Drugs for Migraine Prophylaxis

Background: Frequent or severe migraine attacks are an indication for drug and nondrug prophylaxis.

Methods: In this narrative review, we summarize the guideline of the International Headache Society concerning the treatment and prophylaxis of migraine with drugs, with additional consideration of meta-analyses on monoclonal antibodies and gepants.

Results: In episodic migraine with an average of 8 migraine or headache days/month at baseline, oral prophylactic drugs lowered the number of migraine days per month by 1.27 (beta-blockers), 0.44 (flunarizine), 1.2 (amitriptyline), and 1.4 (topiramate) compared to placebo. Monoclonal antibodies against calcitonin gene–related peptide (CGRP) or the CGRP receptor are effective in both episodic and chronic migraine: Eptinezumab lowered the number of migraine days per month by 0.7–3.2, fremanezumab by 1.3–3.8, galcanezumab by 1.1–3.7, and erenumab by 1.0–2.5. High-level evidence also supports the efficacy of the CGRP receptor antagonist atogepant (0.7–2.4 fewer migraine days per month) in both episodic and chronic migraine. The monoclonal antibodies, atogepant, and onabotulinumtoxinA are well-tolerated and have been found effective even in patients for whom previous oral migraine prophylactic drugs were ineffective, as well as in chronic migraine both with and without acute drug overuse.

Conclusion: The new prophylactic drugs against migraine are effective, well-tolerated, and especially useful for patients for whom traditional oral migraine prophylactic drugs and onabotulinumtoxinA are ineffective, not tolerated, or contraindicated.

Cite this as: Diener HC, Grans J, Reuter U: Drugs for migraine prophylaxis. Dtsch Arztebl Int 2026; 123: 119–26. DOI: 10.3238/arztebl.m2025.0234

The prevalence of migraine in Germany is about 14.8% in women and 6.0% in men (1). The management of migraine consists of two strategies: treatment of acute migraine attacks and migraine prophylaxis aimed at preventing migraine headaches. Migraine prophylaxis, in turn, can be divided into prophylaxis with drugs and without drugs. (2). Three types of migraine are distinguished (3):

• Episodic migraine, defined as less than 15 headache days per month
• Chronic migraine, defined as having headache for more than three months on at least 15 days per month, with at least eight of these headaches meeting the criteria for migraine attack
• Chronic migraine with overuse of analgesics or anti-migraine drugs (medication overuse headache, MOH). With this type of migraine, standard pain killers are used on at least 15 days; or, on at least 10 days, combination analgesic preparations, specific anti-migraine drugs, such as triptans, or opioids are used (4).

The line between frequent episodic migraine and chronic migraine is not clearly drawn. Furthermore, migraine can improve spontaneously over time or even stop completely with advancing age.

Migraine prophylaxis with drugs is indicated in patients with four or more headache days per month, if the migraine attacks have a negative impact on lifestyle and if acute treatment of migraine attacks is not satisfactorily effective, contraindicated or not tolerated (2). An additional criterion is met, if the migraine attacks affect the patient‘s private life, professional life or social environment. About 20–30% of patients with migraine are eligible for migraine prophylaxis. In the following, we will discuss the pharmacological prophylaxis of migraine with a focus on recent advances. For the non-drug prophylaxis of migraine, please refer to the guideline of the German Society of Neurology (DGN, Deutsche Gesellschaft für Neurologie) (2). Pharmacological migraine prophylaxis plays a particularly important role, if the frequency of migraine attacks is increasing or if there is a risk of overuse of anti-migraine drugs or pain medication. Reduction in the number of migraine attacks per month by 50% in patients with episodic migraine and by 30% in patients with chronic migraine is considered a successful treatment outcome.

Methods

This narrative review is based on the Evidence-based Guidelines for the Pharmacological Treatment of Migraine (5) and other relevant literature. The information provided in the guideline (eMethods) is based on pertinent publications retrieved by a systematic literature search in several databases, adherence to Cochrane methods, and a structured framework in the GRADE system for data extraction and interpretation (5, 6). In the case of recommendations that are not adequately supported by evidence from prospective randomized trials, we refer to the practice recommendations of the International Headache Society (7).

Results

Beta-blockers

Beta-blockers are a class of drugs that can effectively be used for the prophylaxis of migraine. With more than 50 studies each, propranolol und metoprolol are the most extensively evaluated drugs of this class. Meta-analyses and reviews have confirmed the preventative effect of beta-blockers (8, 9, 10). One of the meta-analyses included 108 randomized controlled trials, 50 placebo-controlled trials and 58 comparative efficacy trials on propranolol. In patients with episodic migraine, propranolol reduced the number of headache days by 1.5 days/month (95% confidence interval: [−2.3; −0.65]) (10, 11). The most commonly used daily dose of propranolol was 160 mg.

Various studies have demonstrated the superiority of metoprolol at a dose of 200 mg over placebo in patients with episodic migraine (12, 13). The potency of metoprolol is comparable to that of propranolol (14). No placebo-controlled trials evaluating the efficacy of beta-blockers for chronic migraine or MOH have yet been conducted.

Flunarizine

To date, the efficacy, tolerability and safety of flunarizine in patients with migraine have been evaluated in a total of 25 studies. The majority of these studies are methodologically flawed (15). Only five studies with a total of 249 participants were eligible for inclusion in a meta-analysis (16). In comparison to placebo, only a reduction of 0.44 attacks in four weeks was found for the endpoint of headache frequency [−0.61; −0.26]. No studies on the efficacy of flunarizine for chronic migraine or MOH are available.

Amitriptyline

The available evidence to support the efficacy of amitriptyline for migraine is very limited, since only a small number of studies conducted a long time ago exist. A systematic literature search found only three randomized, placebo-controlled trials with a total of 389 patients (17). Only one of these studies with 118 participants found a reduction by 1.2 migraine days per month compared to placebo (18). Since all studies included only patients with episodic migraine, no data on the efficacy of amitriptyline in chronic migraine or MOH are available.

Topiramate

Numerous randomized controlled studies have shown that topiramate is effective in the prophylaxis of episodic migraine (19, 20, 21). A meta-analysis of eight randomized, placebo-controlled trials with topiramate in doses of 50mg to 200 mg per day found a mean reduction in migraine days per month of 0.89–1.4 days (11). Patients treated with topiramate experienced increased numbers of adverse drug reactions, resulting in discontinuation of treatment. Among these were cognitive side effects, which occurred almost exclusively in the titration phase (22), and also depressive moods. Smaller studies and subgroup analyses also provide evidence of its effectiveness in chronic migraine and medication overuse headache (21, 23, 24). Topiramate for migraine prophylaxis is contraindicated in pregnancy.

OnabotulinumtoxinA

Two large placebo-controlled phase III trials including a total of 1384 patients showed the efficacy of onabotulinumtoxinA in chronic migraine (PREEMPT 1 and 2) (25, 26). BoNT-A was injected intramuscularly into 31 sites located on the head, face and neck. The pooled analyses of the two studies found a significant difference for the primary endpoint. In the active arm, the number of headache days decreased by 8.4 days compared to the baseline value of 20 days, while the reduction in the placebo arm was 6.6 days (p<0.001) (27). All further secondary endpoints were also encouraging, except for the frequency of use of acute headache pain medication. Noteworthy in these studies was the high improvement rate achieved with placebo compared to active treatment. The placebo effect is stronger with parenteral administration compared to oral administration (28). The most common treatment-related side effects were neck pain, muscle weakness and ptosis. In patients with acute headache medication overuse (65.3% of patients) and chronic migraine, onabotulinumtoxinA treatment led to a reduction of the primary endpoint by −8.2 days in the active arm and −6.2 days in the placebo arm, respectively (p<0.001) (29). The findings of the PREEMPT trials on the efficacy and tolerability of BoNT-A treatment were confirmed in several further studies (30).

In summary, BoNT-A is effective in the prophylaxis of chronic migraine. This applies to patients with and without overuse of acute headache medication. BoNT-A is not effective in patients with episodic migraine. It can be used during pregnancy in patients with chronic migraine (31).

Monoclonal antibodies against calcitonin gene-related peptide or its receptor

Calcitonin gene-related peptide (CGRP), a neuropeptide playing a key role in the pathophysiology of migraine, is released during a migraine attack. Four monoclonal antibodies have been developed for the prophylaxis of episodic and chronic migraine. Three of these monoclonal antibodies are ligand antibodies, binding to the CGRP molecule: eptinezumab, fremanezumab, galcanezumab. The fourth antibody binds to the CGRP receptor (erenumab). The efficacy of the four monoclonal antibodies was evaluated in large phase III trials. All antibodies are significantly more effective compared to placebo (Tables 1–3). For episodic migraine and chronic migraine, the 50% responder rates ranged from 40% to 62% (32) and 40% to 56%, respectively (33). For erenumab, a head-to-head comparison to topiramate is available (34) which found that erenumab was significantly more effective and better tolerated compared to topiramate. The number of treatment discontinuations due to adverse drug reactions was significantly lower.

A meta-analysis of 17 placebo-controlled trials on episodic migraine found a significant reduction in migraine days per month by 0.7–2.1 days, with a baseline value of nine migraine days (35). These trials also found superiority of monoclonal antibodies over placebo with respect to all secondary endpoints and, in particular, with regard to patient-relevant endpoints, such as quality of life and limitations in everyday life (Table 1).

Table 1

Changes in migraine days per month after preventive drug treatment for episodic migraine compared to placebo (original data)

In patients with chronic migraine, monoclonal antibodies are more effective compared to placebo (35, 36, 37, 38) (Table 2). All placebo-controlled trials evaluating the efficacy of monoclonal antibodies in chronic migraine had subgroups of patients with MOH. These subgroups accounted for 40–60% of the participants. In these subgroups, monoclonal antibodies were equally effective as in patients without MOH (39, 40). For erenumab, a specifically designed, randomized, placebo-controlled trial is available, evaluating patients with medication overuse headache, excluding patients with overuse of opioids (e1). At six months, 134 participants (69.1%) in the group receiving a dose of 140 mg erenumab (odds ratio = 2.01 [1.33; 3.05]; p<0.001 versus placebo) and 117 participants (60.3%) receiving a dose of 70 mg erenumab (odds ratio = 1.37 [0.92; 2.05]; p = 0.13 compared to placebo) achieved MOH remission compared to 102 participants in the placebo group (52.6%). In summary, all monoclonal antibodies demonstrated efficacy in the treatment of patients with chronic migraine and MOH (Tables 2 and 3).

Table 2

Changes in migraine days per month after preventive drug treatment for chronic migraine compared to placebo (original data)

Table 3

Changes in migraine days per month after preventive drug treatment for episodic migraine and chronic migraine compared to placebo (original data)*1

Monoclonal antibodies are, in general, well tolerated (33, e2, e3). Rare adverse drug reactions include local reactions at the injection site (5–10%), nasopharyngitis (3–5%), constipation (5–10%), hypertension (<1%), and, in extremely rare cases, anaphylactic reactions (e4). Head-to-head comparisons of the various monoclonal antibodies have not yet become available (eBox).

eBox

Open questions

In most patients, the rapid onset of the effect of monoclonal antibodies allows to decide within a period of four weeks whether patients have responded to the antibody treatment and whether the treatment should be continued. In individual cases, however, it is necessary to wait three to six months before it can be determined whether or not the treatment is effective (e5).

If a monoclonal antibody fails to produce a satisfactory effect, the use of another monoclonal antibody can be attempted. (e6). In the case of ligand antibodies, treatment should then be switched to erenumab, and if erenumab proves ineffective, to eptinezumab, fremanezumab or galcanezumab. However, switching of the antibody is less effective in migraine patients with daily headache (e6).

The fastest onset of action is observed after intravenous administration of eptinezumab (e7). Open-label long-term studies have demonstrated the sustained effectiveness of monoclonal antibodies over a period of up to five years (e8, e9). To date, no adverse drug reactions exceeding those observed in placebo-controlled studies have been noted in long-term studies.

Atogepant

Atogepant is a competitive, selective antagonist of the human CGRP receptor (e10, e11). In a double-blind phase III trial, 873 adults with episodic migraine and 4 to 14 migraine days per month were randomized into the following four treatment arms (e12): 

• Placebo
• Atogepant 10 mg
• Atogepant 30 mg
• Atogepant 60 mg.

At week twelve, the changes compared to baseline were −4.2 and −2.5 migraine days per month for atogepant 60 mg (N = 214) and placebo (N = 222), respectively (Table 1). The 50% responder rates at three months were 60.8% in the atogepant 60 mg group and 29% in the placebo group (p<0.001).

In another trial, adults aged 18 to 80 years with chronic migraine for at least one year were randomized into the following groups (e13):

• Atogepant 30 mg twice a day
• Atogepant 60 mg once a day
• Placebo.

The mean number of migraine days per month at the start of trial was 18.6 days. The reduction in migraine days per month at 12 weeks was 7.5 days, 6.9 days and 5.1 days with atogepant 30 mg twice a day, atogepant 60 mg once a day, and placebo, respectively (Table 2). The 50% responder rates were 26%, 43% and 41% in the groups receiving placebo, atogepant 30 mg twice a day and atogepant 60 mg once a day, respectively.

In a subgroup analysis of the PROGRESS trial, atogepant was effective in patients with chronic migraine with and without acute medication overuse. Evidence of this was provided by the reduction in the mean number of migraine days per month and days of acute medication use, as well as the reduction in the proportion of participants who met the criteria for acute medication overuse (e14).

Atogepant is very well tolerated and its concentration can be easily controlled due to its short half-life. Hypersensitivity reactions may occur in very rare cases. Other rare adverse drug reactions include nausea (6%), constipation (4–6%), fatigue (4%), drowsiness (3%), and loss of appetite (2%). In summary, atogepant at a dose of 60 mg per day for the prophylaxis of episodic and chronic migraine is effective and approved for use in Europe. To date, no comparative studies have been published on oral drugs for migraine prophylaxis or onabotulinumtoxinA and no comparative studies on monoclonal antibodies.

Rimegepant

Rimegepant is a CGRP receptor antagonist that was developed for both the treatment of acute migraine attacks and for migraine prophylaxis. Its efficacy in migraine prophylaxis was evaluated in a 12-week, randomized, double-blind, placebo-controlled trial (e15). Participants received either rimegepant 75 mg or placebo once every other day. A total of 747 patients with episodic migraine were treated. The number of monthly migraine days in patients treated with rimegepant was found significantly reduced at nine to twelve weeks. Compared to the baseline value of ten days, it was −4.3 days and −3.5 days in the rimegepant and placebo groups, respectively. The 50% responder rate was 49% for rimegepant and 41% for placebo. The most common adverse drug reactions observed with rimegepant were nasopharyngitis and nausea, seen in 4% and 3% of patients, respectively.

According to indirect comparisons, the efficacy of oral treatment with rimegepant is lower than that of antibody treatments (35). However, the only direct comparative study found no difference in efficacy and tolerability between galcanezumab and rimegepant (e16). In the European Union, rimegepant has only been approved for the prophylaxis of episodic migraine.

Recommendations for the prophylaxis of migraine

Tables 4 and 5 list dosages, adverse drug reactions and contraindications for traditional oral migraine prophylactic drugs and onabotulinumtoxinA as well as for monoclonal antibodies against CGRP and the CGRP receptor and for CGRP receptor antagonists (adapted from [2]).

Table 4

Traditional oral migraine prophylactic drugs and onabotulinumtoxinA (adapted from [2, 5, e47])

Table 5

Monoclonal antibodies and gepants for migraine prophylaxis (adapted from 2, 5, e47)

Conclusions

In patients with episodic migraine, traditional prophylactic drugs against migraine can be used. This includes the beta-blockers propranolol and metoprolol, and the antiepileptic drug toparimate. Flunarizine and amitriptyline are less effective. All monoclonal antibodies against CGRP as well as the CGRP receptor antagonists atogepant and rimegepant are effective in the treatment of episodic migraine and have a very favorable side effect profile.

The effectiveness of beta-blockers, flunarizine and amitriptyline in the treatment of chronic migraine is not sufficiently supported by scientific evidence. The use of topiramate for this type of migraine is supported by weak evidence. OnabotulinumtoxinA as well as monoclonal antibodies and atogepant are effective in the treatment of chronic migraine.

The effectiveness of onabotulinumtoxinA in patients with chronic migraine and MOH has been demonstrated in various studies. In studies on the prophylaxis of chronic migraine, post-hoc analyses showed superiority over placebo for monoclonal antibodies and atogepant in subgroups of patients with MOH. For everyday clinical practice, the International Headache Society (HIS) has published practical recommendations that cover the 16 most important questions related to migraine prophylaxis (7).

Conflict of interest
HCD received lecture fees from Lundbeck, Betapharm, Orion, and WebMD. He received consulting fees from Orion Pharma and is a member of the Advisory Board of Ipsen Pharma. HCD received reimbursement of congress fees and travel expenses from Lundbeck. He is the editor of Arzneimitteltherapie, Info Neurologie & Psychiatrie and Neurologie Up2date. The headache research by HCD is supported by the German Research Foundation (DFG, Deutsche Forschungsgemeinschaft). HCD is lead author of the migraine guideline of the German Society of Neurology (DGN) and the German Migraine and Headache Society (DMKG).

UR received institutional lecture fees and consulting fees from AbbVie, Lundbeck, Novartis, Lilly, Pfizer, and TEVA. He received financial support for headache research from Novartis Pharma. UR is President of the European Headache Federation and Associate Editor of the Journal of Headache and Pain. He is contributing to the development of the guideline Migraine.

JG declares no conflict of interests.

Manuscript received on 1 August 2025; revised version accepted on
8 December 2025

Translated from the original German by Ralf Thoene, M.D.

Corresponding author
Prof. Dr. Hans Christoph Diener

References

1. Porst M, Wengler A, Leddin J, et al.: Migraine and tension-type headache in Germany. Prevalence and disease severity from the BURDEN 2020 Burden of Disease Study. J Health Monit 2020; 5: 2–24

2. Diener HC, Förderreuther S, Kropp P, Reuter U, et al.: Therapie der Migräneattacke und Prophylaxe der Migräne, S1-Leitlinie. DGN und DMKG, in: Deutsche Gesellschaft für Neurologie (eds.), Leitlinien für Diagnostik und Therapie in der Neurologie 2025. www.dgn.org/leitlinien (last accessed on 19 January 2026).

3. Headache Classification Committee of the International Headache Society (IHS): The international classification of headache disorders ICHD-3, 3rd edition. Cephalalgia 2018; 38: 1–211.

4. Ashina S, Terwindt GM, Steiner TJ, et al.: Medication overuse headache. Nat Rev Dis Primers 2023; 9: 5.

5. Ornello R, Caponnetto V, Ahmed F, et al.: Evidence-based guidelines for the pharmacological treatment of migraine, summary version. Cephalalgia 2025; 45: 3331024251321500.

6. Ornello R, Caponnetto V, Ahmed F, et al.: Evidence-based guidelines for the pharmacological treatment of migraine. Cephalalgia 2025; 45: 3331024241305381.

7. Puledda F, Sacco S, Diener HC, et al.: International Headache Society global practice recommendations for preventive pharmacological treatment of migraine. Cephalalgia 2024; 44: 3331024241269735.

8. Holroyd KA, Penzien DB, Cordingley GE: Propranolol in the management of recurrent migraine: A meta-analytic review. Headache 1991; 31: 333–40.

9. Silberstein SP, Goadsby PB: Migraine: Preventive treatment. Cephalalgia 2002; 22: 491–512.

10. Jackson JL, Kuriyama A, Kuwatsuka Y, et al.: Beta-blockers for the prevention of headache in adults, a systematic review and meta-analysis. PLoS One 2019; 14: e0212785.

11. Jackson JL, Cogbill E, Santana-Davila R, et al.: A comparative effectiveness meta-Analysis of drugs for the prophylaxis of migraine headache. PLoS One 2015; 10: e0130733.

12. Kangasniemi P, Andersen AR, Andersson PG, et al.: Classic migraine: effective prophylaxis with metoprolol. Cephalalgia 1987; 7: 231–8.

13. Steiner TJ, Joseph R, Hedman C, Clifford Rose F: Metoprolol in the prophylaxis of migraine: parallel group comparison with placebo and dose-ranging follow-up. Headache 1988; 28: 15–23.

14. Linde K, Rossnagel K: Propranolol for migraine prophylaxis. Cochrane Database Syst Rev 2004: CD003225.

15. Stubberud A, Flaaen NM, McCrory DC, Pedersen SA, Linde M: Flunarizine as prophylaxis for episodic migraine: A systematic review with meta-analysis. Pain 2019; 160: 762–72.

16. Deligianni CI, Sacco S, Ekizoglu E, et al.: European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 2: Flunarizine. J Headache Pain 2023; 24: 128.

17. Lampl C, Versijpt J, Amin FM, et al.: European Headache Federation (EHF) critical re-appraisal and meta-analysis of oral drugs in migraine prevention-part 1: Amitriptyline. J Headache Pain 2023; 24: 39.

18. Couch JR: Amitriptyline in the prophylactic treatment of migraine and chronic daily headache. Headache 2011; 51: 33–51.

19. Brandes J, Saper J, Diamond M, et al.: Topiramate for migraine prevention: A randomized controlled trial. JAMA 2004; 291: 965–73.

20. Diener HC, Tfelt-Hansen P, Dahlöf C, et al.: Topiramate in migraine prophylaxis: Results from a placebo-controlled trial with propranolol as an active control. J Neurol 2004; 251: 943–50.

21. Silberstein SD, Lipton RB, Dodick DW, et al.: Efficacy and safety of topiramate for the treatment of chronic migraine: A randomized, double-blind, placebo-controlled trial. Headache 2007; 47: 170–80.

22. Lainez MJ, Freitag FG, Pfeil J, Ascher S, Olson WH, Schwalen S: Time course of adverse events most commonly associated with topiramate for migraine prevention. Eur J Neurol 2007; 14: 900–6.

23. Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ: Topiramate reduces headache days in chronic migraine: A randomized, double-blind, placebo-controlled study. Cephalalgia 2007; 27: 814–23.

24. Silberstein SD: Topiramate in migraine prevention: A 2016 perspective. Headache 2017; 57: 165–78.

25. Aurora SK, Dodick DW, Turkel CC, et al.: OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia 2010; 30: 793–803.

26. Diener HC, Dodick DW, Aurora SK, et al.: OnabotulinumtoxinA for treatment of chronic migraine: Results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 2010; 30: 804–14.

27. Dodick DW, Turkel CC, DeGryse RE, et al.: OnabotulinumtoxinA for treatment of chronic migraine: Pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache 2010; 50: 921–36.

28. Bruijn NRA, Huessler EM, MaassenVanDenBrink A, et al.: Placebo response in acute and prophylactic treatment of migraine: A systematic review and meta-analysis covering 36 years of research. Neurol Clin 2025; 44: 23–45.

29. Silberstein SD, Blumenfeld AM, Cady RK, et al.: OnabotulinumtoxinA for treatment of chronic migraine: PREEMPT 24-week pooled subgroup analysis of patients who had acute headache medication overuse at baseline. J Neurol Sci 2013; 331: 48–56.

30. Blumenfeld AM, Stark RJ, Freeman MC, Orejudos A, Manack Adams A: Long-term study of the efficacy and safety of OnabotulinumtoxinA for the prevention of chronic migraine: COMPEL study. J Headache Pain 2018; 19: 13.

31. Wong HT, Khan R, Buture A, Khalil M, Ahmed F: OnabotulinumtoxinA treatment for chronic migraine in pregnancy: an updated report of real-world headache and pregnancy outcomes over 14 years in Hull. Cephalalgia 2025; 45: 3331024251327387.

32. Deng H, Li GG, Nie H, et al.: Efficacy and safety of calcitonin-gene-related peptide binding monoclonal antibodies for the preventive treatment of episodic migraine—an updated systematic review and meta-analysis. BMC Neurol 2020; 20: 57.

33. Soni P, Chawla E: Efficacy and safety of anti-calcitonin gene-related peptide monoclonal antibodies for treatment of chronic migraine: A systematic review and network meta-analysis. Clin Neurol Neurosurg 2021; 209: 106893.

34. Reuter U, Ehrlich M, Gendolla A, et al.: Erenumab versus topiramate for the prevention of migraine—a randomised, double-blind, active-controlled phase 4 trial. Cephalalgia 2022; 42: 108–118.

35. Haghdoost F, Puledda F, Garcia-Azorin D, Huessler EM, Messina R, Pozo-Rosich P: Evaluating the efficacy of CGRP mAbs and gepants for the preventive treatment of migraine: a systematic review and network meta-analysis of phase 3 randomised controlled trials. Cephalalgia 2023; 43: 03331024231159366.

36. Mistry H, Naghdi S, Brown A, et al.: Preventive drug treatments for adults with chronic migraine: A systematic review with economic modelling. Health Technol Assess 2024; 28: 1–329.

37. Tepper SJ, Lipton RB, Silberstein SD, et al.: Long-term efficacy and safety of erenumab in patients with chronic migraine and acute medication overuse: A subgroup analysis. Headache 2023; 63: 730–42.

38. Frank F, Ulmer H, Sidoroff V, Broessner G: CGRP-antibodies, topiramate and botulinum toxin type A in episodic and chronic migraine: A systematic review and meta-analysis. Cephalalgia 2021; 41: 1222–39.

39. Diener HC, Rizzoli P: Chronic migraine and medication overuse. Handb Clin Neurol 2023; 198: 187–200.

40. Alpuente A, Torres-Ferrus M, Terwindt GM: Preventive CGRP-targeted therapies for chronic migraine with and without medication-overuse headache. Cephalalgia 2023; 43: 03331024221150235.

e1. Tepper SJ, Dodick DW, Lanteri-Minet M, et al.: Efficacy and safety of erenumab for nonopioid medication overuse headache in chronic migraine: A phase 4, randomized, placebo-controlled trial. JAMA Neurology 2024; 81: 1140–9.

e2. Mechtler L, Saikali N, McVige J, Hughes O, Traut A, Adams AM: Real-world evidence for the safety and efficacy of CGRP monoclonal antibody therapy added to onabotulinumtoxinA treatment for migraine prevention in adult patients with chronic migraine. Front Neurol 2022; 12: 788159.

e3. Wang X, Chen Y, Song J, You C: Efficacy and safety of monoclonal antibody against calcitonin gene-related peptide or its receptor for migraine: A systematic review and network meta-analysis. Front Pharmacol 2021; 12: 649143.

e4. Wang Q, Liu J, Sun H, et al.: Adverse event profile of CGRP monoclonal antibodies: findings from the FDA adverse event reporting database. Expert Opin Drug Saf 2024; 23: 107–17.

e5. Ailani J, Burch RC, Robbins MS, the board of directors of the American Headache Society. The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice. Headache 2021; 61: 1021–39.

e6. Overeem LH, Peikert A, Hofacker MD, et al.: Effect of antibody switch in non-responders to a CGRP receptor antibody treatment in migraine: a multi-center retrospective cohort study. Cephalalgia 2022; 42: 291–301.

e7. McAllister P, Winner PK, Ailani J, et al.: Eptinezumab treatment initiated during a migraine attack is associated with meaningful improvement in patient-reported outcome measures: Secondary results from the randomized controlled RELIEF study. J Headache Pain 2022; 23: 22.

e8. Ashina M, Goadsby PJ, Reuter U, et al.: Long-term efficacy and safety of erenumab in migraine prevention: results from a 5-year, open-label treatment phase of a randomized clinical trial. Eur J Neurol 2021; 28: 1716–25.

e9. Raffaelli B, De Icco R, Corrado M, Terhart M, Ailani J: Open-label trials for CGRP-targeted drugs in migraine prevention: A narrative review. Cephalalgia 2023; 43: 03331024221137091.

e10. Moore E, Bell IM, Fraley ME, et al.: Pharmacologic characterization of atogepant: A potent and selective calcitonin gene-related peptide receptor antagonist. Cephalalgia 2024; 44: 3331024231226186.

e11. Boinpally R, Shebley M, Trugman JM: Atogepant: mechanism of action, clinical and translational science. Clin Transl Sci 2024; 17: e13707.

e12. Ailani J, Lipton RB, Goadsby PJ, et al.: Atogepant for the preventive treatment of migraine. N Engl J Med 2021; 385: 695–706.

e13. Pozo-Rosich P, Ailani J, Ashina M, et al.: Atogepant for the preventive treatment of chronic migraine (PROGRESS): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023; 402: 775–85.

e14. Goadsby PJ, Friedman DI, Holle-Lee D, et al.: Efficacy of atogepant in chronic migraine with and without acute medication overuse in the randomized, double-blind, phase 3 PROGRESS trial. Neurology 2024; 103: e209584.

e15. Croop R, Lipton RB, Kudrow D, et al.: Oral rimegepant for preventive treatment of migraine: A phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet 2021: 397: 51–60.

e16. Schwedt TJ, Myers Oakes TM, Martinez JM, et al.: Comparing the efficacy and safety of galcanezumab versus rimegepant for prevention of episodic migraine: results from a randomized, controlled clinical trial. Neurol Ther 2024; 13: 85–105.

e17. Goadsby PJ, Dodick DW, Ailani J, et al.: Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial. Lancet Neurol 2020; 19: 727–37.

e18. Tassorelli C, Nagy K, Pozo-Rosich P, et al.: Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): A randomised, placebo-controlled, phase 3b trial. Lancet Neurol 2024; 23: 382–92.

e19. Ashina M, Saper J, Cady R, et al.: Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia 2020; 40: 241–54.

e20. Sun H, Dodick DW, Silberstein S, et al.: Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15: 382–90.

e21. Goadsby PJ, Reuter U, Hallström Y, et al.: A controlled trial of erenumab for episodic migraine. N Engl J Med 2017; 377: 2123–32.

e22. Dodick DW, Ashina M, Brandes JL, et al.: ARISE: a phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia 2018; 38: 1026–37.

e23. Sakai F, Takeshima T, Tatsuoka Y, et al.: A randomized phase 2 study of erenumab for the prevention of episodic migraine in Japanese adults. Headache 2019; 59: 1731–42.

e24. Wang SJ, Roxas AA, Jr., Saravia B, et al.: Randomised, controlled trial of erenumab for the prevention of episodic migraine in patients from Asia, the Middle East, and Latin America: the EMPOwER study. Cephalalgia 2021; 41: 1285–97.

e25. Takeshima T, Sakai F, Hirata K, et al.: Erenumab treatment for migraine prevention in Japanese patients: Efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study. Headache 2021; 61: 927–35.

e26. Reuter U, Goadsby PJ, Lanteri-Minet M, et al.: Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: A randomised, double-blind, placebo-controlled, phase 3b study. Lancet 2018; 392: 2280–7.

e27. Bigal ME, Dodick DW, Rapoport AM, et al.: Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of high-frequency episodic migraine: A multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 2015; 14: 1081–90.

e28. 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.

e29. Sakai F, Suzuki N, Kim BK, et al.: Efficacy and safety of fremanezumab for episodic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients. Headache 2021; 61: 1102–11.

e30. Ferrari MD, Diener HC, Ning X, et al.: Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): A randomised, double-blind, placebo-controlled, phase 3b trial. Lancet 2019; 394: 1030–40.

e31. Skljarevski V, Oakes TM, Zhang Q, et al.: Effect of different doses of galcanezumab vs placebo for episodic migraine prevention: A randomized clinical trial. JAMA Neurol 2018; 75: 187–93.

e32. Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR: Evaluation of galcanezumab for the prevention of episodic migraine: The EVOLVE-1 randomized clinical trial. JAMA Neurol 2018; 75: 1080–8.

e33. Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY: Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalalgia 2018; 38: 1442–54.

e34. Sakai F, Ozeki A, Skljarevski V: Efficacy and safety of galcanezumab for prevention of migraine headache in Japanese patients with episodic migraine: A phase 2 randomized controlled clinical trial. Cephalalgia Reports 2020; 3.

e35. Mulleners WM, Kim BK, Láinez MJA, et al.: Safety and efficacy of galcanezumab in patients for whom previous migraine preventive medication from two to four categories had failed (CONQUER): A multicentre, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol 2020; 19: 814–25.

e36. Hu B, Li G, Li X, et al.: Galcanezumab in episodic migraine: The phase 3, randomized, double-blind, placebo-controlled PERSIST study. J Headache Pain 2022; 23: 90.

e37. MaassenVanDenBrink A, Terwindt GM, Cohen JM, et al.: Impact of age and sex on the efficacy of fremanezumab in patients with difficult-to-treat migraine: Results of the randomized, placebo-controlled, phase 3b FOCUS study. J Headache Pain 2021; 22: 152.

e38. Dodick DW, Lipton RB, Silberstein S, et al.: Eptinezumab for prevention of chronic migraine: A randomized phase 2b clinical trial. Cephalalgia 2019; 39: 1075–85.

e39. Lipton RB, Goadsby PJ, Smith J, et al.: Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2. Neurology 2020; 94: e1365–e77.

e40. Tepper S, Ashina M, Reuter U, et al.: Safety and efficacy of erenumab for preventive treatment of chronic migraine: A randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 2017; 16: 425–34.

e41. Yu S, Kim BK, Wang H, et al.: A phase 3, randomised, placebo-controlled study of erenumab for the prevention of chronic migraine in patients from Asia: the DRAGON study. J Headache Pain 2022; 23: 146.

e42. Bigal ME, Edvinsson L, Rapoport AM, et al.: Safety, tolerability, and efficacy of TEV-48125 for preventive treatment of chronic migraine: A multicentre, randomised, double-blind, placebo-controlled, phase 2b study. Lancet Neurol 2015; 14: 1091–100.

e43. Silberstein SD, Dodick DW, Bigal ME, et al.: Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 2017; 377: 2113–22.

e44. Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK: Galcanezumab in chronic migraine: The randomized, double-blind, placebo-controlled REGAIN study. Neurology 2018; 91: e2211–e21.

e45. Ashina M, Lanteri-Minet M, Pozo-Rosich P, et al.: Safety and efficacy of eptinezumab for migraine prevention in patients with two-to-four previous preventive treatment failures (DELIVER): A multi-arm, randomised, double-blind, placebo-controlled, phase 3b trial. Lancet Neurol 2022; 21: 597–607.

e46. Lipton RB, Ramirez Campos V, Roth-Ben Arie Z, et al.: Fremanezumab for the treatment of patients with migraine and comorbid major depressive disorder: The UNITE randomized clinical trial. JAMA Neurol 2025; 82: 560–9.

e47. Lampl C, MaassenVanDenBrink A, Deligianni CI, et al.: The comparative effectiveness of migraine preventive drugs: A systematic review and network meta-analysis. J Headache Pain 2023; 24: 56.

e48. Raffaelli B, Terhart M, Overeem LH, et al.: Migraine evolution after the cessation of CGRP(-receptor) antibody prophylaxis: A prospective, longitudinal cohort study. Cephalalgia 2022; 42: 326–34.

e49. Terhart M, Mecklenburg J, Neeb L, et al.: Deterioration of headache impact and health-related quality of life in migraine patients after cessation of preventive treatment with CGRP(-receptor) antibodies. J Headache Pain 2021; 22: 158.