Evidence-Based Symptomatic Treatment of Migraine

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Chapter 13

Evidence-based symptomatic treatment of migraine

DIMOS D. MITSIKOSTAS¹*AND THOMAS N. WARD²

11st Neurology Department, Medical School, Aeginition Hospital, National and Kapodistrian University of Athens, Athens, Greece

2Department of Neurology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States

Abstract

Symptomatic treatment of migraine includes patient education, mainly to avoid medication overuse and known trigger factors, as well as pharmaceutical and nonpharmaceutical interventions. Disease-specific and mechanism-based agents include ergotamine and dihydroergotamine targeting the adrenergic, dopa- minergic, and serotoninergic systems followed by triptans, specific agonists for 5-HT1B/1D/1F receptors, the latest being more favorable in terms of safety and documentation of efficacy. Recently, antagonists of calcitonin gene-related peptide (gepants) and selective agonists of the 5-HT1F receptor (ditans) have been added, with promising efficacy and safety. Triptans stay as the first option treatment when attacks are moderate to severe, followed by nonspecific agents, including aspirin and paracetamol/acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs, ibuprofen and naproxen share the best documentation) for mild-to-moderate migraine attacks. Combinations with caffeine are effective as well, but barbiturates and opioids alone or in combinations should be avoided. Simple analgesics and NSAIDs attenuate cephalic pain via prostaglandin mediated mechanisms and may induce peptic, renal and hepatic adverse effects.

Neuromodulation techniques include single-pulse transcranial magnetic stimulation (s-TMS), external trigeminal nerve stimulation (e-TNS), remote electrical neuromodulation (REN) and noninvasive vagus nerve stimulation (nVNS). All share good documentation and safety profile and are worthy of alternative treatment options along with physical therapy when medicines are contradicted or not well tolerated or unwanted by the patients.

INTRODUCTION

Migraine is a chronic brain disease presenting with episodic attacks consisting of headache and accompanying symptoms causing temporal disability lasting for hours or days. The degree of disability varies interictally and interindividually. However, the patient often rests pain- fully and disabled, unable to function during the attack making its management crucial because of the substan- tial personal burden that also affects the family and the vocational environment. The armamentarium for managing the migraine attacks includes a variety of medicines while lastly, nonpharmaceutical approaches, mainly neuromodulation techniques, have been added. Notably,

migraine has been treated with disease-specific and mechanism-based agents for decades, unlike many other brain disorders. Additionally, new classes of antimigraine medicines have been added recently further increasing the therapeutic options. Beside the benefits, e.g., designing individual therapeutical approaches, the extensive range of symptomatic treatments raises pri- oritizing and other decision-making issues. The best evidence for the relative efficacy and safety of the symptomatic treatments comes from head-to-head randomized clinical trials (RCTs), but other clinical research is significant in this field. In the absence of these data, indi- rect comparisons by using various efficacy and safety

*Correspondence to: Dimos D. Mitsikostas, MD, PhD, FEAN, 1st Neurology Department, Aeginition Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece. Tel/Fax: +30-2107289282, E-mail: [email protected]

Migraine Management

J.W. Swanson and M. Matharu, Editors

https://doi.org/10.1016/B978-0-12-823357-3.00004-5

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metrics, or systematic meta-analyses, together with evidence-based or expert-opinion recommendations have been done (VanderPluym et al., 2021). This article aims to summarize all these data in order to help clinicians in decision-making after considering the individual patient’s preferences.Τhe available evidence for the efficacy and safety of the currently available symptomatic treatments for migraine, following an introduction on the mechanism of action for each one, will be presented.

TREATMENT STRATEGY

The principal goal of symptomatic migraine treatment is to lessen the severity of or, better, to terminate the headache and the associated symptoms and allow the patient to return to normal activities and function. In this context, therapeutic decision-making should be based on three axes: (i) the published clinical evidence for efficacy and safety; (ii) the patients’comorbidities and personal preferences; and (iii) the local/current treatment accessibility. An accurate diagnostic assessment following by detailed patient briefing related to the potential causes of migraine should precede. Regarding the first axis, the available efficacy and safety evidence comes from phase 3 randomized controlled trials (RCTs), meta- analyses and evidence-based recommendations, when available. Not all treatments share the same strength of the evidence, nor the same degree of efficacy/safety.

There are two approaches for the decision-making, stratified and individualized. When possible, individualized treatment suggestions for discussion with the patient may be preferable, resulting in improved outcomes and adherence (Seng et al., 2017). Patients prefer pills instead of injections for symptomatic treatment of migraine, or neuromodulation techniques when available and accessi- ble to avoid potential adverse effects (Mitsikostas et al., 2017). However, these preferences differ between patients, therefore the treating physician has to clarify the preferences of the particular individual, according to his/her lifestyle and personal choices. Previous expe- riences, negative or positive, comorbidities, the severity of migraine attacks, the duration of the condition, the gender of the patient and nocebo behaviors, all play significant roles (Mitsikostas et al., 2017). Regarding the third axis, accessibility, reimbursement and local regula- tory rules should be considered. Because the consistency of response to the treatment is low in symptomatic migraine treatment (McGinley et al., 2019), a rescue medication should always be suggested, preferably with a nonoral route of administration (e.g., subcutaneous, rectal, or nasal spray), because in the late phase of a migraine attack gastric paresis often occurs. Rescue treatment protects the migraineur from the progression of a

migraine attack from mild to a severe one and decreases the risk of visiting the emergency room significantly.

PATIENT EDUCATION

When it comes to managing headaches, the goals of the health care provider and the patient may not always align (Packard, 1979). Ascertaining what the patient wants may help with compliance and adherence. While health care providers may focus on headache pain relief, patients also want an explanation (education). They want reassurance that something ominous is not occurring, they want to understand the nature of their headaches and they want to participate in their care (shared decision making) (Mathew et al., 2014). While there are many sources of information for persons with migraine, most information initially comes from the prescriber’s office.

Patients also receive information from other sources including the pharmacy, peers and the internet.

Initially, the health care provider and the patient need to discuss patient preferences (including nonpharmacologic as well as pharmacologic options) and set reason- able expectations (Taylor, 2017). Stratified care should be utilized and therefore treatment individualized based on the features of the patient’s attack(s) (Lipton et al., 2000). A discussion should ensue regardingifan attack should be treated,whenthe attack should be treated and howthe attack should be treated. Options should be provided for a recurrence of the attack and a rescue plan should the initial options fail. Self-management is ideal (self-efficacy). Patients want to know common possible side effects (Mathew et al., 2014). They also should be informed as to the likely time course for symptom relief to begin and to come to full effect. They should also be warned about the need to avoid medication overuse headache (Lagman-Bartolome et al., 2018).

Increasingly, persons with migraine utilize the internet for both education and peer support. It is important for the health care provider to know what is being accessed. A variety of content is available on the internet, some that is not evidence-based and some which has commercial bias (VanderPluym et al., 2019). Much information is also simply incorrect and/or out of date. In addition to being reviewed for reliability and readability by the provider, there are many useful nonbiased sources of information about migraine including the American Migraine Foundation and the World Headache Alliance (Craven and Shannon, 2003).

PHARMACOLOGICAL TREATMENT There are several pharmacological symptomatic treatments for migraine, with varying quality of supporting evidence. The use of triptans, nonsteroidal antiinflammatory drugs, acetaminophen, dihydroergotamine, calcitonin

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gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments found to be associated with improved pain and function in a recent meta-analysis. The evidence for many other interventions, including opioids, was limited (VanderPluym et al., 2021). Recommenda- tions for treatment stratification, evaluation of treatment response, patients’adherence and management of treatment failures have been provided in a consensus article under the auspices of the European Headache Federation and the European Academy of Neurology (Eigenbrodt et al., 2021). Many of available acute treatments of migraine are disease-specific, whereas some others belong to other drug classes (e.g., analgesics or antiinflammatory agents).

Migraine-specific agents ERGOT ALKALOIDS

Ergotamine (ERG) and dihydroergotamine (DHE) along with methysergide are ergot alkaloids that have been used to treat migraines for decades. Methysergide has been used for prevention and ERG and DHE for acute treatment. They target a variety of receptors within the brain and other organs (Table 13.1), but their mechanism of action in migraine is mediated via their agonistic effect on receptors 5-HT1B and 5-HT1D within the trigeminovascular system, while their effects on other receptors may be responsible for the adverse effects they cause (Dahlof and MaassenVanDerBrink, 2012).

Ergotamine (ERG)is available in combination with caffeine (0.5 and 50 mg, respectively) in most countries either in oral formulations, or in a suppository form (1 and 100 mg, respectively) in some countries (Dahlof and MaassenVanDerBrink, 2012). The evidence for the efficacy of ERG is not consistent (seven RCTs showed favorable and three unfavorable results) and due to safety concerns its use is suggested for a limited number of migraine sufferers who have infrequent or long duration headaches and are likely to comply with dosing restric- tions (Tfelt-Hansen et al., 2000). Adverse events (AEs) of ERG include decrease of blood flow to the brain, heart, or extremities, that occasionally may cause severe complications (ergotism). Commonly reported AEs are nausea, vomiting, weakness, or coldness, numbness, or pain in the hands, feet, arms, or legs. In addition, ERG used to be one of the acute drugs most responsible for medication overuse headache (Tfelt-Hansen et al., 2000).

Dihydroergotamine (DHE).There is good evidence for efficacy in acute treatment of migraine for DHE, rated with level A quality for the nasal spray and level B for intramuscular, intravenous or subcutaneous administration, according to the American Headache Society (AHS) assessment (Marmura et al., 2015). Patients can be taught intramuscular or subcutaneous injection techniques to self-administer dihydroergotamine 1 mg subcutaneous (sc) dihydroergotamine has similar efficacy to 6 mg sc sumatriptan at 2 h with a lower headache recurrence rate at 24 h. A second 1 mg dose can be

Table 13.1

Pharmacological actions of ergot alkaloids

Receptor Location ERG DHE Methysergide SUMA

5-HT1A Brain, TVS +++ +++ ++ ++

5-HT1B Brain, TVS, coronary arteries +++ +++ ++ +++

5-HT1D Brain, TVS +++ +++ ++ +++

5-HT1F Brain, TVS + + ND ++

5-HT1E Brain, TVS + + ND +

5-HT2A Brain, TVS, platelets ND ++ + 0

5-HT2C Brain, PNS ND +++ + 0

alpha1A Brain, PNS ++ ++ 0 0

alpha1B Brain, PNS ++ ++ ND 0

alpha2B Brain, PNS ND +++ 0 0

alpha2C Brain, PNS ND +++ ND 0

D1 Brain, PNS ND ++ ND 0

D2 Brain, PNS +++ +++ ND 0

D3 Brain, PNS +++ ++ ND 0

D4 Brain, PNS +++ ++ ND 0

Adapted with changes from Dahlof C, MaassenVanDerBrink A (2012). Dihydroergotamine, ergotamine, methysergide and sumatriptan—basic science in relation to migraine treatment. Headache 52: 707–714.

Values for dihydroergotamine (DHE), ergotamine, and sumatriptan are affinity IC50(nM). Values for methysergide refer either to KDor K1values.

Values for ND¼not determined. +++, ++, + and 0 indicate IC50 affinities (nM)<5 nM,>5 to<50 nM.>50 to<1500 nM, and>1500 nM, respectively.DHE: dihydroergotamine; SUMA: sumatriptan;ERG: ergotamine;PNS: peripheral nerve system;TVS: trigeminovascular system.

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administered at or after 2 h for headache persistence (Winner et al., 1996). There is no evidence for orally administered DHE. There are two Class I RCTs which tested DHE administered with a breath-synchronized inhaler for the symptomatic treatment of migraine. One tested two doses of DHE and the percentages of patients achieving pain free 2 h post treatment (2HPT) were 44%

(P¼0.15), 35% (P¼0.50) and 7% for DHE 0.5 mg, 1.0 mg and placebo respectively. The percentages of patients achieving headache relief 2HPT were 72%

(P¼0.19), 65% (P¼0.71) and 33%, respectively (Aurora et al., 2009). Another larger Class I phase 3, single-attack RCT compared inhaled DHE 1.0 mg with placebo. 28% of patients treated with DHE achieved pain freedom 2HPT vs 10% of those treated with placebo (P¼0.21). Headache relief 2HPT was experienced by 59% of patients treated with DHE vs 35% of those treated with placebo (P<0.0001). Sustained headache freedom 2–24 h was 23% vs 7%, respectively (P<0.001) (Aurora et al., 2009). Like ERG, DHE may induce decreased blood flow to the brain, heart, or extremities (Dahlof and MaassenVanDerBrink, 2012).

TRIPTANS

Triptans are selective agonists at three serotonin (5-hydroxytryptamine; 5-HT) receptor subtypes, the 5-HT1B, 5-HT1D, and 5-HT1F(Table 13.2) that are located within the trigeminovascular system (TVS) and the cranial and heart vascular smooth muscles (Dahl€of and MaassenVanDerBrink, 2012). Activation of these receptors deactivates the TVS (Mitsikostas et al., 1999) and inhibits calcitonin gene-related peptide (CGRP) release from the peripheral and central nerve endings of the TVS (Durham and Russo, 1999). At marketed doses,

all oral triptans are effective and well-tolerated. Seven triptans are clinically available in most countries currently with different pharmacokinetic, receptor affinity and clinical efficacy. According to a meta-analysis, among the oral formulations of triptans, 10 mg rizatriptan, 80 mg eletriptan, and 12.5 mg almotriptan provide the highest likelihood of consistent success (Ferrari et al., 2001). Sub- sequent meta-analyses confirmed that eletriptan 40 mg is the most efficient triptan for the acute migraine treatment (Mullins et al., 2005;Cameron et al., 2015) (Fig. 13.1).

NSAIDs may be combined with triptans for possible better efficacy. For example, the pharmacologic combination of sumatriptan and naproxen sodium may allow for a more rapid onset of peak sumatriptan concentration with a more prolonged duration of action of naproxen (Haberer et al., 2010).

Sumatriptan. A variety of sumatriptan formulations are available, including tablets 25, 50, and 100 mg, nasal spray, iontophoretic patch and sumatriptan injection 4 and 6 mg. Two large Class I pooled studies (Sheftell et al., 2005) with a total of 2696 patients showed that sumatriptan 100 and 50 mg decreased headache as early as 20- and 30-min posttreatment, respectively. 2HPT pain-free rates were 47% and 40% (placebo 15%, P<0.01), respectively. Drug-related AEs included nausea (3% sumatriptan 100 mg, 2% sumatriptan 50 mg, 1%

placebo) and paresthesias (3% sumatriptan 100 mg, 1%

sumatriptan 50 mg,<1% placebo). A Class I RCT compared the effectiveness of intranasal sumatriptan 20 and 10 mg with placebo (Djupesland et al., 2010). 2HPT pain-free rates were 57%, 54%, and 25%, respectively (P<0.05). Iontophoretic patch formulation of sumatriptan (6.5 mg transdermal with delivery over 4 h) showed 2HPT 18% vs 9% for placebo (Goldstein et al., 2012) (this delivery system has been withdrawn from the

Table 13.2

Pharmacological properties of triptans and ditans

Agent

5-HT1B

(pEC₅₀)^a

5-HT1D

(pEC₅₀)

5-HT1F

(pCE₅₀)

Lipophilicity (logD)^b

T1/2

(hours)

Tmax

(hours)

Sumatriptan 7 8.3 7.9 1.3 2.5 2–2.5

Rizatriptan 7 8.4 6.8 0.7 2–2.5 1–1.5

Eletriptan 8 9.2 8 +0.5 3.6–5.5 1–2

Zolmitriptan 8 8.9 7.2 1.0 2–3 1.5–2

Naratriptan 8 8.7 8.2 0.2 6 2–3

Almotriptan 7 7.7 7.8 +0.3 3.6 2.5

Frovatriptan 7.9 8.3 7.1 1.0 26 2–4

Lasmiditan <5 6.6 8.4 >+ 0.5 5.7 1.8

Modified from Rubio-Beltran E et al. (2019) Characterization of binding, functional activity, and contractile responses of the selective 5-HT1F receptor agonist Lasmiditan. Br J Pharmacol 176: 4681–4695.

aCompounds with higher pEC50 values have higher affinity for the particular receptor.

bCompounds with values higher than1 are considered to be able to cross the brain blood barrier.

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market due to dermatologic adverse effects). Sumatriptan 6 and 4 mg subcutaneously administered showed pain- free 2HPT rates 12% vs 2% for placebo and 70% vs 22% (P<0.001), respectively. AEs at 6 mg included injection site reaction (21% vs 4% for placebo), feeling of heaviness (5% vs 0%) and pressure sensation (5%

vs 1%) (Subcutaneous Sumatriptan International Study Group, 1991;Wendt et al., 2006). Safety and tolerability profiles improve significantly by dose, that is why a new subcutaneous formulation with 3 mg of sumatriptan is been testing currently (Landy et al., 2018) A meta- analysis revealed that subcutaneous sumatriptan 6 mg is the most efficient acute treatment of migraine (Hou et al., 2019).

Eletriptan.Eletriptan showed superiority against placebo for 20, 40, and 80 mg doses in one class I RCT. Sub- jects who received 20, 40, and 80 mg showed 2HPT pain-free rates of 4%, 27%, and 27% vs 4% rate of placebo treated patients (P<0.01) (Eletriptan Steering Committee, 2002). Additionally, eletriptan was effective in patients with a poor response to sumatriptan (Farkkila

et al., 2003). Its safety profile is good. Few adverse events occurred with incidence10% on eletriptan 40 mg (asthenia, 5.0%) or eletriptan 80 mg (asthenia, 10%; nausea, 5.8%). Discontinuations because of adverse events were 0.2% on eletriptan 40 mg, and 1.6% on eletriptan 80 mg (Almas et al., 2014). Apart from Ferrari’s meta-analysis (Ferrari et al., 2001), a recent network meta-analysis showed that eletriptan may be the most suitable therapy for migraine from a comprehensive point of view (e.g., synthesizing several efficacy and safety outcomes) (Xu et al., 2016).

Rizatriptan. Rizatriptan is available in oral dissolvable tablets and oral swallowed tablets. It is rapidly absorbed. Oral tablets of 5 and 10 mg rizatriptan were tested in a Class I RCT and found significantly more effective than placebo (P<0.05) for pain-free 2HPT (36%, 4% and 14% respectively) (Teall et al., 1998).

Another Class I RCT compared rizatriptan oral swallowed tablets, 5 and 10 mg vs placebo. Pain-free 2HPT rates were 35%, 42%, and 10% (P<0.01) (Ahrens et al., 1999). Rizatriptan was effective in patients with Fig. 13.1. Triptan efficacy according to two independent meta-analyses (A:Cameron et al., 2015; B:Mullins et al., 2005).

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a poor response to 100 mg sumatriptan, with pain-free 2HPT rates of 22% vs 12% for placebo (P<0.001) (Seeburger et al., 2011). Furthermore, rizatriptan was significantly more effective than placebo in the treatment of menstrually-related migraine attacks (Mannix et al., 2007). Adverse events included dry mouth, fatigue, and dizziness (<5%) (Mannix et al., 2007).

Zolmitriptan.Zolmitriptan is available in oral dissolvable tablets of 5 and 2.5 mg, in nasal spray of 5 mg and in orally disintegrating tablets of 2.5 mg. In a Class I RCT treatment with zolmitriptan 2.5 mg oral dissolvable tablets had a pain-free 2HPT rate of 40% vs 20% for placebo (P<0.001). Notably, at 60 and 90 min post treatment, headache-free rates were 13% and 25% vs 8% and 15% for placebo, indicating an early efficacy for zolmitriptan (Loder et al., 2005). In the REALIZE study (a class I RCT) zolmitriptan nasal spray 5 mg was superior to placebo early after treatment. The 2HPT pain-free rate was 37.7% for zolmitriptan vs 9% for placebo (P0.0001). Notably, 30- and 60-min post treatment pain-free rates were and 7.7% vs 3.2% (P<0.01) and 17.3% vs 5.8% (P<0.0001), respectively. Total symptom relief including headache and accompanying symptoms was significantly higher than placebo even at 15 min post treatment. The most common AEs recorded were dysgeusia (15.9%), nasal irritation (6.3%), dizziness (6.0%) and fatigue (5.2%) (Gawel et al., 2005).

The zolmitriptan orally disintegrating tablet was also significantly more effective than placebo for 1-, 2- and 4-h pain-free response (8% vs 3%,P¼0.0207, 27% vs

7%,P<0.0001, and 37% vs 11%,p<0.0001, respec-

tively) (Dowson et al., 2002).

Almotriptan.This triptan along with naratriptan and frovatriptan is a second-generation triptan and has longer half-life than the previous ones, resulting in lower recurrence ratio (Geraud et al., 2003;Evers et al., 2009). Early treatment with 12.5 mg oral almotriptan (within 1 h from headache onset) results in a 2HPT pain-free rate of 53%

vs 25% for placebo. Adverse events were low (<5%) with no difference between active drug and placebo (Goadsby et al., 2008). 47.5% of nonresponders to sumatriptan treated with 12.5 mg almotriptan became pain-free 2HPT vs 23.2% of placebo treated patients (P<0.05) (Diener et al., 2005).

Frovatriptan.In all trials, 2.5 mg frovatriptan recipients were significantly more likely to be pain-free 2HPT (9%–19%) than placebo recipients (2%–6%) (Sanford, 2012). Moreover, frovatriptan showed reduced recurrence rates over 48 h post treatment vs rizatriptan, zolmitriptan, and almotriptan (Allais and Chiara Benedetto, 2016). It seems that frovatriptan is also efficacious when taken during the headache phase in migraine attacks with aura (Evers et al., 2015). The most frequent AEs occurring at a frequency1% higher in frovatriptan than placebo

treated patients were dizziness, fatigue, headache, paraes- thesia, flushing, skeletal pain, hot or cold sensation, dry mouth, chest pain and dyspepsia (Sanford, 2012).

Naratriptan.A meta-analysis showed that pooled rate ratio relative to placebo for pain-free 2HPT of 2.5 mg naratriptan was 2.52 (Ashcroft and Millson, 2004). In addition, there is evidence that naratriptan 2.5 mg is effective in menstrually-related migraine (Massiou et al., 2005). It seems that naratriptan is less effective than rizatriptan 10 mg or sumatriptan 100 mg, but had fewer adverse events. Although rare, the most common AEs included malaise, fatigue, nausea, sleepiness and dizziness. (Ashcroft and Millson, 2004).

G^EPANTS

Calcitonin gene-related protein (GCRP) is the most evalu- ated target for migraine treatment (Charles and Pozo- Rosich, 2019). CGRP is released in parallel with pain and successful treatment of migraine attacks aborts both the associated pain and the CGRP release. The first CGRP receptor antagonist BIBN 4096 BS showed efficacy in aborting migraine leading to the development of a new oral drug class, the gepants, a disease-specific and mechanism- based treatment for migraine (Olesen et al., 2004). Unlike BIBN 4096 BS, gepants are small molecules that bind with high affinity to CGRP receptors preventing the interaction between CGRP and its receptor (Negro and Martelletti, 2019). In four different studies (one in animals, two in iso- lated human vessels and one in healthy volunteers), CGRP receptor antagonists did not cause vasoconstriction, offer- ing advantages over the current mainstay of specific acute migraine treatment, but penetrate the brain–blood-barrier causing AEs related to central nervous system functions (Negro and Martelletti, 2019). First generation gepants, although effective in aborting migraine attacks, failed reach the market due to hepatotoxicity. Subsequently, several CGRP receptor antagonists were developed and are under investigation (second generation gepants), but only two are currently approved by the FDA for the acute treatment of migraine. Generally, gepants are suggested for those who failed treatment on triptans or for whom a gepant will be added as an alternative to the patient’s triptan reg- imen, those who are unable to tolerate triptans and those with significant cardiac or cerebrovascular risk factors.

Ubrogepant.This gepant, is the first-in-class, approved by the FDA for the acute treatment of migraine with or without aura in adults in December 2019. The drug has been tested in two large scale class I RCTs. In the ACHIEVE1 trial, the percentage of participants who treated with ubrogepant 50 and 100 mg and had freedom from pain 2HPT was 19.2% and 21.2% vs 11.8% in the placebo group (P<0.002). Adverse events within 48 h after the initial or optional second dose were reported in 9.4%,

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16.3% and 12.8% of participants, respectively. The most common AEs were nausea, somnolence, and dry mouth (reported in 0.4%–4.1%); these AEs were more frequent in the 100 mg ubrogepant group (reported in 2.1%–

4.1%). Serious AEs reported within 30 days in the ubrogepant groups included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none of the AEs occurred within 48 h after the dose (Dodick et al., 2019). In the ACHIEVE2 trial, pain freedom 2HPT was reported by 21.8% in the ubrogepant 50 mg group, 20.7% in the ubrogepant 25 mg group, and 14.3% in the placebo group (P<0.03). Absence of the most bothersome associated symptom 2HPT was reported by 38.9%, 34.1% and 27.4%, respectively. The most common AEs events within 48 h of any dose were nausea 2.0%; 2.5%

and 2.0%) and dizziness (1.4%, 2.1% and 1.6%) (Lipton et al., 2019a,b,c).

Rimegepant.This is the second gepant which was FDA approved in February 2020 for abortive use in patients with migraine, after the publication of two class I RCTs.

In the first one, the percentage of patients who were pain-free 2 HPTwas 19.6% in the rimegepant 75 mg group and 12.0% in the placebo group (P<0.001). The percentage of patients who were free from their most bothersome symptom 2HPT was 37.6% and 25.2% respectively (P<0.001). The most common AEs were nausea (1.8%

vs 1.1%) and urinary tract infection (1.5% vs 1.1%) (Lipton et al., 2019a,b,c). In the second class I RCT, rimegepant 75 mg orally disintegrating tablet was superior to placebo for freedom from pain 2HPT (21% vs 11%, P<0.0001) and freedom from the most bothersome symptom (35% vs 27%,P¼0.0009). The most common AEs were nausea (2% vs 1%) and urinary tract infection (1% vs 1%). One participant in each treatment group had a transaminase concentration of more than 3the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2the upper limit of normal were reported. Treated participants reported no serious AEs (Croop et al., 2019). In addition to the lack of vasoconstriction effects, one recent animal study suggests that gepants may pose a lower risk for medication overuse headache compared to triptans and ditans (Saengjaroentham et al., 2020), but this remains to be proven in a clinical setting.

D^ITANS

As stated above, all triptans, bind with high affinity to 5-HT1B, 5-HT1D, and 5-HT1F receptors (Table 13.2).

The 5-HT1B receptor is localized within the TVS and the vascular smooth muscles. This vascular distribution of 5-HT1Breceptor has been shown to mediate the vasoconstrictive properties of the triptans, responsible for potential cardiac AEs. Activation of the 5-HT1Dsubtype,

although effective in animal models of migraine, was unable to attenuate migraine attacks in clinical trials.

The 5-HT1Freceptor is located both in vessels and within the TVS, but with the difference that the 5-HT1Freceptor lacks vasoconstrictive properties, thus making it an attractive target for new antimigraine drugs (Mitsikostas and Tfelt-Hansen, 2012). Indeed, animal studies showed that activation of 5-HT1Finhibits the activation of the TVS (Mitsikostas et al., 1999, 2002). Thus the 5-HT1F

receptor represents an ideal target for antimigraine drugs (Mitsikostas and Tfelt-Hansen, 2012). Based on these assumptions a new drug class, the ditans, is being developed to target the 5-HT1F receptor to provide acute treatment without vasoconstrictive effects. As with the gepants, the first generation of ditans, although effective in aborting migraine attacks failed to reach the market because of hepatotoxicity (Tfelt-Hansen et al., 2014).

Lasmiditanis an oral, centrally-penetrant second generation ditan, that has been approved by the FDA (October 2019) for the acute treatment of migraine. Two class I RCTs tested the efficacy and safety of lasmiditan (SPARTAN and SAMURAI trials). In the SPARTAN study, lasmiditan 50, 100, and 200 mg was associated with significantly more pain freedom 2HPT (28.6%, 31.4%, and 38.8%, vs placebo 21.3%) and freedom from the most bothersome symptom 2HPT (40.8%, 44.2% and 48.7%, vs placebo 33.5%, P¼0.009). Treatment- emergent AEs were reported by 25.4%, 36.1%, and 39.0% respectively, vs 11.6% on placebo. Most AEs were CNS-related and included dizziness (8.6%, 18.1% and 18% vs 2.5% respectively), somnolence (5.4%, 4.6% and 6.5% vs 2%, respectively) and paraes- thesia (2.4%, 5.8% and 6.6% vs 0.9%, respectively) (Goadsby et al., 2019). In the SAMURAI trial, lasmiditan 100 and 200 mg induced freedom from pain and most bothersome symptoms 2HPT at 28.2% and 32.2% vs 15.3% for placebo and 40.9% and 40.7% vs 29.5%

for placebo, respectively. Superiority over placebo (P<0.05) was noted after 1 h in the lasmiditan 200 mg group and after 1.5 h in the lasmiditan 100 mg group. Treatment-emergent AEs after the first dose of lasmiditan were experienced by 36.3% and 42.7% vs 16.4%, respectively. Again the most common AEs were dizziness (12.5% and 16.3% vs 3.4%), paresthesia (5.7%

and 7.9% vs 2.1%) and somnolence (5.7% and 5.4% vs 2.3%) (Kuca et al., 2018). In an interim analysis of another long-term safety trial (GLADIATOR), lasmiditan 100 and 200 mg resulted in freedom from pain and most bothersome symptoms 2HPT at 28.9% and 32.8% and 41.1% and 43.1% of participants, respectively (no data for the placebo arm have been published so far). The most common AEs included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%).

The frequency of treatment-emergent AEs generally

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decreased with subsequent attacks. No treatment-related serious AEs and no cardiovascular treatment-emergent AEs potentially due to vasoconstriction were observed (Brandes et al., 2019). Patients are cautioned not to drive for 8 h after using lasmiditan and it is indicated for only one dose per day. Lasmiditan is suggested for those who do not respond to gepants and it may be the treatment of choice particularly for people who have migraine at night that interferes with sleep, irrespective of the presence of cardiovascular factors.

Nonmigraine-specific agents A^SPIRIN

Acetylsalicylic acid (ASA) is one of the most used analgesics to treat an acute migraine attack. ASA is a common analgesic, antipyretic and antiinflammatory medication that shows good efficacy in aborting migraine attacks at an oral dose of 1 g. In addition to the inhibitory effects on peripheral prostaglandin synthesis, modulation of pain processing centrally may also be involved (Kroger and May, 2014). The evidence for efficacy in migraine is level A. In a meta-analysis of all RCTs, ASA 1000 mg is an effective treatment for acute migraine headaches, similar to sumatriptan 50 or 100 mg. Addition of metoclopramide 10 mg improves relief of nausea and vomiting. Adverse events were mainly mild and transient, and were slightly more common with aspirin than placebo, but less common than with sumatriptan 100 mg (Kirthi et al., 2010, 2013).

Intravenous administration of ASA 1 g is also effective in acute migraine (Diener, 1999, see below).

P^ARACETAMOL(ACETAMINOPHEN)

Like aspirin, acetaminophen/paracetamol is among the most common medicines in use for migraine attack treatment, especially for those with mild-to-moderate severity, in particular. A meta-analysis of all RCTs with acetaminophen/paracetamol revealed that paracetamol 1000 mg alone is statistically superior to placebo in the treatment of acute migraine, but the efficacy was weak (pain-free 2HPT 19% for paracetamol 1 g vs 10% for placebo). The safety profile of paracetamol does not differ from placebo, however. Given the low cost and wide avail- ability of paracetamol, it may be a useful first choice drug for acute migraine in those with contraindications to, or who cannot tolerate, nonsteroidal antiinflammatory drugs (NSAIDs) or aspirin. Notably, the addition of 10 mg metoclopramide gives short-term efficacy equivalent to oral sumatriptan 100 mg (Derry and Moore, 2013).

NSAIDS

Nonsteroidal antiinflammatory drugs represent the most widely used drug class in acute treatment of migraine.

NSAIDs alleviate inflammation and pain by blocking the action of cyclooxygenase and subsequently reducing the production of prostaglandins. The most significant AEs that limit their use include peptic ulcer or renal disease as well as increasing the risk of cardiovascular disease. Naproxen, diclofenac and ibuprofen are the NSAIDs with best evidence for efficacy. In a meta- analysis of RCTs, treatment of moderate to severe migraine attacks withnaproxen500 or 850 mg showed a 17% pain free 2HPT response, vs 8.5% for placebo.

The proportion of participants experiencing one or more AEs with oral naproxen 500/825 mg was 15% vs 12% for placebo. Notably, there was no significant difference between naproxen 500 mg and placebo for participants with at least one AE and there were no reported serious AEs related to naproxen (Law et al., 2013). In another meta-analysis of RCTs for the acute migraine treatment, the proportion of attacks pain-free at 2HPT with oral diclofenac 50 mg was 22% vs 11% for placebo, while the proportion of attacks experiencing at least one AE with diclofenac was 18%, vs 16% for placebo. No serious AEs were reported in any of the included studies (Derry et al., 2012). The proportion of patients treated withibu- profen200, 400, or 600 mg with pain free response 2HPT was 20% vs 10% for placebo, 26% vs 12%, and 29% vs 13%, respectively. The proportion of participants experiencing any AE with ibuprofen 200 or 400 mg was 22% vs 28% for placebo, and 15% vs 19% respectively. Rates of specific AEs, such as nausea, abdominal pain, dyspepsia, dizziness and somnolence, were below 5% (Rabbie et al., 2013).Tolfenamic acid, another potent inhibitor of prostaglandin biosynthesis and an inhibitor of leukotriene synthesis, is a well-documented and effective drug for symptomatic treatment of migraine. In a class I RCT with three parallel arms (tolfenamic vs placebo vs sumatriptan) which included treatment of two consecutive migraine attacks, 37% of participants received tolfenamic acid 200 mg, experienced pain freedom 2HPT at the first attack and 16% at the second treated migraine attack, vs 7% and 11% of participants treated with placebo and 50% and 26% of participants treated with sumatriptan 100 mg, respectively, while 26% of participants treated with tolfenamic acid experienced at least one AE (tachycardia, chest pressure or pain, dysuria) vs 19% of participants treated with placebo and 38% of participants treated with sumatriptan (Myllyla et al., 1998). Oral ketoprofen 75 mg and 150 mg is also effective in acute treatment of migraine, a class I RCT showed. 26.6% and 31.1% of participants showed pain free 2HPT vs 12.2% or 36.1% for the participants treated with placebo or zolmitriptan 2.5 mg.

Migraine recurred in 23%, 21.6%, 26.2% and 20.7%

of cases, respectively. The proportion of participants resenting any AE was 6%, 10.6%, 9.1% and 15.7%,

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respectively (Dib et al., 2002). Specific cyclooxygenase 2 (COX2) inhibitors, such as valdecoxib and rofecoxib, share evidence for efficacy in acute treatment of migraine.Valdecoxib20 and 40 mg did not reach significant difference vs placebo for the proportion of participants experienced pain free 2HPT, but the primary endpoint in this trial was the headache relief 2HPT, which reached significant difference over placebo (Kudrow et al., 2005). Sumatriptan 50 mg was an active comparator. AEs that occurred at an incidence >2%

were reported by 29.3%, 24.1%, 28.2% and 31.9% of participants treated with placebo, valdecoxib 20 mg, 40 mg, and sumatriptan 50 mg, respectively. The most common AEs included dizziness, somnolence and fatigue (Kudrow et al., 2005). In another RCT 124 patients were randomized intorofecoxib25 mg, ibuprofen 400 mg, and placebo groups. Pain relief 2HPT was achieved by 45.5%, 55.6% and 9.1%, respectively.

No AEs were reported by the tested drug treated participants, whereas five patients in the ibuprofen group experienced abdominal pain, which was severe in one (Mirsa et al., 2004). GW406381, another COX2 inhibitor, was effective in a class I RCT for the acute treatment of migraine, but the medication is not available in the market (Wentz et al., 2008). Of note, both rofecoxib and valdecoxib have been withdrawn from the market due to cardiovascular risk concerns.

C^AFFEINE

Caffeine alone or in combination with other antimigraine medications has been in worldwide use by patients with migraine for decades. The effects of caffeine—a purine alkaloid—on nociception are primarily attributed to its nonselective antagonism of the adenosine A1, A2A, and A2Breceptors and its slightly lower-affinity antagonism for the adenosine A3receptor. Adenosine induces vasodilation via A2Aand A2Breceptors. To limit increased antagonism of these receptors and vasodilation in chronic caffeine users, adenosine receptors are upregu- lated resulting in vasoconstrictive effects (Lipton et al., 2017). In a recent review caffeine was found to enhance the efficacy of aspirin and acetaminophen at a dose of

>100 mg. In three class I RCTs that randomized a total of 1220 patients with migraine, excluding subjects who vomited more than 20% of the time or who usually required bed rest, a combination of aspirin 500 mg, acetaminophen 500 mg, and caffeine 130 mg reached a pain-free 2HPT response in 21% of participants vs 7% for placebo treated (Lipton et al., 1998). The most commonly reported treatment-emergent AEs were nervousness (6.5%), nausea (4.3%), abdominal pain/

discomfort (4.1%), and dizziness (3.2%) (Lipton et al., 2017).

ANTIEMETICS

The oral antiemetics metoclopramide and prochlorpera- zine can be used as supplements to analgesics in order to improve nausea and gastroparesis associated with migraine attacks (Kirthi et al., 2010, 2013; Cooper et al., 2020). In addition, there is evidence that parental metoclopramide significantly contributes to migraine pain relief (odds ratio 2.84 over placebo, 95% CI 1–7.7) (Colman et al., 2004). Domperidone alone, or in combination with acetaminophen, also shares evidence for efficacy in the symptomatic treatment of migraine (MacGregor et al., 1993). Other phenothiazines are also effective for acute migraine treatment and in use in the emergency department (Kelly et al., 2009) (see below). These agents may cause extrapyramidal side effects such as dystonic reactions and akathisia.

Other medicinal treatments

Isometheptene, a symptomatic amine, is used in combination with acetaminophen for the symptomatic treatment of migraine, like antihistamine drugs. The evidence is rather good, but the trials are old, when migraine diagnostic criteria were less rigorous (Ryan, 1974;Diamond, 1976;

Hakkarainen et al., 1978). Intranasal lidocaine (4% solu- tion) was superior in symptomatic treatment of migraine with a 50% reduction in headache pain 15 min post treatment 55% vs 21% for placebo treated participants (Maizels et al., 1996), but a recent trial was negative (Avcu et al., 2017). The use of glucocorticoid agents in the emergency department for acute migraine treatment remains controversial (see below).

What to avoid

Briefly, there are two categories of medications to avoid in the acute treatment of migraine, opioids/opiates and barbiturates. “Opiates” are those agents derived from the naturally occurring alkaloids (from opium), while

“opioids”refers to related semisynthetic and synthetic agents (Levin, 2014). We shall use the term opioids to refer to both categories. The barbiturate we will discuss is butalbital. While most of this section discusses the evidence-based treatment options for acute migraine, there is a very strong evidence base for avoiding these two types of treatments.

The ICHD-III defines medication-overuse headache (MOH) as headache occurring on 15 or more days per month in a patient with a preexisting primary headache and developing as a consequence of regular overuse of acute or symptomatic headache medication (on 10 days per month for opioids or butalbital-containing combination analgesics) for >3 months (Headache Classification Committee of the International Headache

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Society, 2018). Briefly, in MOH increased use of acute medications generally results in increased headaches.

The barbiturate butalbital is found in several analgesic combination preparations (typically with acetaminophen, caffeine and aspirin). Butalbital has never been studied alone, but in combination with these other agents which are also implicated in MOH. It has been associated with birth defects including tetralogy of Fallot, pulmonary valve stenosis and secundum-type atrial septal defect (Browne et al., 2014). The American Migraine Prevalence and Pre- vention AMPP) study included data looking at the relative risk of medications causing “transformation” to MOH/

chronic migraine (migraine “chronification”). Butalbital had the highest risk, even higher than opioids. The risk occurred with only 5 days of monthly usage (Bigal et al., 2008). It has a short analgesic half-life (4–6 h) but a much longer elimination half-life (35–88 h) (Tepper, 2014). Some patients with anxiety may use it for its anxi- olytic effect. There is the potential for a severe withdrawal syndrome (prolonged delirium and/or withdrawal sei- zures). Overuse may occur also due to purchasing butalbital over the internet (Romero et al., 2004). Given these concerns, this medication is best avoided, especially for anyone who might become pregnant (Tepper, 2014).

When used for migraine attacks, opioids decrease signaling into the trigeminal nucleus caudalis without affecting the source of the migraine pain (Levin, 2014). They have many well-known effects including respiratory depression (potentially fatal), sedation/sleep, euphoria, anxiolysis, nausea/vomiting, and constipation.

Regular use can result in tolerance, dependence and addiction. Tolerance to the gastrointestinal and respiratory effects does not occur. From the AMMP study, it was noted that 17% of patients using opioids for migraine had evidence of dependence. Those using opioids had six times as much depression and disability and nine times as much emergency room use compared to those not on opioids (Buse et al., 2012). Opioids are also known to cause migraine chronification with the critical frequency of use being 8 days per month (Bigal et al., 2008). Use of opioids also renders the user less responsive to other acute migraine therapies (Ho et al., 2009).

Use of opioids for treating acute migraine attacks is associated with a high rate of recurrence once the imme- diate analgesic effect wears off (Kelley and Tepper, 2012). They are considered to cause a pronociceptive state, promoting ongoing central sensitization. There are no data from randomized controlled drug trials show- ing pain-free results when opioids are used for migraine treatment (Tepper, 2012). Given this information, an evidence-based determination can be made that opioids also should not be used to treat migraine.

Given this evidence-based information, the Choosing Wisely program advocates for only using opioids as a last

resort and not using either opioids or butalbital as first line agents for acute migraine treatment (Loder et al., 2013). These medications increase the risk of migraine chronification at any frequency of use and reduce the effectiveness of other acute treatments.

NONPHARMACOLOGICAL TREATMENT Neuromodulation

Neuromodulation is emerging as an exciting approach to migraine therapy, especially in the context of failure of commonly used medicines or for patients who do not tolerate common pharmacotherapy AEs (Puledda and Goadsby, 2017). Surprising, a significant proportion of migraineurs prefer to use neurostimulation, while others are unwilling to use pharmacological treatments (Mitsikostas et al., 2017). Notably, the FDA standards for approval of noninvasive devices differ from that for medications. Devices must show evidence of efficacy and safety, but the studies tend to be smaller and may or may not include a sham device (Miller et al., 2016).

On the other side of the Atlantic, the European Medicines Agency does not review data from trials with devices.

SINGLE-PULSE TRANSCRANIAL MAGNETIC STIMULATION

(^S-TMS)

There is good evidence that s-TMS is effective in symptomatic treatment of migraine with aura. TMS is capable of inducing an ionic current in the underlying cerebral cortex. It has been proven to change the firing pattern and excitability of cortical neurons with an effect depen- dent on the frequency of stimulation (Puledda and Goadsby, 2017). In a class I RCT 39% of participants treated with s-TMS reached pain freedom 2HPT vs 22% for those treated with sham stimulation. Sustained pain-free response rates significantly favored sTMS at 24 and 48 h posttreatment. No device-related serious AEs were recorded and the most common AEs (<2%) included headache and sinusitis without difference between treatment groups (Lipton et al., 2010). A later meta-analysis of studies with s-TMS in the acute treatment of migraine confirmed the results of the introduc- tory trial (Lan et al., 2017).

EXTERNAL TRIGEMINAL NERVE STIMULATION(^E-TNS) The use of supraorbital nerve stimulation with a device is FDA approved for both symptomatic and prophylactic treatment of migraine. The mode of action of e-TNS in migraine is not fully understood; it may have segmental

“gate control”mechanisms, as well as supra-segmental actions. Daily neurostimulation induces metabolic brain changes, but this has not been shown after a single stimulation (Magis et al., 2017). In one class I RCT, 1-h

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treatment with external trigeminal nerve stimulation resulted in significant headache pain relief for more than 50% and pain freedom 1HPT (63% and 29%) compared to sham stimulation (31% and 6%, respectively). The same outcomes 2HPT were not significantly superior to sham treated group (54% and 17% vs 41% and 7%, respectively). On the other hand, the primary endpoints of the study (the mean change in pain intensity at 1HPT compared to baseline) were improved significantly over the sham-treated participants. No serious AEs were reported and five minor AEs occurred in the verum group. In terms of minor AEs, three patients (two in the verum group and one in the sham group) were unable to tolerate the paresthesia sensation and the treatment was stopped before proceeding to the full stimulation phase. Four patients (three in the verum group and one in the sham group) discontinued treatment before the end of the full stimulation hour (Chou et al., 2018).

NONINVASIVE VAGUS NERVE STIMULATION(NVNS) Noninvasive vagus nerve stimulation is another neuromodulation technique approved by FDA for both symptomatic and preventative treatment of migraine. In one class I RCT (the PRESTIO study) 248 participants with episodic migraine with/without aura were randomized to receive nVNS or sham within 20 min from pain onset.

nVNS (n¼120) was superior to sham (n¼123) for pain freedom at 30 min (12.7% vs 4.2%; P¼0.012) and 60 min (21.0% vs 10.0%; P¼0.023) but not at 120 min (30.4% vs 19.7%;P¼0.067; primary endpoint) after the first treated attack. The most common AEs were application site discomfort and nasopharyngitis in the nVNS group and application site erythema and pain, dizziness, flu-like symptoms, and nasopharyngitis among controls. Participants reported no SAEs during the study.

Only 2 participants, both controls, discontinued from the study due to AEs (Tassorelli et al., 2018). Results during the open-label period after the double-blind PRESTO trial were consistent with those of the nVNS group during the double-blind period. The incidence of AEs and adverse device effects was low across all study periods, and no serious AEs occurred (Martelletti et al., 2018).

There is additional evidence for efficacy of nVNS in symptomatic treatment of vestibular migraine (Beh and Friedman, 2019).

REMOTE ELECTRICAL NEUROMODULATION(REN) Remote electrical neuromodulation is another noninvasive type of neuromodulation that utilizes a smartphone- controlled device which is applied to the upper arm and is believed to stimulate peripheral nerves with a percepti- ble but nonpainful sensation to cause conditioned pain modulation which results in pain inhibition in a remote

body region, in this case in the head. It has been hypoth- esized that REN activates the descending pain inhibition pathways in the brainstem. In a randomized, double-blind, sham-controlled multicenter trial involving 252 adult patients with migraine, pain relief at 2 h was achieved by 66.7% (vs 38.8% for sham) and pain freedom was achieved by 37.4% (vs 18.4% for sham). Most bothersome symptom relief at 2 h was 46.3% for the verum group vs 22% for sham. The superiority over sham was maintained to 48 h (20.7% vs 7.9% respectively).

Device-related AEs were 3.6% overall (4.8% verum vs 2.4%,P¼0.499). All AEs were mild and resolved within 24 h. The AEs were warm sensation, arm/hand numbness, redness, itching, tingling, muscle spasm and pain in the arm, shoulders and neck (Yarnitsky et al., 2019).

Physical therapy and behavioral techniques Physical or manipulative therapy, alone or in combination to pharmacological management is important for the prevention of migraine but it may have an effect as an acute treatment as well. Relaxation techniques include progressive muscle relaxation, autogenic training and meditation. Biofeedback training uses electronic devices to help the patient understand and monitor certain phys- iological processes associated with the experience of pain, such as muscle tension, blood pressure and heart rate changes. Cognitive behavioral therapy is a form of brief and symptom-oriented psychotherapy focused on managing stress (Silberstein, 2000; Puledda and Shields, 2018). Osteopathic manipulative treatment may be effective as well (Voigt et al., 2011). All these approaches may be helpful in acute migraine management, but they are lacking good evidence, they are not disease-specific, nor mechanism-based. When combined with pharmacological treatments they allow a certain degree of self-management, which can be advantageous for some patients, those they refuse to take medicines, or if they are displaying nocebo behaviors.

RESCUE TREATMENT AND SYMPTOMATIC TREATMENT IN THE EMERGENCY DEPARTMENT In most cases migraine recurs after successful initial treatment (Geraud et al., 2003; Mitsikostas et al., 2010). In this case a second dose of the initial treatment may needed. If frequent recurrences after an initial triptan therapy occur, one may consider switching to eletriptan or frovatriptan for future attacks as these triptans have relatively lower headache recurrence rates given their longer half-lives than other triptans (Thorlund et al., 2014; Ong and De Felice, 2018). Additionally, the consistency of available acute antimigraine treatments remains poor (Ferrari et al., 2001), thus a rescue

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medication should be offered to patients. This medication should be given parentally to avoid potential emesis and to act immediately, since the migraine attack has progressed at that stage. Subcutaneous sumatriptan or nasal triptan formulations are ideal candidates for rescue treatment of migraine outside the emergency room (ER). In the ER intravenous administration may be more efficient in aborting an already progressed migraine attack, or to prevent potential recurrence. There is evidence for intravenous valproate (Leniger et al., 2005), acetylsalicylic acid lysinate (Diener, 1999), and steroids (Fiesseler et al., 2011). Valproate 800 mg iv and acetylsalicylic acid lysinate 1000 mg did not differ significantly in one randomized trial. Percentage of pain relief 1HPT in the valproate and acetylsalicylic acid lysinate groups were 25% and 30%, respectively, and of sustained pain free for 24 h were 20% and 30%, respectively, without significant differences. No AEs were reported (Leniger et al., 2005). Valproate may act on the gabaergic system to abort migraine (Mitsikostas, 1994). Intravenous acetylsalicylic acid lysinate was compared to subcutaneous sumatriptan and parenteral placebo in the acute treatment of migraine, as well. Of the patients in the acetylsalicylic acid lysinate group, 43.7% were pain-free 2HPT; 76.3%

after sumatriptan and 14.3% after placebo. Accompany- ing symptoms (nausea, vomiting; photophobia, phono- phobia, and visual disturbances) improved with both verum treatments to a similar extent. Acetylsalicylic acid lysinate was significantly better tolerated than sumatriptan (AE 7.6%, vs 37.8% for the sumatriptan treated group) (Diener, 1999). The role of corticosteroids in acute migraine treatment remains controversial. Findings from animal experiments indicate that migraine pain may be partly caused by a sterile neurogenic inflammatory process in the dura mater (Moskowitz, 1993). In one trial dexamethasone failed to reduce headache relapse after ER discharge (Donaldson et al., 2008; Rowe et al., 2008;Fiesseler et al., 2011). On the contrary, there is some support for its usage in the prevention of headache recurrence, especially if the migraine attack has lasted longer than 72 h (Friedman et al., 2007; Kelley and Tep- per, 2012;Ong and De Felice, 2017).

UNMET NEEDS AND EMERGING TREATMENTS

Nearly 40% of migraine patients are dissatisfied with their care (Lipton et al., 2013). This is due to multiple issues. Less than 25% of those with episodic migraine receive appropriate consultation, correct diagnosis and then evidence-based acute migraine treatment. Com- plaints include treatment not leading to pain relief or pain freedom quickly enough, treatments do not consistently provide relief, headache pain may recur within 24 h or

side effects accompany therapy. The Migraine in Amer- ica Symptoms and Treatment (MAST) study looked at three aspects of unmet treatments needs for an acute migraine attack (Lipton et al., 2019a,b,c). These were inadequate treatment response (2 h pain freedom rates, rates of recurrence within 24 h), “demanding” attack characteristics (rapid attack onset or headache associated with sleep) and unique patient characteristics (cardiovascular comorbidity, opioid or barbiturate overuse). 95% of these patients had at least one unmet need. Common issues were rapid headache pain onset, inadequate 2 h pain freedom after treatment and headache recurrence within 24 h of treatment. As the number of unmet needs increased there was an associated increase in psycholog- ical symptoms, attack-related cutaneous allodynia and increased migraine symptom severity. It is also known that suboptimal treatment of acute migraine attacks is associated with increased risk increased migraine attack frequency (“chronification” where episodic migraine becomes chronic migraine) (Lipton et al., 2015).

How should these issues be addressed? Early

“guidelines” for acute migraine treatment were not evidence-based instead often based on“expert consensus.”

The Disability in Strategies of Care (DISC) study looked at three types of acute migraine treatment (Lipton et al., 2000). It was based on severity of attacks and attack features based on Migraine Disability Assessment (MIDAS) categories (patients were grades II–IV) with at least mild disability. Step care treatment was described as starting all patients on simple analgesics or combination oral treatments. In the study the initial therapy was oral aspirin plus metoclopramide. Step care within attacks allowed the patients to escalate their level of treatment for failure to respond at 2 h, in the study moving“up”to a triptan (zolmitriptan), a higher level of treatment. Strati- fied care attempted to match the type of treatment with the level of disability and attack features (in this case, a triptan).

Headache response was better for patients receiving stratified care with less disability time. Adverse events (AEs) (side effects) were greater in this group but the AEs were mostly only mild to moderate intensity. Step care within attacks was a real time strategy for dealing with treatment failure with initial therapy. Ultimately, it was shown that initiating effective treatment as early as possible decreased pain and disability and therefore had superior outcomes.

Acute treatments should be matched to the features of the patient’s attacks, including level of disability and attack features such as rapid onset of pain, the presence of nausea/

vomiting (suggesting choosing a nonoral route of administration) and comorbid/coexistent medical conditions such as cardiovascular disease.

A clinical tool for assessing the efficacy of acute treatment has been developed. The Migraine Treatment Opti- mization Questionnaire (M-TOQ) has a longer version

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(M-TOQ-15, proposed for research) and a shorter 5 item version (M-TOQ-5) designed for use in primary care (Lipton et al., 2009). The 5 questions are“are you able to quickly return to your normal activities (i.e., work, family, leisure, social) after taking your migraine medication?,” “can you count on your migraine medication to relieve your pain within 2 h for most attacks?,”

“does one dose of your migraine medication usually relieve your headache and keep it away for at least 24 h?,” “is your migraine medication well-tolerated?,”

and “are you comfortable enough with your migraine medication to be able to plan your daily activities?.”If one or more responses is a“no”then a change in treatment should be considered.

As can be seen from the above information, patient satisfaction with acute treatment is often low and can be improved by matching treatment options with the features of the attacks and incorporating patient input into the selection of treatments.

CONCLUSIONS

Clinicians have many options to offer patients with migraine for acute attacks. Patients benefit from education and the ability to express their preferences in informed discussion with their health care providers.

Pharmacologic options should be matched to the level of disability associated with the attacks and the nature of those attacks, including using nonoral routes of administration when appropriate. Nonpharmacologic options and pharmacologic options are not mutually exclusive. Behavioral Medicine measures and neuromodulation give patients additional options for managing their headache attacks. Utilizing all appropriate treatment options is likely to result in improved outcomes and patient satisfaction.

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