The Chronic Face of Migraine - Two Approaches

*Migraine*

2020;**6**(2):119-125

2019;**31**(2):85-97

2016;**6**:CD001218

2020;60(6):1111-1123

2015;**16**(1):80

[176] Lampl C, Rudolph M,

[177] Ashina S, Bendtsen L,

symptom or part of the attack? The Journal of Headache and Pain.

et al. Associations between lifestyle intervention-related changes in dietary targets and migraine headaches among women in the Women's Health and Migraine (WHAM) randomized controlled trial. Cephalalgia.

review and meta-analysis. 2016;**36**(5):474-492

2013;**310**(24):2622-2630

[180] Powers SW, Kashikar-Zuck SM, Allen JR, LeCates SL, Slater SK, Zafar M, et al. Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: A randomized clinical trial. JAMA.

[181] Sharpe L, Dudeney J, Williams A, Nicholas M, McPhee I, Baillie A, et al. Psychological therapies for the prevention of migraine in adults. Cochrane Database of Systematic Reviews. 2019;**7**:CD012295

[182] Pérez-Muñoz A, Buse DC, Andrasik F. Behavioral interventions for migraine. Neurologic Clinics.

[183] Smelt AFH, Louter MA, Kies DA, Blom JW, Terwindt GM, van der Heijden GJMG, et al. What do patients consider to be the most important outcomes for effectiveness studies on migraine treatment? Results of a Delphi study. PLoS One. 2014;**9**(6):e98933

[184] Peres MFP, Silberstein S, Moreira F, Corchs F, Vieira DS, Abraham N, et al. Patients' preference for migraine

preventive therapy. PLos One.

2007;**47**(4):540-545

2019;**37**(4):789-813

[173] Trinh KV, Diep D, Chen KJQ. Systematic review of episodic migraine prophylaxis: Efficacy of conventional treatments used in comparisons with acupuncture. Medical Acupuncture.

[174] Linde K, Allais G, Brinkhaus B, Fei Y, Mehring M, Vertosick EA, et al. Acupuncture for the prevention of episodic migraine. Cochrane Database of Systematic Reviews.

[175] Hammond NG, Colman I. The role of positive health behaviors in the relationship between early life stress and migraine. Headache.

Deligianni CI, Mitsikostas DD. Neck pain in episodic migraine: Premonitory

Lyngberg AC, Lipton RB, Hajiyeva N, Jensen R. Prevalence of neck pain in migraine and tension-type headache: A population study. The Journal of Headache and Pain. 2015;**35**(3):211-219

[178] Kropp P, Meyer B, Meyer W, Dresler T. An update on behavioral treatments in migraine—Current knowledge and future options. Expert Review of Neurotherapeutics.

[179] Luedtke K, Allers A, Schulte LH, May A. Efficacy of interventions used by physiotherapists for patients with headache and migraine—Systematic

2017;**17**(11):1059-1068

**74**

**Chapter 5**

**Abstract**

Chronic Migraine

symptoms, diagnosis, treatment, prevention

frequent headaches and a history of prior migraine.

than those concerning with EM [5, 6].

**1. Introduction**

disorders.

**77**

*Diana Obelieniene, Ruta Pestininkaite and Daiva Rastenyte*

Chronic migraine as a disease was initially recognized in patients with a large burden of disability from frequent headaches and a history of prior migraines. Over time, this observation was operationalized into multiple diagnostic criteria with requirements for frequent headache days, typically 15 or more, which, on at least 8 days in a month, have the features of migraine headache. Chronic migraine affects 1–2% of the general population, and about 8% of patients with migraine. Understanding disease mechanisms still remains a challenge. Inflammation and central sensitization play significant role in the evolutive mechanisms of chronic migraine. Treatment of this condition should primarily focus on the prevention. The currently available evidence-based prophylactic treatment options are topiramate, valproic acid, onabotulinumtoxin A and recently developed promising anti-CGRP monoclonal antibodies. Chronic migraine research is a dynamic and rapidly advancing area. New developments in this field have the potential to improve the diagnosis, to provide more personalized treatments and to reduce burden of disability.

**Keywords:** chronic migraine, epidemiology, pathophysiology, risk factors,

Chronic migraine (CM) is a distinct and relatively recently defined type of migraine initially recognized in patients with a large burden of disability from

The International Headache Society (IHS) defines CM as more than 15 headache days per month over a 3-month period of which more than eight are migrainous [1]. Disability rates and burden of disease among individuals with CM has moresevere impact on socioeconomic functioning and quality of life than does episodic migraine (EM) [2–4]. About 25% patients with CM report a very severe headacherelated disability, as defined by the Migraine Disability Assessment Scale (MIDAS) to compare with 3% of patients with EM [2]. The proportion of patients with CM who report reduced household productivity, missed family activities and missed household work is two to three times higher than that of EM patients [4]. The annual per-person costs of CM—consisting of direct costs caused by health care utilization and treatment expenses (30%) and indirect costs attributable to absenteeism from work and loss of productivity (70%)—are about fourfold higher

Acknowledgment the severe effect of CM on socioeconomic functioning and quality of life, effective treatment of this disorder and preventing progression from episodic to CM—are one of most important problems in management of headache

## **Chapter 5** Chronic Migraine

*Diana Obelieniene, Ruta Pestininkaite and Daiva Rastenyte*

### **Abstract**

Chronic migraine as a disease was initially recognized in patients with a large burden of disability from frequent headaches and a history of prior migraines. Over time, this observation was operationalized into multiple diagnostic criteria with requirements for frequent headache days, typically 15 or more, which, on at least 8 days in a month, have the features of migraine headache. Chronic migraine affects 1–2% of the general population, and about 8% of patients with migraine. Understanding disease mechanisms still remains a challenge. Inflammation and central sensitization play significant role in the evolutive mechanisms of chronic migraine. Treatment of this condition should primarily focus on the prevention. The currently available evidence-based prophylactic treatment options are topiramate, valproic acid, onabotulinumtoxin A and recently developed promising anti-CGRP monoclonal antibodies. Chronic migraine research is a dynamic and rapidly advancing area. New developments in this field have the potential to improve the diagnosis, to provide more personalized treatments and to reduce burden of disability.

**Keywords:** chronic migraine, epidemiology, pathophysiology, risk factors, symptoms, diagnosis, treatment, prevention

#### **1. Introduction**

Chronic migraine (CM) is a distinct and relatively recently defined type of migraine initially recognized in patients with a large burden of disability from frequent headaches and a history of prior migraine.

The International Headache Society (IHS) defines CM as more than 15 headache days per month over a 3-month period of which more than eight are migrainous [1].

Disability rates and burden of disease among individuals with CM has moresevere impact on socioeconomic functioning and quality of life than does episodic migraine (EM) [2–4]. About 25% patients with CM report a very severe headacherelated disability, as defined by the Migraine Disability Assessment Scale (MIDAS) to compare with 3% of patients with EM [2]. The proportion of patients with CM who report reduced household productivity, missed family activities and missed household work is two to three times higher than that of EM patients [4]. The annual per-person costs of CM—consisting of direct costs caused by health care utilization and treatment expenses (30%) and indirect costs attributable to absenteeism from work and loss of productivity (70%)—are about fourfold higher than those concerning with EM [5, 6].

Acknowledgment the severe effect of CM on socioeconomic functioning and quality of life, effective treatment of this disorder and preventing progression from episodic to CM—are one of most important problems in management of headache disorders.

#### **2. History**

The current definition of CM as outlined in the International Classification of Headache Disorders, 3rd edition (ICHD-3) [1] is relatively new. This definition has been tested multiple times and has gone through multiple revisions.

However, the true prevalence of CM is difficult to estimate because of heterogeneus

CM accounts for about one-third of chronic headache (with more than 180 days per year) in general population [23]. This headache disorder is almost three times more common in women than in men with prevalence rate peaks at the ages of 18–29 years with repeating at 40–49 years [2, 22]. Most studies suggest that annually, from about 2.5% of people with EM evolves CM [25, 26], while only a limited

The course of CM can change—spontaneous or medically induced remission is possible. About 26% of patients can experience remission within 2 years of the onset of CM [24]. Large-scale epidemiological studies have identified various factors associated with progression from episodic to CM, and also factors that promote

Most important nonmodifiable risk factors for migraine chronification are age, female sex and low educational status [2, 7, 14, 23]. Individuals with CM have increased incidence of certain somatic and psychiatric comorbidities—in comparison with people with EM [23, 25]. However, the understanding of complex factors and mechanisms leading to an increased migraine frequency and consequently to the development of CM are only in the beginning and needs further investigations.

Generally the pathophysiology of migraine is intricate and in spite of substantial progress in recognizing its mechanisms over the past several decades, it still remains not fully elucidated. Even more, so is the pathophysiology of CM. Current evidence defines migraine as a disorder of brain dysfunction with genetic background and environmental triggering [28]. To date there is limited number of scientific studies exploring the chronic form of migraine, therefore the reasons why the disease sometimes takes a turn and attacks become more frequent are not fully clarified yet. The key components proposed in the pathogenesis of migraine chronification include atypical pain processing, central sensitization, cortical hyperexcitability and

Distinct phases of migraine are associated with different anatomical areas and driven by different processes. Prodromal symptoms that can develop prior the onset of migraine pain are believed to be a result of abnormal activity in cortical, diencephalic and/or brainstem areas. Migraine aura, experienced by approximately one third of patients, is most probably caused by cortical spreading depression (CSD) a phenomenon defined as a slowly propagating depolarization wave followed by a prolonged period of inhibition of cortical activity [28, 30]. Going further, the pivotal process of the headache phase is activation of the trigeminovascular system. As the brain itself has been known to be rather insensate, the intracranial nociceptive impulses are generated in pain-sensitive structures like pial, arachnoid and dural blood vessels, venous sinuses as well as large cerebral arteries, all of which are innervated by nociceptive nerve fibers originating in the trigeminal ganglion. Activation of these structures by various stimuli is responsible for generation of migrainous pain and its associated features [31–33]. Extracranial afferent nociceptive innervation is largely received through the divisions of trigeminal nerve, mainly the ophthalmic, as well as the upper cervical dorsal root ganglia [34]. The intracranial and extracranial neural afferents enter caudal medulla via trigeminal tract and terminate in the spinal trigeminal nucleus caudalis and upper cervical spinal cord (C1-C3)—the trigeminocervical complex (TCC) [35, 36]. Next, the nociceptive information travels further via ascending pathways to the diencephalon

data collection instruments.

*Chronic Migraine*

migraine remission [27].

**4. Pathophysiology**

**79**

portion with CM revert back to EM [25, 27].

*DOI: http://dx.doi.org/10.5772/intechopen.93314*

neurogenic inflammation [29] (**Figure 1**).

Although migraine as a distinct condition of headache with other accompanying symptoms has been known for thousands of years from the early writings of Aretaeus of Cappadocia in 30–90 A.D. [7]. The first formal modern definition of migraine was outlined in 1962 [8]. This first definition did not contain operational rules for migraine diagnosis and in 1988 the IHS published operational diagnostic criteria entitled the International Classification of Headache Disorders (ICHD-1) [9]. Criticism has been raised by experts that the ICHD-1 was not comprehensive enough to introduce diagnostic criteria for chronic headaches [10].

It was recognized in the 1980s that a chronic frequent headache patient population had a history of migraine [11, 12]. The daily and near daily headache patients were classified with multiple diagnoses but likely represented a single pathophysiological entity of migraine transformation with increased frequency. Recognizing this drawback, the Silberstein—Lipton criteria 1994, 1996 were proposed [13, 14]. They stipulated that chronic daily headaches defined as headaches on 15 or more days a month for at least 1 month, there was a subcategory of transformed migraine (TM) [6].

The term chronic migraine the first time in the literature was used by Manzoni et al. [15]. The results of a population study of chronic daily headache patients in Italy showed that 72% had fulfilled an IHS diagnosis of migraine [15]. For the first time CM appeared in the International Classification of Headache Disorders, 2nd edition (ICHD-2), 2004 [16]. There the CM category was defined as a complication of migraine, in patients having migraine without aura on at least 15 days per month, for at least 3 months, before the diagnosis was established. In the comments were stated that chronicity may be regarded as complication of EM and if medication overuse is present this is the most likely cause of chronic symptoms and it was suggested to code probable CM and probable medication- overuse headache (MOH). The requirement of having 15 migraine days per month was likely too stringent [17] and in a field trial of the ICHD-2 criteria [18] only 5.6% could be classified with CM, and only 10% could be classified to probable migraine with probable MOH.

Further, as it was recognized in prior studies, in the process of migraine transformation or chronification, the migraine features of some of the headaches may be lost [11–14].

Recognizing the drawbacks, in an appendix to ICHD-2R the CM definition was specified by requiring only 8 days per month to meet the definition of migraine or be responsive to migraine specific medications. This criterion is still present in the ICHD-3 [1].

ICHD-3 criteria of CM include a mixture of migraine and tension-type-like headaches and do not account for patients with high-frequency migraine attacks in the absence of other types of headaches [19].

Patients with migraine on eight or more days but not 15 days with headache a month are as disabled as patients with ICHD-3 defined CM [19]. Following this data a criticism regarding the existing CM criteria was raised and suggestion to revise the CM criteria was iniciated [19].

#### **3. Epidemiology**

The prevalence of CM worlwide ranges is reported to be between 0.9–5% [20], in a general population, and about 8% among patients with migraine [2, 21–24].

#### *Chronic Migraine DOI: http://dx.doi.org/10.5772/intechopen.93314*

**2. History**

*Migraine*

lost [11–14].

ICHD-3 [1].

The current definition of CM as outlined in the International Classification of Headache Disorders, 3rd edition (ICHD-3) [1] is relatively new. This definition has

Although migraine as a distinct condition of headache with other accompanying

It was recognized in the 1980s that a chronic frequent headache patient population had a history of migraine [11, 12]. The daily and near daily headache patients were classified with multiple diagnoses but likely represented a single pathophysiological entity of migraine transformation with increased frequency. Recognizing this drawback, the Silberstein—Lipton criteria 1994, 1996 were proposed [13, 14]. They stipulated that chronic daily headaches defined as headaches on 15 or more days a month for at least 1 month, there was a subcategory of transformed migraine (TM) [6]. The term chronic migraine the first time in the literature was used by Manzoni et al. [15]. The results of a population study of chronic daily headache patients in Italy showed that 72% had fulfilled an IHS diagnosis of migraine [15]. For the first time CM appeared in the International Classification of Headache Disorders, 2nd edition (ICHD-2), 2004 [16]. There the CM category was defined as a complication of migraine, in patients having migraine without aura on at least 15 days per month, for at least 3 months, before the diagnosis was established. In the comments were stated that chronicity may be regarded as complication of EM and if medication overuse is present this is the most likely cause of chronic symptoms and it was suggested to code probable CM and probable medication- overuse headache (MOH). The requirement of having 15 migraine days per month was likely too stringent [17] and in a field trial of the ICHD-2 criteria [18] only 5.6% could be classified with CM, and only 10% could

Further, as it was recognized in prior studies, in the process of migraine transformation or chronification, the migraine features of some of the headaches may be

Recognizing the drawbacks, in an appendix to ICHD-2R the CM definition was specified by requiring only 8 days per month to meet the definition of migraine or be responsive to migraine specific medications. This criterion is still present in the

ICHD-3 criteria of CM include a mixture of migraine and tension-type-like headaches and do not account for patients with high-frequency migraine attacks in

Patients with migraine on eight or more days but not 15 days with headache a month are as disabled as patients with ICHD-3 defined CM [19]. Following this data a criticism regarding the existing CM criteria was raised and suggestion to revise the

The prevalence of CM worlwide ranges is reported to be between 0.9–5% [20], in a general population, and about 8% among patients with migraine [2, 21–24].

been tested multiple times and has gone through multiple revisions.

enough to introduce diagnostic criteria for chronic headaches [10].

be classified to probable migraine with probable MOH.

the absence of other types of headaches [19].

CM criteria was iniciated [19].

**3. Epidemiology**

**78**

symptoms has been known for thousands of years from the early writings of Aretaeus of Cappadocia in 30–90 A.D. [7]. The first formal modern definition of migraine was outlined in 1962 [8]. This first definition did not contain operational rules for migraine diagnosis and in 1988 the IHS published operational diagnostic criteria entitled the International Classification of Headache Disorders (ICHD-1) [9]. Criticism has been raised by experts that the ICHD-1 was not comprehensive

However, the true prevalence of CM is difficult to estimate because of heterogeneus data collection instruments.

CM accounts for about one-third of chronic headache (with more than 180 days per year) in general population [23]. This headache disorder is almost three times more common in women than in men with prevalence rate peaks at the ages of 18–29 years with repeating at 40–49 years [2, 22]. Most studies suggest that annually, from about 2.5% of people with EM evolves CM [25, 26], while only a limited portion with CM revert back to EM [25, 27].

The course of CM can change—spontaneous or medically induced remission is possible. About 26% of patients can experience remission within 2 years of the onset of CM [24]. Large-scale epidemiological studies have identified various factors associated with progression from episodic to CM, and also factors that promote migraine remission [27].

Most important nonmodifiable risk factors for migraine chronification are age, female sex and low educational status [2, 7, 14, 23]. Individuals with CM have increased incidence of certain somatic and psychiatric comorbidities—in comparison with people with EM [23, 25]. However, the understanding of complex factors and mechanisms leading to an increased migraine frequency and consequently to the development of CM are only in the beginning and needs further investigations.

#### **4. Pathophysiology**

Generally the pathophysiology of migraine is intricate and in spite of substantial progress in recognizing its mechanisms over the past several decades, it still remains not fully elucidated. Even more, so is the pathophysiology of CM. Current evidence defines migraine as a disorder of brain dysfunction with genetic background and environmental triggering [28]. To date there is limited number of scientific studies exploring the chronic form of migraine, therefore the reasons why the disease sometimes takes a turn and attacks become more frequent are not fully clarified yet. The key components proposed in the pathogenesis of migraine chronification include atypical pain processing, central sensitization, cortical hyperexcitability and neurogenic inflammation [29] (**Figure 1**).

Distinct phases of migraine are associated with different anatomical areas and driven by different processes. Prodromal symptoms that can develop prior the onset of migraine pain are believed to be a result of abnormal activity in cortical, diencephalic and/or brainstem areas. Migraine aura, experienced by approximately one third of patients, is most probably caused by cortical spreading depression (CSD) a phenomenon defined as a slowly propagating depolarization wave followed by a prolonged period of inhibition of cortical activity [28, 30]. Going further, the pivotal process of the headache phase is activation of the trigeminovascular system. As the brain itself has been known to be rather insensate, the intracranial nociceptive impulses are generated in pain-sensitive structures like pial, arachnoid and dural blood vessels, venous sinuses as well as large cerebral arteries, all of which are innervated by nociceptive nerve fibers originating in the trigeminal ganglion. Activation of these structures by various stimuli is responsible for generation of migrainous pain and its associated features [31–33]. Extracranial afferent nociceptive innervation is largely received through the divisions of trigeminal nerve, mainly the ophthalmic, as well as the upper cervical dorsal root ganglia [34]. The intracranial and extracranial neural afferents enter caudal medulla via trigeminal tract and terminate in the spinal trigeminal nucleus caudalis and upper cervical spinal cord (C1-C3)—the trigeminocervical complex (TCC) [35, 36]. Next, the nociceptive information travels further via ascending pathways to the diencephalon

susceptible to migraine attacks. During the interictal period threshold is normal, but when it decreases sufficiently, certain events, like stress or changes in hormonal or sleep rhythm, can provoke a migraine attack [47, 48]. Frequent attacks are among the major risk factors of migraine chronification, as they shorten the interictal period thus preventing restoration of the pain threshold to normal level [27, 49]. Consequently the sensory threshold stays below-baseline for most of the time and susceptibility to migraine attacks increases. Likewise, the most common risk factors, as obesity, physical inactivity, psychiatric illnesses and stress, might affect the

Further alteration of pain threshold and increased sensitivity to attack-inducing triggers can be influenced by central sensitization [45]. Cutaneous allodynia, which represents central sensitization, is significantly more prevalent in chronic migraine patients than those with episodic one, suggesting that frequent attacks and higher pain intensity contribute to the development of central sensitization [50, 51]. This also explains why ineffective attack management is a risk factor for chronification: if migraine attacks are not treated completely, it results in a longer and more intense state of pain, leading to pronounced central sensitization, lowered pain threshold and increased susceptibility to migraine transformation [50, 52]. Overuse of acute pain medications is another risk factor for migraine progression, as it has been shown to promote central sensitization and susceptibility to CSD [27, 53].

There has been increasing evidence on altered cortical excitability in migraine [54]. Studies with transcranial magnetic stimulation have demonstrated reduced visual suppression in CM patients compared with EM patients and healthy controls, which proves the presence of cortical hyperexcitability [42]. In addition, assessment of visual evoked potentials shows that interictal excitability of the visual cortex is persistent and matches that of a migraine attack thus creates a "neverending" migraine [55]. The underlying mechanisms of cortical hyperexcitability have not been uncovered yet, but evidence suggests that it may be induced by

Another contributor to the pathophysiology of CM is neurogenic inflammation [29, 56]. Upon nociceptive stimulation by chemical, mechanical or electrical stimuli, a number of vasoactive substances are released from the axon terminals, causing vasodilation of the blood vessels and further plasma extravasation, edema and mastocyte degranulation. This so-called "sterile inflammation" results in sensitization and activation of the trigeminal meningeal receptors [28, 56], promoting the induction of migrainous pain [56]. Among the best-studdied vasoactive substances are calcitonine gene-related peptide (CGRP), substance P, neurokinin A, serotonin (5-HT) and pituitary adenylate cyclase-activating peptide (PACAP). CGRP is one of the most significant central pronociceptive agents expressed in the trigeminovascular system and associated with pain processing and migraine symptoms. It takes part in the development of peripheral and central sensitization and enhanced abnormal pain perception [28]. Vasoactive intestinal peptide (VIP) is another important parasympathetic neurotransmitter with a headache-eliciting effect [57, 58]. These pro-inflammatory vasoactive substances have been in the spotlight of research for years with regard to their potential role as biomarkers for chronic migraine. The levels of CGRP and VIP have been measured and compared during the interictal state of episodic and chronic migraine, showing an increase of either in the latter [59]. This provides additional evidence on altered interictal activity of the trigeminovascular system in chronic migraineurs. Moreover, the role of other substances, such as leptin, adipoleptin, TNF-α and glutamate, in the processes related with persistence and progression of migraine, has been demonstrated. This provides

reasonable hopes on future implementation of biomarkers for migraine

chronification [57, 58, 60].

**81**

threshold and make individuals more prone to migraine episodes [45].

*Chronic Migraine*

*DOI: http://dx.doi.org/10.5772/intechopen.93314*

dysfunction of the pain modulatory pathways [55].

**Figure 1.** *Components of pathogenesis of migraine chronification. Data from Ref. [29].*

and cortical areas, including insula and cingulate cortex. [28] The role of the limbic system is also significant: central pain processing and further relaying of sensory information depend largely on the thalamus [28, 37]; moreover, the amygdala and hippocampus participate in affective and cognitive perception of pain [38, 39] features contributing to migraine notoriety as a disabling and burden-causing disease with strong emotional implications.

Under normal physiological circumstances activation of the nociceptive system is counterbalanced by pain modulation. It is known that in migraine, descending pain-modulating pathways are dysfunctional and pain inhibition is atypical, therefore susceptibility to migraine attacks is increased [40, 41]. Modulation system originates in the cerebral cortex and is carried out via cortico-trigeminal pathways with participation of brain structures, such as hypothalamus, locus coeruleus, nucleus raphe magnus and rostral ventromedial medulla. A core structure controlling pain and providing endogenous analgaesia is the periaqueductal gray matter (PAG) [42, 43]. Due to repetitive migraine attacks and prolonged exposure to pain, PAG and other structures, comprising the descending pain-modulating network, are excessively activated, which results in oxidative stress and subsequent dysfunction. Thereby adequate pain modulation is not ensured and susceptibility to generation of migraine attacks increases [42–44].

Some authors propose that migraine chronification can be seen as a threshold problem [45]. Pain threshold exists in order to protect from situations where daily non-noxious stimuli could induce pain, therefore it takes a stimulus of certain potency to actually be perceived as painful. Pain threshold is inconstant and shifts depending on cyclic changes that are thought to originate in the limbic system [46]. Those changes allow threshold fluctuations making individuals periodically more

#### *Chronic Migraine DOI: http://dx.doi.org/10.5772/intechopen.93314*

susceptible to migraine attacks. During the interictal period threshold is normal, but when it decreases sufficiently, certain events, like stress or changes in hormonal or sleep rhythm, can provoke a migraine attack [47, 48]. Frequent attacks are among the major risk factors of migraine chronification, as they shorten the interictal period thus preventing restoration of the pain threshold to normal level [27, 49]. Consequently the sensory threshold stays below-baseline for most of the time and susceptibility to migraine attacks increases. Likewise, the most common risk factors, as obesity, physical inactivity, psychiatric illnesses and stress, might affect the threshold and make individuals more prone to migraine episodes [45].

Further alteration of pain threshold and increased sensitivity to attack-inducing triggers can be influenced by central sensitization [45]. Cutaneous allodynia, which represents central sensitization, is significantly more prevalent in chronic migraine patients than those with episodic one, suggesting that frequent attacks and higher pain intensity contribute to the development of central sensitization [50, 51]. This also explains why ineffective attack management is a risk factor for chronification: if migraine attacks are not treated completely, it results in a longer and more intense state of pain, leading to pronounced central sensitization, lowered pain threshold and increased susceptibility to migraine transformation [50, 52]. Overuse of acute pain medications is another risk factor for migraine progression, as it has been shown to promote central sensitization and susceptibility to CSD [27, 53].

There has been increasing evidence on altered cortical excitability in migraine [54]. Studies with transcranial magnetic stimulation have demonstrated reduced visual suppression in CM patients compared with EM patients and healthy controls, which proves the presence of cortical hyperexcitability [42]. In addition, assessment of visual evoked potentials shows that interictal excitability of the visual cortex is persistent and matches that of a migraine attack thus creates a "neverending" migraine [55]. The underlying mechanisms of cortical hyperexcitability have not been uncovered yet, but evidence suggests that it may be induced by dysfunction of the pain modulatory pathways [55].

Another contributor to the pathophysiology of CM is neurogenic inflammation [29, 56]. Upon nociceptive stimulation by chemical, mechanical or electrical stimuli, a number of vasoactive substances are released from the axon terminals, causing vasodilation of the blood vessels and further plasma extravasation, edema and mastocyte degranulation. This so-called "sterile inflammation" results in sensitization and activation of the trigeminal meningeal receptors [28, 56], promoting the induction of migrainous pain [56]. Among the best-studdied vasoactive substances are calcitonine gene-related peptide (CGRP), substance P, neurokinin A, serotonin (5-HT) and pituitary adenylate cyclase-activating peptide (PACAP). CGRP is one of the most significant central pronociceptive agents expressed in the trigeminovascular system and associated with pain processing and migraine symptoms. It takes part in the development of peripheral and central sensitization and enhanced abnormal pain perception [28]. Vasoactive intestinal peptide (VIP) is another important parasympathetic neurotransmitter with a headache-eliciting effect [57, 58]. These pro-inflammatory vasoactive substances have been in the spotlight of research for years with regard to their potential role as biomarkers for chronic migraine. The levels of CGRP and VIP have been measured and compared during the interictal state of episodic and chronic migraine, showing an increase of either in the latter [59]. This provides additional evidence on altered interictal activity of the trigeminovascular system in chronic migraineurs. Moreover, the role of other substances, such as leptin, adipoleptin, TNF-α and glutamate, in the processes related with persistence and progression of migraine, has been demonstrated. This provides reasonable hopes on future implementation of biomarkers for migraine chronification [57, 58, 60].

and cortical areas, including insula and cingulate cortex. [28] The role of the limbic system is also significant: central pain processing and further relaying of sensory information depend largely on the thalamus [28, 37]; moreover, the amygdala and hippocampus participate in affective and cognitive perception of pain [38, 39] features contributing to migraine notoriety as a disabling and burden-causing dis-

Under normal physiological circumstances activation of the nociceptive system is counterbalanced by pain modulation. It is known that in migraine, descending pain-modulating pathways are dysfunctional and pain inhibition is atypical, therefore susceptibility to migraine attacks is increased [40, 41]. Modulation system originates in the cerebral cortex and is carried out via cortico-trigeminal pathways with participation of brain structures, such as hypothalamus, locus coeruleus, nucleus raphe magnus and rostral ventromedial medulla. A core structure controlling pain and providing endogenous analgaesia is the periaqueductal gray matter (PAG) [42, 43]. Due to repetitive migraine attacks and prolonged exposure to pain, PAG and other structures, comprising the descending pain-modulating network, are excessively activated, which results in oxidative stress and subsequent dysfunction. Thereby adequate pain modulation is not ensured and susceptibility to gener-

Some authors propose that migraine chronification can be seen as a threshold problem [45]. Pain threshold exists in order to protect from situations where daily non-noxious stimuli could induce pain, therefore it takes a stimulus of certain potency to actually be perceived as painful. Pain threshold is inconstant and shifts depending on cyclic changes that are thought to originate in the limbic system [46]. Those changes allow threshold fluctuations making individuals periodically more

ease with strong emotional implications.

*Components of pathogenesis of migraine chronification. Data from Ref. [29].*

**Figure 1.**

*Migraine*

**80**

ation of migraine attacks increases [42–44].

In terms of anatomic changes in migraine, white matter lesions are considered to be more common in migraineurs than in general population. Moreover, increase in lesions correlates with attack frequency [61]. Recent neuroimaging studies revealed some other neuroanatomical differences correlating with headache frequency that could even be considered indirect markers of migraine chronification: it showed that migraineurs with more frequent attacks had thicker somatosensory cortex, anterior cingulate cortex and inferior temporal gyrus, compared with those with low-frequency attacks [62]. Also correlation with thickness of left middle frontal gyrus and left central sulcus was noted. Moreover, patients with CM had volumetric changes in amygdala, hippocampus, putamen and brainstem areas [63]. These data once again prove the role of these cerebral structures in the pathogenesis of chronic migraine [64].

thus it can be considered a risk factor for migraine chronification [71]. In fact, similar relation also exists between increased body weight and other headache disorders like MOH and benign intracranial hypertension [78, 79]. The mechanisms linking obesity and frequent headaches are not known yet, but it may be related to hyperleptinemia [80–82]. Next, sleep disorders, including sleep apnea, snoring, disturbed sleep and oversleeping, have been found to elevate the risk for developing CM [83, 84]. Therefore it is obvious that patient education and counseling on lifestyle is extremely important, as reducing caffeine intake, normalizing body weight and sleeping patterns early enough may help to prevent migraine

Another tendency is that patients with CM report various comorbidities more commonly than those with CM. According to the CaMEO study, patients with the most comorbidities were 5 times more likely to progress to CM than those with the fewest [84, 85]. Psychiatric comorbidities, especially anxiety and severe or moderate depression, are particularly prevalent in CM patients [72, 84, 86] as are some personality traits and disorders, in particular obsessive-compulsive, dependent, avoidant and passive-aggressive [87]. Chronic pain conditions, including fibromyalgia, chronic back and neck pain, are also a strong prognostic factor for migraine progression from episodic to chronic state as they are much more commonly reported by chronic migraineurs [88]. Other comorbidities such as cardiovascular disorders, asthma and allergies [25] are also considered risk factors for migraine progression. Moreover, various major life changes, like divorce, change of employment status or being recently widowed also play a role in migraine conversion, partially by accompaniment of anxiety and depression [27]. Therefore it is critically

**Demographic characteristics Treatment-related factors**

Acute medication overuse Insufficient treatment **Comorbidities** Psychiatric disorders Depression Anxiety Bipolar disorder Personality disorders and traits Obsessive-compulsive

Avoidant Dependent Passive-aggressive

Fibromyalgia Back and neck pain Painful neuropathy Cardiovascular disorders Arterial hypertension Hypercholesterolemia

Asthma

Divorce

Grief

Concomitant chronic pain disorders

Stress related with major life changes

Change of employment status

progression.

*Chronic Migraine*

*DOI: http://dx.doi.org/10.5772/intechopen.93314*

Female sex Caucasian race Increasing age Lower level of education Lower economic status Being unmarried Unemployment

**Lifestyle factors**

Obesity Sleep disorders Sleep apnea Snoring Sleep deprivation Excessive sleeping **Headache features** Frequent attacks Cutaneous allodynia

**Table 1.**

**83**

High caffeine consumption

*Risk factors for chronic migraine [27, 51, 71, 72].*

Genetic influence on the progression from episodic to CM is yet to be established as more large-sample studies are needed [64, 65]. However it looks that chronic migrain has a polygenetic background. Data suggest the role of certain gene groups linked to migraine and pain progression, addiction and medication overuse, hyperexcitability and oxidative stress in migraine chronification [66]. Furthermore, it is becoming clear that epigenetics is also related to migraine as to many other multifactorial diseases. Although to date there are no specific genetic studies in chronic migraine patients, there is some evidence that neuronal activity occuring during CSD may cause epigenetic changes involved in neuronal plasticity, neuroprotection and regulation of basal synaptic activity [67, 68].

#### **5. Risk factors**

Not all patients with EM progress into chronic form [69]. The American Migraine Prevalence and Prevention (AMPP) Study [70], the International Burden of Migraine Study (IBMS) [3] and the others have explored at the prevalence of different features in episodic and CM. Some of them have been found to be more prevalent in the chronic form of migraine, suggesting that these features should be seen as risk factors associated with migraine conversion that may serve as prognostic markers enabling prediction of possible migraine progression from episodic to chronic form. Knowing these factors can assist in identifying patients at risk of transformation and take appropriate measures to prevent it (**Table 1**).

The risk factors can be divided into non-modifiable and modifiable. Some of them carry more weight in predisposing CM than the others do. The most significant risk factors are overuse of acute medication [27], ineffective acute treatment [51], obesity [71], depression [72] and stressful life events [27]. The risk factors are listed in **Table 1**.

Studies show that higher prevalence of CM is related to some non-modifiable demographic characteristics, such as female sex [73, 74] and Caucasian race [75]. Regarding age, CM tends to be increasingly more prevalent from 18 to 50 years in both sexes [2]. In terms of the modifiable risk factors, there is evidence for correlation between lower level of education and CM, but data are inconsistent [3, 24, 25, 75]. In addition, some studies propose lower economic status [76], being unmarried [25] and unemployed [3, 25] as risk factors for chronic migraine.

Some modifiable lifestyle features have also been listed as risk factors of CM. First, high caffeine intake is connected with migraine transformation, especially when excessive consumption has started before the onset of chronic daily headache [77]. Second, obesity, especially in women, is more prevalent in chronic than in EM

#### *Chronic Migraine DOI: http://dx.doi.org/10.5772/intechopen.93314*

In terms of anatomic changes in migraine, white matter lesions are considered to be more common in migraineurs than in general population. Moreover, increase in lesions correlates with attack frequency [61]. Recent neuroimaging studies revealed some other neuroanatomical differences correlating with headache frequency that could even be considered indirect markers of migraine chronification: it showed that migraineurs with more frequent attacks had thicker somatosensory cortex, anterior cingulate cortex and inferior temporal gyrus, compared with those with low-frequency attacks [62]. Also correlation with thickness of left middle frontal gyrus and left central sulcus was noted. Moreover, patients with CM had volumetric changes in amygdala, hippocampus, putamen and brainstem areas [63]. These data once again prove the role of these cerebral structures in the pathogenesis of chronic

Genetic influence on the progression from episodic to CM is yet to be established as more large-sample studies are needed [64, 65]. However it looks that chronic migrain has a polygenetic background. Data suggest the role of certain gene groups linked to migraine and pain progression, addiction and medication overuse,

hyperexcitability and oxidative stress in migraine chronification [66]. Furthermore, it is becoming clear that epigenetics is also related to migraine as to many other multifactorial diseases. Although to date there are no specific genetic studies in chronic migraine patients, there is some evidence that neuronal activity occuring during CSD may cause epigenetic changes involved in neuronal plasticity,

Not all patients with EM progress into chronic form [69]. The American Migraine Prevalence and Prevention (AMPP) Study [70], the International Burden of Migraine Study (IBMS) [3] and the others have explored at the prevalence of different features in episodic and CM. Some of them have been found to be more prevalent in the chronic form of migraine, suggesting that these features should be seen as risk factors associated with migraine conversion that may serve as prognostic markers enabling prediction of possible migraine progression from episodic to chronic form. Knowing these factors can assist in identifying patients at risk of

transformation and take appropriate measures to prevent it (**Table 1**).

The risk factors can be divided into non-modifiable and modifiable. Some of them carry more weight in predisposing CM than the others do. The most significant risk factors are overuse of acute medication [27], ineffective acute treatment [51], obesity [71], depression [72] and stressful life events [27]. The risk factors are

Studies show that higher prevalence of CM is related to some non-modifiable demographic characteristics, such as female sex [73, 74] and Caucasian race [75]. Regarding age, CM tends to be increasingly more prevalent from 18 to 50 years in both sexes [2]. In terms of the modifiable risk factors, there is evidence for correlation between lower level of education and CM, but data are inconsistent [3, 24, 25, 75]. In addition, some studies propose lower economic status [76], being unmarried [25] and unemployed [3, 25] as risk factors for chronic

Some modifiable lifestyle features have also been listed as risk factors of CM. First, high caffeine intake is connected with migraine transformation, especially when excessive consumption has started before the onset of chronic daily headache [77]. Second, obesity, especially in women, is more prevalent in chronic than in EM

neuroprotection and regulation of basal synaptic activity [67, 68].

migraine [64].

*Migraine*

**5. Risk factors**

listed in **Table 1**.

migraine.

**82**

thus it can be considered a risk factor for migraine chronification [71]. In fact, similar relation also exists between increased body weight and other headache disorders like MOH and benign intracranial hypertension [78, 79]. The mechanisms linking obesity and frequent headaches are not known yet, but it may be related to hyperleptinemia [80–82]. Next, sleep disorders, including sleep apnea, snoring, disturbed sleep and oversleeping, have been found to elevate the risk for developing CM [83, 84]. Therefore it is obvious that patient education and counseling on lifestyle is extremely important, as reducing caffeine intake, normalizing body weight and sleeping patterns early enough may help to prevent migraine progression.

Another tendency is that patients with CM report various comorbidities more commonly than those with CM. According to the CaMEO study, patients with the most comorbidities were 5 times more likely to progress to CM than those with the fewest [84, 85]. Psychiatric comorbidities, especially anxiety and severe or moderate depression, are particularly prevalent in CM patients [72, 84, 86] as are some personality traits and disorders, in particular obsessive-compulsive, dependent, avoidant and passive-aggressive [87]. Chronic pain conditions, including fibromyalgia, chronic back and neck pain, are also a strong prognostic factor for migraine progression from episodic to chronic state as they are much more commonly reported by chronic migraineurs [88]. Other comorbidities such as cardiovascular disorders, asthma and allergies [25] are also considered risk factors for migraine progression. Moreover, various major life changes, like divorce, change of employment status or being recently widowed also play a role in migraine conversion, partially by accompaniment of anxiety and depression [27]. Therefore it is critically


#### **Table 1.**

*Risk factors for chronic migraine [27, 51, 71, 72].*

important to adequately treat these comorbidities in order to prevent migraine chronification, impaired quality of life and development of disability.

associated symptoms are less pronounced than in those with EM [93]. Some patients report prodromal symptoms up to 48 hours before the onset of pain, including fatigue, asthenia, impaired concentration, irritability and other that can warn against an upcoming attack. However, it can be difficult to distinguish prodromal periods in CM as the attacks are very frequent or continuous [24].

90% is visual [84], but patients can also experience sensory, brainstem or hemiplegia-related aura [69, 84, 94]. Both types of migraine, with and without

without aura and/or should be relieved by specific migraine treatment [1].

aura, can progress into chronic form.

*DOI: http://dx.doi.org/10.5772/intechopen.93314*

characteristics [95, 96].

*Chronic Migraine*

criteria B and C;

**Table 2.**

**85**

Migraine with aura affects 20–40% of all migraineurs [93] and features a selection of transient focal neurological symptoms that usually but not invariably present before the onset of pain. The most common aura type accounting for approximately

According to the newest ICHD-3 criteria (**Table 2**), CM should be diagnosed when headache is experienced on 15 or more days per month over more than 3 months. The headache on 8 or more days per month should meet the criteria for migraine with or

Not always it is easy for the patients to remember the exact number of days of pain per month, hence keeping a headache diary can come to help. Patients should be encouraged to not only mark the days of pain, but also elaborate what the pain was like, what features it was accompanied by, was any medication required and with what outcome. This is a good and easy tool for a physician to not only accurately know the count up of the headache days, but also make a full picture of its

Physician making a diagnosis should obtain a detailed history, as history is where

In case of presentation of typical features of CM and normal examination, no further testing is required. However vigilance is needed to suspect any possible secondary headache causes, such as infections, tumors or hydrocephalus (**Table 3**), when additional investigation is warranted [29]. The set of tests required depends on clinician's judgment in each situation and may include certain blood tests, imaging of brain, cervical spine and sinuses, scanning of cranial and extracranial arteries and performing a lumbar puncture with measuring of the CSF opening pressure. The method of choice for brain imaging is usually MRI [97]. The most consistent indicators for such conditions ("red flags") include thunderclap headache, associated focal neurological deficit or systemic features, headache of onset in patients

After stating that the patient has a primary headache disorder, the pattern of the headache should be established. Episodic headache occurs on less than 15 days per month while chronic headache—on 15 or more days in a month. Headaches lasting up to 4 hours are considered "short" in contrast to "long" headaches that last more

A. Headache (migraine-like or tension-type-like) on ≥15 days/month for >3 months, and fulfilling

B. Occurring in a patient who has had at least five attacks fulfilling criteria B-D for 1.1 *Migraine without*

3. Believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative;

the diagnosis of migraine lies. A thorough neurological examination, including

fundoscopy, should be the following step during consultation [97].

over the age of 50 years and more [29, 97–99].

*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*;

D. Not better accounted for by another ICHD-3 diagnosis.

*Chronic migraine diagnostic criteria, ICHD-3, 2018.*

In addition to what has been set out before, some headache features have been established as risk factors too. One of the majors is headache frequency [27, 69]. Scher et al. has shown that the risk for chronification increases with the increase of headache frequency in a non-linear fashion. A minimum of three attacks per month is enough to elevate the risk for new-onset chronic headache [27]. This is based on the fact that prolonged exposure to pain induces central sensitization and decreases the attack threshold. Hence this once again emphasizes the importance of rapid and adequate treatment of migraine attacks to prevent pathophysiological alterations leading to migraine chronification.

Another specific clinical feature of migraine attack is cutaneous allodynia, which affects approximately 63% of migraineurs [89]. According to Burstein et al. and Louter et al. it is not only a clinical marker of central sensitization but can also be considered an independent predictor of migraine chronification [50, 52]. From therapeutic point of view, triptans should be administered to terminate a migraine attack within 30 minutes for subjects with cutaneous allodynia in order to minimize exposure to pathological processes leading to migraine chronification [90].

Aditionally some treatment-related factors are proven to play a role in the pathogenesis of CM. The Akershus study [91] among other data has confirmed that acute medication overuse has substantial impact to the processes leading to migraine progression. Acute medication overuse is defined as medication intake on 10–15 days per month [92]. Among the different analgesic groups opioids, barbiturates and combination drugs are associated with the highest dose-dependent risk, while triptans show moderate association with migraine progression and it is more likely in patients with higher baseline attack frequency. Interestingly, some data reports protective effect of NSAIDs against migraine progression, but only in patients with less than 10 attacks per month [79, 92]. The impact of medication overuse in migraine progression is supported by the fact, that attack frequency and disability decreases after discontinuation of acute medication, which also allows more effective preventive treatment [91].

On the other hand, the AMPP study states that ineffective or insufficient treatment can also promote chronification processes [90]. Patients using triptans are more likely to successfully abort the attacks than those using NSAIDs and simple analgesics therefore they are at less risk for chronification [51].

In conclusion it is crucial that effort is made to treat migraine attacks rapidly and adequately as well as to modify other risk factors relevant to the patient so that the pathophysiological mechanisms responsible for migraine progression from episodic into chronic form could be precluded [45, 64].

#### **6. Symptoms and diagnosis**

Although the most obvious difference between episodic and CM seems to be the frequency of attacks, clinical migraine features may change too as the disease progresses from less frequent to chronic form. Usually over time the pain becomes more "featureless", thus resembling tension-type headache for most of the time with some more prominent migraine-like attacks interjected [69].

Typical migraine attacks generally manifest as severe, usually unilateral headache of throbbing quality, increasing intensity with physical activity and a combination of associated features: nausea, vomiting, hypersensitivity to visual, auditory, olfactory and cutaneous stimuli. The headache can change sides during or between the attacks [64]. The pain in patients with CM is more commonly bilateral and the

#### *Chronic Migraine DOI: http://dx.doi.org/10.5772/intechopen.93314*

important to adequately treat these comorbidities in order to prevent migraine

In addition to what has been set out before, some headache features have been established as risk factors too. One of the majors is headache frequency [27, 69]. Scher et al. has shown that the risk for chronification increases with the increase of headache frequency in a non-linear fashion. A minimum of three attacks per month is enough to elevate the risk for new-onset chronic headache [27]. This is based on the fact that prolonged exposure to pain induces central sensitization and decreases the attack threshold. Hence this once again emphasizes the importance of rapid and adequate treatment of migraine attacks to prevent pathophysiological alterations

Another specific clinical feature of migraine attack is cutaneous allodynia, which affects approximately 63% of migraineurs [89]. According to Burstein et al. and Louter et al. it is not only a clinical marker of central sensitization but can also be considered an independent predictor of migraine chronification [50, 52]. From therapeutic point of view, triptans should be administered to terminate a migraine attack within 30 minutes for subjects with cutaneous allodynia in order to minimize

exposure to pathological processes leading to migraine chronification [90]. Aditionally some treatment-related factors are proven to play a role in the pathogenesis of CM. The Akershus study [91] among other data has confirmed that

acute medication overuse has substantial impact to the processes leading to

migraine progression. Acute medication overuse is defined as medication intake on 10–15 days per month [92]. Among the different analgesic groups opioids, barbiturates and combination drugs are associated with the highest dose-dependent risk, while triptans show moderate association with migraine progression and it is more likely in patients with higher baseline attack frequency. Interestingly, some data reports protective effect of NSAIDs against migraine progression, but only in patients with less than 10 attacks per month [79, 92]. The impact of medication overuse in migraine progression is supported by the fact, that attack frequency and disability decreases after discontinuation of acute medication, which also allows

On the other hand, the AMPP study states that ineffective or insufficient treatment can also promote chronification processes [90]. Patients using triptans are more likely to successfully abort the attacks than those using NSAIDs and simple

In conclusion it is crucial that effort is made to treat migraine attacks rapidly and adequately as well as to modify other risk factors relevant to the patient so that the pathophysiological mechanisms responsible for migraine progression from episodic

Although the most obvious difference between episodic and CM seems to be the frequency of attacks, clinical migraine features may change too as the disease progresses from less frequent to chronic form. Usually over time the pain becomes more "featureless", thus resembling tension-type headache for most of the time

Typical migraine attacks generally manifest as severe, usually unilateral headache of throbbing quality, increasing intensity with physical activity and a combination of associated features: nausea, vomiting, hypersensitivity to visual, auditory, olfactory and cutaneous stimuli. The headache can change sides during or between the attacks [64]. The pain in patients with CM is more commonly bilateral and the

chronification, impaired quality of life and development of disability.

leading to migraine chronification.

*Migraine*

more effective preventive treatment [91].

into chronic form could be precluded [45, 64].

**6. Symptoms and diagnosis**

**84**

analgesics therefore they are at less risk for chronification [51].

with some more prominent migraine-like attacks interjected [69].

associated symptoms are less pronounced than in those with EM [93]. Some patients report prodromal symptoms up to 48 hours before the onset of pain, including fatigue, asthenia, impaired concentration, irritability and other that can warn against an upcoming attack. However, it can be difficult to distinguish prodromal periods in CM as the attacks are very frequent or continuous [24].

Migraine with aura affects 20–40% of all migraineurs [93] and features a selection of transient focal neurological symptoms that usually but not invariably present before the onset of pain. The most common aura type accounting for approximately 90% is visual [84], but patients can also experience sensory, brainstem or hemiplegia-related aura [69, 84, 94]. Both types of migraine, with and without aura, can progress into chronic form.

According to the newest ICHD-3 criteria (**Table 2**), CM should be diagnosed when headache is experienced on 15 or more days per month over more than 3 months. The headache on 8 or more days per month should meet the criteria for migraine with or without aura and/or should be relieved by specific migraine treatment [1].

Not always it is easy for the patients to remember the exact number of days of pain per month, hence keeping a headache diary can come to help. Patients should be encouraged to not only mark the days of pain, but also elaborate what the pain was like, what features it was accompanied by, was any medication required and with what outcome. This is a good and easy tool for a physician to not only accurately know the count up of the headache days, but also make a full picture of its characteristics [95, 96].

Physician making a diagnosis should obtain a detailed history, as history is where the diagnosis of migraine lies. A thorough neurological examination, including fundoscopy, should be the following step during consultation [97].

In case of presentation of typical features of CM and normal examination, no further testing is required. However vigilance is needed to suspect any possible secondary headache causes, such as infections, tumors or hydrocephalus (**Table 3**), when additional investigation is warranted [29]. The set of tests required depends on clinician's judgment in each situation and may include certain blood tests, imaging of brain, cervical spine and sinuses, scanning of cranial and extracranial arteries and performing a lumbar puncture with measuring of the CSF opening pressure. The method of choice for brain imaging is usually MRI [97]. The most consistent indicators for such conditions ("red flags") include thunderclap headache, associated focal neurological deficit or systemic features, headache of onset in patients over the age of 50 years and more [29, 97–99].

After stating that the patient has a primary headache disorder, the pattern of the headache should be established. Episodic headache occurs on less than 15 days per month while chronic headache—on 15 or more days in a month. Headaches lasting up to 4 hours are considered "short" in contrast to "long" headaches that last more


	- 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.

#### **Table 2.**

*Chronic migraine diagnostic criteria, ICHD-3, 2018.*


#### **Table 3.**

*Possible Causes of Secondary Headaches (alphabetically ordered) [29, 45, 97].*

than 4 hours [100]. CM should be differentiated from other chronic long-duration primary headaches (**Table 3**). *Hemicrania continua* is strictly unilateral continuous headache condition with superimposed exacerbations of pain that display ipsilateral autonomic symptoms. CM can also present with autonomic features, but they are much less pronounced. In addition to this, *hemicrania continua* features a distinguishing absolute responsiveness to indomethacin which is a key factor in differential diagnosis [29]. Chronic tension-type headache usually manifests as bilateral ache of non-throbbing quality and mild to moderate severity, while CM can be unilateral or bilateral and of moderate to severe intensity. Importantly, chronic tension-type headache is considered "featureless"—it is not usually accompanied by migrainous symptoms like nausea, vomiting, photophobia, phonophobia, and is not exacerbated by exertion. As migraine progresses into chronic form, the headache may resemble tension-type on some days [29]; nonetheless, typical migraine features must be present on at least 8 days per month for the diagnosis of chronic migraine to be validated [1].

The main feature of new daily persistent headache is a distinct and clearly remembered onset and rapid development to an unremitting state of pain over 24 hours. This distinguishes it from chronic migraine that develops slowly over the course of months or years while attacks become more and more frequent and merged together. Besides, the localization and accompanying symptoms of new daily persistent headache are usually undefined and nonspecific, thus alleviating the differential diagnosis [29, 45, 97].

should be revoked, as it would seem that the overuse had taken place simply as a result of increased attack frequency [101]. Points of the differential diagnosis are

**Localization Duration Associated and**

or continuous • Headache present on at least 15 days per month

> continuous pain with superimposed exacerbations

• Hours to days or continuous

or continuous

Unilateral or bilateral • Hours to days

Side-locked • Daily,

Undefined • Hours to days

Usually bilateral, but can be

Daily persistent headache with a distinct and clearly remembered onset, with pain becoming continuous and unremitting within 24 hours

unilateral

*DOI: http://dx.doi.org/10.5772/intechopen.93314*

**distinguishing features**

• Throbbing nature • Accompanying nausea, vomiting, photophobia, phonophobia • Exertional exacerbation

• Ipsilateral autonomic features • Indomethacinresponsiveness

• "Featureless" no or rare accompanying symptoms

• History of acute medication overuse • Improved after withdrawal

Undefined Undefined Individual

**Diagnostic tests**

ICH-3 criteria

ICH-3 criteria Indomethacin trial [12]

ICH-3 criteria

ICH-3 criteria

approach: • Brain imaging (CT, MRI) • Lumbar puncture • Blood tests

Migraine Disability Assessment (MIDAS) or Headache Impact Test-6 (HIT-6) should be used for patient assessment in order to evaluate the burden of disease and monitor the effects of prescribed treatment [95]. Episodic and treatment-responsive migraine can be diagnosed and managed in the primary care, while chronic or refractory patients should be referred to a specialist neurologist, preferably with an

Once the diagnosis of CM has been confirmed, standard questionnaires, such as

*.*

summarized in **Table 4**.

*Data from Refs. [29, 45, 97].*

**Headache type/ causative problem**

*Chronic Migraine*

**Chronic migraine**

**Hemicrania continua**

**Chronic tensiontype headache**

**Medication overuse headache**

**New daily persistent headache**

*\**

**Table 4.**

**7. Treatment**

**87**

expertise in the field of headache disorders [95].

*Differential diagnosis for long-duration primary headaches\**

• Lifestyle and trigger management.

There are three broad approaches to treating CM [97]:

Another point to remember is the importance of assessing the patient for possible acute medication overuse, as it is one of the major risk factors for migraine progression. Sometimes it may be challenging to tell if medication overuse is a cause or a consequence of CM. The ICHD-3 criteria encourage coding both CM and MOH diagnoses in case when medication overuse is confirmed [1]. The diagnoses should be reviewed and specified later after assessing the effect of medication withdrawal: the headache may revert to episodic migraine or remain chronic. The former case would suggest that medication overuse indeed was a causative factor that had led to chronification. In the latter scenario the diagnosis of medication-overuse headache


#### **Table 4.**

than 4 hours [100]. CM should be differentiated from other chronic long-duration primary headaches (**Table 3**). *Hemicrania continua* is strictly unilateral continuous headache condition with superimposed exacerbations of pain that display ipsilateral autonomic symptoms. CM can also present with autonomic features, but they are

**Vascular disorders** Stroke, dissection of carotid or vertebral arteries, giant-cell arteritis,

Cervical pain, temporomandibular joint disorders, myofascial pain

Tumor, hemorrhage, brain infection, primary benign intracranial

Post-lumbar puncture, post-epidural/spinal analgesia, spontaneous

Medication overuse headache, medication side-effects, substance

arterial hypertension, CADASIL, venous sinuses thrombosis

hypertension, hydrocephalus, pituitary apoplexy

The main feature of new daily persistent headache is a distinct and clearly remembered onset and rapid development to an unremitting state of pain over 24 hours. This distinguishes it from chronic migraine that develops slowly over the course of months or years while attacks become more and more frequent and merged together. Besides, the localization and accompanying symptoms of new daily persistent headache are usually undefined and nonspecific, thus alleviating the

Another point to remember is the importance of assessing the patient for possi-

ble acute medication overuse, as it is one of the major risk factors for migraine progression. Sometimes it may be challenging to tell if medication overuse is a cause or a consequence of CM. The ICHD-3 criteria encourage coding both CM and MOH diagnoses in case when medication overuse is confirmed [1]. The diagnoses should be reviewed and specified later after assessing the effect of medication withdrawal: the headache may revert to episodic migraine or remain chronic. The former case would suggest that medication overuse indeed was a causative factor that had led to chronification. In the latter scenario the diagnosis of medication-overuse headache

much less pronounced. In addition to this, *hemicrania continua* features a distinguishing absolute responsiveness to indomethacin which is a key factor in differential diagnosis [29]. Chronic tension-type headache usually manifests as bilateral ache of non-throbbing quality and mild to moderate severity, while CM can be unilateral or bilateral and of moderate to severe intensity. Importantly, chronic tension-type headache is considered "featureless"—it is not usually accompanied by migrainous symptoms like nausea, vomiting, photophobia, phonophobia, and is not exacerbated by exertion. As migraine progresses into chronic form, the headache may resemble tension-type on some days [29]; nonetheless, typical migraine features must be present on at least 8 days per month for the diagnosis of

chronic migraine to be validated [1].

**Etiology Examples**

**Intracranial hypertension**

**Intracranial hypotension**

**Trauma** Traumatic brain injury

CSF leak **Infection** Meningitis, encephalitis, sinusitis, abscess

**Metabolic disorders** Uremia, hepatic encephalopathy, hypoxia **Neuralgias** Trigeminal neuralgia, occipital neuralgia **Psychiatric** Somatoform disorder, psychosis, aggravation

*Possible Causes of Secondary Headaches (alphabetically ordered) [29, 45, 97].*

abuse or withdrawal

**Anatomic disorders**

*Migraine*

**Changes in intracranial pressure**

**disuse**

**Table 3.**

**86**

**Medication and substance**

differential diagnosis [29, 45, 97].

*Differential diagnosis for long-duration primary headaches\* .*

should be revoked, as it would seem that the overuse had taken place simply as a result of increased attack frequency [101]. Points of the differential diagnosis are summarized in **Table 4**.

Once the diagnosis of CM has been confirmed, standard questionnaires, such as Migraine Disability Assessment (MIDAS) or Headache Impact Test-6 (HIT-6) should be used for patient assessment in order to evaluate the burden of disease and monitor the effects of prescribed treatment [95]. Episodic and treatment-responsive migraine can be diagnosed and managed in the primary care, while chronic or refractory patients should be referred to a specialist neurologist, preferably with an expertise in the field of headache disorders [95].

#### **7. Treatment**

There are three broad approaches to treating CM [97]:

• Lifestyle and trigger management.


#### **7.1 Lifestyle and trigger management**

Lifestyle modification, as well as trigger reduction can, be helpful in reducing the fequency of migraine attacks and stopping or slowing down the process of migraine chronification. That includes regularity of regimen with regard to meals, hydration, sleep and stress. It could be also helpful to detect and understand the obvious triggers. It is important to know other problems that exacerbate the tendency to headaches: such as: depression, anxiety, other pain syndromes such as fibromyalgia, localized pain in head and neck structures, and conditions that create 'metabolic'strain such as obesity, sleep apnoea or postural orthostatic tachycardia syndrome [102, 103]. It is particularly important to recognize and manage medication overuse (including caffeine overuse), as failure to do so will render most attempts at preventive treatment ineffective [92].

**7.3 Preventive treatment**

*DOI: http://dx.doi.org/10.5772/intechopen.93314*

*Chronic Migraine*

The goals of CM prophylactic treatment are to prevent attacks, thereby reducing headache frequency, severity and associated disability and decreasing reliance on acute treatment, which may be contributing to concurrent MOH [92, 104]. An additional goal may be to prevent progression of EM to CM in patients with highfrequency attacks [45]. The first-line treatment of CM is pharmacological [45]. Numerous orally administered drugs are used for the prophylaxis of CM, including beta-blockers, calcium-channel blockers, tricyclic antidepressants, serotonin antagonists, antihypertensives, and antidepressants [112]. The drugs that are effective for EM are not necessarily effective for CM [54], but evidence for the efficacy of oral agents in CM is generally extrapolated from studies in patients with high-frequency EM [97, 113]. Insufficient efficacy, not suitable route and dose of drug administration and/or adverse events leading to treatment discontinuation

The only currently available evidence-based prophylactic treatment options for CM are topiramate and onabotulinumtoxinA (OBT-A) which is a formulation of botulinum toxin A administered by intramuscular injection, from more than one

To date, OBT-A is the only treatment specifically approved for the prevention of CM in the EU and North America (class of evidence I, level of recommendation A) [116–119]. In the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials [117, 118] OBT-A has been shown to be an effective and generally well tolerated treatment for the prevention of CM, and tends to be better tolerated than various oral prophylactic treatments, including topiramate [120–123]. Based on the PREEMPT clinical trial protocol, OBT-A is administered to at least 31 injection sites across 7 head and neck muscles, and is currently recommended as a second-line option for patients who have not responded adequately or are intolerant of commonly prescribed oral migraine prophylaxis [124]. Treatment should be repeated every 12 weeks. This data was confirmed in recently finished Chronic migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL) study, aim to investigate the long-term safety, efficacy and tolerability of nine cycles of repetitive BoNT-A injections. The Compel Study concluded that OBT-A treatment was well tolerated over 108 weeks, and no new safety signals were identified [125]. The molecular biological mechanism of action of OBT-A is well established, whereby it inhibits fusion of intracellular vesicles with the nerve membrane [125] by cleaving synaptosomal-associated protein (SNAP-25) [126, 127]. By impairing intraneuronal vesicular fusion, OBT-A modulates neuropeptide release and downregulates receptors and ion channels important in nociception [128, 129].

So, it is thought that OBT-A blocks release of CGRP from peripheral nociceptive neurons and interferes with transient receptor potential cation (TRP) channels in the trigeminally-innervated cranio-facial-cervical region, thereby reducing neuronal hyperexcitability and peripheral and central sensitisation [54, 130]. It is hypothesized that trigeminal-targeted preventative treatments counteract the impingement of nociceptive input from highly sensitized trigeminal neurons on brainstem second-order neurons, thus preventing central sensitisation, a key path-

Additionally recent clinical data demonstrates that OBT-A has been shown to reduce serum CGRP concentration in patients with CM (pretreatment median, 74.1 pg/mL; 1 month post-treatment median, 51.9 pg/mL, *P* < 0.001) [132]. One

often occur with these drugs in patients with CM [114, 115].

randomized controlled trial [97, 113].

ophysiological mechanism of CM [131].

**89**

*7.3.1 OnabotulinumtoxinA*

In order to identify the factors mentioned above it is very important to take a detailed history of the particular patient and to evaluate the headache questionnaires and diaries, which are suggestable in many headache centers worldwide.

#### **7.2 Acute headache treatments**

The natural course of CM presents a variation in headache frequency meaning that patients can fluctuate between EM and CM [97] and exacerbations of chronic pain. Acute CM treatments are necessary to treat these conditions; e.g., **migraine attacks or exacerbations of chronic pain**.

For the patients with CM often is difficult to know when to take acute treatments. The physician should discuss this question with the patient and also explain about the possibility of co-existence of MOH, which now is considered a sequela rather than a cause of migraine and can co-exist with CM [1, 92].

In order to prevent the development of MOH, it is very important to avoid using painkillers and triptans too often in the early stages of management [104]. The detailed anamnesis and analysis of patient headache questionnaire and diary will help to understand and count the" good days and bad days "or the days with clearly exacerbated headaches. For the acute headache treatment are recommended the same groups of medications as for migraine attack treatment. This includes simple analgesics, combinated analgetics, triptans if the analgetics are not effective, and neuromodulating procedures [97, 99, 105] (Reference to section on treatment of migraine attacks to be included).

Opioids are not recommended for the treatment of acute headache because of the significant risk of medication overuse and the most protracted withdrawal [106].

Triptans are migraine-specific medications that inhibit the release of CGRP by activation of presynaptic 5HT1 receptors [107, 108]. However, patients should not take triptans more than 10 days in a month to avoid developing MOH [1].

Non-invasive stimulation procedures could be used in patients who refuse to use pharmacological migraine therapy or it is contraindicated or not tolerated. That includes external trigeminal nerve stimulation [109], single transcranial magnetic stimulation [110] and transcutaneus vagal nerve stimulation [111].

Effective acute treatment of migraine attacks may help to prevent progression from EM to CM, but rather than relying on taking drugs to stop migraine attacks after they have started, the aim of treatment for CM should be the prevention of migraine attacks [20].

#### **7.3 Preventive treatment**

• Acute headache treatments.

**7.1 Lifestyle and trigger management**

attempts at preventive treatment ineffective [92].

**7.2 Acute headache treatments**

migraine attacks to be included).

migraine attacks [20].

**88**

**attacks or exacerbations of chronic pain**.

Lifestyle modification, as well as trigger reduction can, be helpful in reducing the fequency of migraine attacks and stopping or slowing down the process of migraine chronification. That includes regularity of regimen with regard to meals, hydration, sleep and stress. It could be also helpful to detect and understand the obvious triggers. It is important to know other problems that exacerbate the tendency to headaches: such as: depression, anxiety, other pain syndromes such as fibromyalgia, localized pain in head and neck structures, and conditions that create 'metabolic'strain such as obesity, sleep apnoea or postural orthostatic tachycardia syndrome [102, 103]. It is particularly important to recognize and manage medication overuse (including caffeine overuse), as failure to do so will render most

In order to identify the factors mentioned above it is very important to take a detailed history of the particular patient and to evaluate the headache questionnaires and diaries, which are suggestable in many headache centers worldwide.

The natural course of CM presents a variation in headache frequency meaning that patients can fluctuate between EM and CM [97] and exacerbations of chronic pain. Acute CM treatments are necessary to treat these conditions; e.g., **migraine**

For the patients with CM often is difficult to know when to take acute treatments. The physician should discuss this question with the patient and also explain about the possibility of co-existence of MOH, which now is considered a sequela

In order to prevent the development of MOH, it is very important to avoid using

Opioids are not recommended for the treatment of acute headache because of the significant risk of medication overuse and the most protracted withdrawal [106]. Triptans are migraine-specific medications that inhibit the release of CGRP by activation of presynaptic 5HT1 receptors [107, 108]. However, patients should not

Non-invasive stimulation procedures could be used in patients who refuse to use pharmacological migraine therapy or it is contraindicated or not tolerated. That includes external trigeminal nerve stimulation [109], single transcranial magnetic

Effective acute treatment of migraine attacks may help to prevent progression from EM to CM, but rather than relying on taking drugs to stop migraine attacks after they have started, the aim of treatment for CM should be the prevention of

take triptans more than 10 days in a month to avoid developing MOH [1].

stimulation [110] and transcutaneus vagal nerve stimulation [111].

painkillers and triptans too often in the early stages of management [104]. The detailed anamnesis and analysis of patient headache questionnaire and diary will help to understand and count the" good days and bad days "or the days with clearly exacerbated headaches. For the acute headache treatment are recommended the same groups of medications as for migraine attack treatment. This includes simple analgesics, combinated analgetics, triptans if the analgetics are not effective, and neuromodulating procedures [97, 99, 105] (Reference to section on treatment of

rather than a cause of migraine and can co-exist with CM [1, 92].

• Preventive treatment.

*Migraine*

The goals of CM prophylactic treatment are to prevent attacks, thereby reducing headache frequency, severity and associated disability and decreasing reliance on acute treatment, which may be contributing to concurrent MOH [92, 104]. An additional goal may be to prevent progression of EM to CM in patients with highfrequency attacks [45]. The first-line treatment of CM is pharmacological [45].

Numerous orally administered drugs are used for the prophylaxis of CM, including beta-blockers, calcium-channel blockers, tricyclic antidepressants, serotonin antagonists, antihypertensives, and antidepressants [112]. The drugs that are effective for EM are not necessarily effective for CM [54], but evidence for the efficacy of oral agents in CM is generally extrapolated from studies in patients with high-frequency EM [97, 113]. Insufficient efficacy, not suitable route and dose of drug administration and/or adverse events leading to treatment discontinuation often occur with these drugs in patients with CM [114, 115].

The only currently available evidence-based prophylactic treatment options for CM are topiramate and onabotulinumtoxinA (OBT-A) which is a formulation of botulinum toxin A administered by intramuscular injection, from more than one randomized controlled trial [97, 113].

#### *7.3.1 OnabotulinumtoxinA*

To date, OBT-A is the only treatment specifically approved for the prevention of CM in the EU and North America (class of evidence I, level of recommendation A) [116–119]. In the Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials [117, 118] OBT-A has been shown to be an effective and generally well tolerated treatment for the prevention of CM, and tends to be better tolerated than various oral prophylactic treatments, including topiramate [120–123]. Based on the PREEMPT clinical trial protocol, OBT-A is administered to at least 31 injection sites across 7 head and neck muscles, and is currently recommended as a second-line option for patients who have not responded adequately or are intolerant of commonly prescribed oral migraine prophylaxis [124]. Treatment should be repeated every 12 weeks. This data was confirmed in recently finished Chronic migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL) study, aim to investigate the long-term safety, efficacy and tolerability of nine cycles of repetitive BoNT-A injections. The Compel Study concluded that OBT-A treatment was well tolerated over 108 weeks, and no new safety signals were identified [125].

The molecular biological mechanism of action of OBT-A is well established, whereby it inhibits fusion of intracellular vesicles with the nerve membrane [125] by cleaving synaptosomal-associated protein (SNAP-25) [126, 127]. By impairing intraneuronal vesicular fusion, OBT-A modulates neuropeptide release and downregulates receptors and ion channels important in nociception [128, 129].

So, it is thought that OBT-A blocks release of CGRP from peripheral nociceptive neurons and interferes with transient receptor potential cation (TRP) channels in the trigeminally-innervated cranio-facial-cervical region, thereby reducing neuronal hyperexcitability and peripheral and central sensitisation [54, 130]. It is hypothesized that trigeminal-targeted preventative treatments counteract the impingement of nociceptive input from highly sensitized trigeminal neurons on brainstem second-order neurons, thus preventing central sensitisation, a key pathophysiological mechanism of CM [131].

Additionally recent clinical data demonstrates that OBT-A has been shown to reduce serum CGRP concentration in patients with CM (pretreatment median, 74.1 pg/mL; 1 month post-treatment median, 51.9 pg/mL, *P* < 0.001) [132]. One month after treatment, CGRP levels significantly decreased in patients defined as OBT-A responders.

(VYEPTI**™**) is the first intravenous (IV) treatment for migraine prevention and the latest in a new class of mAbs. A brief review of all four mAbs, dose and rout of

The anti-CGRP/R antibodies are highly specific for their CGRP/R target, have no ability to cross the blood brain barrier, and bypass liver metabolism so CNS-related effects and hepatotoxicity are unlikely [158]. Their long half-lives allow for dosing once a month for erenumab and galcanezumab, or and once every 3months, for

This very promising treatment with mABs for CM is proved in clinical trials [163]. **Erenumab:** A phase II RCT evaluated the safety and the efficacy of erenumab in subjects aged 18–65years with CM with duration of treatment 3 months and preventive treatment not allowed [164]. Patients (n = 667) were randomized to monthly subcutaneous injection of erenumab 70mg, erenumab 140mg or placebo for 3months. Exclusion by preventive failure of >3 drugs. At weeks 9–12, there was a reduction in monthly migraine days in the erenumab 70mg (LSMD 2.5; SE 3.5 to 1.4; *P* < 0.0001) and in the erenumab 140mg (LSMD 2.5; SE 3.5 to 1.4; P < 0.0001) groups compared to placebo group. There was a reduction in monthly number of days using migraines-specific medication in the erenumab 70mg (LSMD 1.9; SE 2.6 to 1.1; P < 0.0001) and in the erenumab 140mg (LSMD 2.6; SE

adminstration are provided in **Table 5**.

*DOI: http://dx.doi.org/10.5772/intechopen.93314*

*Chronic Migraine*

Erenumab (Aimovig)

Fremanezumab (Ajovy)

Galcanezumab (Emgality

Eptinezumab (VYEPTI**™**)

**Table 5.**

**91**

fremanezumab [159–161] and eptinezumab [162].

3.3 to 1.8; P < 0.0001) groups compared to the placebo group.

**Drug Manufacturer Target Dose of administration Route of**

CGRP receptor

ligand

CGRP ligand

CGRP ligand

Amgen and Novartis Pharmaceuticals

Eli Lilly and Company

Alder Biopharmaceuticals and Lundbeck Seattle BioPharmaceuticals Inc.

*Brief review of administration of CRRP/R monoclonal antibodies.*

Teva CGRP

**Fremanezumab:** In this multicentre, randomized, double-blind, doubledummy, placebo-controlled, parallel-group phase 2b study, were enrolled men and

**administration**

70 mg Once monthly Autoinjector

225 mg Once monthly Syringe or

(q)

may need 140 mg SC once monthly

140 mg Some patients

675 mg Every 3 months

240 mg(2 consecutive 120 mg SC injections) loading dose once, maintainance dose 120 mg monthly

100 mg IV every 3 months (q)

3 months (q)

**Dosing**

70 mg/mL

Autoinjector 140 mg/mL

autoinjector 225 mg/ 1.5 mL

prefilled pen 120 mg/mL and singledose prefilled syringe 100 mg/mL and 120 mg/ mL

Injectable solution

Once monthly Single-dose

Every 3 months

Some patients may benefit from a 300 mg IV dose q3 months

(q)

100 mg/ml 300 mg IV every

There is no consensus in the literature regarding the number of OBT-A cycles required for the preventive treatment of CM. Some trials suggest an increasing efficacy with regular cycle repetition for more than 1 year, including in patients with MOH (three class II trials, level B recommendation) [133–135]. To date, no clinical features predicting responses to OBT-A (recommendation level B) have been identified [136, 137].

The adverse effects of 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 sites (class of evidence I) [117–119, 137–139].

#### *7.3.2 Topiramate*

Although not specifically licensed for CM, orally administered anticonvulsant topiramate is an effective prophylactic treatment for patients with migraine, and may be effective in patients with CM [140]. Topiramate reduced headache days versus placebo and was relatively well tolerated in patients with CM in two large randomized controlled trials [141, 142]. The initial dosage should be started slowly with 2 12.5 mg or 2 25 mg and a dose of 2 50 mg (if necessary up to 2 100 mg) per day as final target dose. Adverse events commonly associated with topiramate include paresthesia, memory and concentration disturbances, fatigue, nausea, and weight loss [143, 144].

It is thought that topiramate has dual effects on neurotransmission—enhancing inhibitory effects while minimizing excitatory effects, both of which are implicated in migraine physiology [145]. The pharmacologic mechanisms underlying this antimigraine activity may include blockade of cell membrane ion channels and neurotransmitter release (e.g., inhibition of glutamate), resulting in inhibition of neuronal hyperexcitability. Studies have demonstrated topiramate's inhibitory effect on excitability in motor and visual cortices [54, 144, 145]. Based on this broad mechanism of action, topiramate may prevent the development of cortical spreading depression by reducing nociceptive transmission and generally inhibiting neuronal hyperexcitability [146]. Similarly, topiramate has demonstrated cognitive adverse events, which are likely a reflection of the central inhibitory effects [54]. Pooled analyses of clinical trial results suggest that preventive topiramate treatment in patients with episodic migraine may reduce the risk of headache-day increase, which in some cases may prevent migraine chronification [147].

#### *7.3.3 Monoclonal antibodies*

Deeper understanding the importance of CGRP and its receptor role in CM pathophysiology and need for more effective, better tolerated prophylactic therapies for CM or high-frequency EM gave background for the development of the new class drugs—anti-CGRP/R monoclonal antibodies (mAbs).

Four anti-CGRP/R antibodies are approved in the US and Europe for the prophylactic treatment of CM: erenumab (Aimovig) [148, 149], which targets the CGRP receptor, fremanezumab (Ajovy) [150, 151] and galcanezumab (Emgality) [152, 153] which target the CGRP ligand; and fourth anti-CGRP/R antibody against the CGRP ligand, eptinezumab (VYEPTI**™**), which was approved by FDA and EMA on year 2020 [154, 155]. These macromolecule anti-CGRP/R antibodies have been specifically designed for prophylactic use in CM and frequent EM, and to overcome safety issues associated with CGRP receptor antagonists [156, 157]. Eptinezumab

#### *Chronic Migraine DOI: http://dx.doi.org/10.5772/intechopen.93314*

month after treatment, CGRP levels significantly decreased in patients defined as

There is no consensus in the literature regarding the number of OBT-A cycles required for the preventive treatment of CM. Some trials suggest an increasing efficacy with regular cycle repetition for more than 1 year, including in patients with MOH (three class II trials, level B recommendation) [133–135]. To date, no clinical features predicting responses to OBT-A (recommendation level B) have

The adverse effects of 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

Although not specifically licensed for CM, orally administered anticonvulsant topiramate is an effective prophylactic treatment for patients with migraine, and may be effective in patients with CM [140]. Topiramate reduced headache days versus placebo and was relatively well tolerated in patients with CM in two large randomized controlled trials [141, 142]. The initial dosage should be started slowly with 2 12.5 mg or 2 25 mg and a dose of 2 50 mg (if necessary up to 2 100 mg) per day as final target dose. Adverse events commonly associated with topiramate include paresthesia, memory and concentration disturbances, fatigue,

It is thought that topiramate has dual effects on neurotransmission—enhancing inhibitory effects while minimizing excitatory effects, both of which are implicated in migraine physiology [145]. The pharmacologic mechanisms underlying this antimigraine activity may include blockade of cell membrane ion channels and neurotransmitter release (e.g., inhibition of glutamate), resulting in inhibition of neuronal hyperexcitability. Studies have demonstrated topiramate's inhibitory effect on excitability in motor and visual cortices [54, 144, 145]. Based on this broad mechanism of action, topiramate may prevent the development of cortical spreading depression by reducing nociceptive transmission and generally inhibiting neuronal hyperexcitability [146]. Similarly, topiramate has demonstrated cognitive adverse events, which are likely a reflection of the central inhibitory effects [54]. Pooled analyses of clinical trial results suggest that preventive topiramate treatment in patients with episodic migraine may reduce the risk of headache-day increase,

to pain at injection sites (class of evidence I) [117–119, 137–139].

which in some cases may prevent migraine chronification [147].

new class drugs—anti-CGRP/R monoclonal antibodies (mAbs).

Deeper understanding the importance of CGRP and its receptor role in CM pathophysiology and need for more effective, better tolerated prophylactic therapies for CM or high-frequency EM gave background for the development of the

Four anti-CGRP/R antibodies are approved in the US and Europe for the prophylactic treatment of CM: erenumab (Aimovig) [148, 149], which targets the CGRP receptor, fremanezumab (Ajovy) [150, 151] and galcanezumab (Emgality) [152, 153] which target the CGRP ligand; and fourth anti-CGRP/R antibody against the CGRP ligand, eptinezumab (VYEPTI**™**), which was approved by FDA and EMA on year 2020 [154, 155]. These macromolecule anti-CGRP/R antibodies have been specifically designed for prophylactic use in CM and frequent EM, and to overcome safety issues associated with CGRP receptor antagonists [156, 157]. Eptinezumab

OBT-A responders.

*Migraine*

*7.3.2 Topiramate*

been identified [136, 137].

nausea, and weight loss [143, 144].

*7.3.3 Monoclonal antibodies*

**90**

(VYEPTI**™**) is the first intravenous (IV) treatment for migraine prevention and the latest in a new class of mAbs. A brief review of all four mAbs, dose and rout of adminstration are provided in **Table 5**.

The anti-CGRP/R antibodies are highly specific for their CGRP/R target, have no ability to cross the blood brain barrier, and bypass liver metabolism so CNS-related effects and hepatotoxicity are unlikely [158]. Their long half-lives allow for dosing once a month for erenumab and galcanezumab, or and once every 3months, for fremanezumab [159–161] and eptinezumab [162].

This very promising treatment with mABs for CM is proved in clinical trials [163]. **Erenumab:** A phase II RCT evaluated the safety and the efficacy of erenumab in subjects aged 18–65years with CM with duration of treatment 3 months and preventive treatment not allowed [164]. Patients (n = 667) were randomized to monthly subcutaneous injection of erenumab 70mg, erenumab 140mg or placebo for 3months. Exclusion by preventive failure of >3 drugs. At weeks 9–12, there was a reduction in monthly migraine days in the erenumab 70mg (LSMD 2.5; SE 3.5 to 1.4; *P* < 0.0001) and in the erenumab 140mg (LSMD 2.5; SE 3.5 to 1.4; P < 0.0001) groups compared to placebo group. There was a reduction in monthly number of days using migraines-specific medication in the erenumab 70mg (LSMD 1.9; SE 2.6 to 1.1; P < 0.0001) and in the erenumab 140mg (LSMD 2.6; SE 3.3 to 1.8; P < 0.0001) groups compared to the placebo group.

**Fremanezumab:** In this multicentre, randomized, double-blind, doubledummy, placebo-controlled, parallel-group phase 2b study, were enrolled men and


**Table 5.**

*Brief review of administration of CRRP/R monoclonal antibodies.*

women (aged 18–65 years) who had CM with duration of treatment 3 months [165]. Patients (n = 264) were randomized to three 28-day treatment cycles of subcutaneous injections of fremanezumab 225mg, fremanezumab 900mg or placebo. Exclusion by preventive failure of >3 drugs. At weeks 9–12, there was a reduction in moderate to severe headache days in the fremanezumab 675/225mg (LSMD 1.84; 95% CI 3.54 to 0.14; *P* = 0.0345) and in the fremanezumab 900mg (LSMD 1.96; 95% CI 3.66 to 0.26; *P* = 0.0237) groups compared to placebo group. There was a reduction in number of days using acute medication in the fremanezumab 900mg (LSMD 2.04; 95% CI 3.9 to 0.2; *P* = 0.027) group compared to placebo group.

analysis of the percentage of patients for whom migraine had a severe impact on life

The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy–2 (PROMISE-2) study was a phase 3, multicenter, randomized, double-blind,

placebo-controlled, parallel-group study with duration of treatment 12 weeks [167]. Adults with CM (n = 1072) were randomly assigned to receive IV eptinezumab 100 mg, eptinezumab 300 mg, or placebo administered on day 0 and week 12. Exclusion is by preventive failure of ≥2 drugs. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) over weeks 1–12. Treatment with eptinezumab 100 and 300 mg was associated with significant reductions in MMDs across weeks 1–12 compared with placebo (placebo 5.6, 100 mg 7.7, *p* < 0.0001 vs. placebo; 300 mg 8.2, *p* < 0.0001 vs. placebo). The mean HIT-6 scores at baseline were 65.0 (eptinezumab 100 mg), 65.1 (eptinezumab 300 mg), and 64.8 (placebo). By week 12, the percentage of patients with HIT-6 scores in the severe range had been reduced to 51.4% in the eptinezumab 100 mg treatment group, 42.9% in the eptinezumab 300 mg treatment group, and 60.1% in the placebo group. Patients in the eptinezumab 300 mg group demonstrated a statisti-

demonstrated a reduction from 90.3% at baseline to 29.9% at week 12 with eptinezumab 300 mg, 86.4–43.0% with eptinezumab 100 mg, compared with

cally significant improvement on the HIT-6 at week 12, with an estimated mean difference from placebo (95% confidence interval) of 2.9 (3.9 to 1.8,

that no serious advers events (SAEs), no deaths deemed to be related to mAbs occurred in clinical trials with all fours mAbs. According the data of clinical trials, the most common adverse events (5 to >10% of the study population) for all three CGRP antagonists (erenumab, fremanezumab, galcanezumab) were injection-site reactions and pain. Specific adverse reactions for erenumab was constipation (1–3% of patients) and cramps, muscle spasms (<3%), hyperintensity for galcanezumab,

and nasopharyngitis (6–8%) and hyperintensity (1–2%) for eptinezumab.

compliance in the group treated with OBT-A [122].

**Recommendations on the use of the mAbs:** Following the clinical studies results and expert opinion EHF on 2019 prepared recommendations about the use three mAbs (erenumab, fremanezumab, galcanezumab) in subjects with CM [163]. In these recommendations due to the then-unpublished original data eptinezumab was not included (**Table 6**). Keeping in mind the fact that this mAb belongs to the same class of drugs (e.g., anti-calcitonin gene-related peptide monoclonal antibodies) with similar profile it seems that the recommendations fits for it too.

The strategy of combining different prophylactic drugs is not supported by highlevel evidence [168]. However, the so-called rational polytherapy—the association of effective drugs with different mechanisms—can be used in monotherapyrefractory patients [169]. Regarding comparative efficacy, one single-center double-blind RCT showed equivalence between OBT-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 OBT-A [121] while one single-center open-label study showed comparable efficacy between amitriptyline (25–50 mg/day) and OBT-A (250 U/15 sites), also with better tolerability and

Preclinical data suggest that anti-calcitonin gene-related peptide monoclonal antibodies and OBT-A have synergistic effects within the trigeminovascular system. Of note, findings indicate that fremanezumab—an antibody targeting the calcitonin

**Adverse events of the mAbs:** The results of four mABs clinical studies showed

79.3–50.9% with placebo.

*DOI: http://dx.doi.org/10.5772/intechopen.93314*

*Chronic Migraine*

*p* < 0.0001).

*7.3.4 Combinations*

**93**

A phase III RCT, the HALO CM, evaluated the efficacy of fremanezumab in subjects aged 18–70years with CM with duration of treatment 3 months [160]. Patients (n = 1130) were randomized to monthly subcutaneous injections of fremanezumab 225mg (loading dose of 675mg), to quarterly fremanezumab 675 mg, or placebo for 3months. Exclusion by preventive failure of ≥2 drugs. During 12-week period, there was a reduction in the average number of headache days per month in the fremanezumab 675mg (LSMD 1.8; SE 0.3; *P* < 0.001) and in the fremanezumab 675/225mg (LSMD -2.1; SE 0.3; P < 0.001) groups compared to placebo group. There was a reduction in the monthly number of days using acute medication in the fremanezumab 675mg (LSMD 1.8; SE 0.3; P < 0.001) and in the fremanezumab 675/225mg (LSMD 2.3; SE 0.3; P < 0.001) groups compared to placebo group. There was an improvement in the HIT-6 [166] score in the fremanezumab 675mg (LSMD 1.9; SE 0.5; P < 0.001) and in the fremanezumab 675/225mg (LSMD 2.4; SE 0.5; P < 0.001) groups compared to placebo group.

**Galcanezumab:** A phase III RCT, the randomized, double-blind, placebocontrolled REGAIN study evaluated the efficacy of galcanezumab in subjects aged 18–65years with CM with duration of treatment 3 months [161]. Patients (n = 1117) were randomized to monthly subcutaneous injections of galcanezumab 120mg (loading dose of 240mg at baseline), galcanezumab 240mg, or placebo for 3 months. Exclusion by preventive failure of >2 drugs During the 3-month period, there was a reduction in monthly migraine days in the galcanezumab 120mg group (LSMD 2.1; 95% CI 2.9 to 1.3) and with galcanezumab 240mg (LSMD 1.9; 95% CI 2.7 to 1.1) compared to placebo groups. There was a reduction in monthly number of days using acute medication use in the galcanezumab 240mg (LSMD 2.0; 95% CI 2.8 to 1.3) but not in galcanezumab 120mg as compared to the placebo group. There was an improvement in the MIDAS score in the galcanezumab 120mg (LSMD 8.7; 95% CI 16.4 to 3.1) but not in galcanezumab 240mg as compared to the placebo group.

**Eptinezumab:** This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial with duration of treatment 12 weeks and preventive treatment, except botulin toxin, not allowed [162]. Men and women aged 18–55 years (n = 616) were included if they had a diagnosis of CM with onset at age 35 years and history of CM 1 year. During the 28-day screening period, patients must have had 15 headache days, including 8 migraine days, with five migraine attacks as recorded in the electronic diary. Exclusion is by preventive failure of ≥2 drugs. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a 75% decrease in monthly migraine days over weeks 1–12 compared with the 28-day screening period. Secondary efficacy endpoints had results favoring the three higher eptinezumab doses versus placebo. The greatest effect of eptinezumab, as measured by the HIT-6 was observed at week 12, with changes in baseline scores of 10.0, 6.9, 6.5, and 6.5 for the 300, 100, 30, and 10 mg groups, respectively, compared with 5.8 for the placebo group. A prespecified

women (aged 18–65 years) who had CM with duration of treatment 3 months [165]. Patients (n = 264) were randomized to three 28-day treatment cycles of subcutaneous injections of fremanezumab 225mg, fremanezumab 900mg or placebo. Exclusion by preventive failure of >3 drugs. At weeks 9–12, there was a reduction in moderate to severe headache days in the fremanezumab 675/225mg (LSMD 1.84; 95% CI 3.54 to 0.14; *P* = 0.0345) and in the fremanezumab 900mg (LSMD 1.96; 95% CI 3.66 to 0.26; *P* = 0.0237) groups compared to placebo group.

There was a reduction in number of days using acute medication in the

compared to placebo group.

*Migraine*

fremanezumab 900mg (LSMD 2.04; 95% CI 3.9 to 0.2; *P* = 0.027) group

placebo group. There was an improvement in the HIT-6 [166] score in the

the placebo group. There was an improvement in the MIDAS score in the

240mg as compared to the placebo group.

**92**

galcanezumab 120mg (LSMD 8.7; 95% CI 16.4 to 3.1) but not in galcanezumab

**Eptinezumab:** This was a phase 2b, parallel-group, double-blind, randomized, placebo-controlled, dose-ranging clinical trial with duration of treatment 12 weeks and preventive treatment, except botulin toxin, not allowed [162]. Men and women aged 18–55 years (n = 616) were included if they had a diagnosis of CM with onset at age 35 years and history of CM 1 year. During the 28-day screening period, patients must have had 15 headache days, including 8 migraine days, with five migraine attacks as recorded in the electronic diary. Exclusion is by preventive failure of ≥2 drugs. Patients were assigned in a 1:1:1:1:1 ratio to eptinezumab 300, 100, 30, 10 mg or placebo, administered as a single IV infusion. The primary endpoint was the percentage of patients with a 75% decrease in monthly migraine days over weeks 1–12 compared with the 28-day screening period. Secondary efficacy endpoints had results favoring the three higher eptinezumab doses versus placebo. The greatest effect of eptinezumab, as measured by the HIT-6 was observed at week 12, with changes in baseline scores of 10.0, 6.9, 6.5, and 6.5 for the 300, 100, 30, and 10 mg groups, respectively, compared with 5.8 for the placebo group. A prespecified

fremanezumab 675mg (LSMD 1.9; SE 0.5; P < 0.001) and in the fremanezumab 675/225mg (LSMD 2.4; SE 0.5; P < 0.001) groups compared to placebo group. **Galcanezumab:** A phase III RCT, the randomized, double-blind, placebocontrolled REGAIN study evaluated the efficacy of galcanezumab in subjects aged 18–65years with CM with duration of treatment 3 months [161]. Patients (n = 1117) were randomized to monthly subcutaneous injections of galcanezumab 120mg (loading dose of 240mg at baseline), galcanezumab 240mg, or placebo for 3 months. Exclusion by preventive failure of >2 drugs During the 3-month period, there was a reduction in monthly migraine days in the galcanezumab 120mg group (LSMD 2.1; 95% CI 2.9 to 1.3) and with galcanezumab 240mg (LSMD 1.9; 95% CI 2.7 to 1.1) compared to placebo groups. There was a reduction in monthly number of days using acute medication use in the galcanezumab 240mg (LSMD 2.0; 95% CI 2.8 to 1.3) but not in galcanezumab 120mg as compared to

A phase III RCT, the HALO CM, evaluated the efficacy of fremanezumab in subjects aged 18–70years with CM with duration of treatment 3 months [160]. Patients (n = 1130) were randomized to monthly subcutaneous injections of fremanezumab 225mg (loading dose of 675mg), to quarterly fremanezumab 675 mg, or placebo for 3months. Exclusion by preventive failure of ≥2 drugs. During 12-week period, there was a reduction in the average number of headache days per month in the fremanezumab 675mg (LSMD 1.8; SE 0.3; *P* < 0.001) and in the fremanezumab 675/225mg (LSMD -2.1; SE 0.3; P < 0.001) groups compared to placebo group. There was a reduction in the monthly number of days using acute medication in the fremanezumab 675mg (LSMD 1.8; SE 0.3; P < 0.001) and in the fremanezumab 675/225mg (LSMD 2.3; SE 0.3; P < 0.001) groups compared to analysis of the percentage of patients for whom migraine had a severe impact on life demonstrated a reduction from 90.3% at baseline to 29.9% at week 12 with eptinezumab 300 mg, 86.4–43.0% with eptinezumab 100 mg, compared with 79.3–50.9% with placebo.

The Prevention of Migraine via Intravenous ALD403 Safety and Efficacy–2 (PROMISE-2) study was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study with duration of treatment 12 weeks [167]. Adults with CM (n = 1072) were randomly assigned to receive IV eptinezumab 100 mg, eptinezumab 300 mg, or placebo administered on day 0 and week 12. Exclusion is by preventive failure of ≥2 drugs. The primary endpoint was change from baseline in mean monthly migraine days (MMDs) over weeks 1–12. Treatment with eptinezumab 100 and 300 mg was associated with significant reductions in MMDs across weeks 1–12 compared with placebo (placebo 5.6, 100 mg 7.7, *p* < 0.0001 vs. placebo; 300 mg 8.2, *p* < 0.0001 vs. placebo). The mean HIT-6 scores at baseline were 65.0 (eptinezumab 100 mg), 65.1 (eptinezumab 300 mg), and 64.8 (placebo). By week 12, the percentage of patients with HIT-6 scores in the severe range had been reduced to 51.4% in the eptinezumab 100 mg treatment group, 42.9% in the eptinezumab 300 mg treatment group, and 60.1% in the placebo group. Patients in the eptinezumab 300 mg group demonstrated a statistically significant improvement on the HIT-6 at week 12, with an estimated mean difference from placebo (95% confidence interval) of 2.9 (3.9 to 1.8, *p* < 0.0001).

**Adverse events of the mAbs:** The results of four mABs clinical studies showed that no serious advers events (SAEs), no deaths deemed to be related to mAbs occurred in clinical trials with all fours mAbs. According the data of clinical trials, the most common adverse events (5 to >10% of the study population) for all three CGRP antagonists (erenumab, fremanezumab, galcanezumab) were injection-site reactions and pain. Specific adverse reactions for erenumab was constipation (1–3% of patients) and cramps, muscle spasms (<3%), hyperintensity for galcanezumab, and nasopharyngitis (6–8%) and hyperintensity (1–2%) for eptinezumab.

**Recommendations on the use of the mAbs:** Following the clinical studies results and expert opinion EHF on 2019 prepared recommendations about the use three mAbs (erenumab, fremanezumab, galcanezumab) in subjects with CM [163]. In these recommendations due to the then-unpublished original data eptinezumab was not included (**Table 6**). Keeping in mind the fact that this mAb belongs to the same class of drugs (e.g., anti-calcitonin gene-related peptide monoclonal antibodies) with similar profile it seems that the recommendations fits for it too.

#### *7.3.4 Combinations*

The strategy of combining different prophylactic drugs is not supported by highlevel evidence [168]. However, the so-called rational polytherapy—the association of effective drugs with different mechanisms—can be used in monotherapyrefractory patients [169]. Regarding comparative efficacy, one single-center double-blind RCT showed equivalence between OBT-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 OBT-A [121] while one single-center open-label study showed comparable efficacy between amitriptyline (25–50 mg/day) and OBT-A (250 U/15 sites), also with better tolerability and compliance in the group treated with OBT-A [122].

Preclinical data suggest that anti-calcitonin gene-related peptide monoclonal antibodies and OBT-A have synergistic effects within the trigeminovascular system. Of note, findings indicate that fremanezumab—an antibody targeting the calcitonin


**8. Management of chronic migraine**

*DOI: http://dx.doi.org/10.5772/intechopen.93314*

treatment plan.

*Chronic Migraine*

cians [95].

therapy

**9. Conclusions**

*disability assessment.*

\*

**Box 1.**

**95**

about it is still continuing,

3 months of treatment [172].

severely affected patients [95].

Complete and correct diagnosis

Explaining realistic expectations to patients Consideration of important exacerbating factors

Treatment of comorbid conditions

With permission: Diener et al. [95].

*Important components of chronic migraine management\**

uted to the patient's headaches (Section 7.1).

CM is underdiagnosed and, thus, untreated disease. Only 20% of patients who meet the criteria for CM are properly diagnosed [65].Treatment options are available for these patients, but only if the patients are properly identified [171]. Successful management of CM will help properly diagnose this disease, optimize treatment and thus reduce the global burden of it. Important components of CM management involve correct diagnosis, optimal treatment plan, patient education, treatment of MOH and comorbid conditions and monitoring of patients response to

It is important for all physicians who are treating the patient to understand the treatment plan, in order to monitor the patient's response to treatment, using as well as continual assessment of the patient's Health-Related Quality of Life

(HRQOL) [95]. Preventive therapy for migraines may take up to 6–8 weeks to begin to demonstrate efficacy, and up to 6 months before full efficacy is established [172]. Support and close follow-up are essential for patients, particularly in the first

Additionally, physicians should try to identify and reduce aggravating risk factors, such as triggers of migraine or other behavioral habits that may have contrib-

Thus, multimodal treatment concepts are superior to simple drug treatment in

**Box 1** contains the key components of chronic migraine management for physi-

Referral to headache specialist/neurologist to confirm CM diagnosis and provide a treatment plan Management of overuse of acute headache pain medications: providing limits to acute and rescue

*CM, chronic migraine; HIT-6, headache impact test-6; HRQoL, health-related quality of life; MIDAS, migraine*

Patient education about CM and importance of treatment compliance

Nonpharmacotherapy, including trigger management and behavioral therapy

CM is associated with higher burden of disease, more severe psychiatric comor-

*.*

bidity, greater use of healthcare resources, and higher total costs than EM. The current definition of CM has gone through multiple revisions, but the discussion

#### **Table 6.**

*Recommendations on use of anti-calcitonin gene-related peptide monoclonal antibodies in subjects with chronic migraine\* .*

gene-related peptide—mainly prevents the activation of Aδ-fibers, whereas botulinum toxin type A prevents the activation of C-fibers [168]. There is currently only indirect preclinical evidence to support a rationale for dual therapy with anticalcitonin gene-related peptide monoclonal antibodies and OBT-A for CM prevention [170]. Rigorous studies evaluating clinical efficacy, safety, and costeffectiveness of dual therapy with mAbs are needed.

#### **8. Management of chronic migraine**

CM is underdiagnosed and, thus, untreated disease. Only 20% of patients who meet the criteria for CM are properly diagnosed [65].Treatment options are available for these patients, but only if the patients are properly identified [171]. Successful management of CM will help properly diagnose this disease, optimize treatment and thus reduce the global burden of it. Important components of CM management involve correct diagnosis, optimal treatment plan, patient education, treatment of MOH and comorbid conditions and monitoring of patients response to treatment plan.

It is important for all physicians who are treating the patient to understand the treatment plan, in order to monitor the patient's response to treatment, using as well as continual assessment of the patient's Health-Related Quality of Life (HRQOL) [95]. Preventive therapy for migraines may take up to 6–8 weeks to begin to demonstrate efficacy, and up to 6 months before full efficacy is established [172]. Support and close follow-up are essential for patients, particularly in the first 3 months of treatment [172].

Additionally, physicians should try to identify and reduce aggravating risk factors, such as triggers of migraine or other behavioral habits that may have contributed to the patient's headaches (Section 7.1).

Thus, multimodal treatment concepts are superior to simple drug treatment in severely affected patients [95].

**Box 1** contains the key components of chronic migraine management for physicians [95].


**Box 1.**

gene-related peptide—mainly prevents the activation of Aδ-fibers, whereas botulinum toxin type A prevents the activation of C-fibers [168]. There is currently only indirect preclinical evidence to support a rationale for dual therapy with anticalcitonin gene-related peptide monoclonal antibodies and OBT-A for CM preven-

*Recommendations on use of anti-calcitonin gene-related peptide monoclonal antibodies in subjects with chronic*

**Recommendation Strength of the**

1. When should treatment with anti-CGRP monoclonal antibodies be offered to patients with

In patients with CM who have failed at least two of the available medical treatments or who cannot use other preventive treatments because of comorbidities, side effects or poor compliance, we suggest the use of erenumab, fremanezumab, or galcanezumab

In patients with CM who are on treatment with any oral drug with inadequate treatment response we suggest to add erenumab, fremanezumab, or galcanezumab and to consider later withdrawal of

In patients with chronic migraine who are on treatment with OBT-A with inadequate treatment response we suggest to stop OBT-A before initiation of erenumab, fremanezumab, or galcanezumab In patients with CM who are on treatment with erenumab, fremanezumab, or galcanezumab and who may benefit from additional prevention we suggest to add oral preventive drugs

3. When should treatment with anti-CGRP monoclonal antibodies be stopped in patients with

In patients with CM, we suggest to consider to stop treatment with erenumab, fremanezumab, and galcanezumab after 6–12months of

In patients with CM and medication overuse, we suggest to use erenumab, fremanezumab, and galcanezumab before or after

4. Should medication overuse be treated before offering treatment anti-CGRP monoclonal antibodies

2. How should other preventive treatments be managed when using anti-CGRP monoclonal antibodies

**recommendation**

Experts' opinion

Experts' opinion

Experts' opinion

Experts' opinion

Experts' opinion

Experts' opinion

tion [170]. Rigorous studies evaluating clinical efficacy, safety, and cost-

effectiveness of dual therapy with mAbs are needed.

**Clinical question**

*Migraine*

migraine?

migraine?

*\**

**94**

**Table 6.**

*migraine\* .*

in patients with migraine?

the oral drug

treatments

to patients with chronic migraine?

withdrawal of acute medications

with severe mental disorders

neutralizing antibodies

*Adapted with permission: Sacco et al. [163].*

6. Should binding and/or neutralizing antibodies be monitored?

5. In which patients anti-CGRP monoclonal antibodies are not to be used?

In patients with migraine, we suggest to avoid anti-CGRP monoclonal antibodies in pregnant or nursing women, in individuals with alcohol or drug abuse, cardio and cerebrovascular diseases, and

In patients with migraine on treatment with anti-CGRP monoclonal antibodies, we suggest not to test binding and/or neutralizing antibodies in daily clinical practice; we suggest to further study the possible implications of binding and/or

> *Important components of chronic migraine management\* .*

#### **9. Conclusions**

CM is associated with higher burden of disease, more severe psychiatric comorbidity, greater use of healthcare resources, and higher total costs than EM. The current definition of CM has gone through multiple revisions, but the discussion about it is still continuing,

The pathophysiology of CM is not fully understood. However, recent advances in electrophysiology and neuroimaging have indicated that atypical pain processing, central sensitization, cortical hyperexcitability and neurogenic inflammation are important in the development of this disorder. The most significant risk factors such as overuse of acute medication, ineffective acute treatment, obesity, depression and stressful life events have been associated with migraine progression.

Unfortunately, CM is still undertreated because of its poor treatment response and limited therapy options. The currently available evidence-based prophylactic treatment options for CM are topiramate and OBT-A. According to the results of the clinical studies the new class of drugs—anti-CGRP/R monoclonal antibodies seems to be a very promising treatment for CM. Complete and correct diagnosis, optimal treatment plan, management of acute medication overuse and exacerbating factors, patient education and monitoring of the patient's response to treatment plan are the most important components for the successful CM management.

The next years seem to be inspiring for the field, as current research areas are being extended and novel areas are being covered, ultimately broadening our understanding of the complex syndrome of CM.

#### **Conflict of interest**

The authors declare that they have no conflict of interest related to the publication of this chapter.

#### **Abbreviations**


**Author details**

*Chronic Migraine*

*DOI: http://dx.doi.org/10.5772/intechopen.93314*

**97**

Diana Obelieniene<sup>1</sup>

(LSMU) Kauno Klinikos, Kaunas, Lithuania

Sciences (LSMU), Kaunas, Lithuania

provided the original work is properly cited.

\*, Ruta Pestininkaite<sup>2</sup> and Daiva Rastenyte<sup>2</sup>

1 Department of Neurology, Hospital of Lithuanian University of Health Sciences

2 Department of Neurology, Medical Academy, Lithuanian University of Health

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: diana.obelieniene@kaunoklinikos.lt

The pathophysiology of CM is not fully understood. However, recent advances in electrophysiology and neuroimaging have indicated that atypical pain processing, central sensitization, cortical hyperexcitability and neurogenic inflammation are important in the development of this disorder. The most significant risk factors such as overuse of acute medication, ineffective acute treatment, obesity, depression and stressful life events have been associated with migraine progression.

Unfortunately, CM is still undertreated because of its poor treatment response and limited therapy options. The currently available evidence-based prophylactic treatment options for CM are topiramate and OBT-A. According to the results of the clinical studies the new class of drugs—anti-CGRP/R monoclonal antibodies seems to be a very promising treatment for CM. Complete and correct diagnosis, optimal treatment plan, management of acute medication overuse and exacerbating factors, patient education and monitoring of the patient's response to treatment plan are the

The next years seem to be inspiring for the field, as current research areas are being extended and novel areas are being covered, ultimately broadening our

The authors declare that they have no conflict of interest related to the publica-

ICHD-3 International Classification of Headache Disorders, 3rd edition ICHD-1 International Classification of Headache Disorders, 1st edition

ICHD-2 Classification of Headache Disorders, 2nd edition

most important components for the successful CM management.

understanding of the complex syndrome of CM.

HIS the International Headache Society

MIDAS Migraine Disability Assessment

MOH medication-overuse headache CSD cortical spreading depression VIP vasoactive intestinal peptide CGRP calcitonin gene-related peptide HIT-6 Headache Impact Test-6

FDA U.S. Food & Drug Administration EMA European Medicines Agency HRQoL health-related quality of life

**Conflict of interest**

*Migraine*

tion of this chapter.

**Abbreviations**

CM chronic migraine

EM episodic migraine

5HT1 serotonin 1a

**96**

OBT-A onabotulinumtoxinA

### **Author details**

Diana Obelieniene<sup>1</sup> \*, Ruta Pestininkaite<sup>2</sup> and Daiva Rastenyte<sup>2</sup>

1 Department of Neurology, Hospital of Lithuanian University of Health Sciences (LSMU) Kauno Klinikos, Kaunas, Lithuania

2 Department of Neurology, Medical Academy, Lithuanian University of Health Sciences (LSMU), Kaunas, Lithuania

\*Address all correspondence to: diana.obelieniene@kaunoklinikos.lt

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1988;**8**:1-96

[10] Manack A, Turkel C, Silberstein S. The evolution of chronic migraine: Classification and nomenclature. Headache. 2009;**49**:1206-1213

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1994;**34**:1-7

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[3] Blumenfeld AM et al. Disability, HRQoL and resource use among chronic and episodic migraineurs: Results from the International Burden of Migraine Study (IBMS). Cephalalgia. 2011;**31**:

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[5] Berra E et al. Cost of chronic and episodic migraine. A pilot study from tertiary headache centre northern Italy. The Journal of Headache and Pain. 2015;

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sociodemographic factors: Results from the American Migraine Prevalence and Prevention Study. Headache. 2012;**52**:

prevalence, disability, and

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[22] Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent headache in a population sample. Headache. 1998;**38**:497-506

[23] Yoon MS et al. Prevalence of primary headaches in Germany: Results of the German Headache Consortium Study. The Journal of Headache and Pain. 2012;**13**:215-223

[24] Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the differences between episodic migraine and chronic migraine. Current Pain and Headache Reports. 2012;**16**(1):86-92

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[27] Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors associated with the onset and remission of chronic daily

headache in a population-based study. Pain. 2003;**106**:81-89

[28] Goadsby PJ, Holland PR, Martinsoliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: A disorder of sensory processing. Physiological Reviews. 2017;**97**:553-622

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wnl.0000113747.18760.d2

**136**(11):3489-3496

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0333102414550108

0333102416630593

2009;**60**:214-225

nrneurol.2016.93

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[37] SWG D, AKP J, Gyulai F, Clark S, Townsend D, Firestone LL. Pain processing during three levels of noxious stimulation produces

differential patterns of central activity. Pain. 1997;**73**:431-445. [PubMed:

[38] Burstein R, Jakubowski M. Neural substrate of depression during migraine. Neurological Sciences. 2009;**30**(Suppl 1):

S27-S31. [PubMed: 19415422]

[PubMed: 14620879]

e3799

[39] Kunkler PE, Kraig RP. Cortical spreading depression bilaterally activates the caudal trigeminal nucleus in rodents. Hippocampus. 2003;**13**: 835-844. [PMCID: PMC2805270]

[40] Moulton EA, Burstein R, Tully S, Hargreaves R, Becerra L, Borsook D. Interictal dysfunction of a brainstem descending modulatory center in migraine patients. PLoS One. 2008;**3**:

[41] Schwedt TJ, Larson-Prior L,

Medicine. 2014;**15**:154-165

[42] Aurora SK, Barrodale PM, Tipton RL, Khodavirdi A. Brainstem dysfunction in chronic migraine as evidenced byneurophysiological and positron emission tomography studies.

Headache. 2007;**47**:996-1003;

[43] Lai TH, Chou KH, Fuh JL, et al. Gray matter changes related to

discussion 1004-7

**100**

Coalson RS, Nolan T, Mar S, Ances BM, et al. Allodynia and descending pain modulation in migraine: A resting state functional connectivity analysis. Pain

10445825]

*Migraine*

9469535]

[52] Burstein R. Deconstructing migraine headache into peripheral and central sensitization. Pain. 2001;**89**(2–3): 107-110

[53] Mathew NT, Kurman R, Perez F. Drug induced refractory headache— Clinical features and management. Headache. 1990;**30**(10):634-638. DOI: 10.1111/j.1526-4610.1990.hed3010634.x

[54] Aurora SK, Brin MF. Chronic migraine: An update on physiology, imaging, and the mechanism of action of two available pharmacologic therapies. Headache. 2017;**57**(1): 109-125. DOI: 10.1111/head.12999

[55] Su M, Yu S. Chronic migraine: A process of dysmodulation and sensitization. Molecular Pain. 2018;**14**: 1744806918767697. DOI: 10.1177/ 1744806918767697

[56] Ramachandran R. Neurogenic inflammation and its role in migraine. Seminars in Immunopathology. 2018; **40**(3):301-314. DOI: 10.1007/ s00281-018-0676-y

[57] Cernuda-Morollón E, Martínez-Camblor P, Ramón C, Larrosa D, Serrano-Pertierra E, Pascual J. CGRP and VIP levels as predictors of efficacy of onabotulinumtoxin type a in chronic migraine. Headache. 2014;**54**(6): 987-995

[58] Cernuda-Morollon E, Martinez-Camblor P, Alvarez R, Larrosa D, Ramon C, Pascual J. Increased VIP levels in peripheral blood outside migraine attacks as a potential biomarker of cranial parasympathetic activation in chronic migraine. Cephalalgia. 2015; **35**(4):310-316

[59] Cernuda-Morollón E, Larrosa D, Ramón C, Vega J, Martínez-Camblor P, Pascual J. Interictal increase of CGRP levels in peripheral blood as a biomarker for chronic migraine. Neurology. 2013; **81**(14):1191-1196. DOI: 10.1212/ WNL.0b013e3182a6cb72

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[61] Toghae M, Rahimian E, Abdollahi M, Shoar S, Naderan M. The prevalence of magnetic resonance imaging hyperintensity in migraine patients and its association with migraine headache characteristics and cardiovascular risk factors. Oman Medical Journal. 2015;**30**(3):203-207

[62] Maleki N, Becerra L, Brawn J, Bigal M, Burstein R, Borsook D. Concurrent functional and structural cortical alterations in migraine. Cephalalgia. 2012;**32**(8):607-620

[63] Magon S, May A, Stankewitz A, Goadsby PJ, Schankin C, Ashina M, et al. Cortical abnormalities in episodic migraine: a multi-center 3T MRI study. Cephalalgia. 2019;**39**(5):665-673

[64] Torres-Ferrús M, Ursitti F, Alpuente-Ruiz A, et al. From transformation to chronification of migraine: Pathophysiological and clinical aspects. The Journal of Headache and Pain. 2020;**21**(1):42. DOI: 10.1186/s10194-020-01111-8

[65] Bigal ME, Serrano D, Reed M, Lipton RB. Chronic migraine in the spopulation: burden, diagnosis, and satisfaction with treatment. Neurology. 2008;**71**(8):559-566

[66] Goldman D, Oroszi G, Ducci F. The genetics of addictions: Uncovering the genes. Nature Reviews. Genetics. 2005; **6**(7):521-532

[67] Vila-Pueyo M, Fernandez-Castillo N, Cormand B, Pozo-Rosich P, Macaya A. Epigenetic changes in a rat model of migraine with aura. The Journal of Headache and Pain. 2014;**15** (Suppl 1):A6. DOI: 10.1186/1129-2377- 15-S1-A6

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[77] Scher AI, Stewart WF, Lipton RB. Caffeine as a risk factor for chronic daily headache: A population-based study. Neurology. 2004;**63**(11):2022-2027

[78] Santos IS, Goulart AC, Passos VM,

[79] Ornello R, Ripa P, Pistoia F, Degan D, Tiseo C, Carolei A, et al. Migraine and body mass index categories: A systematic review and meta-analysis of observational studies. The Journal of Headache and Pain.

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Chronic migraine in women is associated with insulin resistance: A cross-sectional study. European Journal of Neurology. 2014;**21**(2):267-272. DOI:

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Rapoport AM, Scher AI. Obesity and migraine: The effect of age, gender and adipose tissue distribution. Headache. 2010;**50**(1):52-62. DOI: 10.1111/ j.1526-4610.2009.01459.x

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[83] Buse DC, Rains JC, Pavlovic JM, Fanning KM, Reed ML, Manack

del Carmen MM, Lotufo PA, Bensenor IM. Obesity, abdominal obesity and migraine: A crosssectional analysis of ELSA-Brasil baseline data. Cephalalgia. 2015;**35**(5):426-436

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[69] Bigal ME, Lipton RB. Migraine chronification. Current Neurology and Neuroscience Reports. 2011;**11**(2):

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[71] Bigal ME, Lipton RB. Obesity and chronic daily headache. Current Pain and Headache Reports. 2008;**12**(1):

[72] Ashina S, Serrano D, Lipton RB,

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[73] Finocchi C, Strada L. Sex-related differences in migraine. Neurological Sciences. 2014;**35**(Suppl 1):207-213

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15-S1-A6

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[87] Kayhan F, Ilik F. Prevalence of personality disorders in patients with chronic migraine. Comprehensive Psychiatry. 2016;**68**:60-64

[88] Plesh O, Adams SH, Gansky SA. Self-reported comorbid pains in severe headaches or migraines in a US national sample. Headache. 2012;**52**(6):946-956

[89] Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, Reed ML, et al. Cutaneous allodynia in the migraine population. Annals of Neurology. 2008; **63**(2):148-158

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[154] Lundbeck. Vyepti (Eptinezumabjjmr): US Prescribing Information. 2020. Available from: https://www.lundbeck. com/upload/us/files/pdf/Products/ Vyepti\_PI\_US\_EN.pdf [Accessed: 05 March 2020]

[155] Dhillon S. Eptinezumab: First approval. Drugs. 2020;**80**:733-739

[156] Goldberg SW, Silberstein SD. Targeting CGRP: a new era for migraine treatment. CNS Drugs. 2015;**29**(6): 443-452

[157] Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltran E, et al. Blocking CGRP in migraine patients a review of pros and cons. The Journal of Headache and Pain. 2017;**18**(1):96

[158] Edvinsson L. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment. British Journal of Clinical Pharmacology. 2015;**80**(2):193-199

[159] Israel H, Neeb L, Reuter U. CGRP monoclonal antibodies for the preventative treatment of migraine. Current Pain and Headache Reports. 2018;**22**(5):38

[160] Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, et al. Fremanezumab for the preventive treatment of chronic migraine. The New England Journal of Medicine. 2017;**377**:2113-2122

[161] Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic migraine: the randomized, double-blind, placebocontrolled REGAIN study. Neurology. 2018;**91**:e1-e11

[162] Dodic DW, Lipton RB, Silberstein S, et al. Eptinezumab for prevention of chronic migraine: A randomized phase 2b clinical trial. Cephalalgia. 2019;**39**(9):1075-1085

[163] Sacco S, Bendtsen L, Ashina M, et al. European headache federation

guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention. The Journal of Headache and Pain. 2019;**20**:6

[164] Tepper S, Ashina M, Reuter U, Brandes JL, Doležil D, Silberstein S, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurology. 2017;**16**:425-434

[165] Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings EL, Diener HC, et al. Silberstein SD (2015a) safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebocontrolled, phase 2b study. Lancet Neurology. 2015;**14**:1091-1100

[166] Yang M, Rendas-Baum R, Varon SF, et al. Validation of the Headache Impact Test (HIT-6) across episodic and chronic migraine. Cephalalgia. 2010;**31**:357-367

[167] Lipton RB, Goadsby PJ, Smith J, Schaeffler BA, Biondi DM, Hirman J, et al. Efficacy and safety of eptinezumab in patients with chronic migraine PROMISE-2. Neurology. 2020;**94**(13): e1365-e1377. DOI: 10.1212/WNL. 0000000000009169

[168] Kowacs F, Roesler CAP, Piovesan EJ, et al. Consensus of the Brazilian Headache Society on the treatment of chronic migraine. Arquivos de Neuro-Psiquiatria. July 2019:**77**(7): 509-520. DOI: 10.1590/0004- 282x20190078

[169] Peroutka SJ. Beyond monotherapy: rational polytherapy in migraine. Headache. 1998;**38**(1):18-22

[170] Pellesi L, Do TP AH, et al. Dual therapy with anti-cgrp monoclonal antibodies and botulinum toxin for

migraine prevention: Is there a rationale? Headache. 2020. DOI: 10.1111/head.13843

[171] Diener HC, Dodick DW, Goadsby PJ, et al. Chronic migraine— Classification, characteristics and treatment. Nature Reviews. Neurology. 2012;**32**:423

[172] Dodick DW. Finding a fit: Strategies for chronic migraine prophylaxis. Johns Hopkins Advanced Studies in Medicine. 2006;**6**(4D)

**109**

**Chapter 6**

**Abstract**

diagnosis

**1. Introduction**

**2. Epidemiology**

Chronic Migraine in Adolescence

*Marcos Antonio da Silva Cristovam, Daniel Albiero Piélak,* 

Chronic migraine (CM) is a clinically and epidemiologically important disease that generates considerable impairment to those affected by it, since there is evidence of higher incidence of depression, anxiety, and chronic pain in patients with this condition. It is characterized by the occurrence of headache for at least 8 migraine days in a month and at least 15 headache days in the same month. Despite the similarity in CM presented in adults, when in adolescents it has some particularities. Thus, the aim of this chapter was to conduct a literature review, using the databases: PubMed, SciELO, and LILACS, in addition to text books, explaining the definition, epidemiology, risk factors, diagnosis, pathophysiology, treatment, and

**Keywords:** classic migraine, migraine with auras, epidemiology, adolescence,

Chronic migraine (CM) is defined as the occurrence of headache for at least 8 migraine days in a month and at least 15 headache days in the same month [1], being much less common and more debilitating than episodic migraine. Evidence indicates that migraine is a progressive disorder [2–4], and therefore, diagnosis and early management of episodic migraine are recommended, in order to avoid its chronicity, especially in adolescents; however, there is a failure in the accuracy of the diagnosis of CM in this population [5]. Migraine in this population can be misdiagnosed as sinusitis, attempted school skipping, and cerebral neoplasia, which

CM is a common disorder in children, and its incidence in adolescents presents a considerable increase [7]. Irrespective of age, the prevalence of chronic migraine is estimated at 1.5–2% in general population. On the other hand, its prevalence is 3% (from 3 to 7 years of age), 4–11% (from 7 to 11 years of age), and 8–23% (at 11 years of age), with a mean age of onset of 7.2 years for male and 10.9 years for female [8, 9]. Migraine is the 6th most disabling disease worldwide between the ages of 10 and 14 years and the 5th between the ages of 15 and 19 years [10]. In addition to toe the line impact inflicted by pain itself, migraine generates serious consequences

*Lorena Vaz Meleiro Lopes and Luísa Manfredin Vila*

*Júlia Deitos, Júlia Natsumi Hashimoto,* 

prevention of CM in adolescent population.

may culminate in unnecessary testing [6].

#### **Chapter 6**

guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention. The Journal of Headache and Pain. 2019;**20**:6

*Migraine*

migraine prevention: Is there a rationale? Headache. 2020. DOI:

[171] Diener HC, Dodick DW,

[172] Dodick DW. Finding a fit: Strategies for chronic migraine prophylaxis. Johns Hopkins Advanced Studies in Medicine. 2006;**6**(4D)

Goadsby PJ, et al. Chronic migraine— Classification, characteristics and treatment. Nature Reviews. Neurology.

10.1111/head.13843

2012;**32**:423

[164] Tepper S, Ashina M, Reuter U, Brandes JL, Doležil D, Silberstein S, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet

Neurology. 2017;**16**:425-434

[165] Bigal ME, Edvinsson L,

[166] Yang M, Rendas-Baum R, Varon SF, et al. Validation of the Headache Impact Test (HIT-6) across episodic and chronic migraine. Cephalalgia. 2010;**31**:357-367

[167] Lipton RB, Goadsby PJ, Smith J, Schaeffler BA, Biondi DM, Hirman J, et al. Efficacy and safety of eptinezumab in patients with chronic migraine PROMISE-2. Neurology. 2020;**94**(13): e1365-e1377. DOI: 10.1212/WNL.

0000000000009169

282x20190078

**108**

[168] Kowacs F, Roesler CAP, Piovesan EJ, et al. Consensus of the Brazilian Headache Society on the treatment of chronic migraine. Arquivos de Neuro-Psiquiatria. July 2019:**77**(7):

509-520. DOI: 10.1590/0004-

[169] Peroutka SJ. Beyond monotherapy: rational polytherapy in migraine. Headache. 1998;**38**(1):18-22

[170] Pellesi L, Do TP AH, et al. Dual therapy with anti-cgrp monoclonal antibodies and botulinum toxin for

Rapoport AM, Lipton RB, Spierings EL, Diener HC, et al. Silberstein SD (2015a) safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: a multicentre, randomised, double-blind, placebocontrolled, phase 2b study. Lancet Neurology. 2015;**14**:1091-1100

## Chronic Migraine in Adolescence

*Marcos Antonio da Silva Cristovam, Daniel Albiero Piélak, Júlia Deitos, Júlia Natsumi Hashimoto, Lorena Vaz Meleiro Lopes and Luísa Manfredin Vila*

#### **Abstract**

Chronic migraine (CM) is a clinically and epidemiologically important disease that generates considerable impairment to those affected by it, since there is evidence of higher incidence of depression, anxiety, and chronic pain in patients with this condition. It is characterized by the occurrence of headache for at least 8 migraine days in a month and at least 15 headache days in the same month. Despite the similarity in CM presented in adults, when in adolescents it has some particularities. Thus, the aim of this chapter was to conduct a literature review, using the databases: PubMed, SciELO, and LILACS, in addition to text books, explaining the definition, epidemiology, risk factors, diagnosis, pathophysiology, treatment, and prevention of CM in adolescent population.

**Keywords:** classic migraine, migraine with auras, epidemiology, adolescence, diagnosis

#### **1. Introduction**

Chronic migraine (CM) is defined as the occurrence of headache for at least 8 migraine days in a month and at least 15 headache days in the same month [1], being much less common and more debilitating than episodic migraine. Evidence indicates that migraine is a progressive disorder [2–4], and therefore, diagnosis and early management of episodic migraine are recommended, in order to avoid its chronicity, especially in adolescents; however, there is a failure in the accuracy of the diagnosis of CM in this population [5]. Migraine in this population can be misdiagnosed as sinusitis, attempted school skipping, and cerebral neoplasia, which may culminate in unnecessary testing [6].

#### **2. Epidemiology**

CM is a common disorder in children, and its incidence in adolescents presents a considerable increase [7]. Irrespective of age, the prevalence of chronic migraine is estimated at 1.5–2% in general population. On the other hand, its prevalence is 3% (from 3 to 7 years of age), 4–11% (from 7 to 11 years of age), and 8–23% (at 11 years of age), with a mean age of onset of 7.2 years for male and 10.9 years for female [8, 9]. Migraine is the 6th most disabling disease worldwide between the ages of 10 and 14 years and the 5th between the ages of 15 and 19 years [10]. In addition to toe the line impact inflicted by pain itself, migraine generates serious consequences

in children's and adolescent's routine, since it is responsible for school absences, negatively affecting academic performance. It also has social impacts, since it hinders the child's interactions with his peers, and economic, due to the costs generated by the treatment [11]. Migraine has two-fold higher prevalence in females when compared to their peer male adolescents [12–17]. In women, the prevalence of migraine increases during adolescence, presenting a maximum prevalence at 30 years of age, decreasing sharply after menopause [12, 14, 17], since 50–60% of women report having migraine during their menstrual period [18]. In the American Migraine Prevalence and Prevention Study (AMPP), patients with CM presented with depression, anxiety, and chronic pain twice as much as patients with episodic migraine [17]. Abu-Arafeh et al., in 2010, estimated that the overall prevalence of migraine in children is 7.7% (9.7% in female and 6.0% in male), being more common in female after completing 11 years of age, in male before the age of 7, and being equal in both sexes between 7 and 11 years of age [19, 20]. In another study, WöberBingöl et al. reported general prevalence of migraine of 9.1% [21].

### **3. Risk factors**

Among the risk factors for CM, the following are included:


In addition to the factors mentioned above, others still under study may be related to the pathophysiology of CM and, therefore, represent risk factors such as traumatic brain injury, epilepsy, hemodialysis, and excessive use of symptomatic medications.

The existence of correlation between CM and traumatic brain injury was the subject of a systematic review study published by Sowell et al., in 2017, in which was sought to relate it to posttraumatic chronic headache (PTCH) in children and adolescents. In this study, it was observed that 7.6% of children with PTCH presented migraine [24], thus disclosing it to be a relatively common condition and that it should be considered.

Another factor that may be correlated with CM is epilepsy. Both migraine and epilepsy are considered neuronal hyperarousal-related diseases which can be partially prevented by antiepileptic drugs. According to the Center of Disease Control (CDC), 16.2% of adults with no history of epilepsy have severe headache or

**111**

*Chronic Migraine in Adolescence*

*DOI: http://dx.doi.org/10.5772/intechopen.90936*

without excessive use of medication [5].

**4. Diagnosis**

population [1, 5].

phobia [1].

headache [1].

migraine, while those with active epilepsy have 35.5% of prevalence [25]. Therefore, although the correlation between epilepsy and migraine has not been completely

Regarding hemodialysis in pediatric and adolescent patients with chronic kidney disease, Davidovits and Eidlitz Markus, in a study published in the International Headache Society, concluded a three-fold higher prevalence of headache among patients in hemodialysis compared to those with chronic kidney disease without this treatment, the most commonly described type of headache being migraine. Furthermore, other variables were associated with headaches, such as anemia,

Notwithstanding, excessive symptomatic medication is also described in the literature as a risk factor for CM. With this in mind, Rojo et al. made a comparison between patients with CM with and without excessive medication use (analgesics, tryptans, ergotamine, and opioids). In the study, it was observed that individuals overusing symptomatic medication had the onset of migraine at a younger age, with a longer progression time before looking for a specialist, as well as a higher percentage of preventive prior treatment (mainly antidepressants), compared to those

Even though there are differences between the clinical findings of CM in the pediatric population and other age groups, due to the scarce evidence in relation to diagnostic methods aimed specifically at these patients, the International Classification of Headache Disorders, of Headache Classification Committee of the International Headache Society (IHS), 2018, is used, the same applied to the adult

According to IHS, CM is characterized by occurrence of ≥8 days of migraine in a month and ≥15 headache days. Migraine attacks can be with and/or without aura [1]. In this case, migraine without aura is a headache lasting 4–72 h, which has at least two of the following characteristics: (1) unilateral location; (2) pulsatile character; (3) moderate to strong pain intensity; and (4) is exacerbated by routine physical activities and, during the headache, the patient has at least one of the following symptoms: (1) nausea and/or vomiting; (2) photophobia; and (3) phono-

On the other hand, migraine with aura is a headache with the same characteristics mentioned above, plus one or more symptoms of fully reversible aura, and may be visual, sensory, speech and/or language, motor, brain stem, or retinal. Furthermore, crises should have at least three of the following characteristics: (1) at least one symptom of aura gradually spreads for more than 5 min; (2) two or more aura symptoms occur in succession; (3) each individual aura symptom lasts 5–60 min; (4) at least one symptom of aura is unilateral; (5) at least one symptom of aura is positive; and (6) aura is accompanied, or followed within 60 min, by

Although the use of IHS criteria is recommended, the health professional should know the peculiarities of CM in adolescent population in order to complement the diagnosis. The characteristics of the headache tend to be more prominent in this group, since the brain is in the growth and development process. Furthermore, the duration of pain crises may be less than 1 h, contrary to the IHS criteria, which mentions a minimum duration of 2 h [1, 6, 27]. A direct relation between the patient's age and duration of crises is observed, being younger shorter the duration of the crisis [4]. An important information is that adolescents may present

elucidated yet, there are strong indications for such an interdependence.

hyperparathyroidism, and low glomerular filtration [26].

#### *Chronic Migraine in Adolescence DOI: http://dx.doi.org/10.5772/intechopen.90936*

migraine, while those with active epilepsy have 35.5% of prevalence [25]. Therefore, although the correlation between epilepsy and migraine has not been completely elucidated yet, there are strong indications for such an interdependence.

Regarding hemodialysis in pediatric and adolescent patients with chronic kidney disease, Davidovits and Eidlitz Markus, in a study published in the International Headache Society, concluded a three-fold higher prevalence of headache among patients in hemodialysis compared to those with chronic kidney disease without this treatment, the most commonly described type of headache being migraine. Furthermore, other variables were associated with headaches, such as anemia, hyperparathyroidism, and low glomerular filtration [26].

Notwithstanding, excessive symptomatic medication is also described in the literature as a risk factor for CM. With this in mind, Rojo et al. made a comparison between patients with CM with and without excessive medication use (analgesics, tryptans, ergotamine, and opioids). In the study, it was observed that individuals overusing symptomatic medication had the onset of migraine at a younger age, with a longer progression time before looking for a specialist, as well as a higher percentage of preventive prior treatment (mainly antidepressants), compared to those without excessive use of medication [5].

#### **4. Diagnosis**

*Migraine*

**3. Risk factors**

b. age group;

in children's and adolescent's routine, since it is responsible for school absences, negatively affecting academic performance. It also has social impacts, since it hinders the child's interactions with his peers, and economic, due to the costs generated by the treatment [11]. Migraine has two-fold higher prevalence in females when compared to their peer male adolescents [12–17]. In women, the prevalence of migraine increases during adolescence, presenting a maximum prevalence at 30 years of age, decreasing sharply after menopause [12, 14, 17], since 50–60% of women report having migraine during their menstrual period [18]. In the American Migraine Prevalence and Prevention Study (AMPP), patients with CM presented with depression, anxiety, and chronic pain twice as much as patients with episodic migraine [17]. Abu-Arafeh et al., in 2010, estimated that the overall prevalence of migraine in children is 7.7% (9.7% in female and 6.0% in male), being more common in female after completing 11 years of age, in male before the age of 7, and being equal in both sexes between 7 and 11 years of age [19, 20]. In another study,

WöberBingöl et al. reported general prevalence of migraine of 9.1% [21].

a.gender (female, once migraine has been associated with menorrhagia, dysmen-

d. genetic factors: family history of headache, mental disorders [5, 22, 23], anxiety, and depression [5, 23], as well as comorbidities, such as sleep disorders [5, 23] (sleep apnea syndrome and hypopnea, snoring, and insomnia [22]), obesity [23], epilepsy [24], hypertension, asthma, hypothyroidism, genitourinary disorders, musculoskeletal disorders, [22] and gastrointestinal disorders [22, 24];

e. family and environmental factors: divorce [23], socioeconomic class [5, 23],

f. other factors: pro-thrombotic factors [5] and pro-inflammatory factors [5, 23].

In addition to the factors mentioned above, others still under study may be related to the pathophysiology of CM and, therefore, represent risk factors such as traumatic brain injury, epilepsy, hemodialysis, and excessive use of symptomatic

The existence of correlation between CM and traumatic brain injury was the subject of a systematic review study published by Sowell et al., in 2017, in which was sought to relate it to posttraumatic chronic headache (PTCH) in children and adolescents. In this study, it was observed that 7.6% of children with PTCH presented migraine [24], thus disclosing it to be a relatively common condition and

Another factor that may be correlated with CM is epilepsy. Both migraine and epilepsy are considered neuronal hyperarousal-related diseases which can be partially prevented by antiepileptic drugs. According to the Center of Disease Control (CDC), 16.2% of adults with no history of epilepsy have severe headache or

Among the risk factors for CM, the following are included:

orrhoea, and endometriosis [22]);

c. ethnicity: more specifically, white;

and low level of education [5]; and

**110**

medications.

that it should be considered.

Even though there are differences between the clinical findings of CM in the pediatric population and other age groups, due to the scarce evidence in relation to diagnostic methods aimed specifically at these patients, the International Classification of Headache Disorders, of Headache Classification Committee of the International Headache Society (IHS), 2018, is used, the same applied to the adult population [1, 5].

According to IHS, CM is characterized by occurrence of ≥8 days of migraine in a month and ≥15 headache days. Migraine attacks can be with and/or without aura [1]. In this case, migraine without aura is a headache lasting 4–72 h, which has at least two of the following characteristics: (1) unilateral location; (2) pulsatile character; (3) moderate to strong pain intensity; and (4) is exacerbated by routine physical activities and, during the headache, the patient has at least one of the following symptoms: (1) nausea and/or vomiting; (2) photophobia; and (3) phonophobia [1].

On the other hand, migraine with aura is a headache with the same characteristics mentioned above, plus one or more symptoms of fully reversible aura, and may be visual, sensory, speech and/or language, motor, brain stem, or retinal. Furthermore, crises should have at least three of the following characteristics: (1) at least one symptom of aura gradually spreads for more than 5 min; (2) two or more aura symptoms occur in succession; (3) each individual aura symptom lasts 5–60 min; (4) at least one symptom of aura is unilateral; (5) at least one symptom of aura is positive; and (6) aura is accompanied, or followed within 60 min, by headache [1].

Although the use of IHS criteria is recommended, the health professional should know the peculiarities of CM in adolescent population in order to complement the diagnosis. The characteristics of the headache tend to be more prominent in this group, since the brain is in the growth and development process. Furthermore, the duration of pain crises may be less than 1 h, contrary to the IHS criteria, which mentions a minimum duration of 2 h [1, 6, 27]. A direct relation between the patient's age and duration of crises is observed, being younger shorter the duration of the crisis [4]. An important information is that adolescents may present

nonpulsatile and bilateral pain, which may induce the misdiagnosis of tensional headache [2, 6, 27].

Approximately 10% of young people with migraine present aura, from visual, sensory, speech, or language disorders, motor, or brain stem changes, manifesting themselves as scotomas, paresthesias, dysphasias, hemiplegia, ataxia, or confusion. The suspicion of other diseases of the central nervous system should be listed through fever, nuchal stiffness, altered mental status, absence of family history of migraine, occipital or positional headaches, or headaches that constantly awaken the individual during sleep [28–30].

In adolescents, it is common for patients with migraine to have comorbidities such as epilepsy and atopy. The most common atopic disorders reported concomitantly with CM are seasonal rhinitis, conjunctivitis, and asthma, with correlation with positive family history. Regarding epilepsy, it is mainly associated with migraine with aura, which corroborates the role of depression of cortical propagation. Another hypothesis is that both, migraine and epilepsy, have the influence of canalopathies on their pathophysiology [30–32].

#### **5. Pathophysiology**

The mechanisms responsible for the occurrence of CM are not yet fully understood. Thus, the existing model to explain its pathophysiology still has gaps. It is accepted that migraine occurs by complex mechanisms involving activation and sensitization of trigeminal nociceptive pathways, especially its ophythalmic division, changes of the autonomic nervous system function, descending pain modulator system dysfunction, thalamic sensitization, and central sensitization due to the excessive use of medication in the acute treatment of pain crises.

It is noteworthy that the córtex of patients with migraine is hyperexcitable and abnormally sensitive to external stimuli. Due to triggering factors, the so-called cortical spreading depression (CSD) occurs, characterized by a slow propagation wave (2–6 mm/min) of sustained neuronal depolarization, which generates a transient peak of intense activity as it progresses in the tissue, followed by a longterm neural suppression. That is, there is a period of electrochemical hyperactivity followed by cortical inactivity, which results in the release of substances in the extracelular environment (ECE), such as K<sup>+</sup> and H<sup>+</sup> ions, nitric oxide, arachidonic acid, and prostaglandins [33–35]. Such a change in the ECE may activate or sensitize trigeminal afferences. The trigeminal ganglia, once stimulated, releases neuropeptides, causing inflammation of the dura mater. Cernuda-Morollón et al. demonstrate in their studies that interictal levels of calcitonin gene-related peptide (CGRP) and intestinal vasoactive peptide (IVP) are higher in CM [36, 37]. Thus, meningeal inflammation occurs, with vasodilation and endotelial dysfunction, resulting in plasma leakage and release of more inflammatory cytokines by mast cells. Thereby, neurogenic inflammation can lead to activation and sensitization of meningeal trigeminal afferences—a phenomenon known as peripheral sensitization [38–40].

A widely spread hypothesis is that increased peripheral nociceptive processing triggers increased activity of the descending pain modulation system, resulting in increased oxidative stress and consequent nociceptive modulation, further lowering the threshold for new pain crises. However, so far studies have not shown association between gene polymorphisms associated with oxidative stress and the occurrence of CM. On the other hand, repetitive painful stimuli on the trigeminal nerve cause activation of the pain modulating descending system in several portions, including the periaqueductal gray matter, showing that during migraine attacks, the

**113**

*Chronic Migraine in Adolescence*

migraine [44–47].

allodynia [48–50].

the lack of it [33, 53].

treatment adherence [5].

**6.1 General and supportive measures**

**6. Treatment**

tial biomarker of this disease [51].

*DOI: http://dx.doi.org/10.5772/intechopen.90936*

neurons of this region show increased activity, which may lead to oxidative stress and finally dysfunction of nociceptive modulation by such system [33, 41–43].

The overuse of medications to relieve acute migraine may also lead to the chronicity of this condition, through the drug-mediated central sensitization mechanism, leading to increased susceptibility to cortical spreading depression. Central sensitization manifests clinically from increased pericranial sensitivity and

Andersen et al. demonstrated in 2016 that during pain crises serum miRNA changes occur, and in patients with CM such changes persist the same in periods without pain. This implies the possibility of serum miRNA changes as a pathogenic feature of migraine. Thus, the study suggests that serum miRNA dosage is a poten-

According to Oakley et al., there is a possibility that obesity may be involved in the pathophysiology of migraine in the pediatric population. It is hypothesized that there is an overlap of the central and peripheral neural pathways responsible for the regulation of diet and those linked to the pathogenesis of migraine [33, 52]. Peterlin et al. demonstrated that several hypothalamic peptides, proteins, and neurotransmitters involved in the mechanisms of hunger also participate in the pathophysiology of migraine, such as serotonin, orexin, and adipokines. It is possible that the release of these substances, associated with the mechanism of diet and/or obesity states, may act as a trigger or corroborate the development of migraine. There is also the possibility that lifestyle and behavioral differences influence the relationship between migraine and obesity, such as differences in diet and physical exercise, or

The treatment of chronic migraine in adolescents aims not only to reduce frequency, duration, and intensity of the headache attacks, but also to reduce the consequences of this condition on the patient's quality of life, seeing as he or she is going through a process of growth and development. It also aims to treat comorbidities and reduce the social impact of the disease, such as school absences, school underachievement, and reduced peer interactions. Thus, the treatment should be developed from a multiprofessional perspective, with the help of pediatricians, neurologists and psychiatrists, psychologists, educators, and nutritionists, among others [54].

Firstly, family members should receive detailed information about the adolescent's diagnosis and ensure that the condition is not secondary to malignant diseases, in order to transmit confidence to the patient and their parents, thus contributing to

Proper living habits are of paramount importance for treatment. However, the health professional should be careful to not excessively restrict the activities of

young people, as this may lead to difficulties in adherence [55].

Thalamic modulation of trigeminal afferences appears to be related to the development of cutaneous allodynia in migraine, as sensitized thalamic neurons process nociceptive information from cranial meninges, along with sensory information from the scalp, skin, face, body, and limbs. Furthermore, the use of drugs that act modulating trigeminal afferences on the thalamus is effective in the preventive treatment of migraine attacks, such as topiramate, sodium valproate, and CGR66 receptor antagonists, corroborating the role of this structure in the chronicity of

#### *Chronic Migraine in Adolescence DOI: http://dx.doi.org/10.5772/intechopen.90936*

*Migraine*

headache [2, 6, 27].

**5. Pathophysiology**

sensitization [38–40].

the individual during sleep [28–30].

canalopathies on their pathophysiology [30–32].

extracelular environment (ECE), such as K<sup>+</sup>

nonpulsatile and bilateral pain, which may induce the misdiagnosis of tensional

Approximately 10% of young people with migraine present aura, from visual, sensory, speech, or language disorders, motor, or brain stem changes, manifesting themselves as scotomas, paresthesias, dysphasias, hemiplegia, ataxia, or confusion. The suspicion of other diseases of the central nervous system should be listed through fever, nuchal stiffness, altered mental status, absence of family history of migraine, occipital or positional headaches, or headaches that constantly awaken

In adolescents, it is common for patients with migraine to have comorbidities such as epilepsy and atopy. The most common atopic disorders reported concomitantly with CM are seasonal rhinitis, conjunctivitis, and asthma, with correlation with positive family history. Regarding epilepsy, it is mainly associated with migraine with aura, which corroborates the role of depression of cortical propagation. Another hypothesis is that both, migraine and epilepsy, have the influence of

The mechanisms responsible for the occurrence of CM are not yet fully understood. Thus, the existing model to explain its pathophysiology still has gaps. It is accepted that migraine occurs by complex mechanisms involving activation and sensitization of trigeminal nociceptive pathways, especially its ophythalmic division, changes of the autonomic nervous system function, descending pain modulator system dysfunction, thalamic sensitization, and central sensitization due to the

It is noteworthy that the córtex of patients with migraine is hyperexcitable and abnormally sensitive to external stimuli. Due to triggering factors, the so-called cortical spreading depression (CSD) occurs, characterized by a slow propagation wave (2–6 mm/min) of sustained neuronal depolarization, which generates a transient peak of intense activity as it progresses in the tissue, followed by a longterm neural suppression. That is, there is a period of electrochemical hyperactivity followed by cortical inactivity, which results in the release of substances in the

donic acid, and prostaglandins [33–35]. Such a change in the ECE may activate or sensitize trigeminal afferences. The trigeminal ganglia, once stimulated, releases neuropeptides, causing inflammation of the dura mater. Cernuda-Morollón et al. demonstrate in their studies that interictal levels of calcitonin gene-related peptide (CGRP) and intestinal vasoactive peptide (IVP) are higher in CM [36, 37]. Thus, meningeal inflammation occurs, with vasodilation and endotelial dysfunction, resulting in plasma leakage and release of more inflammatory cytokines by mast cells. Thereby, neurogenic inflammation can lead to activation and sensitization of meningeal trigeminal afferences—a phenomenon known as peripheral

A widely spread hypothesis is that increased peripheral nociceptive processing triggers increased activity of the descending pain modulation system, resulting in increased oxidative stress and consequent nociceptive modulation, further lowering the threshold for new pain crises. However, so far studies have not shown association between gene polymorphisms associated with oxidative stress and the occurrence of CM. On the other hand, repetitive painful stimuli on the trigeminal nerve cause activation of the pain modulating descending system in several portions, including the periaqueductal gray matter, showing that during migraine attacks, the

and H<sup>+</sup>

ions, nitric oxide, arachi-

excessive use of medication in the acute treatment of pain crises.

**112**

neurons of this region show increased activity, which may lead to oxidative stress and finally dysfunction of nociceptive modulation by such system [33, 41–43].

Thalamic modulation of trigeminal afferences appears to be related to the development of cutaneous allodynia in migraine, as sensitized thalamic neurons process nociceptive information from cranial meninges, along with sensory information from the scalp, skin, face, body, and limbs. Furthermore, the use of drugs that act modulating trigeminal afferences on the thalamus is effective in the preventive treatment of migraine attacks, such as topiramate, sodium valproate, and CGR66 receptor antagonists, corroborating the role of this structure in the chronicity of migraine [44–47].

The overuse of medications to relieve acute migraine may also lead to the chronicity of this condition, through the drug-mediated central sensitization mechanism, leading to increased susceptibility to cortical spreading depression. Central sensitization manifests clinically from increased pericranial sensitivity and allodynia [48–50].

Andersen et al. demonstrated in 2016 that during pain crises serum miRNA changes occur, and in patients with CM such changes persist the same in periods without pain. This implies the possibility of serum miRNA changes as a pathogenic feature of migraine. Thus, the study suggests that serum miRNA dosage is a potential biomarker of this disease [51].

According to Oakley et al., there is a possibility that obesity may be involved in the pathophysiology of migraine in the pediatric population. It is hypothesized that there is an overlap of the central and peripheral neural pathways responsible for the regulation of diet and those linked to the pathogenesis of migraine [33, 52]. Peterlin et al. demonstrated that several hypothalamic peptides, proteins, and neurotransmitters involved in the mechanisms of hunger also participate in the pathophysiology of migraine, such as serotonin, orexin, and adipokines. It is possible that the release of these substances, associated with the mechanism of diet and/or obesity states, may act as a trigger or corroborate the development of migraine. There is also the possibility that lifestyle and behavioral differences influence the relationship between migraine and obesity, such as differences in diet and physical exercise, or the lack of it [33, 53].

#### **6. Treatment**

#### **6.1 General and supportive measures**

The treatment of chronic migraine in adolescents aims not only to reduce frequency, duration, and intensity of the headache attacks, but also to reduce the consequences of this condition on the patient's quality of life, seeing as he or she is going through a process of growth and development. It also aims to treat comorbidities and reduce the social impact of the disease, such as school absences, school underachievement, and reduced peer interactions. Thus, the treatment should be developed from a multiprofessional perspective, with the help of pediatricians, neurologists and psychiatrists, psychologists, educators, and nutritionists, among others [54].

Firstly, family members should receive detailed information about the adolescent's diagnosis and ensure that the condition is not secondary to malignant diseases, in order to transmit confidence to the patient and their parents, thus contributing to treatment adherence [5].

Proper living habits are of paramount importance for treatment. However, the health professional should be careful to not excessively restrict the activities of young people, as this may lead to difficulties in adherence [55].

Sleep disorders are important comorbidities of chronic migraine. Therefore, regular sleep habits should be advocated in order to promote restful and restorative sleep. For this, the teenager can use some techniques, such as scheduling a daily bedtime, avoid using electronic media when in bed, avoid eating 4 h before bedtime, and avoid daytime naps. Still, sleep deprivation can be a triggering factor for pain crises, corroborating the importance of a well-slept night [56, 57].

Regarding food, it is important to prioritize regular meals, with the consumption of healthy foods and adequate hydration. Caffeine and tobacco should be avoided. The performance of physical activities should be encouraged, as it not only reduces the occurrence of crises, but also is able to assist in the treatment of depression and anxiety comorbidities, when present [58, 59].

Gelfand et al. emphasize that the patient should be alerted about the negative effects of overuse of medications, as it is one of the factors responsible for the chronicity of migraine, from the central sensitization mechanism, as previously explained about the pathophysiology [60].

Kroon Van Diest et al. [61], based on a randomized study, demonstrated the importance of Cognitive Behavioral Therapy (CBT) for adherence to pharmacological treatment and institution of lifestyle changes [62]. CBT aims, through interventions guided by a psychologist, to promote the patient's active learning in order to implement skills to deal with migraine and related conditions and situations to her. Thus, during the sessions, behavioral coping skills are worked out, such as problemsolving and thought restructuring, that is, the adolescent is urged to change their ideas, beliefs, and attitudes regarding his chronic condition [62]. CBT, in combination with amitriptyline, is suggested as a first-line treatment in the context of CM in adolescents [61].

#### **6.2 Acute treatment**

Regarding acute pharmacological treatment, that is, to relieve pain crises, nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans are used [28, 63, 64]. Among NSAIDs, the most used are ibuprofen and naproxen [28]. Evers et al. demonstrated that ibuprofen is better than placebo. There is no evidence regarding the efficacy of acetaminophen in adolescents [63, 65, 66].

In the adolescent population, the following triptans are indicated: sumatriptan, rizatriptan, zolmitriptan, and almotriptan. Studies indicate that such drugs are the most effective in relieving pain during acute crises in adolescents, with no statistically significant differences between them [63]. According to Derosier et al., the combination of naproxen and sumatriptan was superior to placebo when analyzing the permanence of analgesia after 2 h, with sumatriptan + naproxen sodium 10 mg + 60 mg (29%; p = 0,003), 30 mg + 180 mg (27%; p = 0.003), and 85 mg + 500 mg (24%; p = 0.003) versus placebo (10%) [67]. Among the side effects of this class, the most common are mild fatigue, paresthesia, dizziness, and taste disorders [28, 64].

In the case of long-term migraine or migratory status, that is, disabling crisis lasting more than 72 h, hospital treatment may be required for intravenous administration of prochlorperazine with ketorolac, which Brousseau showed that 57% of patients had pain reduction in 60 min [28, 68]. Dihydroergotamine (DHE) has been shown to be well tolerated and effective in acute treatment and is generally administered in hospital setting, and an association with metoclopramide or prochlorperazine is suggested, which is able to attenuate gastrointestinal side effects [28, 69]. Ayulo et al. suggested the use of intravenous lidocaine for the treatment of migratory status in adolescents, but further evidence is needed to ensure the longterm efficacy and safety of this medication [28, 70].

**115**

*Chronic Migraine in Adolescence*

**6.3 Preventive treatment**

prevention will be presented.

6.6 days, respectively).

NSAIDs, and triptans [93].

**7. Conclusion**

economic repercussions.

contribute to the onset or that are correlated.

*DOI: http://dx.doi.org/10.5772/intechopen.90936*

Prevention of chronic migraine attacks in adolescents remains limited [71, 72]. Newly developed therapies, including drugs, biologic products, and neuromodulation devices are safe and well tolerated in adults [73–80]. Studies in the pediatric population are still being developed [81]. Therefore, the current nonpediatric

Epidemiological studies suggest that approximately 38% of migraine patients require preventive therapy, however, only 3–13% currently use it [12]. The prevention of CM currently presents concrete evidence for the following drugs: onabotulinumtoxina [82], topiramate [83, 84], and fremanezumab (TEV-48125) [85]. Other therapies, such as β-blockers and amitriptyline, are often used despite the lack of evidence, as they are not fully effective or poorly tolerated, which may culminate in low adherence rates [85]. However, a randomized study developed by Powers et at. demonstrated that amitriptyline, when combined with Cognitive Behavioral Therapy (CBT), reduces migraine disability and pain days by 1 month—adolescents receiving amitriptyline alone (group A) reduced the number of days with headache in 1 month of 6.8 days, while those who associated amitriptyline with CBT (group B) had a reduction of 11.5 days; headache disability as assessed by the Pediatric Migraine Disability Score (PedMIDAS) decreased by 52.7 points in group B versus 38.6 points in group A [62]. Currently, new forms of prevention have been proposed, based on the understanding of the pathophysiology of the disease. The calcitonin gene-related peptide (CGRP) has increased plasma concentration during a migraine attack [86–88]. Therefore, a human monoclonal antibody against the receptor of CGRP, named Galcanezumab, which was effective in preventing migraine when given at a dose of 150 mg twice a month, was developed in a study by Skljarevski et al. [89]. Treatment with self-administered injections of subcutaneous galcanezumab [90], subcutaneous fremanezumab [91], and enerumab [92] was associated with a reduction in the number of monthly days of migraine (5.6–6.5 days, 1.3–1.5 days, and

Recent studies indicate that nonpharmacological strategies are effective in preventing CM, reducing the activation of peripheral nociceptive terminations. This can be accomplished by manipulation technique, increasing the range of motion and reducing the stiffness of the cervicothoracic spine. In the study by Gandolfi et al., patients undergoing this treatment had lower consumption of analgesics,

Guilbot et al. showed that *Tanacetum parthenium* L., magnesium, and coenzyme Q10, administered prophylactically for 3 months significantly reduced the number of monthly migraine days (4.9 ± 2.6 days) [94]. Silberstein et al. proposed the prevention of CM with noninvasive vagal stimulation, which presented better results in patients who underwent longer treatment times (6 months, in the study) [95].

CM in adolescents is a disease of clinical and epidemiological importance, since it can affect approximately a quarter of the pediatric population with an average of 11 years of age, being considered debilitating due to psychological, social, and

This disorder has intrinsic and nonmodifiable (genetic and comorbidities) risk factors, as well as modifiable risk factors, such as behavioral and socioenvironmental variables, in addition to several other elements still under study that may

#### **6.3 Preventive treatment**

*Migraine*

Sleep disorders are important comorbidities of chronic migraine. Therefore, regular sleep habits should be advocated in order to promote restful and restorative sleep. For this, the teenager can use some techniques, such as scheduling a daily bedtime, avoid using electronic media when in bed, avoid eating 4 h before bedtime, and avoid daytime naps. Still, sleep deprivation can be a triggering factor for

Regarding food, it is important to prioritize regular meals, with the consumption of healthy foods and adequate hydration. Caffeine and tobacco should be avoided. The performance of physical activities should be encouraged, as it not only reduces the occurrence of crises, but also is able to assist in the treatment of depres-

Gelfand et al. emphasize that the patient should be alerted about the negative effects of overuse of medications, as it is one of the factors responsible for the chronicity of migraine, from the central sensitization mechanism, as previously

Kroon Van Diest et al. [61], based on a randomized study, demonstrated the importance of Cognitive Behavioral Therapy (CBT) for adherence to pharmacological treatment and institution of lifestyle changes [62]. CBT aims, through interventions guided by a psychologist, to promote the patient's active learning in order to implement skills to deal with migraine and related conditions and situations to her. Thus, during the sessions, behavioral coping skills are worked out, such as problemsolving and thought restructuring, that is, the adolescent is urged to change their ideas, beliefs, and attitudes regarding his chronic condition [62]. CBT, in combination with amitriptyline, is suggested as a first-line treatment in the context of CM in

Regarding acute pharmacological treatment, that is, to relieve pain crises, nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans are used [28, 63, 64]. Among NSAIDs, the most used are ibuprofen and naproxen [28]. Evers et al. demonstrated that ibuprofen is better than placebo. There is no evidence regarding the efficacy of

In the adolescent population, the following triptans are indicated: sumatriptan, rizatriptan, zolmitriptan, and almotriptan. Studies indicate that such drugs are the most effective in relieving pain during acute crises in adolescents, with no statistically significant differences between them [63]. According to Derosier et al., the combination of naproxen and sumatriptan was superior to placebo when analyzing the permanence of analgesia after 2 h, with sumatriptan + naproxen sodium 10 mg + 60 mg (29%; p = 0,003), 30 mg + 180 mg (27%; p = 0.003), and 85 mg + 500 mg (24%; p = 0.003) versus placebo (10%) [67]. Among the side effects of this class, the most common are mild fatigue, paresthesia, dizziness, and

In the case of long-term migraine or migratory status, that is, disabling crisis lasting more than 72 h, hospital treatment may be required for intravenous administration of prochlorperazine with ketorolac, which Brousseau showed that 57% of patients had pain reduction in 60 min [28, 68]. Dihydroergotamine (DHE) has been shown to be well tolerated and effective in acute treatment and is generally administered in hospital setting, and an association with metoclopramide or prochlorperazine is suggested, which is able to attenuate gastrointestinal side effects [28, 69]. Ayulo et al. suggested the use of intravenous lidocaine for the treatment of migratory status in adolescents, but further evidence is needed to ensure the long-

pain crises, corroborating the importance of a well-slept night [56, 57].

sion and anxiety comorbidities, when present [58, 59].

explained about the pathophysiology [60].

acetaminophen in adolescents [63, 65, 66].

term efficacy and safety of this medication [28, 70].

adolescents [61].

**6.2 Acute treatment**

taste disorders [28, 64].

**114**

Prevention of chronic migraine attacks in adolescents remains limited [71, 72]. Newly developed therapies, including drugs, biologic products, and neuromodulation devices are safe and well tolerated in adults [73–80]. Studies in the pediatric population are still being developed [81]. Therefore, the current nonpediatric prevention will be presented.

Epidemiological studies suggest that approximately 38% of migraine patients require preventive therapy, however, only 3–13% currently use it [12]. The prevention of CM currently presents concrete evidence for the following drugs: onabotulinumtoxina [82], topiramate [83, 84], and fremanezumab (TEV-48125) [85]. Other therapies, such as β-blockers and amitriptyline, are often used despite the lack of evidence, as they are not fully effective or poorly tolerated, which may culminate in low adherence rates [85]. However, a randomized study developed by Powers et at. demonstrated that amitriptyline, when combined with Cognitive Behavioral Therapy (CBT), reduces migraine disability and pain days by 1 month—adolescents receiving amitriptyline alone (group A) reduced the number of days with headache in 1 month of 6.8 days, while those who associated amitriptyline with CBT (group B) had a reduction of 11.5 days; headache disability as assessed by the Pediatric Migraine Disability Score (PedMIDAS) decreased by 52.7 points in group B versus 38.6 points in group A [62].

Currently, new forms of prevention have been proposed, based on the understanding of the pathophysiology of the disease. The calcitonin gene-related peptide (CGRP) has increased plasma concentration during a migraine attack [86–88]. Therefore, a human monoclonal antibody against the receptor of CGRP, named Galcanezumab, which was effective in preventing migraine when given at a dose of 150 mg twice a month, was developed in a study by Skljarevski et al. [89]. Treatment with self-administered injections of subcutaneous galcanezumab [90], subcutaneous fremanezumab [91], and enerumab [92] was associated with a reduction in the number of monthly days of migraine (5.6–6.5 days, 1.3–1.5 days, and 6.6 days, respectively).

Recent studies indicate that nonpharmacological strategies are effective in preventing CM, reducing the activation of peripheral nociceptive terminations. This can be accomplished by manipulation technique, increasing the range of motion and reducing the stiffness of the cervicothoracic spine. In the study by Gandolfi et al., patients undergoing this treatment had lower consumption of analgesics, NSAIDs, and triptans [93].

Guilbot et al. showed that *Tanacetum parthenium* L., magnesium, and coenzyme Q10, administered prophylactically for 3 months significantly reduced the number of monthly migraine days (4.9 ± 2.6 days) [94]. Silberstein et al. proposed the prevention of CM with noninvasive vagal stimulation, which presented better results in patients who underwent longer treatment times (6 months, in the study) [95].

#### **7. Conclusion**

CM in adolescents is a disease of clinical and epidemiological importance, since it can affect approximately a quarter of the pediatric population with an average of 11 years of age, being considered debilitating due to psychological, social, and economic repercussions.

This disorder has intrinsic and nonmodifiable (genetic and comorbidities) risk factors, as well as modifiable risk factors, such as behavioral and socioenvironmental variables, in addition to several other elements still under study that may contribute to the onset or that are correlated.

The diagnosis of migraine is made clinically according to the ICHD-3 criteria, taking into account the particularities of the adolescent population.

Pathophysiology, as well as risk factors and prevention, are still not completely elucidated items in CM. However, it is generally agreed that migraine occurs from complex mechanisms involving activation and sensitization of trigeminal nociceptives pathways, alteration of autonomic nervous system function, pain modulating descending system dysfunction, thalamic sensitization and further central sensitization due to the overuse of medicines in the acute treatment of pain crises.

Treatment, in turn, is multiprofessional and supported by both pharmacological and nonpharmacological measures. Nonpharmacological measures include guidance to parents and family members about the chronic condition, as well as sleep hygiene and adoption of good eating habits by the patient. In the case of drug measures, NSAIDs and triptans are the first option and, in case of migraine status, prochlorperazine associated with intravenous ketorolac added to recent evidence suggesting the use of intravenous lidocaine.

Finally, studies are still needed to fill the gaps present for the complete understanding of this complex and debilitating entity that is chronic migraine. Through a better understanding of the pathophysiological mechanisms responsible for the development of CM, as well as its risk factors, it will be possible to develop more effective prevention and treatment methods in adolescents.

#### **Author details**

Marcos Antonio da Silva Cristovam1 \*, Daniel Albiero Piélak<sup>2</sup> , Júlia Deitos3 , Júlia Natsumi Hashimoto3 , Lorena Vaz Meleiro Lopes3 and Luísa Manfredin Vila<sup>3</sup>

1 Clinical Pediatrics of Western Paraná State University, Cascavel, PR, Brazil

2 Western Paraná Universitary Hospital of Western Paraná State University, Cascavel, PR, Brazil

3 Western Paraná State University School of Medicine, Cascavel, PR, Brazil

\*Address all correspondence to: ma.cristovam@uol.com.br

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**117**

*Chronic Migraine in Adolescence*

**References**

2018;**38**(1):1-211

2015;**55**(2):103-122

2004;**291**(4):493-494

2005;**45**(1):3-13

s11916-016-0538-z

2010;**30**:1065-1072

1992;**267**:64-69

*DOI: http://dx.doi.org/10.5772/intechopen.90936*

[1] Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders. Cephalalgia.

Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet.

[11] Arruda MA, Bigal ME. Migraine

preadolescent children: Association with school performance. Neurology.

Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology.

[13] Bigal ME, Liberman JN, Lipton RB. Age-dependent prevalence and clinical features of migraine. Neurology.

[14] Steiner TJ, Scher AI, Stewart WF, Kolodner K, Liberman J, Lipton RB. The prevalence and disability burden of adult migraine in England and their relationships to age, gender and ethnicity. Cephalalgia. 2003;

[15] Ando N, Fujimoto S, Ishikawa T, et al. Prevalence and features of migraine in Japanese junior high school students aged 12-15 yr. Brain & Development. 2007;**29**:482-485

[16] Zencir M, Ergin H, Sahiner T, et al. Epidemiology and symptomatology of migraine among school children: Denizli urban area in Turkey. Headache.

[17] Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: Data from the American migraine study

II. Headache. 2001;**41**:646-657

2016;**388**:1545-1602

2012;**79**:1881-1888

2007;**68**:343-349

2006;**67**:246-251

**23**:519-527

2004;**44**:780-785

and migraine subtypes in

[12] Lipton RB, Bigal ME,

[2] Lipton RB, Silberstein SD. Episodic and chronic migraine headache: Breaking down barriers to optimal treatment and prevention. Headache.

[3] Lipton RB, Pan J. Is migraine a progressive brain disease? Journal of the American Medical Association.

[4] Lipton RB, Bigal ME. Migraine: Epidemiology, impact, and risk factors for progression. Headache.

[5] Özge A, Yalın OÖ. Chronic

2016;**20**(2):1-7. DOI: 10.1007/

migraine in children and adolescents. Current Pain and Headache Reports.

[6] Gelfand AA. Migraine in young children. Developmental Medicine and Child Neurology. 2015;**57**(6):503

[7] Victor TW, Hu X, Campbell JC, Buse DC, Lipton RB. Migraine prevalence by age and sex in the United States: A life-span study. Cephalalgia.

[8] Stewart WF, Linet MS, Celentano DD, Van Natta M, Siegler D. Age and sexspecific incidence rates of migraine with and without visual aura. American Journal of Epidemiology. 1991;**34**:1111-1120

[9] Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States. Journal of the American Medical Association.

[10] GBD 2015 Disease and Injury

Incidence and Prevalence

### **References**

*Migraine*

The diagnosis of migraine is made clinically according to the ICHD-3 criteria,

Pathophysiology, as well as risk factors and prevention, are still not completely elucidated items in CM. However, it is generally agreed that migraine occurs from complex mechanisms involving activation and sensitization of trigeminal nociceptives pathways, alteration of autonomic nervous system function, pain modulating descending system dysfunction, thalamic sensitization and further central sensitization due to the overuse of medicines in the acute treatment of pain crises.

Treatment, in turn, is multiprofessional and supported by both pharmacological and nonpharmacological measures. Nonpharmacological measures include guidance to parents and family members about the chronic condition, as well as sleep hygiene and adoption of good eating habits by the patient. In the case of drug measures, NSAIDs and triptans are the first option and, in case of migraine status, prochlorperazine associated with intravenous ketorolac added to recent evidence

Finally, studies are still needed to fill the gaps present for the complete understanding of this complex and debilitating entity that is chronic migraine. Through a better understanding of the pathophysiological mechanisms responsible for the development of CM, as well as its risk factors, it will be possible to develop more

\*, Daniel Albiero Piélak<sup>2</sup>

, Lorena Vaz Meleiro Lopes3

1 Clinical Pediatrics of Western Paraná State University, Cascavel, PR, Brazil

2 Western Paraná Universitary Hospital of Western Paraná State University,

3 Western Paraná State University School of Medicine, Cascavel, PR, Brazil

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: ma.cristovam@uol.com.br

, Júlia Deitos3

and Luísa Manfredin Vila<sup>3</sup>

,

taking into account the particularities of the adolescent population.

suggesting the use of intravenous lidocaine.

effective prevention and treatment methods in adolescents.

**116**

**Author details**

Marcos Antonio da Silva Cristovam1

provided the original work is properly cited.

Júlia Natsumi Hashimoto3

Cascavel, PR, Brazil

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[3] Lipton RB, Pan J. Is migraine a progressive brain disease? Journal of the American Medical Association. 2004;**291**(4):493-494

[4] Lipton RB, Bigal ME. Migraine: Epidemiology, impact, and risk factors for progression. Headache. 2005;**45**(1):3-13

[5] Özge A, Yalın OÖ. Chronic migraine in children and adolescents. Current Pain and Headache Reports. 2016;**20**(2):1-7. DOI: 10.1007/ s11916-016-0538-z

[6] Gelfand AA. Migraine in young children. Developmental Medicine and Child Neurology. 2015;**57**(6):503

[7] Victor TW, Hu X, Campbell JC, Buse DC, Lipton RB. Migraine prevalence by age and sex in the United States: A life-span study. Cephalalgia. 2010;**30**:1065-1072

[8] Stewart WF, Linet MS, Celentano DD, Van Natta M, Siegler D. Age and sexspecific incidence rates of migraine with and without visual aura. American Journal of Epidemiology. 1991;**34**:1111-1120

[9] Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States. Journal of the American Medical Association. 1992;**267**:64-69

[10] GBD 2015 Disease and Injury Incidence and Prevalence

Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;**388**:1545-1602

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#### *Chronic Migraine in Adolescence DOI: http://dx.doi.org/10.5772/intechopen.90936*

*Migraine*

[52] Oakley CB, Scher AI, Recober A, Peterlin BL. Headache and obesity in the pediatric population. Current Pain and Headache Reports. 2014;**18**(5):1-12. [61] Kroon Van Diest AM, Ramsey RR, Kashikar-Zuck S, Slater S, Hommel K, Kroner JW, et al. Treatment adherence in child and adolescent chronic migraine patients. The Clinical Journal of Pain. 2017;**33**(10):892-898. DOI: 10.1097/

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ajp.0000000000000481

2013;**310**(24):2622-2630

pxx170

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Linsdell MA, Russell K, Vandermeer B, Crumley ET, et al. Drugs for the acute treatment of migraine in children and adolescents. Paediatrics & Child Health. 2017;**22**(8):454-458. DOI: 10.1093/pch/

[64] Patniyot IR, Gelfand AA. Acute treatment therapies for pediatric migraine: A qualitative systematic review. Headache. 2016;**56**:49-70

[65] Evers S, Rahmann A, Kraemer C, Kurlemann G, Debus O, Husstedt IW, et al. Treatment of childhood migraine

2006;**67**(3):497-499. DOI: 10.1212/01.

[66] Lewis DW, Kellstein D, Dahl G, Burke B, Frank LM, Toor S, et al. Children's ibuprofen suspension for the acute treatment of pediatric migraine. Headache. 2002;**42**(8):780-786. DOI: 10.1046/j.1526-4610.2002.02180.x

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attacks with oral zolmitriptan and ibuprofen. Neurology.

wnl.0000231138.18629.d5

peds.2011-2455

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DOI: 10.1007/s11916-014-0416-5

Headache. 2013;**53**:474-490

[54] De Angelis V, Cherubini F, Nigrelli G, Erbuto D, Marteletti P. Multimodal therapy in the management of MOH: 3 year experience. The Journal of Headache and Pain. 2015;**16**:135

[55] Sieberg CB, Huguet A, von Baeyer CL, Seshia S. Psychological interventions for headache in children and adolescents. The Canadian Journal of Neurological Sciences.

[56] Guidetti V, Dosi C, Bruni O. The relationship between sleep and headache in children: Implications for treatment. Cephalalgia. 2014;**34**(10):767-776

[57] Calhoun AH, Ford S. Behavioral sleep modification may revert transformed migraine to episodic migraine. Headache.

[58] Straube A, Heinen F, Ebinger F, von Kries R. Headache in school children:

Deutsches Ärzteblatt International.

[59] Verotti A, Di Fonzo A, Penta L, Agostinelli S, Parisi P. Obesity and headache/migraine: The importance of weight reduction through lifestyle modifications. BioMed Research International. 2014;**2014**:420858

[60] Gelfand AA, Goadsby PJ. Medication overuse in children and adolescents. Current Pain and Headache

Reports. 2014;**18**(7):1-6

2012;**39**(01):26-34

2007;**478**(11):787-811

2013;**6**(57):811-818

Prevalence and risk factors.

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[81] Hornik CP, Gelfand AA, Szperka CL, Pezzuto T, Utevsky A, Kessel S, et al. Development of a prospective real-world data clinical registry of children and adolescents with migraine. Headache: The Journal of Head and Face Pain. 2019;**0**:2-9. DOI: 10.1111/head.13714

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Section 4

The New Headache

Problem on the Scene

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Section 4
