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. 2026 Mar 6;123(5):119–126. doi: 10.3238/arztebl.m2025.0234

Drugs for Migraine Prophylaxis

Hans Christoph Diener 1,✉, Julia Grans 1, Uwe Reuter 2
PMCID: PMC13137997  PMID: 41572863

Summary

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 onabotulinum-toxinA 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.

Information on CME.

This article has been certified by the North Rhine Academy for Continuing Medical Education. The questions on this article may be found (in German) at http://daebl.de/RY95 (Deutsches Ärzteblatt’s CME portal). Their English translation may be found in the PDF version of this article. The closing date for entries is March 5, 2027.

Participation is possible at cme.aerzteblatt.de

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 antimigraine 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 (8–10). 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 betablockers 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 (19–21). 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.

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

Active ingredient, dose, publication Trial acronym Phase T, months Placebo, N Active, N MD [95% CI]
Atogepant, 60 mg/day
  Goadsby et al., 2020 (e17) -/- 2b/3 3 178 177 −0.7 [−1.4; −0.1]
  Ailani et al., 2021 (e12) ADVANCE 3 3 214 222 −1.7 [−2.3; −1.2]
  Tassorelli et al., 2024 (e18) ELEVATE 3b 3 154 151 −2.4 [−3.3; −1.6]
Eptinezumab, 100 mg/quarter
  Ashina et al., 2020 (e19) PROMISE-1 3 3 222 221 −0.7 [−1.3; −0.1]
Eptinezumab, 300 mg/quarter
  Ashina et al., 2020 (e19) PROMISE-1 3 3 222 222 −1.1 [−1.7; −0.5]
Erenumab, 70 mg/month
  Sun et al., 2016 (e20) -/- 2 3 153 104 −1.1 [−2.1; −0.2]
  Goadsby et al., 2017 (e21) STRIVE 3 6 316 312 −1.4 [−1.9; −0.9]
  Dodick et al., 2018 (e22) ARISE 3 3 288 282 −1.0 [−1.6; −0.5]
  Sakai et al., 2019 (e23) -/- 2 6 136 135 −2.3 [−3.0; −1.6]
  Wang et al., 2021 (e24) EMPOwER 3 3 310 306 −1.1 [−1.8; −0.4]
  Takeshima et al., 2021 (e25) -/- 3 6 81 78 −1.7 [−2.6; −0.8]
Erenumab, 140 mg/month
  Goadsby et al., 2017 (e21) STRIVE 3 6 316 318 −1.9 [−2.3; −1.4]
  Sakai et al., 2019 (e23) -/- 2 6 136 136 −1.9 [−2.6; −1.2]
  Reuter et al., 2018 (e26) LIBERTY 3b 3 120 118 −1.6 [−2.7; −0.5]
  Wang et al., 2021 (e24) EMPOwER 3 3 310 199 −1.7 [−2.5; −0.9]
Fremanezumab, 225 mg/month
  Bigal et al., 2015 (e27) -/- 2b 3 104 95 −2.8 [−4.1; −1.6]
  Dodick et al., 2018 (e28) HALO EM 3 3 290 287 −1.5 [−2.0; −0.9]
  Sakai et al., 2021 (e29) -/- 2/3 3 116 121 −3.0 [−3.7; −2.2]
  Ferrari et al., 2019 (e30)*1 FOCUS 3b 3 111 110 −3.1 [−4.0; −2.3]
Fremanezumab, 675 mg/quarter
  Bigal et al., 2015 (e27) -/- 2b 3 104 95 −2.6 [−3.9; −1.4]
  Dodick et al., 2018 (e28) HALO EM 3 3 290 288 −1.3 [−1.8; −0.7]
  Sakai et al., 2021 (e29) -/- 2/3 3 116 117 −3.0 [−3.8; −2.2]
  Ferrari et al., 2019 (e30)*1 FOCUS 3b 3 167 107 −3.1 [−3.9; −2.2]
Galcanezumab, 120 mg/month
  Skljarevski et al., 2018 (e31)*2 -/- 2b 3 134 69 −1.1 [−2.0; −0.3]
  Stauffer et al., 2018 (e32) EVOLVE-1 3 6 425 210 −1.9 [−2.5; −1.4]
  Skljarevski et al., 2018 (e33)*2 EVOLVE-2 3 6 450 226 −2.0 [−2.6; −1.5]
  Sakai et al., 2020 (e34) -/- 2 6 230 115 −3.0 [−3.8; −2.2]
  Mulleners et al., 2020 (e35) CONQUER 3b 3 132 137 −2.6 [−3.4; −1.7]
  Hu et al., 2022 (e36) PERSIST 3 3 258 260 −1.8 [−2.3; −1.3]
Galcanezumab, 240 mg/month
  Stauffer et al., 2018 (e32) EVOLVE-1 3 6 425 208 −1.8 [−2.3; −1.2]
  Skljarevski et al., 2018 (e33)*2 EVOLVE-2 3 6 450 220 −1.9 [−2.4; −1.4]
  Sakai et al., 2020 (e34) -/- 2 6 230 114 −2.8 [−3.6; −2.0]
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Please refer to the referenced original publications for the statistical models underlying the various values.

*1

The placebo group sizes were supplemented based on the following publication: MaassenVanDenBrink et al., 2021 (e37).

*2

Missing information was completed using values from the Clinical Trials Registry https://clinicaltrials.gov/ (data as of 11 July 2025).

CI, confidence interval; MD, mean difference (migraine days/month), active versus placebo; N, sample size; T, study period

Table 3. Changes in migraine days per month after preventive drug treatment for episodic migraine and chronic migraine compared to placebo (original data)*1.

Active ingredient, dose, publication Trial acronym Phase T, months Placebo, N Active, N MD [95% CI]
Eptinezumab, 100 mg/quarter
  Ashina et al., 2022 (e45) DELIVER 3b 3 298 299 −2.7 [−3.4; −2.0]
Eptinezumab, 300 mg/quarter
  Ashina et al., 2022 (e45) DELIVER 3b 3 298 293 −3.2 [−3.9; −2.5]
Erenumab, 70 mg/month
  Takeshima et al., 2021 (e25) -/- 3 6 128 129 −1.6 [−2.5; −0.7]
Fremanezumab, 225 mg/month
  Ferrari et al., 2019 (e30)*2 FOCUS 3b 3 278 283 −3.5 [−4.2; −2.8]
  Lipton et al., 2025 (e46)*3 UNITE 4 3 178 175 −2.2 [−3.2; −1.2]
Fremanezumab, 675 mg/quarter
  Ferrari et al., 2019 (e30)*2 FOCUS 3b 3 278 276 −3.1 [−3.8; −2.4]
Galcanezumab, 120 mg/month
  Mulleners et al., 2020 (e35) CONQUER 3b 3 230 232 −3.1 [−3.9; −2.3]
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Please refer to the referenced original publications for the statistical models underlying the various values.

*1

In patients receiving preventive treatment with fremanezumab 225 mg/month and galcanezumab 120 mg/month, increased doses of 675 mg and 240 mg, respectively, are administered in the first month.

*2

The placebo group sizes were supplemented based on the following publication: MaassenVanDenBrink et al., 2021 (e37).

*3

Missing information was completed using values from the Clinical Trials Registry https://clinicaltrials.gov/ (data as of 11 July 2025).

CI, confidence interval; MD, mean difference (migraine days/month), active versus placebo; N, sample size; T, study period

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 patientrelevant endpoints, such as quality of life and limitations in everyday life (Table 1).

In patients with chronic migraine, monoclonal antibodies are more effective compared to placebo (35–38) (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).

Active ingredient, dose, publication Trial acronym Phase T, months Placebo, N Active, N MD [95% CI]
Atogepant, 60 mg/day PROGRESS 3 3 246 256 −1.8 [−2.9; −0.8]
  Pozo-Rosich et al., 2023 (e13)
Eptinezumab, 100 mg/quarter -/- 2b 3 116 118 −2.1 [−3.8; −0.4]
  Dodick et al., 2019 (e38)
  Lipton et al., 2020 (e39) PROMISE-2 3 3 366 356 −2.0 [−2.9; −1.2]
Eptinezumab, 300 mg/quarter -/- 2b 3 116 114 −2.7 [−4.4; −0.9]
  Dodick et al., 2019 (e38)
  Lipton et al., 2020 (e39) PROMISE-2 3 3 366 350 −2.6 [−3.4; −1.7]
Erenumab, 70 mg/month -/- 2 3 281 188 −2.5 [−3.5; −1.4]
  Tepper et al., 2017 (e40)
  Takeshima et al., 2021 (e25) -/- 3 6 50 52 −1.6 [−3.4; 0.2]
  Yu et al., 2022 (e41) DRAGON 3 3 274 270 −1.6 [−2.8; −0.3]
Erenumab, 140 mg/month -/- 2 3 281 187 −2.5 [−3.5; −1.4]
  Tepper et al., 2017 (e40)
Fremanezumab, 225 mg/month -/- 2b 3 89 87 −1.7 [−3.7; 0.2]
  Bigal et al., 2015 (e42)
  Silberstein et al., 2017 (e43)*1 HALO CM 3 3 371 375 −1.8 [−2.6; −1.1]
  Sakai et al., 2021 (e29) -/- 2/3 3 190 187 −2.1 [−3.1; −1.1]
  Ferrari et al., 2019 (e30)*2 FOCUS 3b 3 111 173 −3.8 [−4.8; −2.8]
Fremanezumab, 675 mg/quarter HALO CM 3 3 371 375 −1.7 [−2.5; −1.0]
  Silberstein et al., 2017 (e43)*1
  Sakai et al., 2021 (e29) -/- 2/3 3 190 189 −1.3 [−2.3; −0.3]
  Ferrari et al., 2019 (e30)*2 FOCUS 3b 3 167 169 −3.2 [−4.2; −2.2]
Galcanezumab, 120 mg/month REGAIN 3 3 538 273 −2.1 [−2.9; −1.3]
  Detke et al., 2018 (e44)
  Mulleners et al., 2020 (e35) CONQUER 3b 3 98 95 −3.7 [−5.2; −2.2]
Galcanezumab, 240 mg/month REGAIN 3 3 538 274 −1.9 [−2.7; −1.1]
  Detke et al., 2018 (e44)
Open in a new tab

In patients receiving preventive treatment with fremanezumab 225 mg/month and galcanezumab 120 mg/month, increased doses of 675 mg and 240 mg, respectively, are administered in the first month. The information from the trial by Bigal et al., 2015, is based on the analysis of moderate to severe headache days. Please refer to the referenced original publications for the statistical models underlying the various values.

*1

Missing information was completed using values from the Clinical Trials Registry https://clinicaltrials.gov/ (data as of 11 July 2025).

*2

The placebo group sizes were supplemented based on the following publication: MaassenVanDenBrink et al., 2021 (e37).

CI, confidence interval; MD, mean difference (migraine days/month), active versus placebo; N, sample size; T, study period

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.

To date, there is a lack of comparative studies evaluating monoclonal antibodies and gepants against oral drugs for migraine prophylaxis; the only two exemptions are erenumab versus topiramate and atogepant versus topiramate. In chronic migraine, comparative studies with onabotulinumtoxinA are non-existent. So far, only one direct comparative study between erenumab and topiramate has been conducted, focusing on the side effect rate, where, as expected, erenumab was better tolerated than topiramate, but it also achieved a significantly higher reduction in monthly migraine days in the secondary endpoints (34). Topiramate is associated with many adverse drug reactions. Therefore, propranolol should be used in comparative studies, as it is much better tolerated than topiramate. In the majority of patients, a sharp increase in the number of migraine days is noted as soon as a successful anti-CGRP treatment is discontinued (e48, e49). In future studies, successful treatment with monoclonal antibodies should be discontinued after, for example, six months in randomized, placebocontrolled trials, either abruptly—as is currently the case—or gradually, with longer intervals between new injections. Using this approach, it will be possible to prospectively determine the percentage of patients who, after a temporary discontinuation of treatment, will require renewed treatment with the new migraine prophylactic drugs. It is recommended that patients who have not responded to treatment with a monoclonal antibody or a gepants after three or six months should be switched to another antibody or another gepant. No data from randomized studies, addressing this aspect, are available. To date, there have been no studies on combinations of traditional oral migraine prophylactic drugs with monoclonal antibodies or gepants in patients with only partial response to monotherapy (response rate ≤ 30–50%).

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 longterm 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 onabotuli-numtoxinA 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]).

Drug class, drug, dosage RR [95% CI]
(according to [e47])		 Scientific evidence*1
(according to [5])		 Side effects
(selection, according to [2])		 Contraindications
(selection, according to [2])
Beta-blockers
  Bisoprolol 5-10 mg off-label/day orally		 NS ◦◦◦
for 5–10 mg
all migraine types

  • Common: fatigue, arterial hypotension

  • Uncommon: sleep disorders, dizziness

  • Rare: hypoglycemia, bronchospasm, bradycardia, gastrointestinal symptoms, erectile dysfunction

  • Absolute: AV block, bradycardia, heart failure, sick sinus syndrome, bronchial asthma

  • Relative: diabetes mellitus, orthostatic dysregulation, depression
  Metoprolol 40–240 mg/day orally NS ◦◦◦
for 200 mg
all migraine types
  Propranolol 50–200 mg/day orally 1.50 [1.16; 1.94]
For 120–240 mg		 •◦◦
for 160 mg
all migraine types
Calcium channel blockers
  Flunarizine 5–10 mg/day orally; after six months treatment break		 1.37 [0.98;1.91]*2 NS

  • Common: fatigue, weight gain;

  • Uncommon: gastrointestinal symptoms, depression

  • Rare: hyperkinesia, tremor, parkinsonism

  • Absolute: focal dystonia, pregnancy, lactation, depression

  • Relative: Parkinson’s disease in the family
Antiepileptic drugs (anticonvulsants)
  Topiramate 25-100 mg/day orally		 1.45 [1.18; 1.78] for 50-200 mg ••◦
for 100-200 mg
episodic migraine
•◦◦
for 50 mg
episodic migraine /
200 mg
chronic migraine
◦◦◦
for 50-100 mg
chronic migraine

  • Common: fatigue, cognitive disorders, weight loss, paresthesia

  • Uncommon: alteration of taste, psychosis, kidney stones, depression

  • Rare: angle-closure glaucoma

  • Absolute: renal insufficiency, kidney stones, women of childbearing age, angle-closure glaucoma

  • Relative: depression, anxiety disorder, low body weight, anorexia
Tricyclic antidepressants
  Amitriptyline 50–75 mg/day orally		 1.52 [1.13; 2.04] for 25–100 mg ••◦
for 25 mg
episodic migraine

  • Common: Fatigue, dry mouth, dizziness, weight gain

  • Absolute: heart failure, glaucoma, prostate hypertrophy/adenoma
Neurotoxins
  OnabotulinumtoxinA 155-195 IE/quarter IM chronic migraine		 NS •••
for 155–195
IE chronic migraine

  • Uncommon: muscle soreness, cosmetically undesirable effects, neck muscle weakness

  • Absolute: myasthenia gravis

  • Relative: anticoagulation
Open in a new tab
*1

Scientific evidence classified as ooo very low, •◦◦ low, ••◦ moderate, ••• high

*2

The value of calcium channel blockers versus placebo was derived from indirect comparisons in the network meta-analysis. Direct comparisons were available for flunarizine 5 mg/day versus topimarate, cinnarizine 25–75 mg/day versus valproate and flunarizine 5–10 mg/day versus beta-blockers.

AV, atrioventricular; CI, confidence interval; IE, international units; IM, intramuscular; NS, not stated; RR, relative risk for reduction of monthly migraine days by at least 50%, active versus placebo, random effects model, pooled analysis without differentiation between dosages and migraine types

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

Drug class, drug, dosage RR [95% CI]
(according to [e47])		 Scientific evidence*
(according to [5])		 Adverse drug reactions
(selection, according to [2])		 Contraindications/restrictions on
use (selection, according to [2])
Monoclonal antibodies against CGRP or CGRP receptor
Erenumab
  70 or 140 mg/month SC as pre-filled pen/syringe		 1.75 [1.45; 2.12] for 28–140 mg ••◦
for 70-140 mg all migraine types

  • Common: hypersensitivity reactions such as rash, swelling/ edema, angioedema and urticaria, constipation, pruritus, muscle spasms, injection site reactions, anaphylactic reaction, increase in blood pressure

  • Contraindications: hypersensitivity to the substance or other ingredients

  • RoU: Age <18 years (no data available); as a precautionary measure, avoid use during pregnancy

  • No safety data are available for patients with severe cardiovascular disease.
Fremanezumab
  225 mg/month SC as
  pre-filled pen/syringe or
  675 mg/quarter SC as
  pre-filled pen/syringe
  (3 × 225 mg)		 2.24 [1.80; 2.79] •••
for 225–675 mg
episodic migraine
••◦
for 225 mg
chronic migraine
•••
for 675 mg
chronic migraine

  • Very common: pain at the injection site, hardening at the injection site, erythema at the injection site

  • Common: pruritus at the injection site

  • Uncommon: rash at the injection site; hypersensitivity reactions such as rash, pruritus, urticaria, and swelling

  • Contraindications: hypersensitivity to the substance or other ingredients

  • RoU: age <18 years (no data available); as a precautionary measure, avoid use during pregnancy and in patients with severe cardiovascular disease.
Galcanezumab
  Initially 240 mg SC
  (2 × 120 mg pre-filled pen),
  thereafter 120 mg/month as
  pre-filled pen		 1.81 [1.48; 2.22] for 100–300 mg •••
for 120 mg
all migraine types

  • Very common: pain at the injection site, reactions at the injection site

  • Common: vertigo, constipation, pruritus

  • Uncommon: urticaria

  • Rare: anaphylactic reaction possible

  • Contraindications: hypersensitivity to the substance or other ingredients

  • RoU: age <18 years (no data available); as a precautionary measure, avoid use during pregnancy; severe cardiovascular disease
Eptinezumab
  100 or 300 mg/quarter
  IV		 1.63 [1.29; 2.06] for 10–1000 mg ••◦
for 100–300 mg
episodic migraine
•••
for 100–300 mg
chronic migraine

  • Very common: nasopharyngitis

  • Common: hypersensitivity reactions, fatigue

  • Uncommon: infusion-related reactions (usually occur during infusion)

  • Contraindications: hypersensitivity to the substance or other ingredients, HFI

  • RoU: age<18 years (no data available); as a precautionary measure, avoid use during pregnancy; cardiovascular disease; severe neurological disease
CGRP receptor antagonists (gepants)
Atogepant
  60 mg/day orally		 1.53 [1.18; 1.99]
Value from a pooled analysis for three gepants (10–120 mg/ day atogepant, 75 mg/every other day rimegepant and 280–560 mg/day telcagepant) (e47)		 •••
for 60 mg
all migraine types

  • Uncommon: nausea, constipation, weight loss, fatigue

  • Contraindications: pregnant or breastfeeding women
Rimegepant
  75 mg every other day orally
  for episodic migraine		 ••◦
for 75 mg
all migraine types

  • Uncommon: nausea

  • Rare: hypersensitivity

  • Contraindications: pregnancy, end-stage renal failure, concomitant use of CYP3A4 inhibitors or inducers
Open in a new tab
*

Scientific evidence classified as ooo very low,•◦◦ low,••◦ moderate, ••• high

RoU, restrictions on use; CGRP, calcitonin gene-related peptide; HFI, hereditary fructose intolerance; IV, intravenous;

CI, confidence interval; RR, relative risk for the reduction of monthly migraine days by at least 50%; active versus placebo, random effects model, pooled analysis without differentiation between dosages and migraine types; SC, subcutaneous

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).

Footnotes

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.

Supplementary material

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eMETHODS

Methods 1

For the development of the guideline of the International Headache Society, a literature search for randomized trials was performed according to the Cochrane guidelines for systematic reviews of interventions and reviews (5). The Cochrane guidelines were followed for study selection, data extraction and data synthesis; reporting followed the relevant points of the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) Statement. A literature search was performed in 2022 and 2023. For each pharmacological class of migraine prophylactic drugs, two members of the guideline group conducted a literature search: antidepressants, antiepileptic drugs, beta-blockers, calcium channel blockers, antihypertensive drugs, onabotulinumtoxinA, gepants, and monoclonal antibodies, targeting the CGRP signaling pathway. The scientific databases PubMed, Scopus and Cochrane Database were search for publications in English, starting from the beginning of indexing. The PICO methods with the criteria “patients“, “intervention“, “comparison“, and “outcome“ were used. The IHS guideline is founded on the best available evidence from randomized controlled trials (RCTs) and a rigorous assessment of the quality of evidence for each intervention and outcome. Clinically relevant questions were formulated using the PICO format (“patients”, “intervention“, “comparison“, “outcome“). For the Guideline of the German Society of Neurology (DGN) and the German Migraine and Headache Society (DMKG) (2), the literature search was expanded to cover the period mid-2023 to end of 2024.

Methods 2

Literature search for the creation of Tables 1–3

We conducted a search for studies on migraine prophylaxis with drugs in the clini caltrials.gov database (data as of 11 July 2025), applying the following filter settings to all drugs:

  • Condition/Disease = “migraine“

  • Age = „Adult (18–64)“, “Older adults (65 +)“

  • Study Phase = “Phase 2“, “Phase 3“, “Phase 4“

  • Study Results = “With Results“.

In addition, specific search terms were added under Intervention/Treatment for the drugs atogepant (“atogepant“), eptinezumab (“eptinezumab“), erenumab (“erenumab OR amg 334 OR amg334“), fremanezumab (“fremanezumab OR TEV-48125“), and galcanezumab (“LY2951742 OR Galcanezumab“). The search identified nine studies on atogepant, seven studies on eptinezumab, and 24 studies each on fremanezumab and galcanezumab and 24 studies on erenumab. Next, the following exclusion criteria were applied:

  • No placebo arm

  • No calculation of the mean difference in monthly migraine days, migraine headache days, or moderate to severe headache days over the observation period

  • No comparison between active and placebo.

With this approach, a total of four atogepant trials, four eptinezumab trials, nine erenumab trials, eight fremanezumab trials, and seven galcanezumab trials were obtained for inclusion in the Tables.

Questions regarding the article in issue 5/2026: Drugs for Migraine Prophylaxis

The submission deadline is 5 March 2027. Only one answer is possible per question.

Please select the answer that is most appropriate.

  • Question 1

    What is the prevalence of migraine among women in Germany?
    1. Approx. 6%
    2. Approx. 10%
    3. Approx. 15%
    4. Approx. 19%
    5. Approx. 24%

  • Question 2

    How is episodic migraine defined in the article?
    1. The number of headache days per month is less than 15.
    2. Individual headache episodes subside in less than 5 hours.
    3. During an episode, patients experience headache several times a day for a few minutes.
    4. When headaches occur, they persist for several days.
    5. The number of headache days per month is less than 5.

  • Question 3

    What evidence is available regarding the efficacy of beta-blockers in the prophylaxis of migraine?
    1. According to the findings of placebo-controlled trials, beta-blockers are effective in treating chronic migraine.
    2. According to a meta-analysis, propranolol can reduce the number of headache days by 1.5 days/ month in patients with episodic migraine.
    3. In contrast to propranolol, metoprolol has not yet been shown to be superior to placebo with regard to its efficacy in the treatment of episodic migraine..
    4. The daily dose of propranolol most commonly used in trials was 100 mg.
    5. Metoprolol is significantly more potent than propranolol and should thus be used in particularly severe cases of chronic migraine.

  • Question 4

    The effect of topiramate in episodic migraine has been evaluated in numerous studies. In the trials, which side effects led to a higher rate of treatment discontinuation?
    1. Cognitive side effects and depressive moods
    2. Perioral, pruritic rash and dizziness
    3. Extrasystoles and nausea
    4. Rotary vertigo and distorted double vision
    5. Narcolepsy and hyperhidrosis

  • Question 5

    What is a characteristic feature of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor?
    1. They are exclusively effective in patients with episodic migraine.
    2. They have no effect in patients with chronic migraine with medication overuse headache (MOH).
    3. Their effectiveness can only be assessed after 12 months of treatment.
    4. So far, their effectiveness has only been demonstrated in patients with chronic migraine without medication overuse.
    5. They are effective in patients with and without medication overuse.

  • Question 6

    At what dosage is atogepant used for the prophylaxis of episodic and chronic migraine?
    1. 10 mg/day
    2. 30 mg/day
    3. 45 mg/day
    4. 60 mg/day
    5. 85 mg/day

  • Question 7

    What evidence is available with regard to the efficacy of amitriptyline for migraine?
    1. The evidence is good: data from more than 25 studies on the efficacy and tolerability in episodic and chronic migraine are available.
    2. The evidence is poor: data from only a few trials on episodic migraine and none from trials on chronic migraine are available.
    3. The available evidence on episodic migraine comprises only 2 trials, but the evidence on chronic migraine is good, with data from more than 10 trials on chronic migraine being available.
    4. The available evidence is conclusive: all randomized, placebo-controlled trials on episodic migraine have shown a significant reduction by 2 migraine days per months compared to placebo.
    5. No randomized, controlled trials on the efficacy of amitriptyline have yet been conducted; thus, the available evidence can be considered poor.

  • Question 8

    Monoclonal antibodies against calcitonin gene-related peptide or its receptor are used for the prophylaxis of migraine. While these are generally well tolerated, rare adverse drug reactions may occur.

    Which of the following adverse reactions is not mentioned in the article?
    1. Local reaction at the injection site
    2. Nasopharyngitis
    3. Constipation
    4. Hypertension
    5. Hepatic dysfunction

  • Question 9

    The effect of onabotulinumtoxinA in chronic migraine was evaluated in two large trials. Which route of administration was used in these trials?
    1. Oral route
    2. Intravenous route
    3. Transdermal patch application
    4. Intramuscular route
    5. Application as a cream

  • Question 10

    Which drug can also be used during pregnancy in patients with chronic migraine?
    1. Onaulinum toxin A
    2. Flunarizine
    3. Topiramate
    4. Fremanezumab
    5. Atogepant

References (abbreviated)

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