Acute Care and Treatment of Migraine

Migraine is a chronic neurological disease involving the brain and its vasculature, typically characterized by recurrent attacks of moderate or severe throbbing headache, accompanied by sensitivity to light and sound, and associated with nausea, vomiting, and inability to move due to worsening of pain. About 30% of migraineurs have some type of aura, most often visual. Migraine attacks, if untreated or suboptimally treated, usually result in significant disability, requiring bed rest and resulting in poor quality of life. Increased frequency of attacks and overuse of acute care medication are significant risks for chronification, resulting in the transformation of episodic migraine into chronic migraine. We aim to review most acute care treatments for migraine

Disease of the Year 2019 Encore: Migraine Section Editors: Kathleen B. Digre, MD Deborah I. Friedman, MD, MPH Acute Care and Treatment of Migraine Spingos Konstantinos, MD, PgD, Michail Vikelis, MD, MSc, PhD, Alan Rapoport, MD Objective: Migraine is a chronic neurological disease involving the brain and its vasculature, typically characterized by recurrent attacks of moderate or severe throbbing headache, accompanied by sensitivity to light and sound, and associated with nausea, vomiting, and inability to move due to worsening of pain. About 30% of migraineurs have some type of aura, most often visual. Migraine attacks, if untreated or suboptimally treated, usually result in significant disability, requiring bed rest and resulting in poor quality of life. Increased frequency of attacks and overuse of acute care medication are significant risks for chronification, resulting in the transformation of episodic migraine into chronic migraine. We aim to review most acute care treatments for migraine. Methods: Current treatment options for migraine attacks were reviewed from the selected literature and combined with our clinical experience. Results: Current acute treatment options for migraine attacks include over-the-counter analgesics, at times combined with caffeine, nonsteroidal anti-inflammatory medications, opioids, and migraine-specific medications such as triptans and ergots. In the near future, we will probably have 3 gepants (small-molecule calcitonin gene-related peptide [CGRP] receptor antagonists). The first one was just approved in the United States. A ditan acting as a stimulator of 5-HT1F receptors, was also just approved by the FDA. Stimulation of the trigeminal, vagal, occipital, and even upper arm peripheral nerves through electrical nerve stimCorfu Headache Clinic (SK), Corfu, Greece; Headache Clinic (VM), Mediterraneo Hospital, Glyfada, Greece and Glyfada Headache Clinic, Glyfada, Greece; and the David Geffen School of Medicine at UCLA in Los Angeles (RA), Los Angeles, California; Past President of the International Headache Society (IHS), Founder and DirectorEmeritus of the New England Center for Headache, Stamford, Connecticut. M. Vikelis received investigator fees and/or advisory board member and/or consultancy and/or travel grants from Amgen, Allergan, Brain Therapeutics, Novartis, and Reckitt Benckinser. S. Konstantinos received editorial fees and/or travel grants and/or consultancy from Novartis Hellas, Teva, and Brain Therapeutics. He is on the speakers’ bureau for Novartis Hellas. A. M. Rapoport serves as an advisor for Allergan, Amgen, Amneal, Assertio, Autonomic Technologies, Biohaven, Cala Health, Impel, Neurolief, Novartis, Promius, Satsuma, Teva Pharmaceutical Industries, Theranica, Xoc, and Zosano; he is on the speakers’ bureau of Allergan, Amgen, Biohaven, Lundbeck, Novartis, and Teva Pharmaceutical Industries. Address correspondence to Spingos Konstantinos, MD, PgD, Corfu Headache Clinic, Mitropolitou Methodiou 13 Street, Corfu 49100, Greece; E-mail: [e-mail] 472 ulation devices and magnetic stimulation devices are available as alternative, nondrug treatment options. Several devices have already been FDA-allowed for treatment in the United States and/or approved elsewhere, and others will follow soon. Behavioral medicine techniques such as biofeedback training and mindfulness have been available for some time and are often helpful. Conclusion: A wide variety of acute care options to treat migraine are available, and others will soon be and will herein be described in further detail. Some medications have been approved by regulatory authorities in countries other than the United States, and some devices have been given a CE Mark in Europe. Journal of Neuro-Ophthalmology 2020;40:472–484 doi: 10.1097/WNO.0000000000001053 © 2020 by North American Neuro-Ophthalmology Society M igraine is one of the most common neurological diseases, with a prevalence of 13% in most Western countries. It occurs 3 times more in women, and 90% of all patients have to restrict or significantly modify their activity during and even between attacks. The unpredictable emergence of an attack, which can occur infrequently or many times per month, commonly interferes with the professional, social, family, or normal day-to-day activity of the sufferer. Migraine often causes trouble with school attendance and job performance and creates family and social problems. There is much stigma involved with migraine, creating a lot of interpersonal issues for the patient and the people he/ she interfaces with (1). A migraine attack can present with neuro-ophthalmic features including visual auras, which is the most common type of migraine aura. Other auras include unilateral sensory symptoms, less frequently unilateral motor symptoms, and rarely speech arrest. A visual aura may include the classical fortification spectra (a zigzag pattern with or without bright scintillating edges, near the point of fixation that spreads and moves peripherally with time, often evolving into a scotoma); a plain gradually enlarging scotoma, often in a crescentic shape; flashes of light called photopsias; visual distortions such as macropsias and micropsias and kaleidoscope vision; and less typically less Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine specific bilateral visual symptoms including blurring (mostly in children and adolescents) (2). Unilateral trigeminal autonomic symptoms involving the orbit, such as red and tearing eye, miosis and ptosis, eyelid swelling, nasal congestion, or running of the nostril, and redness and sweating above the eyebrow often occurs along with the pain. In migraine, this can be bilateral or unilateral. In cluster headache, autonomic symptoms are more prominent and almost always ipsilateral to the pain; in migraine, they are less often unilateral but usually start or end up bilaterally (2). Pathophysiology of Migraine It is not clear where the migraine process begins, but it involves the brain and secondarily the vasculature. There are 2 leading theories. Cortical spreading depression was first accidentally discovered by a Brazilian physiologist named Aristede Leao, while working at Harvard on an experimental model of epilepsy in rabbits (3). He noted that it began in the occipital lobe and moved slowly anteriorly at 3 mm per second, affecting blood vessels and glia, and we now know that it causes the release of various substances such as potassium, hydrogen ions, nitric oxide, and arachidonic acid (4). More recent findings of a hypothalamic abnormality on scanning during the prodrome phase of migraine suggests that this deep area of the brain may be the starting point of the process, which then spreads to involve the brainstem and eventually the trigeminovascular system (5). Ever since the trigeminovascular system was discussed by Mike Moskowitz as critical to migraine pain in the early 1980s (6), it has been carefully studied. It is known that migraine often first involves the peripheral nervous system in the trigeminovascular nerves and blood vessels (the first branch of the trigeminal nerve, which connects the nociceptors and blood vessels in the meninges with the pons and other areas in the brainstem) (7). Peripheral involvement causes the pain and throbbing nature of migraine. This suggests that early treatment, when the migraine process is still in the periphery, may stop the pain and prevent subsequent central sensitization, when the information reaches the brainstem; this leads to chronification and may result in chronic migraine, increasing the likelihood of medication overuse headache (MOH) and rendering the patient and attacks difficult to treat (8). A clue to one of the causes of migraine pain has been known for many years. Calcitonin gene-related peptide (CGRP) in the trigeminovascular system and other peripheral nerves maybe be related to increased migraine pain and vasodilation; hence, blocking CGRP may be helpful to the patient with migraine. Triptans are now known to limit the release of CGRP peripherally (9), as do the soon-to-beavailable small-molecule CGRP receptor antagonist gepants and the 3 currently available preventive monoclonal antibodies blocking either the CGRP receptor or ligand (see below). Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 Medication Overuse Headache Over 50% of migraineurs use over-the-counter medication and a smaller percentage use prescription medications to stop a migraine in progress (10). Headache specialists usually recommend that patients should not take acute care medication, whether over-the-counter, prescription, or even migraine-specific triptans or ergots, more often than 2 days per week. Overuse may predispose them to MOH (see below), increased adverse effects and disease progression, as well as increased consumption of medical services, higher cost, and iatrogenic morbidity (11). It will also limit the patient’s quality of life and may be associated with more psychological issues such as depression and anxiety (12). Importantly, the proper use of acute care medication, while avoiding overuse, is essential to optimal treatment of migraine. We aim to present the current clinical evidence for the approved treatment options to improve and ideally stop a migraine attack. METHODS Selected published reviews, books, and articles on migraine were consulted to outline the established knowledge included in the present review. Clinical trials published in the recent decade concerning new treatments for migraine were reviewed as well. Our clinical experience is also quoted about some controversial issues. Treatment Targets and Therapeutic Strategies Treatment of migraine almost always includes acute therapy at the onset of an attack, either nonspecific or specific, and sometimes, preventive strategies are used in addition. Prevention should be considered for frequency (1–2 headache days per week or more), intensity (with slow or poor response to therapy), patient preference, impending or present overuse of acute care medication with increasing risk for MOH, and other reasons. Acute care treatment of the migraine attack should be offered to all patients, as it reduces or eliminates disability and pain and it decreases the chance of MOH (2). Table 1 presents the commonly used oral medications for acute migraine treatment in adults, their usual effective doses, and their common class-wide precautions. After confirming the diagnosis of migraine by history (we follow the diagnostic criteria from the International Classification of Headache Disorders, 3rd Edition [ICHD3] of the International Headache Society, Table 2) and ruling out any cause of secondary headaches with appropriate examinations and testing, treatment is guided by the availability of products (injection, nasal products, tablet, patches, or devices), cost and insurance issues, treatment strategy (stratified care, step care within an attack, or step care between attacks), patient preference, specific patient 473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine TABLE 1. Currently approved oral medications for acute migraine treatment in adults (see text for details) Medication Nonspecific therapies Analgesics Acetaminophen Nonsteroidal anti-inflammatory drugs (NSAIDs) Ibuprofen Naproxen sodium Acetylsalicylic acid (ASA) Diclofenac potassium Caffeine Opioids Codeine Antiemetics Metoclopramide Butalbital Specific therapies Ergotamine tartrate† Usual Effective Dose Common Precautions* 500–1000 mg Liver toxicity Peptic ulcer, gastritis, uncontrolled hypertension, and heart failure 200–800 mg 500 mg 500 mg 50 mg 65–200 mg 15 mg 10 mg 50 mg Abuse potential 2 mg Ischemic arteriopathy, coronary disease, and uncontrolled hypertension Ischemic arteriopathy, coronary disease, and uncontrolled hypertension Triptans‡ Almotriptan Eletriptan Rizatriptan Sumatriptan Zolmitriptan Frovatriptan Naratriptan Ditan Lasmiditan Gepants Rimegepant Ubrogepant 12.5 mg 40 mg 10 mg 100 mg 5 mg 2.5 mg 2.5 mg 100 or 200 mg Central effects 75 mg orally disintegrating tablet (ODT) 50 or 100 mg tablet *Not inclusively, not including medication overuse headache and pregnancy. † Dihydroergotamine is available as a tablet or sublingual tablet, as a nasal spray of 2 mg, or injectable doses of 0.5–1 mg IV, IM, or SC. ‡ Triptans are variably available as an ODT, nasal spray, and/or injection. issues (i.e., age and pregnancy), and/or presence of comorbidities. Patients and most doctors prefer tablets; but when these do not work well, bypassing the gastrointestinal (GI) tract with an injection, nasal spray, or patch may be critically effective. Some forms of treatment for migraine can be expensive or unavailable for some patients and/or in some countries. It has been shown that stratified care, giving the right medication the first time, is the best treatment plan for the patient (13). If it is a mild, slow-onset headache by history, and not associated with significant disability, it is fine to use a milder less specific over-the-counter medication first. If the attacks are more severe, the patient might be advised to use a triptan or ergot (or a newly released gepants) at the start of the attack. Then, there is step care within the attack. In this scenario, the patient might start with a nonsteroidal anti-inflammatory drug (NSAID) or acetaminophen, and if 474 not better in 2 hours, then use a stronger or more specific medication, such as a triptan. We prefer to avoid this method, as the triptan might be less effective 2 hours into the headache; dihydroergotamine (DHE) might work better later into the attack. We rarely advocate step care between attacks, as patients often suffer for a month or 2 and even end up in the emergency department, till their treatment can be changed at the next appointment. Triptans and most other acute care medications work best early in the attack, in the first 60–120 minutes, before central sensitization occurs, as manifested clinically by signs of allodynia (8,14). Many specific targets may be activated to stop an ongoing migraine attack. Stimulating serotonin 1B and 1D receptors, as the triptans do, and serotonin 1F receptors, as a ditan does, blocking CGRP receptors or preventing the ligand from reaching the receptor, as well as blocking dopamine receptors, may all be helpful (see below). Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine TABLE 2. Diagnostic criteria of ICHD-3 for migraine without aura (2) A. At least 5 attacks, 1 fulfilling criteria B–D B. Headache attacks lasting 4–72 hours (when untreated or unsuccessfully treated) C. Headache has at least 2 of the following 4 characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs) D. During headache at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not better accounted for by another ICHD-3 diagnosis ICHD-3, International Classification of Headache Disorders, 3rd Edition. Patient preference may be for an over-the-counter medicine or a device rather than a stronger vasoconstrictor such as a triptan with more adverse effects. Older patients may not be able to take vasoconstrictors, and many doctors prefer not to give any medication to a pregnant patient. Comorbidities such as Raynaud syndrome, hypertension, coronary, cerebral and peripheral artery disease, and others may preclude the use of a vasoconstrictor. Attack characteristics are important in helping the physician to decide on the best type of treatment for a patient. If the headache usually builds slowly over a few hours, then acetaminophen or a combination medication with caffeine or an NSAID may work. If the time to peak intensity of the headache is short, or if there is severe nausea or vomiting, or the patient awakens from sleep with a headache already in progress, then a nasal spray or an injectable triptan would be better. If disability is frequently a problem, then stopping the headache quickly, with an injectable or nasal triptan or a triptan–NSAID combination may be used. All these considerations may be helpful, and sometimes treatment guidelines inform doctors about the best therapy for a particular type of patient. Most doctors make decisions on treatment by combining their knowledge of the literature and their own clinical experience. This is practicing evidence-based medicine. Doctors and patients have become more aware of MOH and how to try to avoid it or treat it when it occurs. Until recently, the treatment of MOH and chronic migraine has been the most difficult issue for headache specialists. Our personal opinion is that the new anti-CGRP monoclonal antibodies are making that treatment significantly easier for us and for many of our most difficult-to-treat patients, as they just decrease headache frequency and intensity, even if patients continue to overuse acute care medication. It is critical to understand that inadequate acute care therapy is a risk factor for chronification and may result in Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 transformation from episodic into chronic migraine (15,16); therefore, giving the right treatment the first time (stratified care) is critical for many patients. A high frequency of migraine might be a warning that chronification of migraine (transformation from episodic to chronic) could occur, as it has been suggested (17). All these considerations are important, and the treatment guidelines published by the neurologic and headache societies worldwide combine evidence about scientific data on various acute treatments along with health care information and specialists’ suggestions on local needs (2,18–23). Medication Overuse Headache MOH (formerly known as analgesic rebound headache) is a well-established nosological entity. It is a secondary cause of headache in ICHD-3 (Table 3) and an important risk factor in causing refractory headaches due to the ineffectiveness of typical treatment. It is caused by the frequent use of almost any acute care migraine medications but possibly less so with the NSAIDs. Some medications (e.g., opiates and butalbital-containing formulations) are more prone to cause MOH and should rarely be used as treatments. The frequent use of poorly effective and/or milder medications is linked to MOH, as patients increase the dose size or frequency if the headache is not responding in their attempt to feel better. To prevent MOH, physicians and nurses should ask their patients with frequent headaches to track their medication intake and headaches on an electronic or paper calendar; they should also educate them to keep intake to no more than 2 days per week. This will keep it way lower than the 15 days per month required to diagnose MOH (for aspirin, acetaminophen, or NSAIDs) or the 10 days per month to diagnose the overuse of triptans, ergots, opioids, or any combination of analgesics, including those containing caffeine. If patients exceed those limits for 3 months, they have MOH by definition, even if their headaches do not worsen. Preventive therapy is especially important in patients prone to frequent or severe and disabling headache (2). In general, acute migraine pharmacological treatment is often categorized as either “nonspecific” or “migraine-specific” depending on whether it was developed for general pain relief or targeted to an aspect of migraine pathogenesis, such as trigeminal inflammation or elevated levels of CGRP. In difficult-to-treat cases, specific therapies such as triptans and ergots are preferred to nonspecific analgesics and other medications because they usually do a better job treating the migraine attack. The more powerful, but nonspecific, opioid or butalbital-containing mediations are not usually prescribed by headache specialists in the United States, but they are used by other physicians. Germany and European countries have banned barbiturate-containing medications (24,25). Other nonspecific migraine medications include 475 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine TABLE 3. Combined diagnostic criteria of ICHD-3 for medication overuse headache (MOH) (2) A. Headache occurring on 15 days/month in a patient with a pre-existing headache disorder B. Regular overuse for .3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache On $10 d/mo: Ergotamine One or more triptans, 1 in any formulation One or more opioids One or more combination analgesic medications 1 of ergotamine, triptans, nonopioid analgesics, and/or opioids, without overuse of any single drug or drug class alone One or more medications other than those described above Or, on $15 d/mo: Paracetamol One or more nonsteroidal anti-inflammatory drugs (NSAIDs, including acetylsalicylic acid) or nonopioid analgesic other than paracetamol or NSAIDs C. Not better accounted for by another ICHD-3 diagnosis ICHD-3, International Classification of Headache Disorders, 3rd Edition. off-the-shelf acetaminophen, aspirin, combination medications including caffeine, NSAIDs, or prescription NSAIDs, other analgesics, steroids, and antiemetics. Other than medications, migraine treatments include various behavioral medicine techniques such as biofeedback training, cognitive restructuring and deep muscle relaxation, mindfulness, headache devices, sleep evaluation and therapy, acupuncture, chiropractic, physical therapy, diet, and exercise. Among the above, the ones with the best available evidence are behavioral medicine and various new headache devices. Migraine-specific therapies include ergots (i.e., ergotamine tartrate by tablet or sublingual tablet and dihydroergotamine (DHE), by nasal spray or injection, isometheptene, and triptans), which have various routes of administration. A serotonin 1F receptor (5-HT1F) agonist (a ditan), which works somewhat like a triptan but does not constrict blood vessels, was recently approved by the FDA. A small-molecule tablet CGRP receptor antagonists (gepant) was just approved by the FDA, and another one is expected soon. Devices that are cleared by the Food and Drug Administration (FDA) for the acute treatment of migraine include the external trigeminal (supraorbital) nerve stimulator (Cefaly), which also has a CE Mark in Europe (FDA approval always requires a full but more narrow clinical trial, whereas the CE Mark can be obtained through a review of published data for existing equivalent devices) (26), nonpainful remote electrical neuromodulation (REN) placed on the upper arm (Nerivio), transcranial magnetic stimulation (SpringTMS), and noninvasive vagus nerve stimulation (gammaCore), the last 2 of which have a CE Mark in Europe. There is also a device being studied that stimulates both the supraorbital and occipital nerves simultaneously. Nonspecific Acute Migraine Therapies Analgesics Analgesics include acetaminophen (known as paracetamol in the EU) and its combinations with other medications. 476 Acetaminophen has been widely used as an all-purpose analgesic–antipyretic worldwide for many decades (27). The rationale for its effectiveness in migraine is not well understood because it has no significant action on COX 1 and 2. It is thought to nonselectively modulate central pain pathways (28). The number needed to treat (NNT, an established measure of drug efficacy calculating the dividend of the patients who took the medication by the patients who actually showed response) for pain relief in 2 hours for migraine is 5. It does not act on accompanying symptoms of migraine. Acetaminophen is best used when using a stratified treatment approach, so that a patient with a history of mild intensity migraine of slow onset, who responds well to analgesics, can take a less expensive option with fewer adverse events. Acetaminophen has the advantages of not reducing gastric prostaglandins and not affecting platelet functionality. It may also be combined with other agents such as aspirin and caffeine. That exact combination in the United States is the most commonly used acute care medication for migraine, called Excedrin; unfortunately, it is frequently overused. Acetaminophen can also be given with metoclopramide, which itself can be helpful for migraine (see below). Contraindications include a previous history of MOH and liver dysfunction (27). Acetaminophen should not be used for more than 14 days per month, or more than 9 days if combined with other medication, to prevent MOH (2). A dose of 250 or 500 mg of acetaminophen twice a day, usually taken by mouth, is preferred in adults. Peak effectiveness can be expected after 2 hours when given orally or after 1 hour of intramuscular injection, not commonly used in the United States. Acetaminophen should not exceed 3,000 mg per day because there is a risk of hepatic toxicity (27). It is considered safe in pregnancy and lactation (29). The authors rarely use this medication as their main acute treatment for significant migraine attacks because many patients do not find it helpful. Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine Nonsteroidal Anti-Inflammatory Drugs NSAIDs are commonly used in migraine because of their action on peripheral neurogenic inflammation; they inhibit cyclooxygenase (COX) 1 and 2 enzymes. Specific action on cyclooxygenase-2 (COX-2), with the newer members of the NSAID class, prevents deleterious effects on the gastric mucosa but increases cardiovascular risks. Ibuprofen (30), naproxen sodium (31), acetylsalicylic acid (ASA) (32), and diclofenac potassium (33) are nonselective COX inhibitors that have consistently shown good efficacy and safety profile in many clinical trials. Just like acetaminophen, they should not be overused. The NNT for ibuprofen 400 mg is 3.2 for headache relief at 2 hours. Ibuprofen leads to fewer gastric side effects compared with aspirin (ASA). The dose of 400 mg is commonly used, and it may be repeated if necessary. The over-the-counter dose in the United States is 200 mg, and the prescription dose is 800 mg (30). Naproxen has a longer duration of action than ibuprofen. The NNT for migraine pain relief from naproxen 500 mg is 6. It may be repeated, but its daily dose should not exceed 1375 mg. Naproxen sodium, which is available in the United States over-the-counter at 220 mg (Aleve), is often preferred by headache specialists because of effectiveness, longer duration of action, and the low likelihood of producing MOH (34). ASA is the most famous NSAID, as it has been used for many decades and for many, even more, serious conditions including secondary prevention in stroke and myocardial infarction. It is used mostly at a dose of 500–1,000 mg repeated after 6 hours with a maximum daily dose of 4,000 mg. It has a fast onset of action, especially in its effervescent form, and a long duration of action. When combined with metoclopramide, it may provide effective relief from nausea, a common accompanying symptom of migraine (32). The effectiveness of effervescent ASA 1000 mg is comparable with sumatriptan tablet 50 mg in a metaanalysis, which also shows a better side-effect profile (35). Headache specialists rarely use ASA for the acute treatment of migraine and would not give such high doses on a frequent basis because of GI adverse events such as abdominal pain and bleeding. Diclofenac has well-established efficacy in migraine. Αt 50 mg, it has an onset of action of about 60 minutes as a tablet or capsule and an NNT of 6.2 for migraine pain relief (33). In the United States and some European countries, it exists in a powder formulation (under the brand names Cambia in the United States and Voltfast or Catafast in some European countries) that can be rapidly dissolved in water. In this form, it has a Tmax of just 15 minutes and works much faster (starting in 15 minutes) than the capsule form (60 minutes), according to a double-blind, European study (36). It is approved for migraine treatment in the United States. Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 Ketorolac is an injectable, nonsteroidal antiinflammatory drug that can be given intravenously, usually at a dose of 30 mg, or intramuscularly (usually at a dose of 60 mg). There is a nasal preparation in the United States approved for pain and sometimes given off label for migraine. There is evidence that the ketorolac 31.5 mg nasal spray is not inferior to the sumatriptan 20 mg nasal spray for the acute care of migraine (37). Caffeine-Containing Medications Caffeine is a historically well-known headache treatment and still widely used in combination with other medications, mostly over-the-counter. Such combinations contain acetaminophen, ASA, ibuprofen, and ergots, among others. Caffeine significantly improves migraine in most patients in doses of at least 100 mg, which is approximately the amount in an average cup of coffee. In migraine, it may act by reversing the inflammatory vasodilatation caused by adenosine (38). It may also act with an unknown mechanism as an adjuvant, improving the effectiveness of the other medications in the regimen (39). The adverse events of caffeine are common and widely known including nervousness (6.5%), nausea (4.3%), abdominal pain/ discomfort (4.1%), and dizziness (3.2%), according to a recent review (38). Daily consumption exceeding 200 mg of caffeine may cause headache, which is classified as headache from substance withdrawal (2). Many migraineurs tend to have a large consumption of caffeine if we add up the caffeine contained in their medications, coffee, tea, and chocolate. Treatment often includes a very slow withdrawal of caffeine with the reinstitution of smaller amounts or decaffeinated coffee after they show improvement. Note that caffeine is a double-edged sword, in that it is often overused increasing headache frequency but is helpful on an acute care basis as well. Opioids Opioids like codeine at 15 mg codeine are commonly used in the United States by prescription and Canada without one, but all opioids at any dose are best avoided in migraine treatment, even when used only occasionally. They should be reserved as a last resort or rescue option when nothing else has worked. This is because they do not work on the pathological process of migraine, and therefore, they do not interrupt the migraine attack. In migraine, as well as in most syndromes of recurrent pain, opioids impair the central descending pathway mechanisms for modulation of pain, and this increases the risk of chronic pain and MOH. Episodic migraine may transform into chronic migraine, and the overuse of any acute care migraine medication, especially opioids and butalbital, is a major risk factor for chronification. As mentioned above, to prevent MOH, opioids should not be used for more than 10 days per month (2). It has been shown that only 4 doses per month 477 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine may reduce the responsiveness of headache to other acute and preventive treatments, as suggested in a post hoc analysis (40). Antiemetics The dopamine-antagonist subgroup of antiemetics possesses an important role in migraine, as nausea and vomiting frequently accompany the acute headache phase of the attack (41). As dopamine antagonists, they can also successfully stop a migraine attack, especially when given intravenously (42). The form of the antiemetic, as well as the other acute medications that will be selected, becomes especially important, as nausea suggests reduced GI transit time or reversed GI transit of contents and decreased absorption in the jejunum. That is when the physician who preferred a triptan should turn to nasal sprays, suppositories, intracutaneous patches, subcutaneous, and/or intramuscular injections, which have a certain advantage over tablets and capsules in this situation (38). Melt tablets (orally dissolvable tablets [ODTs]) imply a faster action than usual tablets, but in fact, the 2 triptan ODTs actually have a longer Tmax and their action is slightly slower (43). On the other hand, the major limiting factor in the use of dopamine antagonists is the risk of acute extrapyramidal effects, especially dystonia and akathisia, among other side effects, such as hypotension. This risk is dose dependent and interval dependent, and the symptoms may be severe but fully reversible with anticholinergic medication (44). Metoclopramide is probably the most used antiemetic in adults, including during pregnancy (45). A dose of 10 mg may be safely repeated after 6 hours. It seems that it provides a significant reduction both in nausea and migraine pain (46), the latter, though, to a lesser degree than triptans (47). Chlorpromazine or prochlorperazine is also used, mostly in emergency department settings, although with a higher risk of extrapyramidal side effects than with metoclopramide (48). Many emergency departments in the United States primarily use intravenous prochlorperazine, and it is well documented in the literature (48). Ondansetron and other 5-HT3 antagonists, especially in the effervescent forms, are good antiemetics developed for nausea related to chemotherapy, but they do not seem to stop the migraine process as the dopamine antagonists mentioned above (45). Steroids Although short-lasting corticosteroid administration might be an option as a rescue therapy for refractory migraine or in the prevention of headache recurrence (49), especially in long-lasting migraine attacks, corticosteroid use for migraine relief is not supported by all. Many headache specialists in the United States successfully use a 3-day burst of high-dose steroids in patients who are having either a prolonged migraine attack and/or as a rescue regimen when other acute 478 medications have failed to be effective. A typical dose used by one of us (A.R.) is dexamethasone 4 mg tablet, used three times a day on Day 1, twice a day on Day 2, and once a day on Day 3. Some doctors use a prepackaged, 6day dose of methylprednisolone, which is more convenient but may not work as well. A major review of the literature shows that a generous dose of steroids can shorten a prolonged attack and does decrease the chances of a quick recurrence (50). Migraine-Specific Therapies Among migraine-specific treatments, ergot derivatives, triptans, the just-approved lasmiditan, and serotonin (5HT)1F agonist, in the class called ditans, are currently available in various countries. Also, just approved are ubrogepant and rimegepant, the first 2 of 3 gepants (small-molecule CGRP receptor antagonists), available as acute care treatments for migraine due to their short half-lives. Actually, ubrogepant will be used only for acute care, atogepant only for prevention, and rimegepant for both. Of all the above therapies, only the ergots and triptans are vasoconstrictors. Ergot Derivatives Ergotamine tartrate and dihydroergotamine retain some role in the current and future treatment of migraine. Methysergide is no longer available as a preventive medication, but a small company is planning to bring it back with altered receptor structure, which may avoid its significant adverse events of fibrosis and hallucinations. Ergots have been used since the 1920s. They act as agonists at serotonergic, dopaminergic, and adrenergic receptors. Like the triptans, they should be taken as soon as possible after the onset of the headache. Dihydroergotamine (DHE) is clinically known to work late in the migraine attack and for a long time to prevent a recurrent headache (51). It is available as a nasal spray or injection. Ergotamine tartrate is used less in the United States today that before the triptans were available, but it is frequently used and overused in other countries because of its lower price. It can be given as a tablet or a sublingual tablet, or it can be compounded into a suppository. A typical dose comes in 2 mg containing a small dose of caffeine. The usual dose of the currently used dihydroergotamine mesylate nasal spray is typically 2 mg (52). The safety of exceeding 3 mg per day and 4 mg per week has not been established. One of the authors (A.R.) worked on its development many years ago but rarely uses it today because of limited efficacy, possibly do to poor absorption by the nasal mucosa, as evidenced by the low concentration as seen on comparative pK curves. An injectable form is available in the United States and is quite helpful at 1 mg intramuscularly or subcutaneously and can even be cautiously given in smaller doses intravenously, especially over a few days, for patients with long-term chronic migraine and MOH. An orally inhaled formulation Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine has been favorably tested in a Phase III clinical trial (53), but it will not be coming to the market, because of manufacturing issues. Two other nasal formulations are in Phase III trials; one is a solution that is propelled deep into the nose and one a spray of a fine powder. Both have shown higher concentrations over time in their Phase I trials in comparison with the existing nasal spray formulation in the United States (54,55). The bioavailability of ergots is much higher when delivered intravenously. They can cause significant vasoconstriction, so the precautions of triptans may apply (see below in text). DHE is metabolized in the liver by CYP 3A4, so it should not be used along with macrolide antibiotics and some other medications. Ergots usually cause nausea when given orally or especially intravenously, as well as a sensation of weakness and paresthesia, so patients should be pretreated with antiemetics (52). Sometimes, intravenous therapy may even cause temporary worsening of headache intensity with a change in its character (56); however, it is still often used by headache specialists to help with detoxification in a hospital setting. Triptans Triptans are the first modern, effective specific treatment that received approval from the FDA and global authorities for the acute care of a migraine attack. Sumatriptan was specifically designed by Sir Patrick Humphrey at Glaxo to be a vasoconstrictor with effects similar to intravenous (IV) serotonin, which had been shown by Sicuteri in the 1960s to be an effective migraine treatment. Because IV serotonin had caused a lot of adverse events, Dr. Humprey discovered the 5-HT1 receptor that selectively mediates vasoconstriction of certain cranial blood vessels. He went on to discover sumatriptan, which is a selective agonist at that receptor that is devoid of all the unwanted effects of 5-HT and ergotamine. Later, molecular biological studies confirmed the highly localized presence of the 5-HT1–like receptor, later named the 5-HT1B receptor (57). All triptans are now known to be selective agonists at the presynaptic 1B autoreceptor on blood vessels and the 1D receptors that are anti-inflammatory and prevent the release of certain neurotransmitters such as CGRP and substance P. The 7 currently available triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) moderately differentiate from each other in terms of available doses, different routes of administration, speed of action, and types of metabolism (58). There is a widely accepted practical classification of oral triptans. Those in Group 1 (almotriptan, eletriptan, rizatriptan, sumatriptan, and zolmitriptan) have a faster onset of action by tablet (30 minutes vs placebo) and a lower NNT (3.1–4.7); those in Group 2 (frovatriptan and naratriptan) show a slower onset of headache relief (60 minutes or longer), a higher NNT (8.1–8.2), longer half-lives, lower recurrence rates, and considerably better tolerability (59–65). Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 The subcutaneous injection of 6 mg sumatriptan has the lowest NNT (2.3) and best efficacy for headache relief with the fastest separation from placebo (at 10 minutes in some patients) (64); the 2 triptan nasal sprays (sumatriptan and zolmitriptan) have almost as fast as an action starting at 15 minutes for headache relief. Sumatriptan is not as well or consistently absorbed and tastes worse than zolmitriptan according to most patients, possibly because of its sulfa moiety. Most patients in the United States prefer the zolmitriptan nasal spray if both are available (65); it is the only branded triptan in the United States. Commonly used oral doses of triptans are 12.5 mg for almotriptan (59), 40 mg for eletriptan (60), 2.5 mg for frovatriptan (61), 2.5 mg for naratriptan (62), 10 mg for rizatriptan (63), 100 mg for sumatriptan (64), and 5 mg for zolmitriptan (65). The typical regimen is 1 tablet as early as possible after the start of the migraine attack, which may be repeated in at least 2 hours if there is limited or no benefit. If a patient has not responded to a specific triptan after 2 or 3 trials, when taken early in the attack, a second one should be tried, and there would be a reasonable chance of success. If a patient has not responded to 2 or 3 different triptan tablets, it is not established whether they will respond to the next one. The reason for the lack of efficacy of many tablets may be that patients are nauseated or have some autonomic dysfunction, preventing rapid absorption of the drug from the jejunum; in that situation, they should be given a triptan dose form that can bypass the GI tract. At the present time, that means a nasal spray or an injection, if they are available. Onzetra Xsail is a form of sumatriptan powder that is blown into each nostril by the patient and is currently available in the United States. A new form of the sumatriptan nasal spray at half the usual dose (10 mg) plus a permeation enhancer (called DFN02 or Tosymra) has a very good 2-hour pain-free rate of 43% and was recently approved by the FDA (66). A microneedle application of zolmitriptan (Qtrypta), which has many microneedles inserted into the outer layers of skin without discomfort, has demonstrated a high 41.5% pain-free rate at 2 hours vs placebo in its Phase 3 study (67). Qtrypta is anticipating approval from the FDA by December 2020 (68). Most triptans are metabolized by the liver except the renally metabolized naratriptan (62). Eletriptan has to be used cautiously with CYP/3A4 system inhibitors (60). The rizatriptan dose must be cut in half to 5 mg if the patient is on propranolol (either as a preventive for migraine or as an antihypertensive medication). All triptans have been reported to cause variable amounts of nausea, paresthesias, a warm or hot feeling, chest tightening or neck pain, and other sensations as common side effects but have fewer adverse effects (AEs) than ergots (58). Triptans may cause vasoconstriction (69), so they come with precautions for use if there is a history of cardiac arrhythmias, angina, other vascular conditions involving the heart and/or brain and/or intestines or peripheral vasculature, uncontrolled hypertension, complicated forms of migraine, such as hemiplegic migraine and migraine with 479 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine brainstem aura, and pregnancy. The use of a triptan is not recommended if another triptan or ergot derivative has already been used within the past 24 hours. In addition, triptans should not be used more than twice at the maximum allowable dose in the same 24-hour period to avoid vasoconstriction; they should not be used more than 9 days per month to prevent MOH (2). Most headache specialists limit triptans or any acute care medication use to 2 days per week. An efficient, fixed combination of sumatriptan and naproxen (Treximet) is also currently available as a generic formulation (70). A new medication is being tested, which includes the NSAID meloxicam and rizatriptan. Novel Medical Treatments 5-HT1F agonists (ditans) In addition to the inconsistency of the therapeutic action of the triptans, plus some patients’ lack of response, their vasoconstrictive potential is a major limitation to their use, especially in older patients and those with coronary, peripheral, and cerebrovascular issues. Furthermore, it has now been shown that vasoconstriction is not the critical element in the efficacy of acute headache treatment in migraine, as mentioned above. Lasmiditan (Reyvow in the United States) is a recently FDA-approved, hyperselective 5-HT1F agonist with promising efficacy, good 2hour pain freedom numbers, and some issues of tolerability in Phase II and III studies. It is not a vasoconstrictor, and its antiinflammatory action is caused by stimulating the 1F receptors, which may prevent the release of CGRP, such as triptans (71). Unlike most triptans, it does gain entrance to the central nervous system. The trials done in the United States and Europe show a fairly high percentage of dizziness (14.9%) for all pooled active doses, as well as somnolence, paresthesias, and other AEs to a lesser degree (72). As lasmiditan crosses the blood–brain barrier to exert its action, central side effects are more likely and of greater concern; they are mostly mild to moderate severity though (73). Patients are advised not to drive or operate machinery for at least 8 hours after taking Reyvow, even if they feel well enough to do so (74). It is a controlled substance. Small-Molecule Calcitonin Gene-Related Peptide Receptor Antagonists (Gepants) CGRP is critically involved in the pathophysiology of migraine as mentioned above. The recent approval of monoclonal antibodies targeting CGRP receptors or the CGRP ligand for migraine prevention demonstrated the importance of the CGRP pathway and prompted a closer look at the small-molecule receptor antagonists that were investigated 15–20 years ago. Olcegepant and telcagepant, the first 2 to have undergone evaluation at that time, were never brought to market—olcegepant because it could not be formulated as a tablet and telcagepant because it demonstrated liver toxicity (75). Other molecules were also found effective, without liver toxicity; however, they were never commercialized. There have been recent promising trial 480 results and posters presented at the AAN meeting in Philadelphia in April 2019 about the gepants; there is no significant liver toxicity seen with the 3 treatments being studied. Ubrogepant and rimegepant are 2 medications that have positive Phase 3 data for acute care of migraine (76,77). Ubrogepant was approved by the FDA in December 2019 with the brand name Ubrelvy, is a tablet, and rimegepant, approved on February 27, 2020, is the first ODT and eventually a related compound may be developed as a nasal spray. Atogepant has Phase 3 data for prevention when used once or twice a day as does rimegepant used every other day (78). Headache Neuromodulation Devices External trigeminal nerve stimulation External trigeminal nerve stimulation has shown significant efficacy in the prevention of migraine with reasonable tolerability in recent randomized controlled studies. A recent one was performed on 106 patients for the acute treatment of migraine showed that transcutaneous supraorbital nerve stimulation (t-SNS) provided by the Cefaly device, which is placed on the forehead with a sticky tape for a 60-minute session, significantly reduced pain intensity by nearly 60% compared with 30% for the sham intervention, as recorded on a visual analog scale. No serious adverse events were reported, but paresthesias in the forehead bother some patients, apparently less so with the newer model (79). The Cefaly device is FDA-cleared for the acute treatment and prevention of migraine. The product is purchased with a prescription. Combined Occipital and Trigeminal Stimulation Combined occipital and trigeminal stimulation, provided by Relivion, a device that stimulates the supraorbital and supratrochlear nerves of the trigeminal system in the forehead, as well as the 2 occipital nerves, has shown some good 2-hour pain-free and pain-relief efficacy. It has a CE Mark in Europe but no FDA clearance yet (80). A Phase 3 study was recently resumed, and the company could gain FDA approval in 2020 if the study is positive. Remote Electrical Neuromodulation Another device for headache, cleared in May 2019 by the FDA, is Nerivio. Its mechanism of action is through REN. After the successful completion of its pivotal clinical trial NCT03361423, it launched in the United States. It is placed on the upper arm for 45 minutes, controlled by a smart phone and sends signals to the thalamus, which causes activation of the brain’s descending pain inhibition pathway (an approach called conditioned pain modulation [CPM]). Its 2-hour pain freedom and other measures during the Phase 3 trial, that took place at several centers in Israel and the United States, were excellent. There are no significant AEs, the most common one being a mild feeling of warmth in the arm; it was well tolerated with no safety issues (81). Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine The cost for 12 treatments will be low, and the company is applying for insurance authorization and coverage. After the 12 treatments, the device is discarded. relaxation and cognitive restructuring can be very helpful, especially in children (23). Many other techniques can be tried, such as mindfulness and yoga. Single-Pulse Transcranial Magnetic Stimulation —eNeura Savi Case 1 A 24-year-old female secretary was seen for severe bilateral orbital and occipital throbbing headache that gradually worsened over 8 hours and was associated with blurred vision and nausea. She had a long history of infrequent headaches of the same kind and no other medical history. Examination and testing was normal. This is the type of mild migraine headache that is most responsive to an NSAID. An antiemetic should be added in case the patient develops severe nausea or vomiting. Single-pulse transcranial magnetic stimulation (sTMS) may be an effective, well-tolerated treatment option for migraine prevention and acute care as well. In a double-blind trial for the acute treatment of migraine pain with aura, the 2-hour pain-free response was significantly achieved by 39% of patients using sTMS vs 22% with the sham intervention, with a very low level of trivial side effects. Magnetic pulses disrupt cortical spreading depression, which is the basis for aura, and downregulate thalamocortical pathways (82,83). The treatment is localized in the occipital area. Then, it was found to also help patients who had migraine without aura. It is now FDA-allowed for acute and preventive care of migraine, and it is rented from the company on a monthly basis. Noninvasive Vagus Nerve Stimulation A randomized, sham-controlled trial supports the efficacy of noninvasive vagus nerve stimulation (nVNS, gammaCore) after the onset of a migraine attack, with safety and good tolerance. nVNS was superior to sham for pain freedom at 30 minutes (12.7% vs 4.2%; P = 0.012) and 60 minutes (21.0% vs 10.0%; P = 0.023), but missed significance at 120 minutes, although the pain-free rate is good (84). It is approved for acute and preventive care of migraine and acute care of episodic cluster headache and prevention of episodic cluster in conjunction with other therapies. It has recently gained insurance coverage. Case 2 A 40-year-old man presented with a history of moderately severe headaches since age 18 years that have increased in frequency to almost every day for many months. Ten headaches per month have all the characteristics of migraine and do not fully respond to acetaminophen, NSAIDs, or 3 different oral triptans, the use of which exceeds 25 days per month. He has been repeatedly evaluated by neurologists, had 2 brain MRIs, and has tried propranolol and topiramate at therapeutic doses for 3 months each without success. This patient needs thorough and convincing education about MOH and should be offered a trial of another approved preventive therapy, such as an anti-CGRP monoclonal antibody, along with a detailed detoxification schedule and behavioral medicine therapy. He then needs to be started on the right dose and timing and proper limits of a triptan for acute care. Children and Adolescents CONCLUSION According to the last Cochrane review, low-quality evidence from small trials shows that ibuprofen appears to improve pain freedom for the acute treatment of children with migraine, but the information on adverse events associated with ibuprofen was limited. Triptans were judged as effective in children and adolescents, but they were associated with higher rates of adverse events. Sumatriptan plus naproxen sodium has also been effective in treating adolescents with migraine (85). According to the recently published guidelines in the United States, the ibuprofen oral solution (10 mg/kg) should be the initial treatment for children and adolescents. In addition, certain triptans have been approved for adolescents or even younger ages depending on the country (86). Migraine is a common, painful, disabling disease of the brain and its blood vessels. Acute care therapy, designed for individual patients, can be effective in improving and hopefully stopping an attack. Various pharmacological and behavioral options, as well as devices, have been and will be approved for the acute care of migraine. The clinician has to balance the needs of each patient according to the history and the efficacy and adverse events of each treatment modality considered. This is an exciting time for patients with migraine and headache-interested doctors; there will soon be so many choices that it might be difficult to choose the optimal one. Behavioral Medicine Techniques Biofeedback training, alone or combined with medication, can be helpful both as a migraine preventive and acutely during an attack. Other techniques such as deep muscle Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S. Konstantinos, M. Vikelis, and A. Rapoport; b. Acquisition of data: S. Konstantinos, M. Vikelis, and A. Rapoport; c. Analysis and interpretation of data: S. Konstantinos, M. Vikelis, and A. Rapoport. Category 2: a. Drafting the manuscript: S. Konstantinos, M. Vikelis, and A. Rapoport; b. Revising it for intellectual content: S. Konstantinos, M. Vikelis, and A. 481 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine Rapoport. Category 3: a. Final approval of the completed manuscript: S. Konstantinos, M. Vikelis, and A. Rapoport. 22. REFERENCES 1. GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990– 2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17:954–976. 2. Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018;38:1– 211. 3. Leão AAP. Spreading depression of activity in the cerebral cortex. J Neurophysiol. 1944;7:359–390. 4. Tfelt-Hansen PC. History of migraine with aura and cortical spreading depression from 1941 and onwards. Cephalalgia. 2010;30:780–792. 5. Goadsby PJ, Holland PR. An update: pathophysiology of migraine. Neurol Clin. 2019;37:651–671. 6. Moskowitz MA. The neurobiology of vascular head pain. Ann Neurol. 1984;16:157–168. 7. Ashina M, Hansen JM, Do TP, Melo-Carrillo A, Burstein R, Moskowitz MA. Migraine and the trigeminovascular system-40 years and counting. Lancet Neurol. 2019;18:795–804. 8. Burstein R, Levy D, Jakubowski M. Effects of sensitization of trigeminovascular neurons to triptan therapy during migraine. Rev Neurol. 2005;161:658–660. 9. Kageneck C, Nixdorf-Bergweiler BE, Messlinger K, Fischer MJ. Release of CGRP from mouse brainstem slices indicates central inhibitory effect of triptans and kynurenate. J Headache Pain. 2014;15:7. 10. Wenzel RG, Sarvis CA, Krause ML. Over-the-counter drugs for acute migraine attacks: literature review and recommendations. Pharmacotherapy. 2003;23:494–505. 11. Rapoport AM. Medication overuse headache: awareness, detection and treatment. CNS Drugs. 2008;22:995–1004. 12. Saylor D, Steiner TJ. The global burden of headache. Semin Neurol. 2018;38:182–190. 13. Lipton RB, Stewart WF, Stone AM, Láinez MJ, Sawyer JP. Disability in Strategies of Care Study group. Stratified care vs step care strategies for migraine: the Disability in Strategies of Care (DISC) Study: a randomized trial. JAMA. 2000;284:2599– 2605. 14. Burstein R, Jakubowski M, Rauch SD. The science of migraine. J Vestib Res. 2011;21:305. 15. Bigal ME, Lipton RB. Concepts and mechanisms of migraine chronification. Headache. 2008;48:7–15. 16. Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology. 2008;71:1821–1828. 17. Scher AI, Midgette LA, Lipton RB. Risk factors for headache chronification. Headache. 2007;48:16–25. 18. Huang TC, Lai TH. Taiwan Headache Society TGSOTHS. Medical treatment guidelines for preventive treatment of migraine. Acta Neurol Taiwan. 2017;26:33–53. 19. Worthington I, Pringsheim T, Gawel MJ, Gladstone J, Cooper P, Dilli E, Aube M, Leroux E, Becker WJ. Canadian Headache Society Acute Migraine Treatment Guideline Development Group. Canadian Headache Society Guideline: acute drug therapy for migraine headache. Can J Neurol Sci. 2013;40:S1– S80. 20. Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, Sándor PS. European Federation of Neurological Societies. EFNS guideline on the drug treatment of migraine—revised report of an EFNS task force. Eur J Neurol. 2009;16:968–981. 21. Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, Silberstein S; American Academy of Neurology Quality Standards Subcommittee. Practice Committee of the Child Neurology Society. Practice parameter: pharmacological treatment of migraine headache in children and adolescents: report of the 482 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology. 2004;63:2215–2224. Snow V, Weiss K, Wall EM, Mottur-Pilson C; American Academy of Family Physicians; American College of Physicians-American Society of Internal Medicine. Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med. 2002;137:840–849. Pryse-Phillips WE, Dodick DW, Edmeads JG, Gawel MJ, Nelson RF, Purdy RA, Robinson G, Stirling D, Worthington I. Guidelines for the nonpharmacologic management of migraine in clinical practice. Can Headache Soc CMAJ. 1998;159:47–54. Young WB, Siow HC. Should butalbital-containing analgesics be banned? Yes. Curr Pain Headache Rep. 2002;6:151–155. Tfelt-Hansen PC, Diener HC. Why should American headache and migraine patients still be treated with butalbital-containing medicine? Headache. 2012;52:672–674. CE Marking. Available at: https://ec.europa.eu/growth/singlemarket/ce-marking/. Accessed April 4, 2020. Derry S, Moore RA, McQuay HJ. Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev. 2013;30:CD008040. Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther. 2005;12:46–55. Society for Maternal-Fetal Medicine (SMFM) Publications Committee. Prenatal acetaminophen use and outcomes in children. Am J Obstet Gynecol. 2017;216:B14–B15. Rabbie R, Derry S, Moore RA, McQuay HJ. Ibuprofen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev. 2010;10:CD008039. Suthisisang CC, Poolsup N, Suksomboon N, Lertpipopmetha V, Tepwitukgid B. Meta-analysis of the efficacy and safety of naproxen sodium in the acute treatment of migraine. Headache. 2010;50:808–818. Kirthi V, Derry S, Moore RA, McQuay HJ. Aspirin with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev. 2010;4:CD008041. Derry S, Rabbie R, Moore RA. Diclofenac with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev. 2013;4:CD008783. Law S, Derry S, Moore RA. Naproxen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev. 2013;10:CD009455. Lampl C, Voelker M, Diener HC. Efficacy and safety of 1,000 mg effervescent aspirin: individual patient data meta-analysis of three trials in migraine headache and migraine accompanying symptoms. J Neurol. 2007;254:705–712. Garnock-Jones KP. Diclofenac potassium powder for oral solution: a review of its use in patients with acute migraine. CNS Drugs. 2014;28:761–768. Rao AS, Gelaye B, Kurth T, Dash PD, Nitchie H, Peterlin BL. A randomized trial of ketorolac vs. Sumatriptan vs. Placebo nasal spray (KSPN) for acute migraine. Headache. 2016;56:331– 340. Lipton RB, Diener HC, Robbins MS, Garas SY, Patel K. Caffeine in the management of patients with headache. J Headache Pain. 2017;18:107. Fernández-Dueñas V, Sánchez S, Planas E, Poveda R. Adjuvant effect of caffeine on acetylsalicylic acid anti-nociception: prostaglandin E2 synthesis determination in carrageenaninduced peripheral inflammation in rat. Eur J Pain. 2008;12:157–163. Ho TW, Rodgers A, Bigal ME. Impact of recent prior opioid use on rizatriptan efficacy. A post hoc pooled analysis. Headache. 2009;49:395–403. Marmura MJ. Use of dopamine antagonists in treatment of migraine. Curr Treat Options Neurol. 2012;14:27–35. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36:995– 997. Vikelis M, Rapoport AM. New drug delivery options for migraine. Expert Rev Neurother. 2011;11:771–773. Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine 44. Available at: https://www.ema.europa.eu/en/documents/ referral/metoclopramide-article-31-referral-annex-iii_en-0.pdf. Accessed May 17, 2019. 45. Wells RE, Turner DP, Lee M, Bishop L, Strauss L. Managing migraine during pregnancy and lactation. Curr Neurol Neurosci Rep. 2016;16:40. 46. Colman I, Brown MD, Innes GD, Grafstein E, Roberts TE, Rowe BH. Parenteral metoclopramide for acute migraine: metaanalysis of randomised controlled trials. BMJ. 2004;329:1369–1373. 47. Azzopardi TD, Brooks NA. Oral metoclopramide as an adjunct to analgesics for the outpatient treatment of acute migraine. Ann Pharmacother. 2008;42:397–402. 48. Friedman BW, Esses D, Solorzano C, Dua N, Greenwald P, Radulescu R, Chang E, Hochberg M, Campbell C, Aghera A, Valentin T, Paternoster J, Bijur P, Lipton RB, Gallagher EJ. A randomized controlled trial of prochlorperazine versus metoclopramide for treatment of acute migraine. Ann Emerg Med. 2008;52:399–406. 49. Fiesseler FW, Shih R, Szucs P, Silverman ME, Eskin B, Clement M, Saxena R, Allegra J, Riggs RL, Majlesi N. Steroids for migraine headaches: a randomized double-blind, twoarmed, placebo-controlled trial. J Emerg Med. 2011;40:463– 468. 50. Woldeamanuel YW, Rapoport AM, Cowan RP. The place of corticosteroids in migraine attack management: a 65-year systematic review with pooled analysis and critical appraisal. Cephalalgia. 2015;35:996–1024. 51. Bercel NA. Treatment of migraine—results with dihydroergocornine methanesulfonate (DHO-180) and other ergot derivatives. CA Med. 1950;72:234–238. 52. Silberstein SD, Young WB. Safety and efficacy of ergotamine tartrate and dihydroergotamine in the treatment of migraine and status migrainosus. Working Panel of the Headache and Facial Pain Section of the American Academy of Neurology. Neurology. 1995;45:577–584. 53. Silberstein S. MAP0004: dihydroergotamine mesylate inhalation aerosol for acute treatment of migraine. Expert Opin Pharmacother. 2012;13:1961–1968. 54. Shrewsbury SB, Jeleva M, Satterly KH, Lickliter J, Hoekman J. STOP 101: a phase 1, randomized, open-label, comparative bioavailability study of INP104, dihydroergotamine mesylate (DHE) administered intranasally by a I123 precision olfactory delivery (POD) device, in healthy adult subjects. Headache. 2019;59:394–409. 55. Strom S, Kollins J, Albrecht D Comparison of the Pharmacokinetics of STS101, an Intranasal Dry Powder Formulation of Dihydroergotamine, with Other Intranasal, Injectable, and Oral Inhaled DHE Formulations. Presented at the 19th Congress of the International Headache Society; September 5–8, 2019; Dublin Leincter, Ireland. 56. Queiroz LP, Weeks R, Rapoport A, Sheftell F, Baskin S, Siegel S. Early and transient side effects of repetitive intravenous dihydroergotamine. Headache. 1996;36:291–294. 57. Humphrey PA. The discovery and development of the triptans, a major therapeutic breakthrough. Headache. 2008;48:685– 687. 58. Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, 5-HT1B/1D agonists) in migraine: detailed results and methods of a meta-analysis of 53 trials. Cephalalgia. 2002;22:633–658. 59. Pascual J, Falk RM, Piessens F, Prusinski A, Docekal P, Robert M, Ferrer P, Luria X, Segarra R, Zayas JM. Consistent efficacy and tolerability of almotriptan in the acute treatment of multiple migraine attacks: results of a large, randomized, double-blind, placebo-controlled study. Cephalalgia. 2000;20:588–596. 60. Goadsby PJ, Ferrari MD, Olesen J, Stovner LJ, Senard JM, Jackson NC, Poole PH. Eletriptan in acute migraine: a doubleblind, placebo-controlled comparison to sumatriptan. Eletriptan Steering Committee. Neurology. 2000;54:156–163. 61. Géraud G, Spierings EL, Keywood C. Tolerability and safety of frovatriptan with short- and long-term use for treatment of Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. migraine and in comparison with sumatriptan. Headache. 2002;42(suppl 2):S93–S99. Klassen A, Elkind A, Asgharnejad M, Webster C, Laurenza A. Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebocontrolled, parallel-group study. Naratriptan S2WA3001 Study Group. Headache. 1997;37:640–645. Block GA, Goldstein J, Polis A, Reines SA, Smith ME. Efficacy and safety of rizatriptan versus standard care during long-term treatment for migraine. Rizatriptan Multicenter Study Groups. Headache. 1998;38:764–771. The Subcutaneous Sumatriptan International Study Group. Treatment of migraine attacks with sumatriptan. N Engl J Med. 1991;325:316–321. Tepper SJ, Chen S, Reidenbach F, Rapoport AM. Intranasal zolmitriptan for the treatment of acute migraine. Headache. 2013;53(suppl 2):62–71. Lipton RB, Munjal S, Brand-Schieber E, Rapoport AM. DFN-02, sumatriptan 10 mg nasal spray with permeation enhancer, for the acute treatment of migraine: a randomized, double-blind, placebo-controlled study assessing functional disability and subject satisfaction with treatment. CNS Drugs. 2019;33:375–382. Kellerman DJ, Ameri M, Tepper SJ. Rapid systemic delivery of zolmitriptan using an adhesive dermally applied microarray. Pain Manag. 2017;7:559–567. Available at: http://ir.zosanopharma.com/news-releases/ news-release-details/zosano-announces-fda-submission-newdrug-application-qtrypta. Accessed January 23, 2020. MaassenVanDenBrink A, Reekers M, Bax WA, Ferrari MD, Saxena PR. Coronary side-effect potential of current and prospective antimigraine drugs. Circulation. 1998;98:25–30. Syed YY. Sumatriptan/naproxen sodium: a review in migraine. Drugs. 2016;76:111–121. Raffaelli B, Israel H, Neeb L, Reuter U. The safety and efficacy of the 5-HT 1F receptor agonist lasmiditan in the acute treatment of migraine. Expert Opin Pharmacother. 2017;18:1409–1415. Loo LS, Ailani J, Schim J, Baygani S, Hundemer HP, Port M, Krege JH. Efficacy and safety of lasmiditan in patients using concomitant migraine preventive medications: findings from SAMURAI and SPARTAN, two randomized phase 3 trials. J Headache Pain. 2019;20:84. Kuca B, Silberstein SD, Wietecha L, Berg PH, Dozier G, Lipton RB; COL MIG-301 Study Group. Lasmiditan is an effective acute treatment for migraine: a phase 3 randomized study. Neurology. 2018;91:e2222–e2232. Available at: https://www.fda.gov/news-events/pressannouncements/fda-approves-new-treatment-patientsmigraine. Accessed October 28, 2019. Dodick DW. CGRP ligand and receptor monoclonal antibodies for migraine prevention: evidence review and clinical implications. Cephalalgia. 2019;39:445–458. Dodick DW, Lipton RB, Ailani J, Lu K, Finnegan M, Trugman JM, Szegedi A. Ubrogepant for the treatment of migraine. N Engl J Med. 2019;381:2230–2241. Croop R, Goadsby PJ, Stock DA, Conway CM, Forshaw M, Stock EG, Coric V, Lipton RB. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebocontrolled trial. Lancet. 2019;394:737–745. Holland PR, Goadsby PJ. Targeted CGRP small molecule antagonists for acute migraine therapy. Neurotherapeutics. 2018;2:304–312. Chou DE, Shnayderman Yugrakh M, Winegarner D, Rowe V, Kuruvilla D, Schoenen J. Acute migraine therapy with external trigeminal neurostimulation (ACME): a randomized controlled trial. Cephalalgia. 2019;39:3–14. Reed KL, Black SB, Banta CJ, Will KR. Combined occipital and supraorbital neurostimulation for the treatment of chronic migraine headaches: initial experience. Cephalalgia. 2010;30:260–271. 483 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2019 Encore: Migraine 81. Theranica Announces Results From Pivotal Study of Device for Treating Acute Migraine Press Release. Scottsdale, AZ; Theranica Bio-Electronics, 2018. Available at: prnewswire.com/news-releases/ theranica-announces-results-from-pivotal-study-of-device-for-treatingacute-migraine-832012898.html. Accessed May 17, 2019. 82. Starling AJ, Tepper SJ, Marmura MJ, Shamim EA, Robbins MS, Hindiyeh N, Charles AC, Goadsby PJ, Lipton RB, Silberstein SD, Gelfand AA, Chiacchierini RP, Dodick DW. A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study). Cephalalgia. 2018;38:1038–1048. 83. Lipton RB, Dodick DW, Silberstein SD, Saper JR, Aurora SK, Pearlman SH, Fischell RE, Ruppel PL, Goadsby PJ. Single-pulse transcranial magnetic stimulation for acute treatment of migraine with aura: a randomised, double-blind, parallel-group, sham-controlled trial. Lancet Neurol. 2010;9:373–380. 484 84. Tassorelli C, Grazzi L, de Tommaso M, Pierangeli G, Martelletti P, Rainero I, Dorlas S, Geppetti P, Ambrosini A, Sarchielli P, Liebler E, Barbanti P; PRESTO Study Group. Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study. Neurology. 2018;91:e364–e373. 85. Richer L, Billinghurst L, Linsdell MA, Russell K, Vandermeer B, Crumley ET, Durec T, Klassen TP, Hartling L. Drugs for the acute treatment of migraine in children and adolescents. Cochrane Database Syst Rev. 2016;4:CD005220. 86. Oskoui M, Pringsheim T, Billinghurst L, Potrebic S, Gersz EM, Gloss D, Holler-Managan Y, Leininger E, Licking N, Mack K, Powers SW, Michael S, Cristina Victorio M, Yonker M, Zanitsch H, Hershey AD. Practice guideline update summary: pharmacologic treatment for pediatric migraine prevention. Neurology. 2019;93:500–509. Konstantinos et al: J Neuro-Ophthalmol 2020; 40: 472-484 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.