attacks in the active group compared with the placebo group133. However, a more recent RCT demonstrated a significantly greater reduction in the frequency of headache days in the sham group in relation to the active group134.

Table 7 summarizes level of recommendation and class of evidence for the nonpharmacological modalities in the treatment of chronic migraine. It should be remembered that the evaluation of the efficacy of these methods is compromised by the limited number and heterogeneity of the trials, as well as by the variability of methods and conflicting results.

Table 7 Class of evidence and level of recommendation of nonpharmacological methods used for the treatment of chronic migraine. 

Methods of treatment Evidence Recommendation References
Acupuncture 1 class I trial and 2 class II trials B 85, 124, 125
Psychological and behavioral therapies
Cognitive behavioral therapy 1 class II trial C 115
Biofeedback 3 class II trials B 116-118
Mindfulness 2 class II trials B 119-121
Physiotherapeutic measures (see text 1 class II trial C 123
Aerobic exercises 1 class II trial C 122
Nutraceuticals (see text 1 class II trial C 126
Neuromodulation
Transcutaneous electrical stimulation of supraorbital nerve (Cefaly® 1 class III trial U 127
Transcutaneous electrical vagus nerve stimulation 2 class I trials with opposite results U 128, 129
Invasive electrical stimulation of the occipital nerves 2 class II trials with opposite results and one III positive trial U 130-132
Transcranial magnetic stimulation 1 negative class I trial and 1 positive class II trial U 133, 134

CONCLUSION

Chronic migraine carries a substantial burden and is recognized as a difficult-to-treat condition, particularly when associated with acute medication overuse. Despite this, the use of some oral or non-oral pharmacological approaches are supported by good quality evidence. Additionally, nonpharmacological techniques are currently being subjected to a more profound scrutiny and some of them seem to be probably helpful. Novel biological therapies are currently being tested for efficacy in chronic migraine and new evidence is likely to be available soon.

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Received: January 17, 2019; Revised: March 12, 2019; Accepted: March 29, 2019

Correspondence: Fernando Kowacs; Rua Padre Chagas, 147 Sala 501, Porto Alegre RS, Brasil - 90570-080; E-mail: fernandokowacs@gmail.com

Conflict of interest: There is no conflict of interest to declare.

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