Clinical practice guideline for chronic headache 2013

International Headache Society published the International Classification of Headache Disorders 2nd Edition (ICHD‐II) in 2004. In response to this development, the “Clinical Practice Guideline for Chronic Headache” was compiled in Japan by the Study Group for Chronic Headache Clinical Practice Guideline Development. In 2006, the book entitled “The Clinical Practice Guideline for Chronic Headache (edited by Japanese Headache Society)” was published as the first edition. As triptans have become widely used, clinical practice for chronic headache has also been changed in Japan and there was a need to revise the first edition. Essentially based on the first edition, the new guideline has added the latest information and presented the concept of international standards of chronic headache care. This guideline included eight chapters and appendix: I. headache: general considerations, II. migraine, III. tension‐type headache, IV. trigeminal autonomic cephalalgias, V. other primary headache disorders, VI. medication‐overuse headache, VII. headaches in children, and VIII. genetics. We have published the second version in Japanese in 2013, but 1 month after we published the original guideline, the International Classification of Headache Disorders 3rd Edition beta version (ICHD‐3beta) was published. We changed this guideline to the new version in English based on ICHD‐3beta. This guideline is the final product of the Committee's efforts in 2015, which was opened in the home page of the Japanese Headache Society. This manuscript was written to show the main part of this guideline as Recommendation of each CQ. Among 121 CQs, only five CQ was selected to present full sentences including not only Recommendation but also other parts.


| Procedures and organization
The first task was to decide how to structure the contents, and it was decided to adopt the same format as in the second edition. Since the second edition used the format of clinical questions (CQ), this format was maintained with the contents divided into the following eight chapters, as in the second edition. In addition to the above eight chapters, it was decided also to include the "Guideline for Self-injection of Sumatriptan at Home," "Guideline for Migraine Treatment by Valproic Acid (Provisional Edition)," and "Guideline for Migraine Treatment by Propranolol (Provisional Edition)" as Appendix A, Appendix B, and Appendix C.
Search for scientific evidence was conducted by a systematic approach. Using the criteria as shown in Table 1, the literature was

| Contents of guideline
As was also stated in the 2006 version, this guideline is intended to support clinical practice, and not to restrict clinical practice. In the clinical setting, in addition to the guideline, physicians' experience is important. We hope that this guideline will facilitate better clinical decision-making and will improve patients' quality of life (QOL).
The new guideline adopted the CQ used in the 2006 version and added 19 new CQs. All the previous CQs were reviewed and rewritten.  Hamada who had contributed enormously to the development of the guideline. We would like to convey our sincere condolences. We hope that this book will help many people around the world to understand the clinical practice for headache disorders in Japan.

| CQ I-1 How is headache classified and diagnosed?
Recommendation Headache should be classified and diagnosed according to the ICHD-3beta. Grade A.

| CQ I-2 How are primary headaches and secondary headaches differentiated?
Recommendation Secondary headache should be suspected for the following: (1) headache with sudden onset, (2) headache never experienced before, (3) headache different from the customary headache, (4) headache that has increased in frequency and intensity, (5) headache begins after age 50, (6) headache with neurological deficit, (7) headache in a patient with cancer or immunodeficiency, (8) headache in a patient with psychiatric symptoms, and (9) headache in a patient with fever, neck stiffness, or meningeal irritation. Intensive investigations are required. Grade A.

| CQ I-3 How is subarachnoid hemorrhage diagnosed?
Recommendation When subarachnoid hemorrhage is suspected, a rapid and precise diagnosis and treatment by a specialist are necessary.
The typical symptom is "sudden excruciating headache never experienced before." Subarachnoid hemorrhage may manifest warning symptoms from mild bleeding. Pay attention when there is abrupt onset of headache accompanied by nausea or vomiting, dizziness, diplopia or impaired vision, and delirium.
Regarding neuroimaging, early-stage CT or fluid-attenuated inversion recovery (FLAIR) MR imaging has high diagnostic value.
When subarachnoid hemorrhage is strongly suspected, a lumbar puncture should be considered even when neuroimaging is negative.
Several days following the onset of headache, cerebral ischemic symptoms may appear due to cerebral vasoconstriction. Grade A.

Recommendation
Dentists should differentiate between headache and temporomandibular disorder.
In the differential diagnosis of toothache of unknown cause, the possibility of the involvement of the teeth by primary headaches and secondary headaches has to be considered.

Comments and evidence
The following interview sheets and screening tools for headache have been evaluated for reliability and validity. The HIT-6 9 was developed through the construction of the HIT.
The questionnaire can be used as a paper-based test and consists of six questions. The questions are on pain intensity, impact on daily activities, impact on social activities, and mental burden due to headache.
There are five choices for each question. Each choice has a predetermined score, and the total score for all six questions is calculated. Based on the total score, the impact of headache on daily living is classified into four grades. The short questionnaire can be completed within one minute. The HIT-6 has been translated into more than 25 languages.
The reliability of the Japanese version has also been validated. 10 Questionnaires on patient QOL The MTAQ 14 is a 9-item questionnaire that requires a response of "yes or no" to each question. The questionnaire was developed to assess therapeutic effect and identify patients who require changes in treatment.
The Migraine-ACT 15 further simplifies the MTAQ. The therapeutic effect and whether the patient need to change treatment can be assessed by answering "yes" or "no" to four questions: (1) Does your migraine medication work consistently, in the majority of your attacks? (2) Does the headache pain disappear within 2 hours? (3) Are you able to function normally within 2 hours? (4) Are you comfortable enough with your medication to be able to plan your daily activities? Due to its sensitivity and simplicity, this questionnaire is recommended to be used also in primary care.
Although the MIDAS questionnaire is a tool for evaluating disability, by performing this test before and after treatment, the change in score or grade may indicate the effectiveness of treatment.
For HIT and HIT-6 also, by performing the test before and after treatment, the change in score may indicate treatment efficacy. 16 • Search terms and secondary sources

| CQ I-11
How is the headache diary used?

Recommendation
The headache diary provides a wealth of information for the management of headache, including the number of days with headache, the number of days of taking medications, and the treatment effect.
It is also useful from the viewpoint that it reinforces patient-physician communication. Use the headache diary in combination with clinical interview is recommended. Grade A.

Recommendation
The primary headache is a target for treatment if the patient is suffering from it, regardless of the severity. When it is evident that the headache causes disability in daily living, the headache should to be treated aggressively. Grade A.

| CQ I-13
What types of primary headache require hospitalized treatment and what are the treatment methods?

Recommendation
The primary headaches that require hospitalized treatment include (1) when life-threatening secondary headache cannot be excluded; (2) rare headaches that require diagnosis and treatment; (3) for the purpose of confirming the efficacy of special treatment; (4) status migrainosus and refractory or chronic cluster headache; and (5) for the purpose of treating medication overuse headache.

Recommendation
The choice of pharmacotherapy depends on the severity of headache, the frequency of headache, and the degree of disability.

| CQ I-16
What other therapies are available, apart from pharmacotherapy?

Recommendation
Apart from pharmacotherapy, other therapies for primary headaches include behavioral therapy, physical therapy, and supplements.
Because these therapies are not covered by health insurance in Japan, and some adverse events have also been reported, use of these therapies should consider the characteristics of individual patients and also accountability. Details of nonpharmacotherapy for migraine and tension-type headache can be found in the respective sections. Grade B, C (depending on therapy).

| CQ I-17
Is cognitive-behavioral therapy effective for primary headaches?

Recommendation
As a nonpharmacotherapy for primary headaches, cognitive-behavioral therapy has been evaluated by randomized controlled trials in European and North American countries, and the therapeutic effect has been confirmed. Using cognitive-behavioral therapy, headache can be ameliorated in 30%-50% of the patients and therapeutic effect comparable to pharmacotherapy may be expected. The therapeutic effect increases when cognitive ounselling therapy is combination with pharmacotherapy. However, the number of facilities in Japan offering cognitive-behavioral therapy for headache is limited. Grade B.

Recommendation
Patients with migraine and tension-type headache tend to develop psychological states such as anxiety and depression as a level of symptom, and these psychological states are associated with chronicity of headache. In addition, psychiatric disorders such as mood disturbances (major depression) and anxiety disorder (including panic disorder) are common comorbidities. Paying attention to the coexistence of these psychological states and psychiatric disorders is clinically important. Grade B.

| CQ I-19
How should occupational health physicians and brain health checkup physicians manage headache?

Recommendation
Occupational health physicians and brain health checkup physicians should participate actively in providing headache medical care for workers and brain checkup examinees with headaches. Grade A.

Recommendation
In addition to primary headaches such as migraine and tensiontype headache, headaches encountered in schools also include headache as one form of psychosomatic pain. In schools, school nurses look after children who complain of headache, but school physicians are also sometimes consulted regarding headaches. Therefore, school physicians should possess correct knowledge on primary headaches (especially migraine). Headaches may be related to the circumstances surrounding the children, such as stress with teachers and classmates in school or problems at home. Therefore, understanding the background of the children and the mental issues during the developmental process is sometimes necessary. Grade A.

| CQ I-24
How is headache or facial or neck pain attributed to cervical carotid or vertebral artery dissection diagnosed?

Recommendation
Headache or facial or neck pain attributed to cervical carotid or vertebral artery dissection is new, acute-onset headache, with facial or neck pain, usually unilateral (ipsilateral to dissecting artery), and severe.
The pain of vertebral artery dissecting aneurysm is mostly localized in the back of the head or the neck, whereas pain due to internal carotid artery dissection occurs commonly in the front of the head or the forehead.
The pain is persistent, but resolves within 1 month.

| CQII-1-1 How is migraine classified?
Recommendation Migraine is classified in accordance with the ICHD-3beta. The ICHD-3beta adopts a hierarchical classification system. Although classification to the first digit level (headache type) or second digit level (subtype) is usually applied to general practice, classification to the third digit level (subform) is recommended for clinical settings such as specialist practice and headache center. Grade A.

Recommendation
Migraine is diagnosed according to the diagnostic criteria of the ICHD-3beta. The ICHD-3beta adopts a hierarchical classification system. In general practice, the use of the diagnostic criteria up to the second digit level (subtype) is recommended. In specialist practice and headache centers, diagnosis according to the diagnostic criteria to the second digit level (subtype) or to the highest level of the third digit (subform) is recommended. Grade A.

Recommendation
In Japan, the annual prevalence of migraine is 8.4%; comprising migraine with aura 2.6% and migraine without aura 5.8%. The prevalence of migraine is high in women aged 20-40 years. In juveniles, the prevalence is 9.8% among senior high students and 4.8% among junior high students. Grade A.

Recommendation
The definite pathophysiological mechanisms of migraine have not been established. In the past, the vascular theory, neuronal theory, and trigeminovascular theory were proposed as the pathological hypotheses of migraine. Currently, the trigeminovascular system, the descending pain modulatory network in the brainstem, and various peptides are considered to play important roles in migraine.
Especially, serotonin and its receptor (5-HT1B/1D receptor) as well as calcitonin gene-related peptide (CGRP) released from the trigeminal nerve endings may be closely associated with the pain in migraine attacks. On the other hand, aura of migraine is considered to be a phenomenon due to cortical spreading depression (CSD). Grade A.

| CQII-1-4-2 What are the types of auras in migraine?
Recommendation Apart from the typical aura observed in migraine with aura, migraine aura also includes the aura observed in hemiplegic migraine and migraine with brainstem aura.
Typical aura observed in migraine consists of visual symptoms, sensory symptoms, and speech symptoms. Aura in hemiplegic migraine includes motor weakness in addition to the typical aura.
Aura in migraine with brainstem aura includes dysarthria, vertigo, tinnitus, hypacusis, diplopia, ataxia, and decreased level of consciousness. Grade A.

| CQII-1-4-3 What is the proposed mechanism for aura in migraine?
Recommendation At present, aura in migraine is considered to be caused by CSD or spreading oligemia. Grade B.

Recommendation
No definitive mechanism has been established for the pathophysiology of pain in migraine. Two main hypotheses regarding the genesis of pain have been proposed: the peripheral origin theory of pain generated from cerebral blood vessels and trigeminal nerve endings, and the central origin theory of pain generated from the brainstem. Currently, the trigeminovascular system, the descending pain modulatory system in the brainstem, and various peptides are considered to play important roles in migraine pain. Especially, there is high probability that serotonin and its receptor (5-HT1B/1D receptor) and CGRP released from the trigeminal nerve endings are closely associated with pain in migraine attack. Grade A.

Recommendation
The involvement of platelet serotonin (5-hydroxytriptamine: 5-HT) abnormality in the pathology of migraine was hypothesized.
However, subsequent examinations of plasma or serum serotonin levels yielded no consensus, and there are few reports on serotonin and its metabolism. On the other hand, serotonin receptors; 5-HT1B and 5-HT1D receptors, are widely distributed in the trigeminovascular system consisting of intracranial large ounsel blood vessels, trigeminal peripheral nerve endings, trigeminal ganglion, and subnucleus caudalis of the spinal trigeminal nucleus.
Since the advent of triptan (5-HT1B/1D receptor agonist), the relationship between migraine and serotonin receptor has been highlighted. Grade A.

| CQII-1-4-6 How does cerebral blood flow change during migraine attack?
Recommendation Change in cerebral blood flow during migraine attack is discussed focusing on CSD. In an attack of migraine with visual aura, reduced cerebral blood flow in the occipital lobe is observed. In an attack of migraine without aura, the opinion is divided. In addition, regional cerebral blood flow has been shown to increase during headache attack. Grade B.

Recommendation
The precipitating factors of migraine (from epidemiological studies) include the followings: •

Background and objective
Literature was searched to identify the risk factors associated with the outcome and chronification of migraine and to clarify the current assumptions of the biological mechanism for the chronification of migraine.

Comments and evidence
The outcome of migraine can be broadly classified into four patterns: What kind of disease is chronic migraine?"). The mechanisms leading to progression or chronification remain unclear. However, epidemiological studies identified several risk factors related to chronification of migraine (note: these epidemiological studies often target chronic daily headache). These risk factors are listed below. [21][22][23][24][25][26] (1) Congenital factors

Family history
The risk of onset in a child increases when the mother has chronic daily headache.

Prenatal exposure
Mother's drinking and smoking during gestation are risk factors. When compared with other chronic diseases, migraine patients experience greater impairment in QOL in some domains. Grade B.

Recommendation
The comorbid disorders of migraine include hypertension, heart diseases, cerebrovascular diseases, depression, bipolar disorder, anxiety disorder, epilepsy, asthma, allergic diseases, and autoimmune diseases. Grade B.

| CQII-1-8 What kind of disease is chronic migraine?
Recommendation Chronic migraine is a condition that starts off as episodic migraine but migraine attacks increase in frequency during the course of disease resulting in headache occurring on many days of a month.
The diagnosis should be made according to the diagnostic criteria of the ICHD-3beta. Grade A.

Recommendation
In women younger than 45 years of age, the presence of migraine with aura may slightly increase the risk of cerebral infarction. However, the annual incidence of ischemic stroke in this age group is very low. However, the risk is increased by smoking and oral contraceptive (OC). Migraine without aura does not increase the risk. Grade A.

Recommendation
Estrogen-containing OCs are in principle contraindicated in women who have migraine with aura, and other contraceptive methods are recommended. Although these OCs are not contraindicated in women who have migraine without aura, these agents should be administered with caution. Grade B.

Background and objective
Hormonal contraception is one of the most effective contraception methods and include low-dose combined OC containing estrogen and progestogen, progestin-releasing intrauterine contraceptive device (IUD), and progestin-only pill (not yet approved in Japan). In Japan, OC is the most widely used method.
Migraine is prevalent in women reaching sexual maturity. Apart from contraception, use of combined OC is often considered for the purpose of treating ounsellingl and dermatological diseases.
Literature was searched to examine the tolerability and safety of OC use in migraine patients.

Comments and evidence
Combined OC exhibits contraceptive effect by acting on the hypothalamic-pituitary-ovarian endocrine system to suppress follicle development and ovulation and by exerting effects on the cervical mucosa and endometrium.
Combined OC is generally taken for 21-24 consecutive days, followed by 3-7 days of no pills or placebo pills. During this period, the endometrium sloughs off resulting in withdrawal bleeding. For women who desire no bleeding, continuous taking of OC without a pill-free period is also possible. 32 The types of hormone contained in combined OC differ depending on the formulation, which may be one-phase pills containing the same doses of hormones every day or multiple-phase pills containing different amounts of hormones on different days.
Headache has been reported to be one of the most common adverse effects associated with taking OC. 33 Use of OC may aggravate ounselling headache or induce new onset of headache. 34 In the ICHD-II, exogenous hormone-induced headache and estrogen-withdrawal headache are defined. However, in most of the patients with aggravated and new-onset headache, the headache occurs during early cycles of OC use, and with continued use, the difference between OC use and control becomes insignificant. 34 Headache associated with OC use tends to occur during the placebo or pill-free period, and the impact on headache has been reported to differ depending on the administration regimen. To control headache during the pill-free period, continuous OC regimen 35 and estrogen supplementation during the pill-free period have been In a large-scale cross-sectional study, the incidence of migraine among 13,944 women using OC was approximately 18%, and the odds ratio of OC use compared with non-OC use was 1.4 (95% confidence interval: 1.2-1.7). 37 A cohort study in patients who had migraine without aura comparing subjects using and those not using OC reports that use of OC exerts only subtle differences on the course of migraine. 38 In several retrospective studies, use of OC aggravates the frequency and intensity of migraine in 24.1%-34.8% of patients who had migraine without aura, and in 18.6%-69.2% of patients who had migraine with aura. [39][40][41][42] In a meta-analysis of 13 case-control studies and 10 cohort studies reported in 2009, the relative risk of cerebral infarction with aura as category 4 (unacceptable health risk) and a past history (≥5 years ago) of migraine with aura as category 3 (risks outweigh advantages). 45 In Japan, the package insert of OC also lists migraine with aura as a contraindication.

Recommendation
The mainstay of acute treatment for migraine is pharmacotherapy.
The drugs used include (1) acetaminophen, (2) NSAIDs, (3) ergotamines, (4) triptans, and (5) antiemetics. Stratified treatment according to the severity of migraine is recommended: use NSAIDs such as aspirin and naproxen for mild-to-moderate headache, and use triptans for moderate-to-severe headache, or even mild-to-moderate headache when NSAIDs were ineffective in the past. It is necessary to give guidance and cautions to patients having acute attacks and explain the methods of using medications (timing, dose, frequency of use) and medication use during pregnancy and breast-feeding. Grade A.

Background and objective
The objective of acute treatment is to resolve the migraine attack completely and rapidly and restore the patient's normal functions.
An ideal treatment should have the following characteristics: (1) resolves pain and associated symptoms rapidly; (2) is consistently effective; (3) no recurrence; (4) no need for additional use of medication; (5) no adverse effects; (6) can be administered by the patients themselves; and (7) low cost. Literature was searched to identify acute treatments that satisfy the above conditions.

| CQII-2-2 What is the timing of taking triptans?
Recommendation Triptans are effective if taken when headache is mild or in the early stage of headache attack (up to around one hour after onset). When taken during the aura phase or the premonitory phase of migraine, triptans have no negative effect but may fail to relieve headache. Grade A.

Recommendation
Although all the triptans have proven efficacy, individual triptans differ slightly in characteristics. The efficacy and preference vary depending on patients, but adequate evidence is lacking. Grade C.

| CQII-2-4 When and how are nonoral formulations of triptans used for the treatment of migraine?
Recommendation As acute treatment for migraine, nonoral formulations of triptan are effective for severe migraine attacks. Especially, use of injection and nasal spray formulations is indicated when severe migraine attacks cause serious disability in daily and social living, or when frequent vomiting impairs oral administration resulting in poor headache control. The time to response is the shortest for injection, followed by nasal spray. The appropriate formulation should be selected depending on the intended use in individual patients. Grade A (injection, nasal spray).

Recommendation
The acute phase of migraine with brainstem aura and hemiplegic migraine is managed in the same manner as acute treatment for migraine. However, the use of triptans and ergotamines is not actively recommended at present. Grade B.

| CQII-2-6 How are ergotamines used?
Recommendation Ergotamine-caffeine combination has little effect when headache has already become moderate to severe, but there is value to use in patients with frequently relapsing headache while on triptans. Its use is limited because early treatment is as effective as or inferior to NSAIDs and adverse effects including vomiting are present. In addition, its use during pregnancy and breast-feeding is contraindicated. Grade B.

| CQII-2-7 Are acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) effective acute treatments for migraine?
Recommendation Acetaminophen monotherapy and NSAIDs monotherapy are safe and low-cost treatments and are recommended as first-choice drugs for mild-to-moderate migraine attacks. However, their effectiveness is limited compared with triptans. For migraine patients not responding to acetaminophen or NSAIDs, early use of triptan should be considered. Grade A.

Recommendation
For acute treatments of migraine, intravenous corticosteroids (dexamethasone), intravenous magnesium, intramuscular tramadol, and oral tramadol-acetaminophen combination may be considered.
However, because of a lack of adequate evidence, they are not the first-choice drugs. Intravenous, intramuscular, suppository, and combination formulations of prochlorperazine are recommended in the literature, but their use for migraine treatment is not covered by health insurance in Japan. Grade B and C (prochlorperazine: B; dexamethasone, magnesium, tramadol, and tramadol-acetaminophen combination: C).

| CQII-2-10 What are the acute treatments for severe migraine attacks and status migrainosus?
Recommendation 1. Rule out secondary headaches.

Recommendation
When attacks are severe and require treatment, acetaminophen is recommended as an acute treatment. The safety of using triptans during pregnancy has not been established, but there is no report that using triptans during early pregnancy increases the rate of fetal teratogenicity. Since most migraine patients experience reduced frequency of migraine attacks during pregnancy, few patients require prophylactic drugs. Although administration of prophylactic drugs is not recommended, beta-blocker may be used where necessary. For breast-feeding women who are using triptans, it is recommended to avoid breast-feeding for 12 hours after taking sumatriptan and for 24 hours after taking other triptans. Grade B.

Recommendation
Menstrual migraine is diagnosed according to the ICHD-3beta.
To establish the relationship between menstrual cycle and migraine attack, confirmation of the headache diaries is required (for three menstrual cycles). Since headache attacks tend to be severe in menstrually related migraine without aura, triptan is recommended for acute treatment when previous attacks did not respond to NSAIDs.
Prophylactic treatment is conducted according to that used for TA B L E 4 Acute medications categorized by efficacy

Anxiolytics, antipsychotics, anesthetics, antiemetics
Drugs not currently available in Japan are written in italics. a Covered by health insurance as off-label use for migraine. b Not covered by health insurance. general migraine, but when attacks occur mainly in association with menstruation, short-term prophylactic therapy may be one option.
Grade B.

| CQII-3-1 What kinds of patients requires prophylactic therapy?
Recommendation For patients who have migraine attacks two times or more or 6 days or more a month, consideration of prophylactic therapy is recommended. Prophylactic therapy is recommended when migraine-induced disability in daily living remains with acute treatment alone, when acute treatment drugs cannot be used, and for special types of migraine with a risk of causing permanent neurological defects. Grade B.

Recommendation
The drugs used in prophylactic therapy for migraine are shown in Table 5.
Furthermore, the prophylactic drugs for migraine can be classified into five efficacy groups as shown in Table 6, taking into consideration various factors including the strength of evidence, the effects, and risk of adverse events. Grade B.

Background and objective
In many guidelines, various medications have been evaluated based on evidence and consensus. These medications have also been classified into efficacy groups based on evidence and consensus concerning their effectiveness and safety.

| CQII-3-3 How should multiple prophylactic therapies be used differentially?
Recommendation For prophylactic therapy, select a drug with scientific evidencebased efficacy and few adverse effects, and start from a low dose.
In the absence of adverse events, increase the dose gradually until a dose that yields adequate clinical efficacy and evaluate the effectiveness for a period of 2-3 months. If no adequate response is obtained even after increasing to an adequate dose and after a sufficiently long observation period, then change to another drug.
Select drugs taking into account comorbid conditions other than migraine as well as the physical condition. Grade B.

| CQII-3-4 How long should prophylactic therapy be continued?
Recommendation It takes at least 2 months before the effectiveness of prophylactic therapy can be evaluated. Continue prophylactic therapy for 3-6 months if there is no adverse event. If good migraine control is achieved, taper the prophylactic drug slowly, and discontinue where possible. Grade B.

| CQII-3-5 Are beta-blockers (propranolol) effective for migraine prevention?
Recommendation Beta-blockers (propranolol) are effective in preventing migraine attacks. Propranolol at an initial dose of 20-30 mg/day followed by 30-60 mg/day is recommended as one of the first-choice drugs for patients with migraine attacks that impair QOL. Beta-blockers have the additional merit that they can be used in patients with coexisting hypertension and coronary artery disease and that they can be used to treat these comorbid conditions simultaneously. Grade A.

Scientific evidence
Clinical impression (2) Adverse effect

Recommended dose
Antiepileptic drugs Valproic acid (3) Recommendation grade: according to the descriptions in the main text of this guideline. Drugs approved for health insurance in Japan and drugs with high-quality evidence are described. Quality of evidence is not necessarily equal.
(4) See Table 6. (5) Recommended dose: according to the evidence and consensus obtained in Japan.
Drugs not currently available in Japan are written in italics.
a Covered by health insurance as off-label use for migraine in Japan.
b Not covered by health insurance in Japan.

| CQII-3-8 Are antiepileptic drugs (valproic acid) effective for migraine prevention?
Recommendation When migraine patients with 2 or more headache attacks

| CQII-3-9-1 Are antidepressants effective for migraine prevention?
Recommendation Amitriptyline is effective for migraine prevention. In September 2012, amitriptyline was approved for off-label use for migraine and tension-type headache in Japan. Start from a low dose (5-10 mg/day before bedtime) and titrate upward while confirming the effect. A dose of 10-60 mg/day is recommended. Grade A.

| CQII-3-10 Are magnesium, vitamin B12, feverfew, and analgesics effective for migraine prevention?
Recommendation Magnesium, vitamin B2, and feverfew can be expected to prevent migraine to some extent. Because of the absence of serious adverse reactions and the low cost, these medications may be considered as an option for migraine prophylaxis. Non-steroidal anti-inflammatory

Calcium channel blockers
Drugs not currently available in Japan are written in italics. a Covered by health insurance as off-label use for migraine in Japan. b Not covered by health insurance in Japan. drugs and naproxen have significant migraine prophylactic effect compared with placebo, but medication-overuse headache and drug dependence are issues and therefore should be used only for shortterm prophylactic therapy.

| CQII-3-11 Are other prophylactic therapies effective for migraine prevention?
Recommendation Since dihydroergotamine has long been used as a migraine prophylactic drug, and large-scale trials have proven its effectiveness, this drug can be considered appropriate as a prophylactic agent.
In actual fact, however, dihydroergotamine is not used as the first

Recommendation
Multiple randomized placebo-controlled trials have proven that botulinum neurotoxin type A is effective in reducing symptoms of chronic migraine. Moreover, several studies have verified that its symptom-reducing effect for chronic migraine is equivalent to that of topiramate. On the other hand, the effect on episodic migraine is not clear. Therefore, botulinum neurotoxin type A may be considered for chronic migraine when other treatments have failed. In Japan, this treatment is not covered by health insurance. Grade A.

Diagnosis
Typical aura without headache is diagnosed according to the diagnostic criteria of the International Classification of Headache Disorders 2nd Edition (ICHD-II). Grade A.

Treatment
Although the absolute number of cases is small, the risk of cerebral infarction is increased in patients who have migraine with aura. On the other hand, there is no report that typical aura without headache increases the risk of cerebral infarction. Therefore, active treatment is currently considered unnecessary for typical aura without headache.
However, in the case of frequent occurrence and long duration, and in the case of strong patient anxiety, use of prophylactic drugs such as valproic acid and lomerizine may be considered. Grade C.

Recommendation
When migraine becomes chronic, implement appropriate prophylactic therapy (initiate prophylactic drug for migraine, or increase the dose, or change prophylactic drug, or add prophylactic drug) as early as possible. Investigate the reason for chronification, and simultaneously treat comorbid conditions if present. Grade B.

Recommendation
Since 1962, various classifications for tension-type headache have been proposed. Currently, classification according to the ICHD-3beta published in 2013 is recommended. Grade A.

| CQ III-2 How is tension-type headache diagnosed?
Recommendation Tension-type headache is diagnosed according to the diagnostic criteria of the ICHD-3beta. Grade A.

| CQ III-3 How common is tension-type headache? What are the risk factors, triggers, and prognosis? What is the real prevalence of tensiontype headache?
Recommendation Tension-type headache is the most common headache among the primary headaches, and the prevalence varies widely among surveys. To find the precise prevalence, it is necessary to establish suitable survey methods and correct the problems of diagnosis. The risk factors and triggers of tension-type headache have not been defined. The prognosis of episodic tension-type headache is good in majority of the cases, but there exist some cases of poor outcome with progression to chronic tension-type headache. Grade B.

Recommendation
The pathophysiology and the pathogenetic mechanism of tension-type headache remain unknown. Evidence is accumulating supporting the possibility that peripheral pain mechanism plays a role in infrequent episodic tension-type headache and frequent episodic tension-type headache, while central pain mechanism plays a more important role in chronic tension-type headache. Grade B.

| CQ III-5 What is the relationship between transformed migraine and tension-type headache?
Recommendation When headache episodes are diagnosed individually, differentiation between transformed migraine and chronic tension-type headache is difficult. The two can be discriminated by a comprehensive approach to diagnosis considering the treatment, headache response and clinical course. Chronic migraine in the ICHD-3beta includes the concept of transformed migraine. Grade B.

| CQ III-6 How is tension-type headache treated?
Recommendation and their efficacy has been proven. There is little evidence on differential use of these drugs. It is important to always pay attention to medication-overuse headache that results in treatment failure.
Specifically, use for more than two to three times per week should be avoided.
Grade A-C.

Recommendation
Prophylactic therapy for tension-type headache can be broadly divided into pharmacotherapy and nonpharmacotherapy.
Pharmacotherapy using mainly antidepressants and nonpharmacotherapies using electromyographic biofeedback therapy, physical therapy, acupuncture, exercise therapy (exercise to relax neck and occipital muscles), psychotherapy, and cognitive-behavioral therapy (such as lifestyle guidance) are being conducted. Regarding the treatment duration for pharmacotherapy using mainly antidepressants, assess the outcome after around 3 months (the longest 6 months) and decide whether to continue or discontinue medication. On the other hand, evidence for the treatment duration for nonpharmacotherapies has not been established.
Grade A-C.

Recommendation
The prevalence of cluster headache has been reported to be around 56-401 per 100 000 population and is lower than that of migraine. The onset age of cluster headache is usually from the twenties to the forties. The prevalence is three to five times higher in men than in women. During the cluster period, attacks occur regularly and may be provoked by alcohol, histamine or nitroglycerin. Grade B.

Recommendation
The hypotheses of the pathophysiology for cluster headache and other trigeminal autonomic cephalalgias are classified as follows: 1. Generator in the hypothalamus.

Treatment
Although no randomized controlled trials of treatment for these headaches have been reported, indomethacin is considered effective in most cases for these headaches. As adverse effect of indomethacin, gastrointestinal symptoms may be an issue when used long-term. Other drugs have been tried, but are limited to case reports and small case series. Grade C.

Diagnosis
Primary headache associated with sexual activity is diagnosed according to the ICHD-3beta. This headache is precipitated by sexual activity and is diagnosed after excluding intracranial disorders by brain imaging study and cerebrospinal fluid examination. Grade A.

Treatment
To treat primary headache associated with sexual activity, it is necessary for the patient and the partner to understand the disorder. Pharmacotherapy using indomethacin, triptans and propranolol is effective in some cases. Grade C.

Diagnosis
Hypnic headache is diagnosed according to the ICHD-3beta. Grade A.

Treatment
Caffeine is used not only as an acute treatment but also as a prophylactic drug. Lithium is another frequently used prophylactic drug. Grade C.

Recommendation
The treatment principles for medication-overuse headache are as follows: (1)

| CQ VII-2 How is migraine in children diagnosed?
Recommendation Migraine and tension-type headache, which are representative primary headaches in children, are diagnosed according to the ICHD-3beta. Grade A.

Recommendation
The most common secondary headache in children is headache attributed to infection, followed by traumatic injury to the head.
Secondary headaches are not frequently seen at headache clinics.
Headaches encountered in pediatric emergency departments are most commonly infections other than neurological diseases, such as viral diseases and sinusitis, followed by traumatic injury to the head.
Although serious central nervous system disorders are rare, brain CT or MRI should be conducted in the presence of risk factors. Grade B.

| CQ VII-4 What kinds of acute and prophylactic medications are available
for the treatment of migraine in children, and how effective are they?

Recommendation
As first-choice acute medications for migraine in children, ibuprofen and acetaminophen are effective, safe, and low-cost drugs, and ibuprofen exhibits the best analgesic effect. Among triptans, sumatriptan nasal spray is effect and safe for migraine in children, and rizatriptan tablet is also effective and safe. The recommended strategy is to start acute medication as early as possible after onset of headache and at an adequate dose. For prophylactic treatment of migraine in children, the anti-epileptic drug topiramate is effective and well tolerated, but is currently not covered by health insurance in Japan. Grade A.

| CQ VIII-3 Are there genetic factors associated with tension-type headache?
Recommendation Environmental factors are considered to be strongly associated with the development of tension-type headache. However, the presence of genetic factors in some subtypes is possible. Grade C.

ACK N OWLED G M ENTS
We thank seven evaluation/coordination members listed below for evaluating the English version of this guideline.

CO N FLI C T O F I NTE R E S T
The authors declare no conflict of interests related to this guideline.

R E FE R E N C E S
How to cite this article: Araki N, Takeshima  The major adverse effects include nausea, chest discomfort, palpitation, bleeding at injection site, malaise, and somnolence.
This treatment should not be given to patients with familial hemiplegic migraine, sporadic hemiplegic migraine, basilar-type migraine (migraine with brainstem aura), or ophthalmoplegic migraine; patients with a history of heart disease, cerebrovascular disorders, or periphery circulatory disturbance; patients with uncontrolled hypertension; patients with server liver disorder; and patients on treatment with monoamine oxidase (MAO) inhibitor or within 2 weeks after discontinuation. For patients who are prescribed sumatriptan self-injection while also taking oral ergotamine or triptans other than sumatriptan, they should be instructed to use the two agents separately with an interval of at least 24 hours. Grade A CQ2 How should self-injection of sumatriptan at home be initiated and explained to the patient? What is the appropriate amount to be prescribed?

Recommendation
Initiation of self-injection of sumatriptan at home starts when the doctor prescribes the drug to the patient who is judged to be capable of using self-injection properly. At the time of prescription, provide patient education including method of use. Use "Imigran Kit Subcutaneous Injection 3 mg Training Set" to instruct and explain to patients. Explain in detail the adverse effects that may occur by selfinjection of this drug. Instruct patients to follow doctor's directions if any abnormality occurs after self-injection. Also instruct the patients on appropriate method to dispose of the used injection product.
Since sumatriptan is highly effective and fast acting, self-injection of sumatriptan is recommended for patients with migraine or cluster headache who do not respond adequately to other treatments. Prescribe an appropriate amount taking into consideration for use on an as-needed basis.
For migraine, the amount of each prescription is two kits (four ampoules) to five kits (10 ampoules). However, for patients who have

Recommendation
For patient who has never received sumatriptan subcutaneous injection and patient who self-injects at home for the first time, instruct the patient to inject in the presence of an observer such that contact with a medical institution is possible in case of emergency.

Recommendation
When oral valproic acid therapy is used for the prevention of migraine attacks, the optimal blood level is considered to range from 21 to 50 µg/mL, and response does not improve even when the blood level increases to above 50 µg/mL. Therefore, regular measurement of blood valproic acid level during prophylactic therapy and adjustment of the dose to maintain the optimal blood level are rec-

Recommendation
Propranolol has been used as a therapeutic agent for hypertension, angina pectoris, and arrhythmia since 1966, and data of adverse reactions have been accumulated adequately. As a prophylactic drug for migraine, adequate data including meta-analysis indicates good tolerability. The same applies to interactions.
When used as a prophylactic drug for migraine, special attention has to be given to the contraindication for co-administration with rizatriptan. Grade A