The Pharmacologic Management of Migraine

RELEASE DATE

January 1, 2022

EXPIRATION DATE

January 31, 2024

FACULTY

George A. DeMaagd, PharmD, BCPS
Professor of Pharmacy
Associate Dean of Academic Administration
Union University College of Pharmacy
Jackson, Tennessee

Kathryn Norville, PharmD, PGY1 Pharmacy Resident
Mayo Clinic, Department of Pharmacy
Phoenix, Arizona

Ashok Philip, PhD
Director of Assessment and Professor of Pharmaceutical Sciences
University of Arkansas for Medical Sciences, College of Pharmacy
Little Rock, Arkansas

FACULTY DISCLOSURE STATEMENTS

Drs. DeMaagd, Norville, and Philip have no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT

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UAN: 0430-0000-22-003-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

TARGET AUDIENCE

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL

To update participants on the epidemiology, pathophysiology, clinical presentation, diagnostic process, and treatment of migraine.

OBJECTIVES

After completing this activity, the participant should be able to:

  1. Describe the pathophysiological mechanisms and the clinical signs and symptoms of migraine.
  2. List some nonpharmacologic interventions for the management of migraine.
  3. Discuss the commonly used abortive (acute) and preventive (prophylactic) medications and their role in managing migraine.
  4. Understand the etiology and management of medication overuse headache.

ABSTRACT: Migraine headache has major effects on patients and their families, results in significant disability, and is a leading cause of outpatient and emergency-department visits. The pathophysiology of migraine has evolved over the years, and the most recent evidence points to the role of the trigeminovascular system. The clinical presentation of migraine is heterogeneous, and although it is described as having four phases, not all patients experience each phase. The management of migraine may include both abortive and preventive interventions, and although there is no cure for this disease, appropriate treatment can have an impact on quality of life. Pharmacists are often the front line for patients seeking advice on headaches, and an understanding of when to refer patients is important.

Migraine headache (HA) is a chronic neurologic disorder that has major effects on patients and their families, results in significant disability, and is a leading cause of outpatient and emergency-department (ED) visits. Migraine is the third most prevalent disease globally, affecting 14% of adults; it is three times more common in females, and 70% of patients have a family history. The common occurrence of migraine in young adults during their productive years impacts employment, relationships, parenting, and overall quality of life (QOL).1-8 Migraine results in billions of dollars in direct and indirect costs, and appropriate management has a significant effect on overall disease burden.9,10

PATHOPHYSIOLOGY

The pathophysiology of migraine has evolved over the years, and the most recent evidence points to the role of the trigeminovascular system (TGVS). Activation of the TGVS, with its peripheral components (meningeal vasculature) and central components (higher brain centers), involves the release of neuropeptides, e.g., calcitonin gene–related peptide (CGRP), neurotransmitters, and other proinflammatory substances, resulting in vasodilation and neurogenic inflammation. The result is a propagation of noceptive transmission throughout the TGVS that results in a hypersensitized pain environment, which now can be targeted by specific therapies that act on receptors within this system.11-15

DIAGNOSIS, PRESENTATION, AND CLASSIFICATION

The clinical presentation of migraine is heterogeneous and the diagnostic process is challenging, often requiring a practitioner with experience in HA management. A comprehensive medical history should be conducted in order to rule out secondary HA causes, including potentially serious etiologies that require further evaluation (TABLE 1).16-20


The Headache Classification Subcommittee of the International Headache Society has developed a comprehensive system for the classification of migraine (International Classification of Headache Disorders, 3rd edition; ICHD-3) that can assist in the diagnostic process (TABLE 2).21 ICHD-3 defines episodic migraine (EM) as fewer than 15 HA days/month and chronic migraine (CM) as 15 or more HA days/month for more than 3 months. EM and CM may be used to gauge treatment patterns and success, as patients may transition between these two HA phases.22,23 Because 60% of female migraine patients experience HAs associated with their menstrual cycle, the ICHD-3 also includes menstrual migraine types in its classification system.24,25


CLINICAL PRESENTATION

As noted, the clinical presentation of migraine is heterogeneous, and although it is described as having four phases, not all patients experience each phase. The phases—premonitory, aura, HA, and postdrome—and their features are described in FIGURE 1.12,21,26-28


TRIGGERS, RISK FACTORS, AND ASSOCIATED COMORBIDITIES

Migraine HAs are influenced by risk factors and triggers, and each patient’s individualized therapeutic plan should include a self-evaluation of potential triggers and exacerbating factors and their documentation in an HA diary. Triggers include stress, menses, weather changes, exposure to bright flashing lights, altered sleep patterns, allergens, and various odors. Food and chemical triggers include various substances found in foods (e.g., tyramine, caffeine, alcohol). Risk factors include altered sleep patterns, skipping meals, and dehydration.29-32 Migraine HAs are also associated with numerous comorbidities, including cerebrovascular disease (CBVD) and cardiovascular disease (CVD), psychiatric conditions (e.g., depression, anxiety), and others, including sleep disorders and autoimmune diseases. These comorbid conditions may complicate migraine presentation and affect its management.33-37

TREATMENT OVERVIEW

A comprehensive and individualized treatment approach should include patient and family education, risk factor evaluation, nonpharmacologic interventions, and pharmacologic therapies. Considerations should include frequency and severity of attacks, associated symptoms, level of disability, comorbidities, contraindications, concomitant medications, pregnancy/lactation status, prior treatment successes and failures, patient preference, costs, and expectations of the plan.38,39 Management may involve both acute (abortive) and preventive (prophylactic) interventions, and although there is no cure for migraine, appropriate treatment can have an impact on QOL.40-42

ABORTIVE (ACUTE) TREATMENT

Abortive (acute) treatment of migraine may include risk management, nonpharmacologic options, or the use of abortive pharmacotherapies (TABLE 3). Therapy should be initiated early (e.g., premonitory phase), with the goals being pain and symptom relief/freedom within 2 hours, limited repeat dosing, avoidance of side effects, reduced disability, and lessened use of resources (e.g., ED visits).38,39,42,43 Nonpharmacologic abortive HA management includes interventions and devices supported by the recent consensus statement from the American Headache Society (AHS). Education on lifestyle modifications (e.g., proper nutrition, trigger identification, psychosocial interventions, sleep and stress management, quiet dark rooms, reduced sensory input, aerobic exercise, yoga, cold packs, acupuncture) may also offer relief.38,45-53 Neuromodulating devices should also be considered, especially in patients who are unable to tolerate or have contraindications to drugs or who prefer nondrug options. Four such devices are FDA approved (TABLE 3); they work by using electrical current or magnetic fields to modulate pain transmission, and they may be used alone or in combination with pharmacotherapy.54,55


Options for pharmacologic management include ergot derivatives, 5-hydroxytriptamine (5-HT) receptor agonists (triptans), various analgesics, antiemetics, and the recently approved migraine mechanism–specific drugs—ditans and gepants, which further target the 5-HT and CGRP receptor systems, respectively.11-15,55-58

TABLE 3 lists the available agents and notes their established or probable efficacy as reported by the recent AHS consensus statement.38,42,43,56-58 Treatment usually involves a stratified approach, with analgesics used for mild attacks and additional options including triptans, dihydroergotamine (DHE), gepants, or ditans considered for moderate-to-severe attacks.38,39,59-62 In some cases, repeat dosing or combinations of these medications may be needed to relieve the migraine and accompanying symptoms.38,42,43,56-58 Other factors that require consideration in the abortive treatment plan include gastric stasis and nausea/vomiting, which may influence drug absorption and compliance.38,42,43 Management should also include education on the risk of medication overuse headache (MOH; discussed below).44

Analgesics

The analgesics, including aspirin (ASA; alone or in combination with caffeine), other nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen (APAP), may be useful for mild-to-moderate migraine attacks.63-78 APAP is less effective than NSAIDs, although it is beneficial as a component of combination analgesics (e.g., combined with ASA and caffeine), as it works synergistically.65,79-88 In doses of 900 mg to 1,000 mg, ASA may be beneficial and cost-effective, although tolerability may be problematic; this can be improved if it is combined with an antiemetic.66,89-96 Other NSAIDs are reported to be effective options for mild-to-severe migraine pain and associated symptoms, either as an alternative to or in combination with a triptan.67-78 Pharmacokinetic (PK) differences between NSAIDs provide options for faster onset (e.g., ibuprofen) or longer duration (e.g., naproxen).73,74 Recently, an oral solution of celecoxib with improved solubility and absorption was approved for migraine treatment. NSAIDs’ side effects may limit their role in some patients, although the addition of an antiemetic may improve tolerability.97 Other analgesics, including tramadol, which has limited data, and isometheptene, which is no longer available and therefore must be compounded, are not recommended.98-100

Although previously they were commonly prescribed for migraine, opiates or compounds containing a barbiturate (butalbital) should be avoided in migraine owing to lack of efficacy, abuse potential, additive disability, and strong association with MOH.44,101-111 MOH is a chronic, often unrecognized disorder that affects millions of people in the United States and has a worldwide prevalence of 1% to 2%.44,112-117 The ICHD-3 defines MOH as HAs occurring on ≥15 days per month for ≥3 months while the patient is using opioids, barbiturates, combination analgesics, triptans, or ergots ≥10 days per month or simple analgesics ≥15 days per month.21 The pathology of MOH includes a central hypersensitivity (opioids) and/or dysregulation of glutamatergic/serotonergic transmitter systems.118-120 Management includes treatment protocols that involve tapering off the offending agent, preventive therapy, and education to avoid patterns of overuse that result in this syndrome.121,122

Serotonergic Drugs

The serotonergic drugs utilized in the acute treatment of migraine include historical ergotamine derivatives, 5-HT receptor agonists (triptans), and the recently approved ditan (lasmiditan). Each of these drug classes is beneficial for migraine pain and related symptoms, with action at various 5-HT receptors and other neurotransmitter systems, e.g., ergots.123-128

Ergots or Ergot Alkaloids (EAs): Derived from a fungus, the EAs were first identified for HA efficacy in the 1800s, but their use is limited today because of the availability of better-tolerated alternatives.127-129 Their broad spectrum of 5-HT, adrenergic, and dopaminergic receptor activity provides efficacy in migraine similar to that of the triptans, although side effects and adverse reactions (ARs) are problematic. The two available EAs are ergotamine (rarely used in U.S.) and DHE; DHE is the preferred agent owing to fewer vasoconstrictive properties, improved efficacy, tolerability, and multiple administration options, including intravenous (IV), intramuscular (IM), subcutaneous (SQ), and intranasal (IN). DHE’s onset occurs within minutes, with the IN formulation offering the fastest response and the option of patient self-administration.127-130

EAs’ side effects and ARs are well documented, including nausea/vomiting, altered sense of taste, difficulty swallowing, dizziness, flushing, cramps, paresthesia, rhinitis, and fatigue. More serious ARs are associated with these agents’ vasoconstrictive properties, including ergotism, gangrene, cerebral ischemia and cardiac concerns (boxed warning), resulting in numerous contraindications in the vascular area, along with pregnancy, lactation, postmenopausal status, and basilar and hemiplegic migraine. Potential drug interactions include serotonergic drugs, some antidepressants, triptan use within 24 hours, and ischemic potentiation (boxed warning) from use with CYP3A4 pathway inhibitors (e.g., antifungals, others).131-138

The role of ergots in migraine is limited, although they may have utility in some triptan nonresponders, refractory patients, and patients with HA-recurrence issues. First-dose clinic administration is recommended based on risk assessment, along with concurrent use of antiemetics.139-142 A novel DHE IN delivery formulation released in 2021 uses a breath-triggered system to improve drug delivery.143 Education on the appropriate use of these products by providers and pharmacists is essential to ensure the best outcomes.

Selective 5-HT Receptor Agonists (Triptans): The triptans have had the greatest impact on acute migraine treatment over the past 30 years. Their 5-HT1B and 5-HT1D receptor action provides vasoconstriction, inhibits release of vasoactive peptides, and blocks nociceptive pain transmission, offering a more selective receptor profile versus the ergots.144-149

The approval of sumatriptan (SMT) in 1990 was followed by the arrival of six more triptans and an SMT combination with naproxen. All of the triptans have demonstrated efficacy in the abortive treatment of migraine, although PK differences may provide some differentiation within the class.150-157 Agents with the fastest onset of action include SQ, SMT, and IN SMT and zolmitriptan, with onset in 10 to 20 minutes.

The oral agents have an onset of action ranging from 30 to 120 minutes, with faster onset related to improved bioavailability and/or central nervous system (CNS) penetration. Orally disintegrating tablets (ODTs) are perceived to have a faster onset versus other forms. Frovatriptan (FVT) and naratriptan (NAT) have the longest half-life, supporting longer duration and potential for less HA recurrence. Metabolism is via the CYP450 and/or monoamine oxidase (MAO)-A system, supporting evaluation for significance in patients with hepatic disease or on concurrent drugs. NAT and almotriptan have a greater dependence on renal elimination, supporting dose adjustments in some patients.158-162 Owing to their greater receptor selectivity, the triptans are usually well tolerated; side effects include dizziness, flushing, myalgias, paresthesias, mild injection-site reactions (SQ), and nasal-cavity discomfort (IN). More severe ARs, although rare, include cardiac events; however, chest sensations may be due to effects on esophageal motor function.150-156,163-168

Contraindications to triptans include CVD and CBVD (or family history) and certain risk factors, e.g., postmenopausal status, age >40 years, smoking, obesity, diabetes, other ischemic disorders, and hemiplegic or basilar migraine. Considerations for use in high-risk patients include pretreatment screening and first-dose observation. Although triptans are not recommended in pregnant patients, there is lack of evidence supporting harmful outcomes.165-174 Drug interactions include multiple concurrent serotonergic agents, ergots within 24 hours, inhibitors of CYP450 3A4 and 2D6 systems (e.g., paroxetine, ketoconazole), and MAO inhibitors, with triptans metabolized by this pathway.175-182 Another potential interaction with questionable significance is propranolol’s inhibition of MAO-A metabolism in triptans metabolized by this pathway, e.g., rizatriptan.183

Clinical trials of the triptans for abortive treatment of migraine have reported efficacy in 50% to 90% of patients, with similar, improved, or faster onset and greater HA freedom reported in some trials versus comparator abortives.184-187 The combination of SMT and naproxen was found to have additive effects and good tolerability in the acute management of migraine.188 The triptans are considered first-line options in patients with moderate-to-severe attacks, or for mild migraine in patients intolerant or nonresponsive to analgesics. The choice of triptan may involve multiple factors. The use of SQ and IN may be good options if a faster onset is needed or if the patient is experiencing nausea/vomiting or responded poorly to oral agents. The use of FVT and NAT may be beneficial in patients with HA-recurrence issues or for short-term prophylaxis of menstrual migraine (5-6 days).24,25,189-196 Other considerations include cost, previous response and/or tolerability, and patient preference.197-211 Administration should occur at the first sign or symptom of migraine, ideally in the premonitory phase. Approximately 30% of patients have an unsatisfactory response to triptans; however, an adequate trial of at least two drugs in the class is recommended prior to considering other options.38,39,212,213 Although MOH is uncommon with triptans, it is recommended to limit triptan use to ≤10 days per month.214

When dispensing triptans, pharmacists should play a major role in monitoring and educating patients about their appropriate use, potential side effects, and expected efficacy.

Recently Approved Abortive Agents

Ditans: The oral ditan lasmiditan (LMT; Reyvow), which was approved in 2019, has selective properties targeting 5-HT1F receptors throughout the TGVS, and its lack of vasoconstrictive properties differentiates it from the triptans. LMT binds to the 5-HT1F receptor ≥400 times more versus the triptans, providing a potentially safer agent for CVD and CBVD.215-217

LMT’s approval was based on two randomized, placebo-controlled, double-blind trials in more than 3,000 patients with migraine, with results at all doses, that reported a reduction in pain and other migraine symptoms similar to triptan responses; no additional abortives were administered during the study, but 20% of patients were on concurrent preventives.218-222 LMT is rapidly absorbed within 2 hours without interference from food, and metabolism is primarily via non-CYP enzymes with no active metabolites and insignificant renal clearance. The drug was not studied in severe hepatic disease. Significant side effects with LMT are primarily CNS-related (25%-40%) and include lethargy, dizziness, and sedation, resulting in labeling advising patients not to drive or perform activities requiring mental alertness for 8 hours post dose; the drug is labeled FDA schedule V although there is no evidence of high-level abuse. Other significant side effects include gastrointestinal effects and paresthesias. Drug interactions include cautious use with alcohol/other CNS depressants and other serotonergic agents, including avoidance of ergots and triptans within 24 hours. Dosing is 50-mg to 200-mg tablets as one dose per 24 hours regardless of original dose, and the safety of treating four or more attacks over 30 days is unclear. Similar to the triptans, caution is advised in order to avoid MOH.215-217 The AHS recommends the use of LMT as an option in migraine patients who are older than 18 years and are intolerant or unresponsive to two or more tripans, as determined by a validated screening tool or clinician verification.38,39,223

Gepants: The gepants, the first of which became available in 2020, are a class of small-molecule, oral CGRP antagonists approved for the abortive treatment of migraine. Their small size, short half-lives, and penetration of the blood-brain barrier enable targeting of the CGRP receptor in the peripheral and central TGVS.38,39,224-228 In addition to abortive use, approval has been granted to some agents in the class for the prevention of migraine (discussed below).

Ubrogepant (UBP), the first approved agent in this class, peaks after oral absorption in 1.5 hours, with high-fat foods delaying peaks only. Metabolism is via the CYP3A4 pathway, with insignificant metabolites and 40% of the parent drug recovered unchanged in the feces or urine. Initial dosing is 50 mg to 100 mg, and the dose may be repeated in 2 hours (maximum 200 mg/24 hours); a reduction of 50% is recommended in severe renal or hepatic disease, and avoidance is recommended in the case of end-stage disease. Approval of UBP was based on data from two randomized, double-blind, placebo-controlled trials that found a significant reduction in migraine pain, associated symptoms, and functional disability within 2 hours after administration. Trial patients were on concurrent preventive therapies, including topiramate, botox, propranolol, and amitriptyline. UBP may be used to treat up to eight migraines in a 30-day period. Reported side effects include nausea, somnolence, dry mouth, and treatment-emergent respiratory infections. The liver-enzyme elevations reported in the trials were considered unlikely related to UBP, and the drug appeared safe and well tolerated at 1 year. Use in pregnancy and lactation is not recommended based on embryofetal effects and weight loss, respectively, in animal models. UBP is associated with significant drug interactions involving the CYP3A4 pathway. Recommendations include avoidance with strong inhibitors of the CYP3A4 pathway (e.g., clarithromycin), dose reductions with weak or moderate inhibitors (e.g., fluconazole), and avoidance with strong CYP3A4 inducers (e.g., phenytoin, rifampin). In addition, UBP dose reductions are recommended with concurrent use of breast cancer resistance protein (BCRP) or P-glycoprotein (P-gp) inhibitors.229-234

Rimegepant (RMP), which was approved soon after UBP, offers an ODT option for the abortive treatment of migraine. RMP’s PK profile is similar to that of UBP, and the drug is dosed at 75 mg daily with no additional dosing for 24 hours. Approval of RMP was based on results from a randomized, double-blind, placebo-controlled trial that demonstrated significant reductions in moderate-to-severe migraine and associated symptoms at 1 to 2 hours post dose. Rescue abortive therapy was allowed, but the majority of patients used only their RMP dose in 24 hours. As with the UBP studies, some patients were on other preventive therapies. RMP was well tolerated, with nausea and urinary tract infections found to be more common versus placebo. Contraindications include history of hypersensitivity and severe hepatic impairment.235-238 Human data in pregnancy are lacking, but animal studies report fetal variations and weight loss at higher doses. No information supports a role for this agent in renal and hepatic impairment. Similar to UBP, RMP is associated with significant drug interactions involving the CYP3A4 system, and recommendations include avoidance with strong inhibitors, avoidance of additional doses within 48 hours with moderate inhibitors, and avoidance with moderate and strong CYP3A4 inducers. In addition, this agent should be avoided with concurrent inhibitors of the P-gp and BCRP efflux systems.224,226-228 The AHS recommends gepants as an alternative option in migraine patients older than 18 years who are intolerant or unresponsive to two or more tripans, as determined by a validated screening tool or clinician verification.38,39,223

Other Abortive Agents: Other nonmigraine mechanism– specific, non–FDA-approved abortive agents used for migraine include a variety of traditional therapies.239-243 Antiemetics, including the phenothiazine derivatives (chlorpromazine, prochlorperazine), metoclopramide, and the butyrophenones (droperidol), are useful for nausea associated with migraine but may benefit HA pain as well. Their action against pain may involve reduction of hypersensitivity to dopamine or suppression of the TGVS activation and/or nociception occurring in migraine.244 Small trials, case reports, and anecdotal evidence on various antiemetics of varying dosages and formulations reported efficacy versus placebo as well as similar, less, or greater efficacy versus comparators within 2 hours of administration.245-271

Although antiemetics are reported as safe, the butyrophenone droperidol has a boxed warning for proarrhythmic risk, and the entire class carries a dose-related risk of extrapyramidal side effects.272 Antiemetics may offer an alternative to other migraine abortives, including analgesics, triptans, ergots, and others, and may be a more appropriate option versus opioids in the ED setting.273-276 Low magnesium levels and their correlation with migraine attacks have suggested a role for magnesium sulfate in the treatment of migraine. Small trials have yielded inconsistent findings, although the AHS considers IV forms as probably effective in migraine with aura, offering a nonsedating alternative for selected patients.38,277-286 Small multicenter studies and cases series of valproate (VPA) IV have reported reductions in HA intensity and other migraine symptoms as well as similar or less efficacy versus comparators. VPA should be avoided in women of childbearing years but may be an alternative for some patients.287-292

Small trials of IN lidocaine have demonstrated inconsistent findings, although synergy has been reported to reduce migraine intensity when used in combination with antiemetics or NSAIDs.293-297 Other formulations of lidocaine have been used for migraine as a component of nerve blocks.298-300 The benefits and tolerability of glucocorticoids in acute migraine were reported in small trials and case reviews as dose-dependent responses, with one report noting less HA recurrence compared with opioids, suggesting an option in the ED setting.301-311 Other agents with limited data to support a role in aborting migraine include calcium channel blockers, granisetron, diphenhydramine, trimethobenazamide, and complementary agents such as feverfew, ginger, and peppermint oil.312-323

PREVENTIVE (PROPHYLACTIC) PHARMACOTHERAPY

Prevention, the other component of migraine therapy, refers to the regular administration of medications for 6 to 12 months or longer while assessing response and tolerability. The overall goals of preventive (prophylactic) therapy include reducing the frequency, severity, and duration of HA attacks and reducing the need for and/ or improving responsiveness to abortive therapies and improving QOL. Criteria for qualifying a patient for preventive therapy (TABLE 4) are based on HA frequency, disability, and tolerability of acute therapies in addition to patient preference.38-41,324-331


Evidence on the use of existing oral migraine preventive therapies indicates that approximately 3% to 13% of patients receive therapy, although up to 40% of EM and the majority of CM patients could benefit.38-41 Selection of the appropriate preventive therapy should be individualized using the frequency criteria in TABLE 4, along with considerations that include medication history (responses, tolerability), route, frequency of administration, pregnancy and breastfeeding status, comorbidities, potential drug interactions, and patient and provider preference. In addition, therapies should be coupled with patient and family education, lifestyle modifications, trigger tracking, and documentation in an HA diary.332-336 The AHS recently published an updated consensus statement on medications with “established efficacy”for migraine (supported by ≥2 class I trials) or “probably effective” (based on one or two class II trials), as defined by the American Academy of Neurology (AAN) evidence classification system.38-39,337 Preventive medications comprise nonmigraine mechanism–specific drug classes including beta-blockers, antiseizure agents, antidepressants (ATs), angiotensin receptor blockers (ARBs), and ACE inhibitors (TABLE 5) as well as migraine mechanism–specific agents including onabotulinumtoxinA (OBT), monoclonal antibodies (mAbs) targeting CGRP (TABLE 6), and recently approved gepants.338-340



Current first-line preventive options recommended by the the AHS are the nonmigraine mechanism–specific oral agents, including beta-blockers, antiepileptics, antidepressants, and the ARB candesartan, each of which has established efficacy in preventing migraine.38,39 The basic principles for starting these oral therapies are to initiate therapy with low doses and titrate upward every 2 weeks based on response and tolerability with trials of ≥2 to 3 months, although full benefits may take up to 6 months.

Success in migraine prevention includes reductions in attack frequency, defined as a 50% reduction in monthly migraine days (MMDs); decreases in attack severity and duration; improved response to acute treatments; reductions in disability and psychological distress; and improvements in QOL. If a patient experiences tolerability issues or lack of response after an adequate trial with one medication, alternative medications and/or combinations may be considered.324-339

Beta-Blockers

Beta-blockers, which have been used for preventive treatment of migraine since the mid-1900s, are FDA approved and are considered a treatment of choice in patients without contraindications. The in-class choices with trials supporting utility include propranolol, timolol, metoprolol, and nadolol; data are limited for atenolol, and avoidance of agents with intrinsic sympathomimetic activity is recommended. Migraine patients usually tolerate beta-blockers well, and trials have reported a 50% reduction in the frequency of MMDs.341 Beta-blockers’ mechanism of action (MOA) in migraine may involve modulating adrenergic and/or serotonergic neurotransmission in cortical or subcortical pathways.338 In addition to their co-benefits in patients with other comorbidities, the usual precautions and/or contraindications need to be considered, including asthma, bradycardia, and male sexual-function concerns.338,341

Antiseizure Medications

The antiseizure medications divalproex sodium and topiramate are FDA approved for migraine, with data reporting a ≥50% reduction in MMDs. Their proposed MOA includes enhancement of gamma-aminobutyric acid and/or modulation of neurotransmitter activity. The major limitation to their use is the risk of teratogenic effects, especially with valproic acid derivatives, and to a lesser extent with topiramate. Both should be avoided in pregnancy and in women of childbearing years. Their side-effect profile may also be problematic, especially their CNS effects (e.g., sedation, cognitive issues), which are more common with topiramate and may impact work and school performance. Divalproex sodium and topiramate should be dosed with slow titration to response and tolerability. Both agents may be options for patients with concurrent seizure disorders, and some patients may benefit from topiramate’s effect on weight loss. Contraindications and cautions include teratogenicity, hepatotoxicity (with divalproex sodium), and the risk of metabolic acidosis, myopia, and oligohydrosis (with topiramate).342-346 Other anticonvulsants that are utilized for aborting migraine include zonisamide, lamotrigine, and levetiracetam, although information supporting their role is limited.344

Antidepressants

ATs used in migraine prevention include the tricyclic antidepressants (TCAs) amitriptyline and nortriptyline and the serotonin-norepinephrine reuptake inhibitors (SNRIs) venlafaxine and duloxetine, with proposed MOAs involving modulation of neurotransmitters. The TCA class has the majority of data for use in migraine, especially amitriptyline, with a 50% response reported in trials. Nortriptyline may be a better-tolerated option; however, the sedating effects of both agents may benefit comorbid insomnia. Low initial dosing at bedtime is recommended with slow titration and monitoring, especially for anticholinergic side effects. Contraindications include a history of cardiac-rhythm disturbances. SNRIs have limited evidence supporting their role, but they may be an option in patients with comorbid depression and anxiety. Awareness of antidepressants’ boxed warning for suicidality risk is a relevant factor in young migraine patients.347,348

ARBs and ACE Inhibitors

The AHS lists the ARB candesartan as having established efficacy in migraine prevention based on clinical trials and a systematic review that reported a significant reduction in MMDs versus placebo and similar efficacy versus propranolol.349-352 Open-label and systematicanalysis data with ACE inhibitors in migraine prevention demonstrated a reduction in migraine frequency and severity with lisinopril/ramipril and enalapril, respectively.351,352 Although the MOAs of ARBs and ACE inhibitors are not entirely clear, serum levels of ACE are lower and angiotensin II and angiotensin levels are elevated in migraine patients, suggesting a relationship. In addition, the lipophilic agents in these drug classes appear to be more effective. The role of ARBs and ACE inhibitors in migraine will continue to evolve, and these agents are a preventive option, especially in patients with concurrent hypertension.349-352

MIGRAINE MECHANISM–SPECIFIC INJECTABLE PHARMACOTHERAPY

Currently, five injectable FDA-approved migraine mechanism–specific preventive therapies are available in the U.S.: OBT injection (approved in 2010) and four mAbs that target CGRP (approved between 2018 and 2020).38,39 In addition, two oral gepants, RMP and atogepant, were recently approved for the prevention of migraine.224,226,227,340

OBT (Botox)

The benefits of OBT in the prevention of migraine were discovered during the drug’s use for cosmetic purposes. It is proposed that OBT’s MOA in migraine is that it blocks the release of neuropeptides (e.g., CGRP, other proinflammatory substances, acetylcholine) and reduces the peripheral sensitization associated with migraine.353,354 Clinical trials and systematic reviews have reported an increase in HA-free days and a reduction in migraine frequency in 30% to 50% of patients, along with improved QOL and a favorable safety profile in CM and MOH patients.355-357 Another study found that 66% of patients who obtain a >50% response to OBT within their third course of treatment maintain this response over time.358

The AHS supports OBT use in patients with CM unless they cannot tolerate or have an inadequate response to a minimum of two quarterly injections (6 months).38,39 Nonserious ARs, reported in 60% of OBT patients versus 47% of placebo patients, included neck pain and weakness, spasms, stiffness, bronchitis, diplopia, ptosis, and facial paresis.355-358 OBT has a boxed warning for distant spread of toxin effect beyond injection areas in hours to weeks after treatment, and case reports describe dysphagia, breathing difficulties, and deaths, with the highest risk in children. Other serious events include hypersensitivity reactions and a rare risk of transferring (albumin content) the fatal viral disease/ variant Creutzfeldt-Jakob disease. In addition, caution is recommended for coadministration with drugs that interfere with neuromuscular transmission, e.g., aminoglycosides, and drugs with an additive anticholinergic side-effect profile. OBT is administered with follow-up and evaluation for response at dosing intervals. The recommended dosing protocol is injection of 155 units (optimal dose) at 31 to 39 sites every 12 weeks; higher doses have been administered, however, and a higher dose protocol is approved by the European Union.354,357

CGRP Antagonist mAbs

The mAbs targeting CGRP or its receptor have had a significant impact on the preventive management of migraine over the past 4 years. As discussed in the Pathophysiology section, CGRP and its association with TGVS are integral to migraine pain and related features.359 The four available agents (TABLES 5, 6) are erenumab (ENB; Aimovig), a CGRP receptor blocker, and galcanezumab (GZB; Emgality), fremanezumab (FZB; Ajovy), and eptinezumab (EZB; Vyepti), which act as ligand binders to CGRP. Each of these agents has reported efficacy in migraine prevention, may be administered without regard to dose titration, has an onset of action of days to weeks, and is effective and recommended in nonresponders or those intolerant to other preventives (TABLE 7).38,39,359-362 General properties of the four mAbs are listed in TABLE 6, including adverse drug reactions (ADRs) and basic kinetics, and other properties are discussed in the following sections.


ENB: ENB, the first mAb to be approved (2018), differs from the others in its class by acting as a CGRP receptor antagonist. It is administered as a monthly SQ dose, peaks in 6 days, reaches steady state in 3 months, and is metabolized by nonspecific proteolytic pathways. Clinical studies in both EM and CM noted reductions in MMDs, associated symptoms, and acute medication use, along with improved QOL and effectiveness in nonresponders to previous preventive therapies.361-367 No drug interactions were reported and the safety profile was similar to placebo. Reported ADRs are listed in TABLE 6, and the one side effect that appears unique to ENB versus other mAbs is constipation.361 In addition, the FDA recently added the potential for elevated blood pressure to ENB labeling based on reports of this finding during postmarketing surveillance, and monitoring is required.368 ENB should be used with caution in patients with underlying hypertension and avoided in patients with latex allergies and constipation issues.

GZB: GZB is one of the three mAbs that antagonize the activity of CGRP by binding to the ligand itself. Dosing is SC and involves a loading dose followed by monthly dosing. Its PKs are similar to other agents in the class, with peak levels in 5 days and metabolism via catabolic pathways similar to endogenous immunoglobulin G, and no drug interactions reported. Clinical studies in both EM and CM found reductions in MMDs, associated symptoms, and disability as well as effectiveness in nonresponders to previous preventive therapies.369-373 In addition, GZB was considered safe and well tolerated and had minimal side effects, with recent data compiled from controlled trials reporting no severe adverse effects.362,374,375

FZB: FZB’s MOA is similar to that of GZB. Dosing is SC, and administration may be monthly or quarterly. Its PKs are similar to other agents in the class, with peak levels in 5 to 7 days, steady state in 6 months, and metabolism by enzymatic proteolysis, and no drug interactions were reported. Clinical studies in EM and CM using both dosing regiments reported reductions in HA frequency, associated symptoms, and acute medication use as well as efficacy in refractory patients who had failed up to four previous preventives.360,376-379

EZB: Similar to FZB and GZB, EZB’s MOA is via binding to the CGRP ligand, but this agent is the first in its class to be administered quarterly by IV infusion. The IV formulation offers the fastest onset of action in the class although its PK and other properties are similar to the other agents.359 Clinical studies in EM and CM reported reductions in MMDs and associated symptoms as well as an early and sustained response; in addition, EZB was well tolerated and had an acceptable safety profile.380-383

Safety of CGRP Antagonist mAbs

The primary concern with any new class of medications is its safety profile over time, and data are accumulating in this area for the mAbs.384-392 mAbs and anti-CGRP agents have been 90% to 100% humanized but still have the potential to provoke an immune reaction; the prevalence is low, however, ranging from <1% to 18%, and ARs related to these reactions are rare.359-362,384 Additional concerns with the mAbs are their antagonism of CGRP and this neuropeptide’s baseline involvement in various physiological processes. These concerns are related to CGRP’s involvement in compensatory processes and its chronic inhibition and theoretical risks, e.g., response to ischemia in patients with comorbid brain pathology.385 Although these concerns need further evaluation, some study data indicated that plasma CGRP is detectable in patients treated chronically with anti-CGRP agents, suggesting that a level of this peptide and receptor activity are maintained.390

Safety data from open-label extension trials with ENB reported no increased risk of CVD, CBVD, or peripheral vascular disease in low-risk populations, e.g., no vascular events within 12 months.386,387 Regarding ENB’s influence on exercise time in stable angina patients, no significant differences were found in time to onset of ≥1 mm ST-segment depression, exercise-induced angina, and duration, and there were no reports of infarctions or failing compensatory mechanisms.388

Analysis of GZB trial data demonstrated no significant CVD adverse events related to blood pressure, pulse, or ECG parameters in the treatment groups.389 As noted above, based on recent labeling changes, patients placed on ENB, especially those with a history of hypertension, must be monitored for blood pressure elevation during the first few weeks of therapy.361,391 mAb use during pregnancy and lactation continues to be evaluated; data are limited, and no controlled studies are available. Recent reports in women who received mAbs prior to and during pregnancy and in lactating women suggested that mAbs may be safe. More research is needed to ensure the safety of these agents in pregnant and lactating women, and at the present time they are not recommended.392 Although initial data from clinical trials and follow-up analysis appear to indicate tolerability and safety, continued surveillance, monitoring, and reporting are necessary to ensure safety with long-term use.38,39,359-362

Gepants and Other Preventive Therapies

Two agents in the gepant class recently were approved for prevention of EM, adding to the body of oral preventive options. RMP, initially approved for abortive treatment of migraine, is now indicated for migraine prevention as well, and up to 18 doses per month may be used for both aspects of migraine care.340 Additionally, atogepant was recently approved for prevention of EM, with daily dosing.393

Many other medications and complementary therapies have been utilized for prevention of migraine, with variable results. The presence of elevated glutamate levels in migraine led to assessment of the glutamate antagonist memantine, with a small trial and a systemic review suggesting benefits.394,395 The antiseizure drug lamotrigine has been reported to improve aura in an open-label study. Small clinical trials and case reports have evaluated numerous supplement therapies for migraine prevention, with mixed results; some of the supplements studied include oral magnesium, riboflavin, feverfew, vitamin B6/folic acid, melatonin, omega-3 fatty acids, vitamin D, ginger extract, and their combinations.396-399 Mindfulness-based stress-reduction programs, yoga, and tai chi may be adjunctive treatment options for some patients, as reduced HA frequency, pain intensity, and acute medication use, as well as improved QOL, have been reported. Manual therapies include osteopathic manipulation, massage and reflexology, acupuncture, and exercise programs. Small trials examining some of these therapies have reported reduced migraine days, frequency, duration, intensity, and disability compared with controls. The AAN is currently in the process of updating its guidance document for complementary therapies.45,57,317,318

Three neuromodulation devices—electrical trigeminal nerve stimulation, noninvasive vagus nerve stimulation, and single-pulse transcranial magnetic stimulation (TABLE 3)—are FDA approved for migraine prevention as monotherapy or used adjunctively, as described in the Abortive Treatment section. Although studies using these devices exhibit positive results, their use in clinical practice has been limited. A trial of one of these devices should be considered for migraine prevention in all patients as an adjunct to existing treatment. Patients with inadequate responses or poor tolerability to medications, those at risk for MOH or chronic HA, and those who prefer to avoid medications are particularly good candidates for these devices.38,39,46,54,55

Combination Preventive Therapy

Up to 60% of patients achieve some improvement with preventive monotherapy, but approximately 30% fail to respond or cannot tolerate the available medications, especially the nonmigraine mechanism– specific oral agents. Numerous combination preventives have been used, especially combinations of nonmigraine mechanism–specific agents. Some experts recommend monotherapy trials of at least two different agents for approximately 6 to 8 weeks prior to considering combination therapy.38,400 Medications studied and utilized in combination for migraine prevention include beta-blockers (propranolol, nadolol), amitriptyline, valproate, and topiramate. Additive reductions in MMDs have been reported for combinations of beta-blockers plus amitriptyline, divalproex, or topiramate. Considerations for these combination therapies include additive side-effect profiles and potential drug interactions, e.g., metabolic inhibition of amitriptyline by divalproex.401-405 Other reported combinations include riboflavin or magnesium and lamotrigine (when auras are bothersome) and atorvastatin and magnesium in combination with sodium valproate.406,407 The combination of amitriptyline and cognitive behavioral therapy was found to be effective in children and adolescents with migraine.408

The anti-CGRP mAbs have been investigated in patients on concurrent nonmigraine mechanism–specific therapies (e.g., beta-blockers, antiseizure drugs), and they are often initiated in patients on these existing preventive therapies. A recent retrospective chart review demonstrated reductions in MMDs, HA intensity, and disability and indicated tolerability in patients receiving mABs and OBT.409 Because mAbs are often initiated in patients on oral preventives (e.g., beta-blockers, antiseizure drugs), plans to reduce the dosage or taper off dual therapy should involve patient and practitioner working together based on response and tolerability.359-362

Selection and Management of Preventive Therapy

Selection of initial preventive therapy should take an individualized approach that considers HA severity, concurrent medications, contraindications, comorbidities, previous responses, pregnancy or childbearing age, patient preferences, and clinician experience. Partial responses or dose-limiting ARs may warrant alternative or—in some cases—combination therapies. Minimizing polypharmacy is important, but practitioners contemplating a single drug for multiple comorbidities should consider the risk of undertreating one condition. Drug therapy should be avoided in pregnant or lactating females and women trying to conceive; rather, nonpharmacologic interventions, plans, and education should be used.410 Neuromodulatory devices may also be effective in combination with other therapies and should be considered in all patients, especially if medications must be limited or avoided.

With the availability of the mAbs and OBT, the clinician has more options for preventive therapy and must balance efficacy, tolerability, and cost-effectiveness. The AHS recommends the use of evidence-based preventive treatments, when indicated, based on the options in TABLE 5, and the criteria in TABLE 7 should be followed regarding when to use the mAbs and OBT.38,39 Migraine is a disease that can fluctuate over time, with periods of remission and potentiation, and therapy should be evaluated on an ongoing basis. Discontinuation of therapy should involve joint decisions between patient and practitioner, as stopping and reinstituting therapy does not always restore HA control.411

Patient compliance with oral preventive treatment is poor, likely because of lack of effectiveness or tolerability issues. Compliance declines with time; only 17% to 20% of patients remain on oral preventives after 1 year, although recently approved monthly or quarterly injectables may result in improvement. Involving the patient in the therapeutic plan is important, as is clinician- and pharmacist-provided education on treatment expectations and goals, the importance of compliance, and the knowledge that overuse of the abortive agent can interfere with response to the preventive.412-415

THE PHARMACIST’S ROLE

Pharmacists are often the front line for patients seeking advice regarding HAs, and an understanding of when to refer patients is important. Pharmacists can triage patients based on red flags and can use available migraine screening tools, including the ID Migraine Screener and the Migraine Disability Assessment Questionaire (MIDAS).416 In addition, resources such as the National Headache Foundation and American Migraine Foundation websites provide essential information. Pharmacists can also assist with appropriate use of OTC medications and educate patients on the risks of MOH. Pharmacists should be involved in the interprofessional team approach to migraine care, ensure appropriate education, assist in the triage of HAs, perform therapeutic drug monitoring, and interact with third-party payers to help ensure optimal outcomes and cost-effective migraine care.19,47,95,417

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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