AUTHORS
Cynthia Sheppard Solomon, BSPharm, RPh, FASCP, CTTS, NCTTP, Clinical Associate Professor, Department of Internal Medicine and Neurology, Wright State University Boonshoft School of Medicine, Dayton, OH
Glen D. Solomon, MD, FACP, Professor and Chair, Department of Internal Medicine and Neurology, Wright State University Boonshoft School of Medicine, Dayton, OH
PEER REVIEWER
Alina Masters-Israilov, MD, Assistant Professor of Clinical Neurology, Weill Cornell Medical College
EXECUTIVE SUMMARY
Migraine is a highly prevalent and debilitating condition that causes significant impairment in quality of life. It affects people during their most economically productive years. Worldwide, migraine is one of the leading causes of disability from neurologic disease.
- The efficacy of preventive medications for migraine has been consistent across all classes of medication. Roughly half of patients taking a preventive medication have a 50% reduction in migraine frequency.
- The newest additions to migraine prevention medications are the calcitonin gene-related peptide (CGRP) antagonists. They are monoclonal antibodies to either the CGRP receptor (erenumab) or the CGRP ligand (galcanezumab and fremanezumab). Another CGRP ligand antagonist, eptinezumab, was approved by the Food and Drug Administration in 2020.
- Two oral CGRP receptor antagonists (gepants), rimegepant and ubrogepant, for the acute treatment of migraine have been approved recently. Both drugs have been shown to reduce migraine pain within 60 minutes.
- Unlike the triptans and ergots, the gepants do not have vasoconstrictive effects and are not contraindicated in patients with vascular disease. The most common side effects of nausea and somnolence occur in less than 5% of patients.
- Patients who fail a trial of therapy should try a medication from a different drug class. It is reasonable to try different types of antihypertensives or anti-epileptic drugs. Verapamil has been shown to be effective when other medications have failed. Patients failing multiple preventive therapies may be candidates for more expensive treatments, such as CGRP antagonists or, for chronic migraine, onabotulinumtoxin A. The CGRP antagonists may be effective when other preventive medications have failed.
- Therapeutic trials with the CGRP antagonists should last for three months.
- Cost considerations are a major factor in the use of CGRP antagonists. Several resources for patients are provided.
Introduction
Migraine is a highly prevalent and debilitating condition that causes significant impairment in quality of life. It affects people during their most economically productive years.1 Worldwide, migraine is one of the leading causes of disability from neurologic disease.1
Preventive therapy for migraine is indicated when migraine attacks interfere with quality of life or are frequent and debilitating. The ability to prevent migraine with pharmacologic therapy has long been a goal of both patients and their physicians. The ideal preventive (prophylactic) migraine treatment should be effective, safe, and well tolerated, with few or no contraindications, few or no drug interactions, safety in pregnancy and breastfeeding, and dosed in a manner to ease adherence. Current medications have not been able to meet these goals.2
The efficacy of preventive medications for migraine has been consistent across all classes of medication. Roughly half of patients taking a preventive medication have a 50% reduction in migraine frequency. Whether in placebo-controlled trials or head-to-head studies, no medication or drug class has shown significant superiority in efficacy.2
A Brief History of Migraine Preventive Medications
Methysergide was introduced into practice in the early 1960s.3 Its use was limited by both contraindications and safety issues. Contraindications included pregnancy, peripheral vascular disorders, atherosclerotic vascular disease, fibrotic disorders, lung diseases, liver or renal function impairment, and valvular heart disease. Methysergide can induce retroperitoneal fibrosis and pleural and heart valve fibrosis, with an estimated incidence of 1 in 5,000 treated patients. The sale of methysergide in the United States was discontinued in 2002.4
Antidepressants have long been used for migraine prophylaxis but are not Food and Drug Administration (FDA)-approved for this use. Monoamine oxidase inhibitors (MAOIs) were studied in the late 1960s, but their use is limited by drug and food interactions that can lead to hypertensive crises. Amitriptyline was shown to reduce migraine frequency in the mid-1970s.3 Side effects, including weight gain and sedation, limit its use. Although selective serotonin reuptake inhibitors (SSRIs) have not been shown to be effective migraine preventives, serotonin norepinephrine reuptake inhibitors (SNRIs), such as duloxetine and venlafaxine, appear to provide benefit. Side effects include nausea, fatigue, and insomnia.
Antihypertensive medications have been a mainstay of migraine prophylaxis. Beta-blockers, such as propranolol and timolol, are FDA-approved for migraine prophylaxis. Propranolol was studied initially for migraine in the late 1960s, after the discovery that a patient diagnosed with cardiac disease and treated with propranolol had improvement in his migraines.3 The use of beta-blockers is limited by side effects, including diarrhea, impotence, and fatigue. Relative contraindications include asthma, heart failure, sinus bradycardia, certain cardiac arrhythmias, Raynaud’s disease, and depression.
Verapamil, a calcium channel blocker, was first studied for migraine in the early 1980s.5 Its use is limited by multiple drug interactions, constipation as a common side effect, and contraindications, including certain cardiac arrhythmias and heart failure.
Flunarizine, a calcium channel blocker not FDA-approved for use in the United States, also is effective for migraine prophylaxis.
A few small studies suggest that other calcium channel blockers, such as amlodipine, diltiazem, and nicardipine, may be beneficial in migraine prevention. Calcium channel blockers are not FDA-approved for migraine prevention.
Candesartan, an angiotensin receptor blocker, was found to be noninferior to propranolol for prevention of migraine.6 Use of this medication in migraine is limited by teratogenicity. It is not FDA-approved for migraine prevention.
Anti-epileptic agents, including valproic acid and topiramate, are FDA-approved for migraine prophylaxis. Valproic acid has been used for migraine since 1983 and topiramate has been used since 2004. The use of these agents is limited by teratogenicity. Adverse effects include cognitive impairment, weight loss, paresthesia, and nephrolithiasis with topiramate and weight gain, alopecia, and hepatic dysfunction with valproic acid.
Calcitonin Gene-Related Peptide
Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide that is widely found in both the peripheral and central nervous system. CGRP is a potent vasodilator and mediator of pain signals. Alpha-CGRP is highly expressed in the central nervous system, especially in the trigeminovascular system, while beta-CGRP is expressed in the enteric nervous system.7
In the cardiovascular system, CGRP is present in nerve fibers that innervate blood vessels and the heart. CGRP participates in the regulation of blood pressure. It is believed to have a role in the maintenance of cardiovascular homeostasis during ischemic events and in tissue remodeling in pulmonary hypertension.8
In the gastrointestinal tract, CGRP acts as a sensory transmitter to promote gastrointestinal motility. Blocking CGRP receptors in the gut has the potential to impair gastrointestinal motility and peristalsis, predisposing some individuals to constipation.7
Other effects of CGRP include facilitating wound healing in the skin and possibly regulating the hypothalamic-pituitary tract functions.8
During pregnancy, systemic CGRP levels rise, peaking during the last trimester and falling after delivery. CGRP expression and functional responses of the CGRP receptor are increased in the omental arteries of pregnant women, contributing to the vascular changes during pregnancy. In women with preeclampsia, CGRP levels are lower than in women with a normotensive pregnancy.9
CGRP stimulates the release of inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin 1-beta, and interleukin-6, from human leukocytes. These cytokines play an important role in physiological and pathological settings, such as inflammation and pain.10
During a migraine attack, CGRP levels increase in external jugular venous blood. When a migraine is relieved by treatment with sumatriptan, CGRP levels are reduced. Intravenous infusion of CGRP in migraine patients induced both an immediate moderate headache and a delayed headache that completely mimicked their migraine. CGRP infusions did not induce pain in other parts of the body.7
CGRP Antagonists
Monoclonal Antibodies
The newest additions to migraine prevention medications are the CGRP antagonists. The first three of these drugs entered the market in 2018 and are monoclonal antibodies to either the CGRP receptor (erenumab) or the CGRP ligand (galcanezumab and fremanezumab). Another CGRP ligand antagonist, eptinezumab, was FDA-approved in 2020. Erenumab, galcanezumab, and fremanezumab are injected subcutaneously once per month (fremanezumab also can be given every three months), and eptinezumab is given intravenously every three months.11
To summarize the efficacy of these drugs in migraine prevention, studies have shown the number of migraine attack days per month were reduced by one to two days compared with placebo in patients with either episodic or chronic migraine. These drugs may be effective when other preventive medications have failed, with a reduction of three to four migraine attack days per month compared with placebo in patients who have failed at least two classes of prophylactic treatment.12 Currently, there are no head-to-head studies comparing these drugs to other preventive medications or to each other.11,12
Unlike the drugs discussed earlier, the CGRP monoclonal antibodies were designed specifically to treat migraine based on currently proposed pathophysiology. Despite being designed specifically for migraine, the efficacy of CGRP monoclonal antibodies or gepants is not better than older medications.
The different mechanisms of action may explain the variation of adverse effects between the CGRP receptor blocker erenumab and the CGRP ligand antagonists galcanezumab, fremanezumab, and eptinezumab. CGRP ligand antagonists trap the CGRP peptide in the vasculature when it is released, preventing its ability to activate CGRP receptors in tissues. At therapeutic anti-migraine doses, ligand antagonists are unlikely to affect CGRP within gastrointestinal or vascular tissues. Erenumab blocks CGRP receptors throughout the body. This effect occurs whether the CGRP is from visceral sensory afferents or from the circulation. The CGRP receptor blockade may reduce CGRP-mediated gastrointestinal motility and peristalsis as well as alter vascular tone, leading to hypertension.7
Although clinically relevant drug interactions with concomitantly administered medications are rare in this group of drugs, hypersensitivity-type reactions, including angioedema, are possible and should be taken into consideration before prescribing. Generally, metabolism of monoclonal antibodies occurs through proteolytic degradation pathways.13
The use of chronic monoclonal antibodies can be highly immunogenic, often creating anti-drug antibodies (ADAs), presenting in the first six to seven months of treatment.14,15 ADAs can change the drug interaction landscape through ADA induction manipulating the elimination of drugs and altering the pharmacokinetic profiles, leading to serious adverse effects.14-16
Erenumab is a monoclonal antibody directed against the CGRP receptor. Recommended doses are 70 mg and 140 mg administered subcutaneously once per month. No food-drug interactions of significance have been reported. Other monoclonal antibody therapies and some vaccines may interact with erenumab. Constipation from erenumab may be severe. Pain, swelling, and redness at the injection site can be problematic.
An FDA analysis of post-marketing case reports suggested an association between elevated blood pressure and the use of erenumab. The median systolic increase in blood pressure was 39 mmHg and the median diastolic blood pressure increase was 28 mmHg. Hypertension is seen most commonly after the first dose of erenumab. Elevated blood pressure can occur at any time during treatment but is reported most frequently within seven days of erenumab administration. In April 2020, the FDA prescribing information for erenumab was amended to include hypertension along with constipation in the Warnings and Precautions section.17
Three monoclonal antibody drugs are directed against the CGRP ligand: fremanezumab, galcanezumab, and eptinezumab.
- Fremanezumab: This drug is administered subcutaneously and may be given once per month (225 mg) or every three months (675 mg). Higher body weight may affect the total exposure of the drug.18 No dosage modification is necessary for the elderly or for patients with renal or hepatic impairment.19,20
- Galcanezumab: This drug is administered as a subcutaneous injection, with dosing once per month. The first dose is recommended as a loading dose
(240 mg) followed by a maintenance dose of 120 mg every four weeks thereafter. Indication includes treatment of episodic cluster headache as well as prevention of migraine. Hypersensitivity reactions are possible.
- Eptinezumab: This drug is administered intravenously for migraine attacks, given over 30 minutes with a dose range of 100 mg to 300 mg every three months.21-23
One vexing issue with monthly dosing of injectable CGRP antagonists is the wear-off phenomenon, in which the preventive effect does not last through the entire dosing period. This has been reported to occur in nearly 20% of patients, with efficacy waning six to 10 days before the next scheduled dose.24 Management of the wear-off phenomenon is challenging; CGRP antagonists are not approved for more frequent dosing than every 28 days, and their safety and efficacy with shorter dosing intervals is untested. Using CGRP antagonists with additional migraine prophylactic drugs is a potential option but comes with additional cost, inconvenience, and potential for side effects and interactions.
Gepants
In 2020, the FDA approved two oral CGRP receptor antagonists (gepants), rimegepant and ubrogepant, for the acute treatment of migraine with or without aura. Both drugs have been shown to reduce migraine pain within 60 minutes. At two hours, about 20% of patients are headache pain-free.11 In studies comparing gepants with triptans, the gepants consistently showed less efficacy at the two-hour pain-free endpoint.7,25 Zavegepant is a third-generation small molecule CGRP receptor antagonist that is in development as a nasal spray for the acute treatment of migraine.
Unlike the triptans and ergots, the gepants do not have vasoconstrictive effects and are not contraindicated in patients with vascular disease.11 Both rimegepant and ubrogepant were well tolerated in clinical trials, with the most common side effects of nausea and somnolence occurring in less than 5% of patients.
The recommended dose of ubrogepant is 50 mg or 100 mg, depending on pain intensity, up to two doses per day. Ubrogepant is a weak inhibitor of CYP2C8, CYP2C9, CYP2D6, CYP2C19, MAO-A, and UGT1A126-29 and should be avoided with potent CYP3A4 inhibitors, such as ketoconazole, itraconazole, and clarithromycin, since they would cause an increased plasma level of ubrogepant.26,28,30,31 With moderate CYP3A4 inhibitors, such as ciprofloxacin, fluconazole, fluvoxamine, and verapamil (also a P-glycoprotein inhibitor), dose adjustments of ubrogepant, a sensitive CYP3A4 substrate, may be necessary.28,32 The manufacturer recommends a 50 mg starting dose with this scenario, skipping a second dose within the first 24 hours.28 When used with a weak CYP3A4 inhibitor, a second dose of ubrogepant may be considered at least two hours after the first dose.28,30
Ubrogepant should be avoided in patients taking potent CYP3A4 inducers, such as phenytoin, barbiturates, rifampin, or St. John’s wort, because of decreased efficacy.26,28,30,33 Dose adjustments for renal and hepatic impairment may be required.13 Grapefruit juice may increase the plasma levels of ubrogepant by inhibiting its metabolism in the intestinal wall and liver.13 Studies of other medications, such as ethinylestradiol- and norgestimate-containing contraceptives, acetaminophen, naproxen, or esomeprazole, have not shown clinically meaningful interactions to date.28,34,35
Rimegepant is an orally disintegrating tablet that is approved for the acute treatment of migraine with or without aura. It should be placed on or under the tongue to dissolve. The maximum dose per day is 75 mg in 24 hours, with a duration of action of 48 hours.35,36 When administered with a high-fat meal, the half-life is extended. Rimegepant also has been approved for the prevention of migraine. Rimegepant 75 mg taken every other day was more effective than placebo for the preventive treatment of migraine. Migraine days per month were reduced by one day compared with placebo in patients with episodic migraine. Tolerability was similar to placebo.
Rimegepant should be avoided in patients taking potent CYP3A4 inhibitors.37-40 Rimegepant is a substrate of CYP3A4 and CYP2C9.37-40
The efficacy and bioavailability of rimegepant when given with rifampin, a potent CYP3A4 inducer, is significantly reduced.40 Co-administration of rimegepant with potent or moderate CYP3A4 inducers should be avoided. When administered with a CYP2C9 inhibitor only, exposure of rimegepant should not be significant.40 Rimegepant should be avoided in severe hepatic impairment.33,39,40
If grapefruit juice has been consumed, hold doses for 48 hours post-grapefruit.13,18,19,36,40,41 Rimegepant should not be given with P-glycoprotein inhibitors, such as quinidine, or breast cancer resistance protein (BCRP) efflux transporters, such as curcumin. ABCG2, more commonly referred to as BCRP, is an efflux transporter to restrict the distribution of its substrates to specific organs and across the gastrointestinal tract.
Atogepant is an oral CGRP receptor antagonist that was FDA-approved for migraine prophylaxis in October 2021. Atogepant has a half-life of 11 hours and is largely eliminated within two days. Daily doses of 10 mg, 30 mg, and 60 mg reduced monthly migraine frequency by 1.2 to 1.7 days compared with placebo. A reduction of 50% or more in the three-month average of migraine days occurred in 56% to 61% of those taking atogepant compared with 29% taking placebo.42 The most common adverse effects of atogepant in the clinical trials were nausea, constipation, and fatigue. Atogepant appears to cause more gastrointestinal adverse effects than rimegepant (6% to 9% vs. 2%), but no direct comparisons are available.43
For preventive treatment of episodic migraine, 10 mg, 30 mg, and 60 mg doses are available, to be given by mouth once daily with or without food. With severe renal impairment, 10 mg per day is recommended based on creatinine clearance values. In patients taking potent CYP3A4 inhibitors, 10 mg doses also are recommended.44 Concomitant administration with potent or moderate CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, efavirenz, or etravirine, results in decreased exposure to atogepant. Use of atogepant should be avoided in patients with severe hepatic impairment. Concomitant use of organic anion transporting polypeptide (OATP, responsible for mediating organic anions across cell membranes, especially in the liver and kidney) inhibitors, such as cyclosporine, requires either 10 mg or 30 mg doses because of increased exposure of atogepant.44
When used for migraine prophylaxis, the gepants are dosed orally either daily (atogepant) or every other day (rimegepant). The CGRP monoclonal antibodies are dosed monthly by subcutaneous injection (erenumab, galcanezumab, and fremanezumab) or every three months by intravenous infusion (eptinezumab) or subcutaneous injection (fremanezumab).45 The half-life of both rimegepant and atogepant is 11 hours, compared with one month for the injectable monoclonal antibodies. This may be important for patients who have a planned or unplanned pregnancy or adverse events that might require rapid discontinuation of drug exposure.46
Pharmacodynamic and Pharmacokinetic Challenges
The majority of patients with migraine are women in their most productive years. Although often quite healthy, many struggle with the severity and frequency of migraine, which causes a reduction in their quality of life.1 Migraine patients may be prescribed both preventive medications as well as acute headache treatment, leaving otherwise healthy migraine patients no choice but to consume several daily medications to manage their disease. If the patient also has comorbidities, such as hypertension, diabetes, or depression (seen in more than half of all migraine patients), the number of medications increases, creating opportunities for both drug-drug interactions and drug-food interactions. Full disclosure of other products used regularly or as needed, such as herbs and dietary supplements, assists clinicians in proper medication therapeutic management to reduce problems associated with concomitant medications.
With the gepants, significant effects with cytochrome P450 enzymes and liver metabolism are possible. These effects are not specific across the drug class, but instead can differ between products. Clinicians need to be comfortable with their ability to make subtle changes in therapy to remove concomitant medications that are inducers, substrates, or inhibitors of cytochrome P450 enzymes, to replace, when necessary, with other non-reactive agents and to choose from the new agents the medication that will be most suitable to the patient’s overall drug regimen. Because drugs within the CGRP receptor antagonist and gepant categories may not be administered daily, patients need to be informed that drug responses will span a longer period. They also should keep in mind that unexpected or untoward effects could occur throughout several weeks or a month. Adjusting some of their chronic medications may allow for fewer drug-drug interactions with these long-acting, potentially powerful new entities for chronic or episodic migraines.13
Helping Patients Manage the High Cost of Newer Medications
Patient adherence has been directly related to out-of-pocket costs for prescription medications. Nowhere are there better examples of the high cost for newer medications than with the new CGRP antagonists and gepants. For CGRP antagonists or gepants, the yearly expense can range from $6,900 to $20,000 per patient.
The pricing of CGRP antagonists, anti-CGRP monoclonal antibodies, or various gepants is at the high end of the price scale for medications approved for migraine.11 With eptinezumab, which requires intravenous infusion, costs can be even higher than the cost of the drug because the cost of its infusion needs to be added in.
Patients value their treatment as a direct function of their ability to access and consume the product, making it imperative to remove stressors surrounding acquiring such products. Historically, patient assistance programs directly involving specific manufacturers have been helpful, but still may not fulfill all the patient’s financial needs. Those patients receiving federal assistance (Medicaid and Medicare) cannot access drug cards from pharmaceutical manufacturers. As pricing barriers have begun to be more commonplace, nonprofit organizations have come online to assist patients in navigating various options.
Pharmaceutical cost containment, a long-term concern of private insurers and government programs, has created incentives for insurers and other payers to use both therapeutic and nontherapeutic stepped care as a cost-reductive tool for pharmacologic treatments. Increased costs often have driven barriers to access (i.e., nontherapeutic stepped care, formulary tiers, and prior authorizations). These requirements may not always align with state and federal patient protection laws.
As drug pricing has increasingly become complex, patient advocacy has demanded transparency in pricing, with trusted institutions acting as facilitators to keep direct patient costs reasonable.
One of these coalitions, constructed of patient advocacy groups empowering patient outreach, is named, appropriately, Coalition for Headache and Migraine Patients (CHAMP). CHAMP enhances communication, coordination, and collaboration to allow patients effective access to treatments. Identifying selective organizations to assist in helping patients access important treatments is key. However, some organizations may be proprietary to one specific product, representing the pharmaceutical company, not the patient. (See Table 1.)
Table 1. Options for Helping Patients with Financial Assistance to Purchase Needed Medications* |
HeadacheMigraine.org
MigraineDisease.org
Simplefill.com
Copays.org
NeedyMeds.org
HealthWellFoundation.org
AmericanMigraineFoundation.org
One example of the many manufacturer-sponsored financial assistance programs is Biohaven Patient Assistance through ASPN pharmacies, which helps patients gain access to certain brand-name products (specifically Nurtec ODT) for lower costs, using a copay card for rimegepant. Within a few days, the patient can receive medication by mail or through their own pharmacy at a lower cost (1-800-468-7832). See other manufacturers for more of these similar types of offers. For Ubrelvy (ubrogepant), patients might text 48764, while answering specific qualifier questions to be evaluated for a free or lower-priced drug. |
*It is important for clinics to work with insurers, advocacy groups, and nonprofit organizations for optimum patient benefit. |
With new products, such as CGRP antagonists and gepants, the “fail first” concepts are in play to allow patients and clinicians access to specific therapeutic products only when clinical success with more traditional treatments has not been possible. (See Table 1.) With FDA approval received despite having no comparator studies between CGRP-directed therapies and alternative existing first-line agents, most agencies and insurers are restricting coverage to only those who have experienced several treatment failures.12 (See Table 1.)
Pregnancy Issues Surrounding These Agents
With any long-acting medication, concerns regarding a patient’s needs can be challenging. Patients desiring or requiring therapeutic changes may be limited in choices if drug levels and effects linger for weeks or months. In patients with longstanding migraine, this can lead to difficulty in switching gears for a planned pregnancy or for other health-related changes. Instead of parenteral administration, the oral gepants might provide a valuable choice for patients requiring this level of treatment but needing enhanced flexibility for their life choices. Currently, no long-term lactation-related information is available for these medications. Pregnancy and breastfeeding data are accumulating from clinical trials not yet completed.
CGRP Antagonists for Prevention of Migraine
The choice of a preventive therapy should be guided by comorbid conditions, potential for pregnancy, adverse effects, possible drug interactions, and cost. Efficacy should be judged by a 50% reduction in migraine frequency, a significant reduction in severity or duration of attacks, or a major improvement in quality of life. An adequate trial of at least six weeks at the optimal dose should be considered before a treatment is considered a failure.47
As a basic approach to prophylactic medication therapy, the clinician should assess contraindications to medications, such as comorbid conditions, drug interactions, potential pregnancy, or allergies. Prior medication exposure (efficacy and duration of therapy as well as adverse effects) should be reviewed. Comorbidities, such as hypertension or depression, that could be managed using a migraine preventive therapy should be considered.
The clinician should discuss potential side effects, costs, and risks with the patient to incorporate their preferences. Counseling to prevent potential adverse effects, such as employing dietary changes and exercise to prevent potential weight gain or adding dietary fiber and hydration to prevent constipation, can help patients to maintain medication adherence. (See Table 2.)
Table 2. Commonly Used Medications for Migraine Prophylaxis | |
Medication Class |
Drug |
Beta-blocker |
|
Other antihypertensive medications |
|
Antidepressants |
|
Anticonvulsants |
|
CGRP-blocking monoclonal antibodies |
|
Gepants |
|
*Food and Drug Administration-approved for migraine prophylaxis SNRI: serotonin-norepinephrine reuptake inhibitor; CGRP: calcitonin gene-related peptide | |
For example, for a young woman with no comorbid conditions, one might prescribe a low dose of a once-daily beta-blocker or verapamil. If a patient had migraine and concomitant insomnia, the clinician might choose a sedating tricyclic antidepressant, if weight gain was not a concern.
For a young man with no comorbid conditions, one might prescribe a low dose of a once-daily beta-blocker or verapamil or candesartan (which should be avoided in women of childbearing years).
Patients who fail a trial of therapy should try a medication from a different drug class. It is reasonable to try different types of antihypertensives (beta-blocker, calcium channel blocker, or angiotensin receptor blocker), antidepressants (tricyclic, SNRIs), or anti-epileptic drugs (topiramate, valproate).
Verapamil has been shown to be effective when other medications have failed.48 Patients failing multiple preventive therapies may be candidates for more expensive treatments, such as CGRP antagonists or, for chronic migraine, onabotulinumtoxin A. The CGRP antagonists may be effective when other preventive medications have failed. (See Figure 1.)
Figure 1. Preventive Treatment Algorithm for Episodic Migraine |
 |
*Food and Drug Administration-approved for migraine prophylaxis SNRI: serotonin-norepinephrine reuptake inhibitor; CGRP: calcitonin gene-related peptide |
Therapeutic trials with the CGRP antagonists should last for three months. If one CGRP antagonist is ineffective, a different agent from a different class (a ligand antagonist vs. a receptor blocker) might be tried, but studies to support this approach are lacking.
Gepants for the Acute Treatment of Migraine
The acute treatment of migraine often is based on the level of disability caused by the attack. For mild to moderate attacks, therapy with a nonsteroidal anti-inflammatory drug, acetaminophen, or combination product with caffeine can be helpful. For moderate to severe attacks, triptans usually are the agents of choice. With triptans, 20% to 30% of patients will be pain-free at two hours.47
The gepants appear to be somewhat less effective than triptans for the acute treatment of migraine.25 Their role likely will be for migraine patients who cannot take triptans because of cardiovascular disease or risk factors, intolerance, or fear of side effects.7
CGRP Antagonists in Cluster Headache
Like migraine, cluster headache activity is associated with alterations in CGRP levels.
Galcanezumab 300 mg monthly was studied for the prevention of episodic cluster headache in an eight-week, double-blind, placebo-controlled trial. The mean reduction in the weekly frequency of cluster headache attacks was 8.7 in the galcanezumab group compared to 5.2 in the placebo group. At week three, the percentage of patients with at least a 50% reduction in headache frequency was 71% of the galcanezumab group compared to 53% in the placebo group.49 Galcanezumab has not been shown to be effective for patients with chronic cluster headache.
Verapamil (with an initial target dose of 240 mg daily) generally is considered the drug of choice for episodic cluster headache prevention.50 Lithium (up to 900 mg daily) is an alternative. Because these drugs take at least one week to begin reducing cluster attacks, bridging with short-term steroid therapy (either two to three weeks of oral prednisone or greater occipital nerve injection with steroid) should be considered.47 If these drugs are ineffective or contraindicated, galcanezumab should be considered.
Summary
The CGRP antagonists have some clear advantages over existing preventive therapies, but also present some new challenges for the prescribing clinician. These drugs have many of the characteristics desired in prophylactic migraine treatment. Although they are only as effective as our current drugs, they are well tolerated, have few contraindications, and can be dosed either monthly or quarterly to improve adherence.12
CGRP monoclonal antibodies have no reported drug interactions as of the time of publication. The safety of long-term CGRP blockade remains a concern. CGRP and its receptor are present throughout the vasculature and in the peripheral and central nervous system. In addition to its role in cranial nociception, CGRP is a potent arterial vasodilator. Potential safety concerns include loss of vasodilation during ischemic events, difficulties with wound healing, problems with gastrointestinal motility and mucosal integrity, and dysregulation of pituitary function.5 Although these issues have not been demonstrated in clinical trials, long-term use of these medications and use in patients with significant medical comorbidities has not yet been studied.12
There are no data on the safety of CGRP blockade in pregnancy, when levels of CGRP are expected to increase. CGRP levels are lower in women with preeclampsia compared with normotensive pregnancies, suggesting that CGRP blockade during pregnancy might be harmful.6 This is a concern for a therapy aimed at a disease most prevalent in women during their childbearing years. With many pregnancies unplanned, the long half-life of the injectable CGRP monoclonal antibodies may prove to be a disadvantage. Preclinical data have not shown fetal abnormalities or problems with organogenesis when CGRP antagonists were given during pregnancy in animal models. Data on humans is not yet available.
With these concerns, clinicians will need to determine the appropriate place for CGRP antagonists in practice. These medications should be avoided in pregnant women or in women of childbearing potential not using contraception. The oral gepants, rather than long half-life injectable monoclonal antibodies, might provide a valuable choice for patients considering pregnancy. These medications should be used with caution in patients with significant risk of ischemic cardiovascular or cerebrovascular disease. Patients should be advised of the potential risks of CGRP blockade if they have gastrointestinal disease or are planning surgery.
The CGRP antagonists are a welcome addition to migraine prophylaxis. They have many of the properties that we desire for migraine prophylaxis. As with any new class of medication, we need to be considerate of the potential safety risks and risks to a developing fetus.
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- Solomon GD. Preventing migraine: The old and the new. Cleve Clin J Med 2020;87:219-221.
- Diamond S, Dalessio DJ, eds. Diamond and Dalessio’s The Practicing Physician’s Approach to Headache. Third edition. WB Saunders; 1982.
- Silberstein SD. Methysergide. Cephalalgia 1998;18:421-435.
- Solomon GD, Steel JG, Spaccavento LJ. Verapamil prophylaxis of migraine. A double-blind, placebo-controlled study. JAMA 1983;250:2500-2502.
- Stovner LJ, Linde M, Gravdahl GB, et al. A comparative study of candesartan versus propranolol for migraine prophylaxis: A randomised, triple-blind, placebo-controlled, double cross-over study. Cephalalgia 2014;34:523-532.
- Hargreaves R, Olesen J. Calcitonin gene-related peptide modulators – The history and renaissance of a new migraine drug class. Headache 2019;59:951-970.
- Deen M, Correnti E, Kamm K, et al. Blocking CGRP in migraine patients – a review of pros and cons. J Headache Pain 2017;18:96.
- MaassenVanDenBrink A, Meijer J, Villalon CM, Ferrari MD. Wiping out CGRP: Potential cardiovascular risks. Trends Pharmacol Sci 2016;37:779-788.
- Han D. Association of serum levels of calcitonin gene-related peptide and cytokines during migraine attacks. Ann Indian Acad Neurol 2019;22:277-281.
- [No authors listed]. Drugs for migraine. Med Lett Drugs Ther 2020;62:153-160.
- Hwang TJ, Vokinger KN, Kesselheim AS. New treatments for migraine – Therapeutic ratings and comparative coverage in the US, Canada, and Europe. JAMA Intern Med 2021; Dec. 13. doi:10.1001/jamainternalmed.2021.7168. [Online ahead of print].
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Migraine is a highly prevalent and debilitating condition that causes significant impairment in quality of life. Preventive therapy for migraine is indicated when migraine attacks interfere with quality of life or are frequent and debilitating. The ability to prevent migraine with pharmacologic therapy has long been a goal of both patients and their physicians. The ideal preventive (prophylactic) migraine treatment should be effective, safe, and well tolerated, with few or no contraindications, few or no drug interactions, safety in pregnancy and breastfeeding, and dosed in a manner to ease adherence.
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