Migraine preventive therapy is indicated for patients with 4 or more migraine headache days per month, significant disability associated with individual attacks, or frequent acute medication use. Other indications for preventive therapy are unusual migraine type at any frequency, (eg, brainstem aura or hemiplegic migraines), and previous migrainous infarction.1-4 Unfortunately, available preventive therapy has been inadequate even when delivered optimally, with more than 80% of patients discontinuing preventive treatment within a year of initiation.5 Reasons for discontinuation include daily dosing, lack of efficacy, safety concerns, intolerance, drug–drug interactions, cost, and the development of medication overuse headache (MOH) in patients reaching too often for abortive medications for symptomatic relief.
With the development, approval, and recent release of monoclonal antibodies (MAb) to calcitonin gene-related peptide (CGRP) or the CGRP receptor for prevention of migraine, the field of headache medicine has the first treatment specifically designed for migraine prevention. CGRP is a main inflammatory mediator in migraine pathophysiology and therefore provides a useful target for therapy (Table 1).6-12
Oral Preventive Medications
When considering migraine preventive treatment, it is important to distinguish between episodic migraine (fewer than 15 headache days monthly) (EM) and chronic migraine (15 or more headache days monthly) (CM). Of the oral preventives listed in Tables 2 and 3, topiramate has the most evidence for treatment of CM. Use of topiramate is limited, however, by cognitive side effects and contraindications in pregnancy. In contrast, topiramate can be helpful for people with comorbid epilepsy or idiopathic intracranial hypertension.
It is helpful to obtain a detailed history to identify potential triggers and identify comorbidities, such as depression and anxiety. Effectively identifying common comorbidities can guide medication choices for migraine prevention. For example, if a patient is hypertensive, a beta-blocker may be considered, or, if a patient has comorbid depression, a tricyclic antidepressant or venlafaxine may be considered. Pregnancy and pregnancy planning are also important factors to consider; for example, topiramate may interfere with the metabolism of oral contraceptives and render them ineffective. (See Migraine During Pregnancy in this issue.)
If a patient with CM does not respond to at least 1 medication from at least 2 classes of oral medications, botulinum toxin is an option. It is important to note that MAb CGRP antagonists have changed the treatment landscape significantly. With this migraine-specific preventive treatment available as a monthly injection, many patients choose to use it as a first option.
It is not necessary for the nonmigraine specialist to be familiar with all preventive treatment options available. Each practitioner should become comfortable with offering 1 option from each class of oral medication and at least 1 therapeutic MAb. More important than being able to deliver preventive treatments is being able to recognize when prevention is needed and refer appropriately.
Injectable Preventive Medications
OnabotulinumtoxinA is approved by the Food and Drug Administration (FDA) for prevention of CM (Table 4). It would be an understatement to say that its entry into the arsenal for migraine was short of revolutionary (See Procedural Treatments for Headache Disorders in this issue). OnabotulinumtoxinA does not cross the blood-brain barrier, and it is thought to prevent CM by blocking CGRP release from peripheral C fibers.12,30
The CGRP Monoclonal Antibodies
In 2018, the FDA approved 3 MAb CGRP antagonists for prevention of EM and CM (ie, erenumab, fremanezumab, and galcanezumab) (see Table 4). In clinical trials, all 3 MAbs show clinical improvement through reduced headache frequency compared with placebo for patients with EM and CM. The profiles of these 3 medications are similar, with rapid onset of action, minimal side effects, ability to initiate at therapeutic doses without titration, and parenteral administration monthly or quarterly via self-administered subcutaneous injection. These attributes will likely increase patient adherence.
The MAb CGRP antagonists are approved to prevent both episodic and CM, whereas onabotulinumtoxinA is approved to prevent CM only. There are no head-to-head trials comparing the MAbs to onabotulinumtoxinA. Ease of administration and rapid onset of action are 2 benefits of using the MAbs. They are packaged in disposable prefilled autoinjectors or disposable prefilled syringes.
The MAbs have a serum half-life of 20 to 50 days,27 allowing monthly or quarterly injections, which translates to increased patient adherence vs oral prophylactic medications. The parenteral delivery route bypasses the decreased gastrointestinal absorption that often accompanies migraine, resulting in greater bioavailability than oral agents. As with most subcutaneous injections, the bioavailability of the CGRP antagonists ranges from 40% to 74%.28,29 In contrast to oral preventive medications, which require up to 3 months to reach therapeutic doses and maximal efficacy and onabotulinumtoxinA, which can take 2 to 3 cycles to demonstrate benefit, the MAbs are effective as early as 1 week, and produce meaningful reduction in migraine days per month within 1 month.30
The safety profile of all 3 MAbs is close to that of placebo. Treatment-related adverse effects in clinical trials were injection site reactions for all 3 MAbs plus constipation for erenumab; postmarketing data suggest that constipation may be a side effect of all 3. Because CGRP is involved in cardiovascular homeostasis, glomerular filtration, bone metabolism, and the gastrointestinal mucosa,31-33 there needs to be close monitoring for adverse effects postmarketing. Whether chronic blockade of CGRP, a potent vasodilatory agent, results in hypertension and cardiac dysfunction and impedes its safeguard action in the face of cardiac and cerebral ischemia is of particular concern.34,35 Patients who received 140 mg of erenumab intravenously had no change from baseline in exercise duration, time to onset of ST segment depression, or time to onset of exercise-induced angina compared with those who took placebo; this was interpreted as a 97.6% likelihood of cardiovascular safety.36 A low percentage of patients using the MAb CGRP antagonists develop antidrug antibodies (1%-18%), which may explain why no immunoallergic hypersensitivity reactions have been seen to date.37,38 The significance of antidrug antibodies remains unclear, and longitudinal monitoring will be necessary to determine if they reduce therapeutic effectiveness. A possible explanation for why there have been no serious immune-mediated adverse interactions is that these MAbs are human or fully humanized with few to no nonhuman amino acids. Because these MAbs are eliminated by the reticuloendothelial system and not metabolized by the liver or the kidney, there are fewer potential drug-drug interactions.11 Without breakdown into peptides and amino acids, no toxic metabolites are produced.39
Differences among erenumab, fremanezumab, and galcanezumab are in dosages and intervals of administration (Table 4) and whether the antibody binds to CGRP or the CGRP receptor. Erenumab has been shown to work equally well in persons with CM who have or who do not have concomitant MOH40,41 compared with topiramate, which did not perform as well in patients with migraine plus MOH.30 Erenumab may resolve medication overuse in patients with CM.40
Erenumab. Because a less selective monoclonal antibody could be more likely to cause adverse side effects,42 it is notable that erenumab is highly selective for the CGRP receptor. Evaluated in patients whose migraine was not prevented by 2 or more prophylactic agents,30 erenumab proved beneficial in those patients with more refractory migraine. Erenumab is the only 1 of the 3 MAbs that is fully human and is administered in 1 or 2 doses of 70 mg monthly via an autoinjector.42,43 The response is dose-dependent with a 10.5 day decrease in migraine days per month at 52 weeks with the 140-mg dose and an 8.5 day decrease in migraine days per month at 52 weeks with the 70-mg dose compared to baseline.44 In the open-label extension trial for erenumab, 65% of patients experienced a 50% or greater reduction in headache days, 42% experienced a 75% or greater reduction in headache days, and 26% experienced a 100% reduction in headache days.45 In the pivotal trial of erenumab for CM, after 1 year in the open-label extension, patients had 10.5 fewer migraines per month, which translates to a 4-month drop in migraines per year.46
Fremanezumab. A 95% fully humanized MAb (remaining 5% is murine) that binds CGRP, fremanezumab was also studied in patients with migraine refractory to treatment.47 Fremanezumab is administered monthly via a prefilled 225-mg syringe or quarterly with the injection of 3 syringes (total 675 mg). This flexibility may be desirable for patients who have difficulty adhering to monthly injections because the quarterly injections can are administered in the physician’s office. In a placebo-controlled add-on trial for both EM and CM, use of fremanezumab in combination with other migraine prophylactic agents (eg, anticonvulsants, antidepressants, and beta-blockers), patients had close to a 50% reduction in headache days.47 In an open-label extension trial, Migraine Disability Assessment Scale (MIDAS) scores continued to drop over 6 months in patients who had monthly injections.48,49
Galcanezumab. A 90% fully humanized MAb (the remaining 10% is murine), galcanezumab binds to CGRP and is administered with a loading dose of 2 injections of 120 mg followed by monthly 120-mg injections. In clinical trials, 62% of patients treated with 120 mg of galcanezumab had a 50% or more reduction in the number of migraine days per month, 39% had more than a 75% reduction. For those with EM treated with galcanezumab, 16% had an average of 1 month of headache freedom during the 6-month study.50
Access. Insurance coverage may drive how these drugs fit into our treatment paradigm. Given the safety and efficacy of the MAbs, they could be used as first-line treatment; however, they are expensive, and many insurance companies require documentation of patients’ migraine being refractory to treatment with 2 or 3 different oral prophylactic agents before approving the MAbs. Further, some insurance companies will not approve this therapy for 4 months after the last set of onabotulinumA injections—a requirement can increase patient disability while patients await treatment approval.
The field of headache medicine and the therapeutic options available to patients and physicians have expanded dramatically in just the last year. Several of the oral preventive medications and onabotulinumtoxinA continue to offer excellent migraine prevention to many patients. The addition of the anti-CGRP and anti-CGRP receptor MAbs to the physician’s armamentarium has revolutionized migraine treatment. Our focus now must include ascertaining the long-term safety profile of these agents, encouraging untreated patients to seek treatment, and overcoming insurance barriers to make these advances available to all patients with migraine.
CDL is a member of the Amgen Advisory Board and a BeCare Link Medical advisor. SS has nothing to disclose.
1. Lehman C. The CGRP antagonists are here. Now how do you use them? Neurology Today. 2019;19(1):1, 23-34.
2. Silberstein SD. Preventive migraine treatment. Continuum. 2015;21(4 Headache):973-989.
3. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55(6):754-762.
4. Dodick DW, Silberstein SD. Migraine prevention. Pract Neurol. 2007;7(6):383-393.
5. Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-488.
6. Estemalik E, Tepper S. Preventive treatment in migraine and the new US guidelines. Neuropsychiatr Dis Treat. 2013;9:709-720.
7. Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol. 2013;75:365-391.
8. Amin FM, Asghar MS, Hougaard A, et al. Magnetic resonance angiography of intracranial and extracranial arteries in patients with spontaneous migraine without aura: a cross-sectional study. Lancet Neurol. 2013;12:454-461.
9. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the quality standards subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1137-1345.
10. Lassen LH, Haderslev PA, Jacobsen VB, et al. CGRP may play a causative role in migraine. Cephalalgia. 2002;22:54-61.
11. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019;59:1-18.
12. Zhang X, Strassman AM, Novack V, Brin MF, Burstein R. Extracranial injections of botulinum neurotoxin type A inhibit intracranial meningeal nociceptors’ responses to stimulation of TRPV1 and TRPA1 channels: are we getting closer to solving this puzzle? Cephalalgia. 2016;36:875-886.
13. Brandes JL, Saper JR, Diamond M, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291(8):965-973.
14. Storey JR, Calder CS, Hart DE, Potter DL. Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache. 2001;41:968-975.
15. Freitag FG, Collins SD, Carlson HA, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 2002;58(11):1652-1659.
16. Shaygannejad V, Janghorbani M, Ghorbani A, et al. Comparison of the effect of topiramate and sodium valproate in migraine prevention: a randomized blinded crossover study. Headache. 2006;46:642-648.
17. Diener HC, Tfelt-Hansen P, Dahlof C, et al. Topiramate in migraine prophylaxis: results from a placebo-controlled trial with propranolol as an active control. J Neurol. 2004;251(8):943-950.
18. Diener HC, Hartung E, Chrubasik J, et al. A comparative study of oral acetylsalicylic acid and metoprolol for the prophylactic treatment of migraine. A randomized, controlled, double-blind, parallel group phase III study. Cephalalgia. 2001;21(2):120-128.
19. Stellar S, Ahrens SP, Meibohm AR, Reines SA. Migraine prevention with timolol: a double-blind crossover study. JAMA. 1984;252(18):2576-2580.
20. Edvardsson B. Atenolol in the prophylaxis of chronic migraine: a 3-month open-label study. Springerplus. 2013;2:479.
21. Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, Disci R. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. 2005;45: 144-152.
22. Saper JR, Silberstein SD, Lake AE, Winters ME. Double-blind trial of fluoxetine: chronic daily headache and migraine. Headache. 1994;34:497-502.
23. Keskinbora K, Aydinli I. A double-blind randomized controlled trial of topiramate and amitriptyline either alone or in combination for the prevention of migraine. Clin Neurol Neurosurg. 2008;110(10):979-984.
24. Ziegler DK, Ellis DJ. Naproxen in prophylaxis of migraine. Arch Neurol. 1985;42(6):582-584.
25. Millán-Guerrero RO, Isais-Millán R, Barreto-Vizcaíno S, et al. Subcutaneous histamine versus sodium valproate in migraine prophylaxis: a randomized, controlled, double-blind study. Eur J Neurol. 2007;14:1079-1084.
26. Rai BS, Das DG, TaraKnath VR, Sarma Y. A double blind controlled study of propranolol and cyproheptadine in migraine prophylaxis. Neurol India. 2000;48(3)223-226.
27. Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies: successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):338-350.
28. Ju MS, Jung ST. A glycosylated full-length IgG antibodies: steps toward next-generation immunotherapeutics. Curr Opin Biotechnol. 2014;30:128-139.
29. Monteith D, Collins EC, Vandermeulen C, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the CGRP binding monoclonal antibody LY2951742 (galcanezumab) in healthy volunteers. Front Pharmacol. 2017;8:740.
30. Tepper SJ. History and review of anti-calcitonin gene-related peptide (CGRP) therapies: from translational research to treatment. Headache. 2018;58:238-275.
31. Gnaedinger MP, Uehlinger DE, Weidmann P, et al. Distinct hemodynamic and renal effects of calcitonin gene-related peptide and calcitonin in man. Am J Physiol. 1989;257:E848-E854.
32. Bernard GW, Shih C. The osteogenic stimulating effect of neuroactive calcitonin gene-related peptide. Peptides. 1990;11:625-632.
33. Lenz HJ, Mortrud MT, River JE, Brown MR. Central nervous system actions of calcitonin gene-related peptide on gastric acid secretion in the rat. Gastroenterology.1985;88:539-544.
34. MaassenVanDenBrink A, Meijer J, Villalon CM, Ferrari MD. Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci. 2016;37:779-788.
35. Aubdool AA, Argunhan F, Thakore P, Brain SD. A novel alpha-calcitonin gene-related peptide analogue protects against end-organ damage in experimental hypertension, cardiac hypertrophy, and heart failure. Circulation. 2017;137(11):367-383.
36. Depre C, Antalik L, Starling A, et al. A randomized, double-blind, placebo-controlled study to evaluate the effect of erenumab on exercise time during a treadmill test in patients with stale angina. Headache. 2018;58(5):715-723.
37. Stallmach A, Giese T, Schmidt C, Meuer SC, Zeuzem SS. Severe anaphylactic reaction to infliximab: successful treatment with adalimumab: report of a case. Eur J Gastroenterol Hepatol. 2004;26:627-630.
38. Adkins JC, Spencer CM. Edrecolomab (monoclonal antibody 17-1A). Drugs. 1998;56:619-626.
39. Silberstein S, Lenz R, Xu C. Therapeutic monoclonal antibodies: what the headache specialists needs to know. Headache. 2015;55(8):1171-1182.
40. Pellesi L, Guerzoni S, Pini LA. Spotlight on anti-CGRP monoclonal antibodies in migraine: the clinical evidence to date. Clin Pharm Drug Dev. 2017;6(6):534-547.
41. Tepper SJ, Diener H-C, Ashina M, et al. EP-01-013 Efficacy of erenumab for the treatment of patients with chronic migraine in presence of medication overuse (E-poster). Presented at: 18th International Headache Congress; September 8, 2017; Vancouver.
42. Shi L, Lehto SG, Zhu DX, et al. Pharmacologic characterization of AMG 334, a potent and selective human monoclonal antibody against the calcitonin gene-related peptide receptor. J Pharmacol Exp Ther. 2016;356:223-231
43. Tepper SJ. Anti-calcitonin gene-related peptide (CGRP) therapies: update on a previous review after the American Headache Society 60th Scientific Meeting, San Francisco, June 2018. Headache. 2018;58:276-290.
44. Tepper SJ , Ashina M, Reuter U, et al. Assessment of the long-term safety and efficacy of erenumab during open-label treatment in subjects with chronic migraine (poster PF115LB) (E-poster, late-breaking abstracts). Presented at: American Headache Society 60th Scientific Meeting; June 2018; San Francisco.
45. Edvinsson L. Headache advances in 2017: a new horizon in migraine therapy. Lancet. 2018;17:5-6.
46. Tepper S, Ashina M, Reuter U, et al. P24 Assessment of the long-term safety and efficacy of erenumab during open-label treatment of subjects with chronic migraine (E-poster). Presented at: 12th European Headache Federation Congress; September 28, 2018; Florence.
47. Ashina M, Goadsby P, Silberstein SD, et al. Safety and tolerability of erenumab: Three-plus year results from on ongoing open-label extension study in episodic migraine. Poster IOR01. Headache. 2018;58(suppl 2):72-73.
48. Brandes J, Yeung PP, Cohen JM, et al. Long-term impact of fremanezumab on response rates, acute headache medication use, and disability in patients with episodic migraine: interim results of a one-year study. Poster PS35. Headache. 2018;50(suppl 2):170.
49. Dodick DW, Silberstein SD, Bigal ME, et al. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018;319:1999-2008.
50. Stauffer VL, Dodick DW, Zhang Q, et al. Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol. 2018:75(9):1080-1088.