Migraine: Clinical Guidelines

List of Abbreviations

BF – Biofeedback

VAS – visual analogue scale

GP – general practitioner

IV – intravenous

GB – headache

GBN – tension-type headache

DPM – pericranial muscle dysfunction

DCE – dyscirculatory encephalopathy

VLEL – vital and essential drugs

CGRP – calcitonin gene-related peptide

KN – comorbid disorders

LIGB – medication-induced (overuse) headache

M – migraine

MA – migraine with aura

MwoA – migraine without aura

mAb – monoclonal antibody

ICD-10 – International Classification of Diseases, 10th Revision

ICHD-3 – International Classification of Headache Disorders, 3rd edition

MRI – magnetic resonance imaging

SM – status migrainosus

MTS – muscle-tonic syndrome

MFS – myofascial syndrome

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs

NS – neurostimulation

PS – peripheral sensitization

CSD – cortical spreading depression

TVS – trigeminovascular system

Dura – dura mater

TCA – tricyclic antidepressants

CDU – color duplex ultrasonography

HGBN – chronic tension-type headache

HM – chronic migraine

CNS – central nervous system

CS – central sensitization

EGBN – episodic tension-type headache

CGRP – Calcitonin Gene-Related Peptide – calcitonin gene-related peptide (CGRP)

PREEMPT – Phase III REsearch Evaluating Migraine Prophylaxis Therapy.

Terms and Definitions

Causative drugs (abused drugs) – medicications that, when used excessively, can lead to medication-overuse headache (MOH) (all classes of analgesics).

Secondary headaches – headaches that are a symptom of another (symptomatic) disorder, occurring de novo in close temporal relation to another causative disorder which, according to scientific evidence, is capable of causing headache.

Tension-type headache (TTH) – one of the most common forms of primary headache, manifesting as pain episodes lasting from 30 minutes to several days.

Pericranial muscle dysfunction (PMD) – painful tension of the muscles of the head, face, and neck.

Inhibitory antinociceptive mechanisms – the descending pain-modulating or antinociceptive control system.

Calcitonin gene-related peptide (CGRP) – the main mediator of pain impulse transmission and a direct participant in migraine pathogenesis.

Comorbid disorders (CD) – one or more pathological conditions observed in a single patient, etiopathogenetically related or coinciding in time of onset regardless of the activity of each.

Medication-overuse headache (MOH) – a clinical subtype of secondary chronic headache developing in patients with primary cephalalgias due to the excessive use of acute headache medications.

Medication overuse – the excessive use of any pain-relieving medications for acute headache treatment.

Monoclonal antibodies (mAbs) targeting CGRP or its receptor – the first class of drugs specifically developed for targeted (pathogenetically grounded) migraine prevention.

Primary headaches – idiopathic (benign) cephalalgias not associated with organic brain pathology, cerebral vascular disorders, other head and neck structures, or systemic diseases.

Peripheral sensitization (PS) – an increased response of excited nociceptive neurons of the peripheral nervous system to normal and/or subthreshold stimulation.

Targeted migraine preventive therapy – therapy with monoclonal antibodies (mAbs) directed against the primary migraine mediator CGRP or its receptor, acting on the core pathogenetic mechanism of migraine.

Migraine triggers – endogenous and exogenous factors capable of provoking a migraine attack.

Chronification factors – genetic, metabolic, environmental, behavioral, and/or psychological factors promoting an increase in headache frequency.

Migraine chronification – a gradual increase in the number of headache days per month.

Chronic migraine (CM) – headache occurring on ≥15 days per month for >3 months, with headache attacks exhibiting migraine features on at least 8 days per month.

Central sensitization (CS) – an enhancement of neural signaling within the CNS that leads to systemic hypersensitivity to pain. CS reflects hyperexcitability of pain-processing systems, reduced activity of descending pain-inhibitory pathways, and consequently a disruption of endogenous pain control.

Cephalalgia – headache (synonym).

Headache specialist – a neurologist specializing in the diagnosis and treatment of headaches.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Migraine is a primary headache disorder manifested by attacks of throbbing unilateral headache lasting 4–72 hours, accompanied by photophobia, phonophobia, nausea, and/or vomiting.

Migraine typically begins at a young age, before 20 years. In childhood, the condition is more common in boys; adult women are affected 2.5 to 3 times more often than men. At ages 35–45, the frequency and intensity of migraine attacks peak, whereas after 55–60 years the disease course softens or attacks cease completely. At the same time, some patients over 50 may retain typical migraine attacks and/or isolated migraine aura (late-life migraine accompaniments) [1–3].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Migraine is a chronic neurovascular disorder with a genetic predisposition. The core pathogenetic mechanism is the periodic development of perivascular neurogenic inflammation of cerebral vessels, primarily the meningeal vessels of the dura mater. Patients with migraines are known to exhibit increased excitability of the cerebral cortex and trigeminovascular system neurons [3, 4]. Upon exposure to endogenous and exogenous migraine triggers, the excitability of the trigeminal system, hypothalamus, cortex, and certain other brain structures increases, leading to activation of the trigeminal ganglion, the sensory spinal trigeminal nucleus, and trigeminal nerve fibers innervating the dural vessels – trigeminovascular fibers. Activation of the trigeminovascular system (TVS) is accompanied by the release of pain-inducing pro-inflammatory vasodilator peptides (primarily calcitonin gene-related peptide (CGRP), as well as neurokinin A and substance P) from trigeminovascular terminals [3, 4]. Subsequent vasodilation and neurogenic inflammation activate pain receptors in the dural vessel walls. Pain impulses reach the sensory cerebral cortex, generating the sensation of throbbing headache. Persistent hyperexcitability of the TVS, central nociceptive structures, and exhaustion of the anti-nociceptive system gradually lead to permanent hypersensitivity (sensitization) of pain structures, which promotes more frequent headache attacks and ultimately drives M chronification [1–4].

The mechanism of migraine aura is associated with the generation and propagation of a wave of neuronal depolarization (excitation) spreading from the visual cortex to the somatosensory and frontotemporal brain regions – cortical spreading depression (CSD). The velocity and topography of CSD determine the rate, nature, and sequence of aura symptoms [1, 3].

1.3 Epidemiology of the Disease or Condition

The prevalence of M in the general population of Europe and the USA averages 14% (17% among women and 8% among men) [1, 3, 5]. According to a population-based house-to-house survey conducted in 2009–2011 across 35 cities and 9 rural districts in Russia, the 1-year prevalence of M was 20.8%, which slightly exceeds the figures reported in most other countries [6]. According to another Russian study, the 1-year prevalence of M was 15.9% (M without aura 13.5%, M with aura 2.4%) [7].

1.4 Features of Coding the Disease or Condition

G43 – Migraine

G43.0 – Migraine without aura [common migraine]

G43.1 – Migraine with aura [classic migraine]

G43.2 – Status migrainosus

G43.3 – Complicated (including chronic) migraine

G43.8 – Other migraine (ophthalmoplegic, retinal)

G43.9 – Migraine, unspecified

G44.0 – Cluster headache syndrome

G44.1 – Vascular headache, not elsewhere classified

G44.4 – Drug-induced headache, not elsewhere classified

Comments: M can be combined with TTH (G43.0/1, G44.2). Frequent episodic and especially chronic migraine (CM) can be combined with medication-overuse headache (MOH, G44.4).

1.5 Classification of the disease or condition

In accordance with the latest version of the International Classification of Headache Disorders (ICHD-3, 2018), M belongs to primary (benign) cephalalgias (Part I of ICHD-3), which are not associated with organic lesions of the brain, cerebral vessels, other structures located in the head and neck region, or systemic diseases (Tab. 1) [8].

Table 1. Table of Contents of the International Classification of Headache Disorders, 3rd edition (ICHD-3, 2018) [8]

According to ICHD-3, there are two main forms of M: migraine without aura (MO), which is the most frequent – up to 80% of cases, and migraine with aura (MA) – up to 20% of cases [1, 3]. The main clinical manifestation of MO is a headache attack; in MA, the pain phase of the attack is preceded by an aura stage. Other forms of MA are less common: migraine with brainstem aura (formerly "basilar-type M"), retinal migraine, and hemiplegic migraine.

The ICHD-3 separately defines chronic migraine (CM), complications of migraine, and episodic syndromes that may be associated with M (more common in childhood) [8]. If one of the diagnostic criteria is not met, a diagnosis of "Probable M" can be made (Tab. 2) [8].

Table 2. Classification of migraine (according to ICHD-3, 2018) [8]

Comments: episodic syndromes are more common in childhood and may precede the onset of typical migraine attacks without or with aura.

The Appendix to ICHD-3 also defines true menstrual migraine, in which M attacks occur exclusively during the perimenstrual period (2–3 days before and during the first 3 days of menstruation), and migraine associated with menstruation, in which headache attacks may also occur on other days of the month (i.e., triggers of M attacks include not only menstruation but other triggers as well) [8].

1.6 Clinical presentation of the disease or condition

Migraine without aura (MO) manifests as recurring, generally stereotyped attacks of intense, usually unilateral, pulsating headache predominantly in the temporal, ocular, and parietal regions, though it often begins in the occipital region. The headache is frequently accompanied by nausea, vomiting, photophobia, and phonophobia, and is aggravated by physical activity. The duration of an attack is from 4 hours to 3 days; the frequency of headache days in episodic M ranges from 1 day per year to 14 days per month (on average 2–4 headache days per month), and in CM it is 15 or more headache days per month [1, 9, 10].

In migraine with aura (MA), the headache phase is preceded by transient neurological symptoms. Migraine with typical aura is the most common, presenting with fully reversible visual, sensory, and/or speech symptoms, but without motor or brainstem deficits [11, 12]. In rare cases, headache does not develop after the aura – typical aura without headache. In migraine with brainstem aura, in addition to visual, sensory, and/or speech disturbances, two or more fully reversible brainstem symptoms occur: dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia, or altered level of consciousness. Hemiplegic migraine, which is extremely rare and almost always hereditary, is characterized by fully reversible visual, sensory, and/or speech symptoms combined with motor deficits (hemiparesis or hemiplegia). Non-motor symptoms last for 5–60 minutes, and motor disorders last for up to 72 hours. In familial hemiplegic migraine, at least one first- or second-degree relative has or has had headache attacks meeting the criteria for hemiplegic migraine; sporadic hemiplegic migraine lacks this hereditary predisposition. In retinal migraine, the aura consists of fully reversible monocular positive and/or negative visual phenomena (scintillations, scotomas), the presence of which is confirmed by ophthalmological visual field examination during M attacks, and/or the patient can draw or describe the monocular visual field defect present at that time [9, 10].

An M attack can be triggered by various exogenous and endogenous factors. The most frequent migraine triggers include [2, 9, 10, 13]:

• psychological factors: stress or relaxation after stress, anxiety or depressive disorders, fatigue;

• weather changes;

• hormonal factors: menstruation (perimenstrual "window"), ovulation, use of estrogen-containing hormone replacement therapy or oral contraceptives;

• dietary factors: hunger, consumption of certain foods (cheese, chocolate, nuts, smoked foods, chicken liver, avocado, citrus fruits, or caffeine-containing products); alcohol consumption (especially red wine);

• other factors: lack or excess of night sleep, stuffiness, aerobic physical exertion, visual stimuli (bright or flashing light), noise, staying at high altitudes.

Chronic migraine (CM) is a severe form characterized by a high frequency of headache days (15 or more per month), long duration, and high intensity of attacks, leading to maladaptation and a decreased quality of life in patients. CM is characterized by the following manifestations: the development of comorbid disorders, primarily psychiatric ones (depression, anxiety disorders), sleep disturbances, decreased efficacy of acute treatment medications, and a high risk of their overuse (medication overuse). The main modifiable factors of migraine chronification are emotional stress, depression, excessive intake of analgesic drugs, and caffeine [14 - 17].

CM and frequent episodic migraine are often combined with medication-overuse headache (MOH). In this case, the headache has a mixed character: migraine headaches are combined with tension-type-like cephalalgias presenting as a diffuse, monotonous, most commonly morning or nighttime pressing or constricting headache that increases in intensity as the effect of the previously taken analgesic medication wears off. Typical manifestations of long-standing MOH include nighttime intake of analgesic drugs, taking them at the stage of mild headache to prevent its intensification (prophylactic intake), as well as complaints of difficulty concentrating, impaired memory, and reduced work capacity. MOH generally improves after the withdrawal of the overused drug(s).

Complications of migraine include several conditions.

Migraine status is a typical debilitating migraine attack lasting more than 72 hours, during which remissions of up to 12 hours associated with sleep or medication effects are permitted.

Persistent aura without infarction refers to one or more aura symptoms lasting for more than one week, without radiographic evidence of brain infarction.

Migrainous infarction (stroke) is the combination of one or more migraine aura symptoms with ischemic brain injury confirmed by neuroimaging methods. True migrainous infarction occurs during a typical migraine attack with aura, with one or more aura symptoms lasting for more than 60 minutes. Brain infarctions that do not coincide in time with a migraine attack with aura cannot be classified as migrainous infarctions.

Migraine aura as a trigger for an epileptic seizure is an epileptic seizure occurring during a migraine with aura attack or within 1 hour after it.

Episodic syndromes that may be associated with migraine. These disorders occur predominantly in childhood and are significantly less common in adults.

Cyclic vomiting syndrome is characterized by episodically recurring attacks of severe nausea and vomiting, usually stereotyped for each patient and with a predictable start time; the attacks are accompanied by skin pallor and lethargy; symptoms resolve completely between attacks.

Abdominal migraine is an idiopathic disorder occurring predominantly in children, presenting as recurring episodes of moderate to severe abdominal pain (in the midline) lasting 2 - 72 hours; nausea and/or vomiting are typical; no headache occurs during these episodes. The patients' condition is normal between attacks. The vast majority of children with abdominal migraine later develop typical migraine headaches.

Benign paroxysmal vertigo – recurring brief attacks of vertigo in children that both start and resolve suddenly.

Benign paroxysmal torticollis is recurring episodes of head tilt to one side, possibly with a slight head rotation, which resolve spontaneously. This condition occurs in infants and young children, beginning within the first year of life. Older children may develop ataxia.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Comments: ICHD-3, approved by the International Headache Society in 2018, is the primary diagnostic tool for any forms of headache and facial pain, including migraine variants. Tables 3a to 3c present the diagnostic criteria for migraine without aura, migraine with aura, and chronic migraine according to ICHD-3.

Diagnosis of migraine complications and episodic syndromes that may be associated with migraine is also carried out in accordance with the diagnostic criteria of ICHD-3 [8, 12].

Table 3a. Diagnostic criteria for migraine without aura (according to ICHD-3, 2018) [8]

Comments: if a migraine aura is identified, it is recommended to assign the appropriate diagnosis, such as "Migraine with typical aura" or "Migraine with brainstem aura" [8, 11, 12, 18 - 20]. Aura should not be confused with prodromal symptoms, which may occur several hours before the onset of a migraine attack: increased sensitivity to light, sound, and smells, appetite changes, thirst, emotional excitement, or, conversely, malaise, etc.

Table 3b. Diagnostic criteria for migraine with aura (according to ICHD-3, 2018) [8]

Notes:

¹ - if 3 aura symptoms occur, the maximum permissible duration is 180 minutes. Motor symptoms may last up to 72 hours;

² - aphasia is always regarded as a unilateral symptom; dysarthria may occur;

³ - oscillations and tingling sensations are regarded as positive aura symptoms [8].

Table 3v. Diagnostic criteria for chronic migraine (according to ICHD-3, 2018) [8]

Comments: by interviewing the patient and analyzing the headache diary (if available), the number of headache days per month over the last 3 months should be established, including the number of migraine days per month, the clinical characteristics of the pain should be clarified, and these data should be compared with the diagnostic criteria for CM (Table 3v). An important diagnostic criterion for CM is also the presence of typical episodic migraine attacks at the disease onset [15, 21, 22].

Combination of migraine and medication-overuse headache (MOH). Frequent episodic migraine (more than 10 headache days per month) and especially CM (more than 15 headache days per month) can be combined with the excessive use of pain-relieving medications (medication overuse) [8, 16]. Significant medication overuse can lead to the development of MOH, presented in section 8.2 of ICHD-3 “Medication-overuse headache” (Table 4a) [8]. Medication overuse contributes to an increased frequency of headache episodes and is considered one of the leading factors in migraine chronification [14–17].

Table 4a. Diagnostic criteria for medication-overuse headache (according to ICHD-3, 2018) [8]

Comments: the diagnosis of MOH is based on the clinical evaluation of the headache, analysis of data on the number and frequency of intake of pain-relieving medications, and the type of overused drugs [8]. To clarify these characteristics, it is advisable for the patient to keep a headache diary (Appendix G). MOH manifests as a diffuse, dull, most often morning or nocturnal headache that increases in intensity as the previously taken pain-relieving medication wears off. The similarity of the clinical characteristics of MOH and CM often complicates the differential diagnosis of these cephalalgias.

It is important to determine the type of overused drugs and establish the "number of days per month with intake of pain-relieving medications" — the main diagnostic criterion for MOH (Table 4b). For example, the diagnosis of “headache associated with excessive intake of medications containing components from different pain-relieving classes” is made when one or more such drugs are regularly taken ≥ 10 days per month for more than 3 months, while “headache associated with excessive intake of other NSAIDs” – when one or more NSAIDs are regularly taken ≥ 15 days per month for more than 3 months [8]. The highest risk of MOH is observed with the use of pain-relieving medications containing narcotic components (codeine, etc.), barbiturates, and caffeine** [8, 17, 23]. Instrumental diagnostic methods are not used for MOH diagnosis due to their low informativeness [14].

If clinical signs of MOH are identified in a patient with CM, two diagnoses should be made. For example, "Chronic migraine. MOH associated with excessive triptan use" [9, 15, 17].

Table 4b. Classification of MOH forms (according to ICHD-3, 2018) [8]

2.1 Complaints and Anamnesis

Patients with migraine present with typical complaints of recurring attacks of unilateral pulsating headache in the frontotemporal or parietal region, of moderate or severe intensity (more than 7 scores on the visual analogue scale for pain (VAS, Appendix G2), lasting 4–72 hours, aggravated by routine physical activity, accompanied by nausea and/or vomiting, as well as photophobia and phonophobia [1, 2, 3, 8]. Complaints of visual, sensory, speech, and less frequently motor disturbances are possible, which gradually develop over 5–20 minutes before or during the headache attack, usually last no more than 60 minutes (motor disturbances up to 72 hours), and then completely disappear, which is characteristic of a migraine aura [8, 11, 12, 18–20]. Migraine attacks are most often triggered by stress or relaxation after stress, lack or excess of night sleep, weather changes, menstruation, hunger, stuffiness, bright or flickering light, noise, physical exertion, alcohol, or caffeine-containing beverages [1, 3]. The frequency of migraine attacks and the regularity of medication intake to abort pain during a migraine attack can vary significantly, which is also clarified during the collection of complaints.

The anamnesis of patients with migraine has characteristic features [1, 2, 3, 9]. It is typical for the first attacks to occur at a young age, before 20 years, and for similar headaches to occur in relatives (family history). Patients report specific periods in their lives during which the course of migraine changed: a decrease in frequency or complete cessation of headache attacks during pregnancy or with the onset of menopause; worsening/progression/chronicization of migraine under the influence of emotional stress, depression and/or anxiety, excessive use of analgesic drugs, use of hormonal oral contraceptives, and during the premenopausal period in women [14 - 17]. The anamnesis of patients with migraine often indicates various concomitant somatic and mental disorders, among which the most common are emotional and affective disorders (depression, anxiety disorders), sleep disorders (insomnia, bruxism, restless legs syndrome, sleep apnea), other chronic pain syndromes, including back pain and temporomandibular joint pain dysfunction, as well as irritable bowel syndrome, allergies, obesity, and cardiovascular diseases [14, 15].

Comments: CD contribute to a more severe course and increased frequency of migraine attacks (chronicization of migraine), worsen the patient's condition between headache attacks, and lead to more pronounced maladaptation and a worse prognosis. Therefore, the identification and treatment of comorbid disorders is an important task in the management of patients with migraine.

2.2 Physical Examination

Clinical diagnosis of migraine, along with the analysis of complaints and anamnesis, includes a neurological examination of the patient.

Comments: in a typical course of migraine, no pathological changes are found in the neurological status. There may be a depressed mood, signs of increased anxiety, autonomic disorders (hyperventilation, palmar hyperhidrosis, signs of increased neuromuscular excitability in the form of Chvostek's sign grade I - III), tension and tenderness of pericranial muscles upon palpation.

If organic symptoms (meningeal, general cerebral, and/or focal neurological signs) are detected in the neurological status, additional instrumental and laboratory examinations are performed, the choice of which is determined by the nature of the pathological changes and the suspected underlying disease causing the detected disorders [8, 15, 18 - 20].

2.3 Laboratory Diagnostics

Since the diagnosis of migraine is clinical, laboratory methods are not mandatory.

Comments: Laboratory methods are not informative in the diagnosis of migraine because they do not reveal changes specific to this disease.

2.4 Instrumental Diagnostics

Instrumental examinations in patients with migraine are uninformative as they do not reveal changes specific to migraine.

Comments: in the majority of patients with migraine, instrumental examination methods do not reveal any specific changes. In a number of patients, standard T2-weighted brain MRI may reveal isolated subclinical hyperintense foci in the subcortical white matter of the cerebral hemispheres, less commonly in the brainstem structures [26]. It is hypothesized that these focal changes are a consequence of transient cerebral perfusion disturbances recorded during repeated migraine attacks by magnetic resonance imaging. It has been shown that migraine may be an independent risk factor for the development of subclinical focal ischemic brain lesions [11]. Since these foci lack specific morphological features, they cannot be considered neuroimaging markers of migraine.

Comments: If technical facilities are unavailable or there are medical contraindications for MRI, A06.23.004 Computed tomography of the brain, A06.12.056 Computed tomography angiography of cerebral vessels, A06.23.004.007 Computed tomography of cerebral vessels with intravenous bolus contrast enhancement are indicated.

Comments: If technical facilities are unavailable or there are medical contraindications for MRI, A06.23.004 Computed tomography of the brain, A06.12.056 Computed tomography angiography of cerebral vessels, A06.23.004.007 Computed tomography of cerebral vessels with intravenous bolus contrast enhancement are indicated.

Table 5. List of red flag symptoms («warning signs») in patients with headache

2.5 Other Procedures

To establish the clinical characteristics of the attack, the number of headache days per month (determining the migraine form), and the number of days using analgesic medications, it is advisable for the patient to keep a headache diary (Appendix G1). Keeping a headache diary for 1 to 3 months prior to the examination helps the patient and the physician differentiate one type of headache from another (e.g., a migraine attack from an episode of tension-type headache), determine the number of headache days per month, and the number of days per month with analgesic medication intake.

2.5.1 Differential Diagnosis

Differential diagnosis in patients with migraine is most frequently performed with tension-type headache, cluster headache, chronic paroxysmal hemicrania, and cervicogenic headache. A differential diagnosis requires a thorough interview and physical examination of the patient, analysis of medical history and triggering factors; maintaining a headache diary is advisable. Less commonly, migraine must be differentiated from rare secondary cephalalgias associated with neurological and somatic diseases [2, 9, 20, 21]. Headaches resembling migraine may occur in the following conditions:

• transient ischemic attack (TIA) and stroke;

• giant cell arteritis;

• arterial dissection, aneurysms, and arteriovenous malformations;

• cerebral venous thrombosis;

• brain tumor;

• subarachnoid hemorrhage;

• antiphospholipid syndrome and thrombophilias;

• epilepsy (when migrainous headache is combined with an epileptic seizure);

• MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes) and CADASIL syndrome (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy).

Unlike typical migraine as a primary headache form, the aforementioned diseases and syndromes always manifest with corresponding neurological deficit symptoms or other "red flags" not typical of migraine (see Section 2.4).

In a single patient, migraine may coexist with other cephalalgias, both primary (tension-type headache; primary headaches associated with physical or sexual activity, cold stimuli, etc.) and secondary (medication-overuse headache, cervicogenic headache, headache associated with temporomandibular joint dysfunction). In such cases, all identified headache forms should be included in the diagnosis; for example, "Migraine without aura. Episodic tension-type headache with pericranial muscle dysfunction" or "Chronic migraine. Medication-overuse headache associated with the use of selective serotonin 5-HT1 receptor agonists (triptans). Headache associated with temporomandibular joint dysfunction" [9, 16, 21].

Comments: migrainous aura is typically characterized by a gradual progression of clinical manifestations in a specific sequence over 10–30 (up to 60) minutes on one side of the body, presenting as a so-called "march" with alternating "positive" and "negative" symptoms: visual symptoms (scintillations, brilliant zigzag lines or flashes, dark spots, scotomas, visual field defects), followed by paresthesias, numbness spreading from the hand up to the shoulder and facial area; speech disorders may subsequently develop; at the end of the migrainous aura, migrainous headache develops. Unlike a migraine attack with aura, neurological deficits in TIA are "negative" in character (visual field defects, scotomas, numbness of one limb), appear acutely (within minutes) simultaneously, and headache development is not typical; patients generally have no history of migraine. If technical capabilities are lacking or there are medical contraindications for MRI, performing A06.23.004 Computed tomography of the brain, A06.12.056 Computed tomography angiography of cerebral vessels, A06.23.004.007 Computed tomography of cerebral vessels with intravenous bolus contrast enhancement is indicated.

Comments: difficulties in the differential diagnosis between chronic migraine and chronic tension-type headache are related to the fact that the leading clinical manifestations of chronic migraine include both persistent frequent migraine attacks and tension-type-like "background" pain. In such cases, one should rely on early history data: in patients with chronic migraine, unlike chronic tension-type headache, the onset of the disease is marked by typical episodes of episodic migraine and other characteristic migraine features (family history, typical migraine triggers, relief of headache during pregnancy) [15, 22, 27]. In the presence of medication overuse, chronic migraine combined with medication-overuse headache should be differentiated from chronic tension-type headache combined with medication-overuse headache.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Comments: the main goals of migraine treatment are: reducing the frequency and severity of headache attacks, decreasing the intake of analgesic medications, correcting comorbid disorders (CDs), preventing disease chronification, and improving patients' quality of life.

3.1 Behavioral therapy

Comments: informing and educating a migraine patient can be carried out by a physician or nursing staff either during an in-person conversation or remotely using popular literature and internet resources. The main provisions of behavioral therapy include: explaining the benign nature and mechanisms of migraine (reassuring the patient against organic causes of the headache); substantiating the inadvisability of additional tests (except for suspected symptomatic migraine); discussing the role of headache triggers and the need to avoid them; discussing risk factors for disease chronification (stress, medication overuse, psychiatric and other comorbidities) and the need for their prevention; explaining the goals of migraine treatment, mechanisms of action of preventive drugs, and the benefits of non-pharmacological methods. Patients abusing analgesic medications should be informed about the role of medication overuse in migraine chronification, the need for temporary cessation of intake, and strict continuous monitoring of the number of analgesic medications taken [15, 18, 20].

3.2 Acute migraine treatment

Comments: a mild migraine attack is an episode during which the patient is able to perform routine household and professional activities; a moderate attack is one where these activities are significantly limited; a severe migraine attack requires bed rest [20, 28].

3.2.1 Treatment of mild to moderate migraine attacks

Analgesics and antipyretics, nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs) should be used to abort migraine attacks (Table 6a).

Table 6a. Analgesics, antipyretics, and NSAIDs recommended for aborting migraine attacks

Comments: the principles of using other analgesics, antipyretics, and NSAIDs imply that the choice of drug should be based on their efficacy and adverse effect profile [28, 30 - 39]:

- NSAIDs and acetylsalicylic acid** are more effective than paracetamol**;

- ibuprofen** at a dose of 400 mg is considered the drug of first choice, as it has the lowest potential for gastrointestinal complications;

- keeping a headache diary is advisable to monitor the correct use of analgesic medications;

- when using NSAIDs, adverse effects must be taken into account, primarily gastrointestinal effects and the risk of bleeding;

- rapid-dissolving forms of NSAIDs act faster compared to their standard tablet counterparts (ketoprofen** as lysine salt in granules for oral solution in doses of 40 or 80 mg, diclofenac** 50 mg as a powder for oral solution [38, 45].

Comments: antiemetic drugs (gastrointestinal motility stimulants) reduce gastroparesis, which typically accompanies a migraine attack, and improve the absorption of analgesic medications [1 - 3, 20].

Table 6b. Antiemetic drugs recommended for treating migraine attacks (ATC: Gastrointestinal motility stimulants)

3.2.2 Treatment of severe migraine attacks

Table 6c. Selective serotonin 5-HT1 receptor agonists (triptans) recommended for aborting migraine attacks

Comments: selective serotonin 5-HT1 receptor agonists (triptans) exhibit the highest efficacy and can also be used for moderate migraine attacks [28, 48 - 50, 53 - 55]. Table 6c lists the selective 5-HT1 receptor agonists registered in the Russian Federation. For more effective treatment of migraine attacks without aura, selective 5-HT1 receptor agonists (triptans) should be taken at the very onset of the headache – within the first 30 minutes of headache onset [53]; it is also recommended to take sumatriptan at a dose of at least 50 mg, eletriptan – at least 40 mg, zolmitriptan – at least 2.5 mg, and rizatriptan – at least 10 mg [172]. In migraine with aura, selective serotonin 5-HT1 receptor agonists must not be administered during the aura phase: if the headache occurs simultaneously with or at the end of the aura, selective serotonin 5-HT1 receptor agonists can be taken at the end of the aura phase or at the beginning of the headache phase [54]. Selective serotonin 5-HT1 receptor agonists should not be used for more than 10 days per month to avoid medication overuse and the development of medication-overuse headache (MOH). Re-administration of selective serotonin 5-HT1 receptor agonists is possible 2 hours after the first dose; no more than 2 doses of selective serotonin 5-HT1 receptor agonists should be taken per day; if one selective serotonin 5-HT1 receptor agonist is ineffective, other drugs from this class should be tried. The main contraindications for prescribing selective serotonin 5-HT1 receptor agonists include ischemic heart disease, peripheral occlusive vascular disease, uncontrolled arterial hypertension, and migraine with brainstem aura.

Due to its minimal constrictor effect on coronary arteries, eletriptan is the safest selective serotonin 5-HT1 receptor agonist in patients with potential cardiovascular disease risk [55].

All adverse effects associated with triptan intake are generally mild, resolve quickly, and do not require treatment. Triptan tolerability is individual, and if one is poorly tolerated, another triptan should be prescribed.

Zolmitriptan, a selective serotonin 5-HT1 receptor agonist nasal spray, is preferred in patients who require a rapid onset of action (begins acting within 15 minutes), as well as in the presence of severe nausea and vomiting [48].

Rizatriptan, a selective serotonin 5-HT1 receptor agonist orally disintegrating tablet, does not require swallowing with water and dissolves on the tongue, making it successful for use in the presence of severe nausea and vomiting, since the liquid required to swallow a conventional tablet may exacerbate the accompanying dyspeptic symptoms of a migraine attack [54].

3.2.3 Treatment of status migrainosus

Treatment of migrainous status (MS) is aimed at reducing the intensity and duration of headache and accompanying symptoms, and restoring the patient's general condition via A25.23.001 Prescription of medicinal products for central nervous system and brain diseases and A25.23.003 Prescription of a therapeutic and health-improving regimen for central nervous system and brain diseases.

metoclopramide** [29, 39, 43],

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

#chlorpromazine [56, 57],

GCR BLOC 2Level of recommendations grading — B (level of evidence certainty - 2).

#dexketoprofen** [40, 58],

GCR BLOC 2Level of recommendations grading — B (level of evidence certainty - 2).

#ketorolac** [41],

GOR ALOE 1Grade of Recommendation – A (Level of Evidence – 1).

#magnesium sulfate** [59 - 61],

GCR BLOC 2Level of recommendations grading — B (level of evidence certainty - 2).

#valproic acid** [44, 62, 63],

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

#dexamethasone** [64 - 68]

GoR ALoE 1Grade of Recommendation – A (Level of Evidence – 1).

Comments: The choice (combination) of agents is determined by the clinical picture, severity of MS, and the patient's individual characteristics. Upon hospitalization, the patient undergoes B01.023.003 Daily examination by a neurologist with observation and care by nursing and junior medical staff in the inpatient department.

Table 7. Medicinal products recommended for aborting migrainous status

Comments: Fewer adverse events are observed with metoclopramide** compared to droperidol** and haloperidol** [72]. Adverse effects of antipsychotics may include extrapyramidal symptoms (akathisia, tardive dyskinesia, etc.), decreased blood pressure, and drowsiness. Prolonged QT interval is a contraindication to prescribing antipsychotics; therefore, electrocardiography is recommended prior to their administration.

In status migrainosus (SM), #dexamethasone** is used not to abort the headache, but to prevent headache recurrence during the SM attack; #dexamethasone** is administered intravenously at a mean dose of 10 mg (dose range from 10 to 24 mg) [64 - 68]. Parenteral fluid administration for headache relief in SM is not indicated; however, in case of recurrent vomiting and dehydration, parenteral fluid administration for rehydration is possible [73]. Patients with SM also experience significant discomfort from light and sound exposure; therefore, therapeutic procedures should be performed in a quiet and darkened room.

3.3 Preventive therapy

Comments: other indications for migraine prophylactic treatment include [9, 15, 20, 74 - 78]:

- inefficacy or poor tolerability of acute migraine medications;

- chronic migraine;

- medication overuse, medication-overuse headache (MOH);

- migraine subtypes posing a risk of brain damage (stroke): history of migrainous infarction or status migrainosus, migraine with brainstem aura, hemiplegic migraine;

- severe comorbid disorders (primarily psychiatric ones – depression, anxiety, phobias, sleep disorders);

- patient preference for prophylactic therapy to alleviate the course of migraine and improve quality of life.

Comments: prophylactic treatment in patients with migraine is carried out in compliance with the following principles:

- explaining to the patient the rationale, mechanisms of action, and potential side effects of prophylactic agents;

- medications with proven efficacy should be used, initiating treatment with monotherapy;

- drugs must be prescribed in adequate therapeutic doses for a sufficient duration for the clinical effect to develop (3 months or more);

- in the absence of effect within 3 months, the chosen prophylactic agent should be replaced with another drug; the efficacy of botulinum toxin type A (BoNT-A) should be assessed after at least 6 months of therapy;

- upon achieving an effect, prolonged (6-12 months) use of the selected prophylactic agent at an adequately tolerated dose is necessary;

- an attempt to gradually taper off the drug(s) may then be undertaken;

- slow dose titration is advisable to minimize side effects;

- situations should be avoided where insufficiently effective prophylaxis (due to an improperly selected drug or its inadequate dose) leads to overuse of acute migraine medications (more than 2 days per week);

- when choosing a prophylactic agent, concomitant/comorbid conditions should be taken into account. In particular, a drug that is also effective in treating the comorbid condition should be selected (e.g., an antidepressant in a patient with migraine and comorbid depression);

- therapy for a comorbid condition that may contribute to migraine exacerbation or increased medication overuse should be avoided;

- the duration of prophylactic therapy should be 6 months for episodic migraine and 12 months for chronic migraine.

First-line prophylactic agents (Table 8):

Comments: lower doses of beta-blockers may be used in patients with arterial hypotension [2, 3, 9].

Comments: topiramate** is prescribed in a long-term course (up to 12 months) with dose titration from 25 mg to the recommended dose of 100 mg; the dose may be increased up to 200 mg per day; taking the main dose of the drug in the evening is preferred.

Comments: botulinum toxin type A – hemagglutinin complex** is used for migraine only in patients with the chronic form. After reconstituting 100 IU of the drug in 2 ml or 200 IU in 4 ml of sodium chloride** solution, it is injected according to the PREEMPT protocol into the projection of 7 head and neck muscle groups (bilaterally into mm. frontalis; mm. corrugator supercilii; mm. temporalis; mm. occipitalis; mm. trapezius; mm. paraspinalis cervicis, and m. procerus) [85, 99, 100]. The total dose of the drug per procedure is 155 - 195 IU. The efficacy of a single procedure (reduction in the number of headache days by 50% or more) usually persists for 3 months, therefore repeat injections of the drug are recommended every 12 weeks. Patients may simultaneously receive other medications for migraine prevention. Botulinum toxin type A-hemagglutinin complex** is also effective in patients with chronic migraine combined with medication-overuse headache [108, 109, 131].

Comments: calcitonin gene-related peptide (CGRP) antagonists (monoclonal antibodies against the main migraine pain mediator calcitonin gene-related peptide or its receptor (or anti-CGRP monoclonal antibodies)) represent the first class of drugs specifically designed for targeted (pathogenetically substantiated) prophylactic therapy of episodic and chronic migraine in adults. mAb therapy can be used when the frequency is 4 or more migraine days per month.

Fremanezumab and erenumab may be prescribed for a duration of 6 to 12 months or more, depending on the efficacy and tolerability of the therapy. The efficacy of therapy should be evaluated 3 months after its initiation. According to real-world clinical practice studies, treatment with calcitonin gene-related peptide antagonists can reduce the number of headache days per month by 50%, 75%, as well as by 100% (temporary remission). In real-world clinical practice in the USA and Europe, calcitonin gene-related peptide (CGRP) antagonists are used for several years (continuous use period up to 5 years). The decision on the duration of treatment is made by the attending physician and depends on the efficacy and tolerability of the therapy. For chronic migraine, extending the course of therapy to 18 months is indicated [86 - 89].

Second-line preventive agents (Tab. 8):

Comments: the listed antidepressants possess their own analgesic effect [1, 2, 9, 15]. The use of antidepressants is especially useful in patients with comorbid disorders (depression, anxiety disorders, insomnia) [1, 2, 9, 15].

Comments: the prescription of #valproic acid** is undesirable in women of childbearing potential due to the high risk of teratogenic effects [81, 82].

Table 8. Medications recommended for migraine prevention

¹ – PREEMPT – Phase III Research Evaluating Migraine Prophylaxis Therapy – Phase III clinical research program to evaluate migraine prophylactic therapy.

3.4 Specifics of the management of migraine combined with medication-overuse headache (MOH)

Comments: patients with frequent episodic migraine (8 or more migraine headache days per month and about 8 - 10 days of analgesic drug intake per month) represent a risk group for developing MOH. In at-risk patients, preventing medication overuse via behavioral therapy is more effective than treating already established MOH [102].

The main strategies for preventing MOH in the risk group include: educating patients on the safe regimen of acute migraine medication intake (no more than 2 days a week – no more than 8 days a month) and controlling other risk factors for migraine chronification (emotional status, stressful life events, sleep quality, caffeine intake, body weight). It is necessary to explain to the patient that abusing acute migraine medications contributes to an increased frequency of headache days (migraine chronification and development of MOH), and that the only way to relieve headaches is to withdraw the abused drug(s).

Comments: these methods are insufficiently effective in patients with comorbid psychiatric disorders (depression, anxiety) who abuse opioids, anxiolytics, barbiturates, or multiple classes of analgesic drugs simultaneously and have a history of failed attempts to withdraw the abused drugs.

Comments: both full and partial withdrawal of the "offending" medication(s) can be used. The number of days with intake of any analgesic medications should not exceed 2 per week (8 per month). Discontinuation of other analgesics and antipyretics, as well as selective 5-HT1 serotonin receptor agonists (triptans), can be performed in an outpatient setting; discontinuation of opioids, antispasmodics, psychotropic drugs, and combination analgesics, including cases combined with benzodiazepine derivative abuse, should be performed in an inpatient/day hospital setting [105].

Table 9. Medicines recommended for the treatment of withdrawal headache in patients with MOH

Comments: treatment of headache and other withdrawal symptoms (detoxification) should be carried out during the first two weeks of the withdrawal period. The choice of drugs is determined by clinical manifestations (e.g., in the presence of vomiting, the use of antiemetic drugs is advisable) [128].

During the withdrawal of analgesic medications, alternative pharmacological agents with analgesic properties may include classes of drugs that the patient has not previously abused (e.g., in a patient with frequent episodic or chronic migraine and MOH associated with the abuse of medications containing components from different classes with analgesic properties, selective 5-HT1 serotonin receptor agonists [triptans] may be recommended for aborting migraine attacks during the withdrawal period. Celecoxib and naproxen [see below] may also be used during the withdrawal period as alternative analgesic drugs provided the patient has not previously abused them).

When prescribing systemic corticosteroids or NSAIDs, proton pump inhibitors must be added to reduce the risk of gastrointestinal adverse events. Patients abusing opioids, benzodiazepine derivatives, or barbiturates require monitoring of blood metabolic parameters, blood pressure, and rehydration [including abundant fluid intake].

Comments: preventive therapy for migraine combined with MOH is preferably initiated simultaneously with the withdrawal of the medication[s] that caused MOH and the treatment of withdrawal headache [119], although therapy can also be initiated prior to the withdrawal of the "offending" analgesics and antipyretics [107, 110, 112, 113].

Table 10. Drugs recommended for the preventive treatment of frequent episodic and chronic migraine combined with MOH

3.5 Non-pharmacological treatment

Comments: combined treatment can be considered as a viable treatment option for primary headache, including in patients resistant to pharmacological treatment [134, 135].

Comments: classic CBT includes two methods: behavioral (aimed at patient activation, individual prevention of migraine attacks, and coping skills) and cognitive (includes working with negative thoughts and misconceptions about the disease, as well as reducing pain catastrophizing) [137–141].

Comments: biofeedback can be recommended as an alternative effective non-pharmacological treatment for patients with chronic migraine for long-term prevention of migraine attacks. BFB combined with home relaxation training is more effective than without it [143].

Comments: reflexology can be considered an effective and safe treatment option, as no side effects are noted with its use [144–146].

Comments: light-intensity exercises are indicated for patients with migraine; endurance training, such as on a treadmill or stationary bicycle; Nordic walking; general physical exercises; relaxation and functional training. Number of training sessions: maximum 3–4 times a week; session duration: from 20 to 60 minutes [149].

Comments: greater occipital nerve block can be an effective acute treatment for a migraine attack and may be effective in the short term for chronic migraine [150].

Comments: the effect of high-frequency repetitive rTMS in migraine is associated with a neuromodulatory effect on cortical hyperexcitability, which is one of the basic pathophysiological mechanisms of migraine [154 - 155].

Comments: the efficacy of NS in chronic migraine / refractory chronic migraine is associated with its action on the trigeminocervical complex and the mediated inhibition of the pathological activity of pain structures in the brain [157]. It has been shown that NS reduces the frequency and severity of migraine attacks, decreases the amount of medication consumed, and improves the patients' quality of life [159, 160.]. Referral of patients for invasive NS should be carried out jointly by a headache specialist and a neurosurgeon.

Comments: although diet therapy is not used to treat migraine, it is advisable to advise patients to exclude certain foods from their diet that can potentially trigger a migraine attack (chocolate, bananas, nuts, citrus fruits, high-fat cheeses, alcohol) [1, 2, 3, 9] as part of primary (B04.070.003) or follow-up (B04.070.004) individual in-depth preventive counseling on the correction of risk factors for non-communicable diseases during the initial (B01.023.001) and/or follow-up (B01.023.002) appointment (examination, consultation) with a neurologist, based on A01.23.001 Collection of anamnesis and complaints in central nervous system and brain pathology.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: rehabilitation measures may include post-isometric relaxation, therapeutic exercise (A19.23.002 Therapeutic exercise for central nervous system and brain diseases; A19.23.002.001 Therapeutic exercise for central nervous system and brain diseases in a swimming pool; A19.23.002.025 Therapeutic exercise using apparatuses and simulators for central nervous system and brain diseases; A19.24.001 Therapeutic exercise for peripheral nervous system diseases), breathing exercises, massage (A21.01.003 Medical neck massage; A21.01.003.001 Collar zone massage; A21.03.007 Medical back massage), reflexology (A21.23.002 Reflexology for central nervous system diseases; A21.24.002 Reflexology for peripheral nervous system diseases; A17.01.002 Stimulation of acupuncture points with other physical factors), posture correction, and workplace ergonomics training.

5. Prevention and Dispensary Observation

Comments: to prevent an increase in the frequency of migraine attacks, patients should be educated about the role of migraine triggers and the need to avoid them. To prevent the chronification of the disease, it is necessary to explain the role of migraine chronification factors (stress, depression, medication overuse, excessive caffeine intake, obesity, sleep apnea syndrome) and the need for lifestyle modification. It is necessary to monitor the efficacy and tolerability of preventive therapy, as well as adherence to the regimen and rules of drug administration. To ensure such monitoring, communication with the patient is required throughout the entire treatment period, including via telephone consultations. Educational work can be carried out by general practitioners and neurologists whom patients with migraine consult.

6. Organization of Medical Care

Indications for emergency hospitalization of a patient in the neurological department:

1. Headache accompanied by altered consciousness;

2. Headache accompanied by fever and meningeal signs;

3. Headache with progressive focal neurological symptoms;

4. Headache with progressive general cerebral symptoms;

5. Thunderclap headache;

6. Status migrainosus.

Indications for elective hospitalization of a patient in the neurological department:

1. Progressive headache;

2. Refractory headache;

3. Severe medication-overuse headache associated with the excessive use of opioids, antispasmodics, psychotropic drugs, and combination analgesics;

4. Atypical aura lasting more than 1 hour;

Indications for discharging patients from the neurological department:

1. Abortion of headache;

2. Reduction of headache to 3 - 4 points on the visual analogue scale;

3. Successful replacement of the overused drug with adequate analgesic drug therapy.

7. Additional Information

In routine clinical practice, migraine is poorly diagnosed [9, 15]; in the Russian Federation, patients presenting with a headache are often given erroneous diagnoses, which determines the choice of incorrect treatment tactics and may contribute to the progression (chronification) of the disease. Examples of erroneous diagnoses:

• dyscirculatory encephalopathy with cephalgic syndrome;

• cervical spine osteoarthrosis with migrainous paroxysms;

• vegetative-vascular dystonia with cephalgic syndrome;

• cervicogenic headache;

• headache associated with arterial hypertension.

Erroneous diagnoses are usually the result of misinterpreting non-specific findings on instrumental studies as signs of organic brain or cerebral vascular lesions [2, 9, 15]. For example, a minor decrease in linear blood flow velocity in craniovertebral arteries on Doppler ultrasonography serves as the basis for the incorrect diagnosis of "dyscirculatory encephalopathy" or "chronic cerebral ischemia," while degenerative changes in the cervical spine serve as the basis for the diagnosis of "cervical spine osteoarthrosis with cephalgic syndrome" or "cervicogenic headache." Making an incorrect diagnosis leads to the choice of inadequate treatment (e.g., psychostimulants and nootropics), which does not improve the course of migraine, but rather contributes to its chronification.

7.1 Assessment of therapeutic efficacy

Comments: additional efficacy criteria include a reduction in the use of pain-relieving medications and the severity of cognitive impairment (improved mood, reduced anxiety, normalized sleep), as well as improved working capacity, level of social adaptation, and overall quality of life of the migraine patient.

Criteria for Evaluating the Quality of Medical Care

Quality criteria for specialized medical care for adults with migraine [2, 18, 20, 76].

References

Appendix A1. Working Group Composition

Yulia E. Azimova, D.Sc. in Medicine, neurologist at the University Headache Clinic. Leading Research Fellow at the Research Institute of General Pathology and Pathophysiology of the Ministry of Science and Higher Education. Member of the all-Russian public organization "Russian Headache Research Society". Member of the European public organization "European Headache Federation".

Vera V. Alferova, D.Sc. in Medicine, Chief Researcher at the Research Laboratory of Cerebral Vascular Diseases, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation.

Alexander V. Amelin, D.Sc. in Medicine, Professor at the Department of Neurology, Head of the General Neurology Division at the Research Institute of Neurology of the National Medical Research Center, Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation. Head of the Headache Committee of the Russian Interregional Pain Society, member of the Russian Headache Research Society.

Ada R. Artemenko, D.Sc. in Medicine, Professor at the Department of Nervous Diseases of the Institute of Professional Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University) and the Center for Interdisciplinary Dentistry and Neurology, Moscow. Member of the Russian Headache Research Society, member of the European Headache Federation, member of the International Headache Society, member of the European Academy of Neurology.

Leila R. Akhmadeeva, D.Sc. in Medicine, Professor at the Department of Neurology, Bashkir State Medical University of the Ministry of Health of the Russian Federation. Member of the Russian Headache Research Society, Head of the Bashkir Branch, member of the Interregional Association of Botulinum Therapy Specialists.

Veronika A. Golovacheva, Ph.D. in Medicine, Associate Professor at the Department of Nervous Diseases and Neurosurgery, Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University). Member of the all-Russian public organization "Russian Headache Research Society".

Alexey B. Danilov, D.Sc. in Medicine, Professor, Head of the Department of Nervous Diseases, Institute of Professional Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University). Director of the Institute of Interdisciplinary Medicine. Executive Director of the Russian Headache Patients Association. Board Member of the European Migraine and Headache Alliance (EMHA).

Evgenia V. Ekusheva, D.Sc. in Medicine, Head of the Department of Nervous Diseases and Neurorehabilitation, Academy of Postgraduate Education under the Federal Scientific and Clinical Center of the Federal Medical and Biological Agency of Russia; Academician Aleksandr Veyn Headache and Autonomic Disorders Clinic; GUTA Clinic, Moscow. Member of the all-Russian public organization "Russian Pain Society". Member of the Headache and Facial Pain Committees of the Russian Interregional Pain Study Society. Member of the interregional public organization of botulinum therapy specialists. Member of the European public organization "European Headache Federation" and the international public organization "International Headache Society".

Emil D. Isagulyan, Cand. Sc. (Med.), Senior Researcher, Neurosurgeon-Algologist at the Burdenko National Medical Research Center of Neurosurgery of the Russian Ministry of Health. FIPP 1298/01 (International fellow of interventional pain practice / in Russia). President of the National Neuromodulation Society in Russia (NNSR). Vice-President of the Association for Interventional Pain Treatment (AIPT).

Kovalchuk Nadezhda Alexandrovna, PhD in Medicine, Assistant Professor at the Department of Nervous Diseases and Neurosurgery, Sklifosovsky Institute of Clinical Medicine, Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University). Member of the Russian Society for the Study of Headache (RSSH).

Marina I. Koreshkina, D.Sc. in Medicine, Head of the Headache Treatment Center at Adel Med Medical College Clinic LLC, Saint Petersburg, editor of the "All About Headaches" portal. Member of the Russian Headache Research Society. Member of the International Headache Society.

Olga V. Kurushina, D. Sc. (Med.), Head of the Department of Neurology, Neurosurgery, and Medical Genetics, Volgograd State Medical University of the Russian Ministry of Health. Board Member of the All-Russian Society of Neurologists. Member of the Russian Headache Research Society.

Nina V. Latysheva, D.Sc. in Medicine, Professor at the Department of Nervous Diseases of the Institute of Professional Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University) and Academician Alexander Wayne Headache and Autonomic Disorders Clinic, Moscow. Member of the Russian Headache Research Society. Member of the European Headache Federation. Member of the International Headache Society.

Elena R. Lebedeva, D.Sc. in Medicine, Professor at the Department of Hospital Therapy, Ural State Medical University of the Ministry of Health of the Russian Federation, Head of the "Europe-Asia" International Headache Center, Yekaterinburg. Member of the Russian Headache Research Society. Member of the International Headache Society. Member of the European Headache Federation. Member of the Headache Section of the European Academy of Neurology. Russian representative in the Education Committee of the European Academy of Neurology.

Margarita V. Naprienko, D.Sc. in Medicine, Professor at the Department of Sports Medicine and Medical Rehabilitation of the N.V. Sklifosovsky Institute of Clinical Medicine, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University). Chief Medical Officer of the Academician Alexander Wayne Headache and Autonomic Disorders Clinic. Member of the Russian Headache Research Society. Member of the Interregional Association of Botulinum Therapy Specialists. Member of the European Headache Federation.

Vera V. Osipova, D.Sc. in Medicine, neurologist at the University Headache Clinic. Leading Researcher at the Solovyov Research and Practical Center for Mental Health of the Moscow Healthcare Department. Member of the Russian Headache Research Society (RHRS). Member of the European Headache Federation (EHF). Member of the Lifting the Burden (LTB) campaign. Member of the Classification Committee of the International Headache Society (ICHD IHS).

Nikolay A. Pavlov, Cand. Sc. (Med.), Leading Researcher at the Research Laboratory of Cerebral Vascular Diseases, Pirogov Russian National Research Medical University of the Ministry of Health of the Russian Federation.

Vladimir A. Parfenov, D. Sc. (Med.), Professor, Head of the Department of Nervous Diseases and Neurosurgery, Institute of Clinical Medicine, Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University). Board member of the All-Russian Society of Neurologists, board member of the National Stroke Association, member of the "General Neurology" panel of the European Academy of Neurology.

Andrey P. Rachin, MD, PhD, Professor, President of the National Association of Experts in Comorbid Neurology. Board Member of the All-Russian Society of Neurologists. Presidium Member and Auditor of the Russian Headache Research Society (RHRS).

Alexey V. Sergeev, PhD, Associate Professor at the Department of Nervous Diseases and Neurosurgery, Institute of Clinical Medicine, FSAEI HE I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University). Member of the All-Russian Public Organization «Russian Headache Research Society» (RHRS). Member of the All-Russian Public Organization «Russian Pain Society» (RPS) and Head of the Pediatric Pain Study Committee of the RPS. Member of the European public organization «European Headache Federation». Russia Representative in the international public organization «International Headache Society».

Kirill V. Skorobogatykh, PhD, Neurologist, Head of the University Headache Clinic (Moscow). Member of the All-Russian Public Organization «Russian Headache Research Society». RF Representative in the European public organization «European Headache Federation». Member of the Education Committee of the international public organization «International Headache Society».

Gyuzal R. Tabeeva, MD, Professor at the Department of Nervous Diseases and Neurosurgery, Institute of Clinical Medicine, FSAEI HE I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University). President of the All-Russian Public Organization «Russian Headache Research Society». Member of the European public organization «European Headache Federation».

Elena G. Filatova, MD, Professor at the Department of Nervous Diseases, Institute of Professional Education, FSAEI HE I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University) and Academician Aleksandr Wayne Headache and Autonomic Disorders Clinic, Moscow. Member of the All-Russian Public Organization «Russian Headache Research Society». Member of the European public organization «European Headache Federation».

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. neurologists, general practitioners, family physicians;

2. medical students, residents, postgraduate students;

3. faculty members, researchers;

In these clinical guidelines, all information is graded by the level of reliability (evidence) depending on the quantity and quality of studies on the given issue (Table 1, Table 2, Table 3).

Table A1. Levels of Evidence (LoE) scale for diagnostic methods (diagnostic interventions).

Table S2. Scale for assessing levels of evidence reliability (LER) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table А3. Scale for assessing levels of recommendation certainty (LRC) for methods of prevention, diagnostics, treatment, and medical rehabilitation, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions).

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

The procedure for updating clinical guidelines for migraine provides for their systematic updating at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of migraine, and in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

These clinical guidelines were developed taking into account the following regulatory legal documents:

1. Federal Law No. 323-FZ dated November 21, 2011, "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation"

2. Procedure for the provision of medical care to the adult population for nervous system diseases (Order of the Ministry of Health of the Russian Federation No. 926n dated November 15, 2012).

3. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Timeframes for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of the Information Included in Clinical Guidelines."

4. State Register of Medicines https://grls.rosminzdrav.ru/GRLS.aspx

Appendix A3.1. HEADACHE DIARY

DIARY COMPLETION INSTRUCTIONS

Before your consultation at the Headache Center, it is very important that you fill out this diary daily. The information you record in the diary will help the physician accurately determine the diagnosis and severity of your headache (HA), as well as promptly prescribe the optimal treatment for you.

At the top, write your full name, date of birth, and the date you started filling out the diary. Then, opposite Question 1 in the 1st column, write the date (day of the month) when the diary is filled out. You can enter dates in all columns right away, as you will need to fill out the diary daily.

Please fill out the diary every evening before going to bed, checking [√] the boxes (1) in the vertical column. This data represents summarized information about any headache(s) if they occurred on that day. If you did not have a headache on that day, answer only Questions 2 and 15. If you have finished filling out one page of the diary, please continue on the next page (several copies are attached).

Instructions for answering the questions are provided below.

1. Indicate only the day (e.g., 12); month and year do not need to be specified.

2. Check «Yes» or «No» in the boxes opposite all questions, or proceed directly to Question 15 (if there was no headache on that day).

3. Indicate the time (hour in 24-hour format) when you first noticed the onset of the headache. If you woke up already with a headache, indicate the waking time. (If the morning headache is a continuation of the evening one, put an X in the column).

4. Indicate the time (hour and minutes in 24-hour format) when the headache completely stopped. If the headache was still present on that day before going to bed, leave the box blank. If the headache was absent in the morning, indicate the bedtime. If the headache persisted in the morning, put an X in that day's column, as well as an X in the Question 3 column on the next page. Continue your entries on the next day as usual.

5. Some people experience certain visual disturbances within 1 hour before the onset of a headache. These may include flashes of light, luminous zigzag lines, «blind» spots, or «black holes» that persist even when eyes are closed. Check «Yes» if you experienced something similar, or «No» if such phenomena did not occur. If you were simply bothered by light (see Question 12) and nothing else, check «No».

6. Check the box corresponding to the localization of the headache (predominantly on one side of the head or on both sides).

7. While there are many descriptions of headache character, most headaches are either "pulsating" (the pain intensifies synchronously with the heartbeat) or "pressing/tightening" (like a "band" or "helmet"). Check the characteristic that best reflects your type of headache.

8. Some types of headaches worsen even with minor physical exertion (e.g., climbing stairs) or force a person to avoid such activity. Check «Yes» if this applies to your headache, and «No» if this is not characteristic of you.

9. Headache intensity (severity) is an important component of the diagnosis. Rate the severity of your headache by checking the appropriate box: "mild" headache is a headache that does not disrupt normal activities (i.e., your working capacity and regular activity), "moderate" - makes normal activities difficult but does not completely prevent them, and finally, "severe" pain is a headache that completely disrupts your normal activity. Try to assess the headache intensity throughout the day as a whole. For example, if the pain was mild in the first half of the day and then became severe, check the "moderate" box. If the pain was very intense for almost the entire day, check "severe".

10. Check «No» if you had no nausea at all during the day. If you experienced mild nausea that hardly bothered you, did not cause belching or retching, check «mild», or in case of more pronounced nausea, «marked».

11. Check «Yes» or «No». Belching and retching are not considered vomiting.

12. The question concerns normal daylight or indoor light, not very bright light. Check «Yes» if normal light bothered you or you tried to avoid it by darkening the room or wearing sunglasses. Otherwise, check «No».

13. The question concerns normal noise, not very loud sounds. Check «Yes» if the noise bothered you or you tried to avoid it by secluding yourself in a quiet room. Otherwise, check «No».

14. Please list any causes (factors) that you think might have triggered the headache. Perhaps you ate, drank, or did something (e.g., skipped lunch, stayed up all night, did physical work), or there were other causes (weather change, stress, menstruation).

15. Please list the names of any medications (tablets, suppositories, injections, nasal sprays) you took for headache or any other pain. For each medication, indicate the number of doses taken, as well as the time of administration (hours in 24-hour format) for each medication. Do not list medications taken for other indications.

Headache diary

Full Name: ________________________________________________

Date of Birth (d/m/y) ___________________________________

Diary start date: _____________________________

Diary end date: ___________________________

Read the instructions carefully before filling out the diary! Fill out one column every evening, checking the appropriate boxes.

Please make sure you have filled out all columns!

Appendix B. Physician Action Algorithms

Note: HA – headache; M – migraine; ICHD-3 – International Classification of Headache Disorders; CD – comorbid disorders

Appendix C. Patient Information

What is migraine?

“During a migraine attack, I feel completely shattered and totally torn out of my daily life for a day or even more. The pain starts gradually in the temple area, then builds up, becoming stronger and stronger; nausea appears, sometimes I might vomit; even ordinary sounds and light are irritating. I feel so awful that I am forced to lie down in bed. After taking an analgesic medication, the pain may subside in a couple of hours, but not always. The next day I feel heaviness in my head and malaise, but still significantly better than the day before.”

Description of migraine

Migraine is a benign neurological disorder manifested by headache attacks that can occur with varying frequency: from 1–2 times a year to several times a month. The main manifestations of a migraine attack are severe pulsating headache in the frontotemporal region, usually on one side of the head, nausea, less commonly vomiting, intolerance to light, sounds, odors, and exacerbation of pain by routine physical activity. During a migraine attack, work capacity and habitual activity are significantly impaired.

Why does migraine occur?

A migraine attack is a consequence of the excitation of certain brain structures, as well as the release of pain mediators into the bloodstream and dilation of the blood vessels of the dura mater, which covers the brain. Migraine is a hereditary disease: people suffering from this disorder inherit “migraine” genes from one of their parents and can “pass” them on to their children.

Who gets migraines?

Migraine is the most common form of cephalalgia after tension-type headache; it occurs in 14% of people. Every seventh adult suffers from migraines; women experience migraines three times more often than men. The disease usually begins in childhood or adolescence. In girls, migraines frequently start during puberty.

What are the types of migraine?

The most frequent type of migraine is migraine without aura, occurring in 75% of patients. Less common is migraine with aura, where the pain attack is preceded by transient and fully reversible neurological deficits. Most frequently, visual disturbances are noted (luminous zigzags, flickering, visual field defects), less commonly sensory disturbances (numbness of one hand, half of the face, and tongue spreading from bottom to top) and speech disorders. A combination of both forms of migraine in the same patient is possible, as well as the occurrence of a migraine aura without headache.

The most severe form is chronic migraine, in which headaches may occur 15 or more days per month or even daily. The main factors leading to an increased frequency of migraine attacks are emotional stress, depression, overuse of analgesic medications, and caffeine (strong tea, coffee, energy drinks).

How does migraine manifest?

A migraine attack has four stages, although not all may be fully present in every patient. The premonitory phase of migraine (prodrome) occurs earlier than other symptoms of the attack and can manifest a few hours or even a day before the development of the headache with the following symptoms: neck pain, irritability, depressed mood, fatigue or, conversely, increased activity, appetite, sensitivity to light and odors.

Aura, if present, is the next phase. Only a third of patients with migraine have ever experienced an aura, and it may not develop in every attack. Aura is not dangerous to health; it lasts 10–30 minutes, rarely longer, and resolves completely. Visual aura is most common. You may “see” blind spots, flashes of light, or a multicolored zigzag line spreading from the center of the visual field to the periphery. Sensory symptoms occur less frequently—a tingling sensation or numbness starting in the fingertips on one side, spreading up to the shoulder, and sometimes moving to the cheek or tongue on the same side. Sensory symptoms are almost always accompanied by visual disturbances. In addition, during an aura, there may be speech difficulties or trouble finding words.

The headache phase is the most severe for most people, lasting from several hours to 2–3 days. Migraine headache can be very severe, most often occurring in the frontal or temporal region of one side of the head, but it can start in the occipital region, involve other areas, and the entire head. Usually, it is a pulsating or throbbing pain that worsens with movement and physical exertion. Nausea and even vomiting often occur, which relieves the headache. During an attack, light and sounds of even ordinary intensity are very frequently unpleasant, so patients prefer to remain alone in a quiet, darkened room.

The headache phase is followed by the resolution phase. During this period, you may again feel tired, irritable, or depressed, and find it difficult to concentrate. These symptoms can persist for up to a day before you feel completely healthy.

What are migraine triggers?

Every patient with migraine would like to know what can trigger an attack. As a rule, this is difficult or impossible because each patient has their “own” triggers; even for the same patient, different attacks can be triggered by different factors. The most common precipitants of a migraine attack include:

Psychological factors: emotional stress, as well as relaxation after stress.

Environmental factors: bright or flickering light, sharp odors, weather changes, staying in stuffy or hot environments.

Dietary factors: certain foods (citrus fruits, nuts, chocolate, bananas, smoked foods, full-fat cheeses) and alcohol (red wine, beer, champagne), skipping meals (hunger), inadequate nutrition, caffeine withdrawal, and insufficient water intake.

Sleep: changes in sleep patterns, both sleep deprivation and excessive sleep (e.g., on weekends).

Hormonal factors in women: menstruation, hormonal contraceptives, and hormone replacement therapy.

Other life factors: intense physical exertion, long trips, especially with time zone changes, air travel.

Identifying your individual triggers and learning to avoid them (if possible) is an important task for every patient and can significantly reduce the number of attacks.

What might you feel between migraine attacks?

Between migraine attacks, most people feel well. However, some individuals outside of pain attacks may complain of increased anxiety and even panic attacks, lowered mood up to severe depression, poor sleep, other types of pain (e.g., tight, “helmet-like” tension-type headaches [TTH], back pain, etc.), soreness and tension in the neck and occipital muscles, and gastrointestinal disturbances. These disorders, frequently comorbid with migraine, can impair general well-being and require treatment. Be sure to tell your doctor about these complaints so that they can prescribe the necessary treatment.

How is migraine treated?

Medications used to relieve an attack are called abortive migraine therapies. Properly selected drugs can be very effective if taken correctly and in small quantities. Such remedies include over-the-counter analgesic medications, most of which contain acetylsalicylic acid, ibuprofen**, or paracetamol**. Soluble formulations of these drugs, such as effervescent tablets, act faster and better.

If you are greatly bothered by nausea or vomiting, antiemetic medications can be used. Some of them actually enhance the effect of analgesic medications by increasing their absorption in the gastrointestinal tract. If you experience severe nausea or vomiting, you can use these drugs in the form of rectal suppositories.

Your doctor may prescribe one of the specific antimigraine medications. These drugs must be resorted to if analgesics, antipyretics, and antiemetics prove insufficiently effective. Antimigraine agents differ from standard analgesic medications. They do not act on the pain itself, but on the pathological processes occurring in the brain during a migraine attack. These agents include selective 5-HT1 receptor agonists (triptans)—the most effective in aborting a migraine attack—and preparations containing ergotamine. If necessary, you can combine these agents with NSAIDs and antiemetics.

There are several approaches to increase the effectiveness of drug therapy for a migraine attack.

1 Take the medication at the very onset of the attack…

Always keep at least one dose of the medication recommended by your doctor with you. Take the medication at the very beginning of the headache. There are no medications capable of stopping a migraine aura. During a migraine attack, the gastrointestinal tract slows down, so oral medications are absorbed into the bloodstream slower than usual. If your condition permits, drink something sweet (strong sweet tea).

2 … but not too frequently

Always strictly follow the instructions for use of the medication. In particular, do not use headache relief medications too often, as this can lead to medication-overuse headache (MOH) associated with excessive use of analgesics. To prevent MOH, under no circumstances should you use medications to stop migraines and other types of pain more frequently than 8 days per month. Excessive intake of any classes of medications with analgesic properties contributes to an increased frequency of headaches (not only migraines, but also tension-type headaches).

What to do if this treatment does not help?

If your migraine attacks are very frequent or severe and respond poorly to analgesics, a course of preventive treatment prescribed by a doctor is indicated for you. Unlike acute attack abortive medications, preventive therapy requires daily intake, as this treatment aims to prevent the development of migraine attacks.

Most preventive medications were originally developed for the treatment of other conditions, so you should not be surprised if you are prescribed a medication from the antidepressant or anticonvulsant groups, or one used to lower blood pressure. You have not been prescribed treatment for these indications; these medications simply also possess anti-migraine properties.

When prescribed one or more medications, carefully follow their instructions for use. Studies have shown that the most common cause of insufficient efficacy in preventive treatment is non-adherence to the therapy regimen. Preventive migraine treatment should last from 3 to 12 months depending on the severity of the disease (on average 6 months).

For the treatment of very frequent (chronic) migraines (when the number of headache days exceeds 15 per month), you may be recommended botulinum toxin type A injections into the head and neck muscles. In clinical trials, this method has demonstrated high efficacy and is widely used globally for the treatment of severe migraines.

What else can you do to help yourself?

Regular exercise, water procedures, psychological relaxation techniques, walks, and hobbies will improve your well-being. If there is pain and tension in the neck and occipital muscles, collar-zone massage and cervical spine gymnastics are useful. It is important to avoid attack triggers, primarily emotional stress, excessive workloads, sleep deprivation, and long gaps between meals.

Keeping a headache diary

Keeping a diary will help gather important information about your headache: how often your head hurts, how long the headache lasts, what triggers it, what symptoms accompany it, how many analgesics you take, and how frequently. This information is extremely valuable for making a correct diagnosis, identifying medication overuse and headache-triggering factors, and evaluating treatment efficacy.

What to do if you suspect you are pregnant?

You need to consult a doctor, as some anti-migraine medications are contraindicated during pregnancy.

Do you need additional diagnostic workup?

In most cases, after a thorough interview, diagnosing a migraine is straightforward for the doctor. Diagnosis is based on your description of the headache characteristics, concomitant symptoms, and triggering and relieving factors; the absence of any abnormalities on neurological examination is mandatory. Try to describe your headache to the doctor in as much detail as possible. It is very important to report how often and in what quantities you take analgesics or other medications.

There are no diagnostic tests that confirm a migraine diagnosis. Brain imaging (CT, MRI), electroencephalography, rheoencephalography (REG), ultrasound of head vessels, and an ophthalmologist consultation are generally uninformative, as no migraine-specific abnormalities are detected during these tests. Minor abnormalities detected can often also be found in individuals without headache complaints.

If your doctor is unsure of the diagnosis, they may order additional tests to rule out other causes of headaches. As a rule, this is unnecessary. If the doctor did not order additional tests, it means they are confident in the diagnosis of "Migraine" and performing tests will in no way facilitate the prescription of treatment.

Can migraine be cured?

There is no complete cure for migraine. Nevertheless, modern therapeutic approaches can significantly reduce the frequency, duration, and severity of migraine attacks and alleviate associated disorders in the interictal period. In most people, migraine attacks become less frequent with age and typically stop after 50 years. To prevent an increase in migraine frequency, it is necessary to avoid factors of chronification, primarily stress, low mood (depression), excessive intake of analgesics, and caffeine.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Visual Analogue Scale for pain

Russian name: Visual Analogue Scale for Pain (VAS)

Original title: Visual Analogue Scale (VAS) [164 - 166]

Type: rating scale

Purpose: intended for measuring pain intensity (in the case of TTH – tension-type headache)

Content: The VAS is a continuous scale in the form of a horizontal or vertical line 10 cm long with tick marks every 1 cm from 0 to 10, where 0 points = "no pain" and 10 points = "worst imaginable pain."

Key (interpretation): A higher score indicates greater pain intensity.

Explanation: For example, a score of 2 to 4 points indicates mild pain intensity, 5 to 7 moderate pain, 8 to 9 very severe pain, and 10 unbearable, extreme pain.