- Research article
- Open Access
CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs
The Journal of Headache and Pain volume 22, Article number: 128 (2021)
Several drugs are available for the preventive treatment of both episodic and chronic migraine. The choice of which therapy to initiate first, second, or third is not straightforward and is based on multiple factors, including general efficacy, tolerability, potential for serious adverse events, comorbid conditions, and costs. Recently, a new class of migraine preventive drugs was introduced, i.e. monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor.
The present article summarizes the evidence gathered with this new migraine preventive drug class from randomized placebo-controlled clinical trials. It further puts this into perspective next to the evidence gained by the most widely used agents for the prevention of episodic and chronic migraine with an emphasis on efficacy and the robustness with which this efficacy signal was obtained.
Although being a relatively new class of migraine preventive drugs, monoclonal antibodies blocking the CGRP pathway have an efficacy which is at least comparable if not higher than those of the currently used preventive drugs. Moreover, the robustness of this efficacy signal is substantiated by several randomized clinical trials each including large numbers of patients. In addition, because of their excellent tolerability and with long-term safety data emerging, they seem to have an unprecedented efficacy over adverse effect profile, clearly resulting in an added value for migraine prevention.
Balancing the data presented in the current manuscript with additional data concerning long term safety on the one hand and cost issues on the other hand, can be of particular use to health policy makers to implement this new drug class in the prevention of migraine.
The treatment of migraine remains an important and challenging task. In a substantial part of patients with episodic migraine (EM), and nearly all patients with chronic migraine (CM), next to an adequate acute medication strategy, a preventive treatment is indicated. Several drugs are currently available for migraine prevention but studies show poor adherence to oral migraine prophylactics [1,2,3,4]. Adverse events are cited as the most common reason for discontinuation, next to lack of efficacy. The main causes for their lack of high efficacy and poor tolerability are considered related to the fact that they were not specifically developed for migraine and that most of them have multiple mechanisms of action [5, 6].
The presence of calcitonin gene-related peptide (CGRP) in the trigeminovascular system, the observation of CGRP release during the headache phase of a migraine attack and the induction of a migraine-like headache after intravenous administration of exogenous CGRP, have led to the assumption that CGRP plays a major role in the pathophysiology of migraine . The discovery of this new drug target resulted in the development of the first disease-specific preventive treatment class for both EM and CM, being monoclonal antibodies against the CGRP molecule (eptinezumab, fremanezumab and galcanezumab) or its receptor complex (erenumab) (CGRP mAb).
Over the past few years, several clinical trials with CGRP mAb for the preventive treatment of EM [8,9,10,11,12,13,14,15,16,17,18,19,20,21] and CM [14, 22,23,24,25,26,27] were performed worldwide. Safety and efficacy results were consistently convincing, resulting in the approval of erenumab, fremanezumab and galcanezumab by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the preventive treatment of EM and CM in adults in 2018 and 2019. Eptinezumab received FDA approval in February 2020.
The positioning of these new drugs in the preventive treatment strategy of EM and CM compared to the currently used prophylactic agents remains unclear, since no results from head-to-head trials are yet available. It was already suggested in a recent review that the major added value of the CGRP mAb might be their more favorable efficacy over adverse event profile . The objective of this manuscript is to present a comprehensive overview on currently available results of all four CGRP mAb for the treatment of EM and CM. Secondly, these results are put into perspective next to the available evidence from the most widely used agents for the prevention of EM and CM with an emphasis on efficacy, the robustness of this efficacy signal and tolerability.
Selection of prophylactic migraine drugs
As for the currently used prophylactic agents in EM and CM, only those with a level A evidence as determined by either the European Federation of Neurological Societies (EFNS)  or American Academy of Neurology (AAN)  were included. Candesartan and amitriptyline were added because they are first line treatments for migraine in several countries. Besides, for both agents a relevant clinical trial was published after the aforementioned guidelines were assembled [31, 32]. Flunarizine was not included in the final analysis despite its level A recommendation in the EFNS guideline. The main reasons are its unavailability in several countries and the fact that the endpoint used in the present manuscript could not be retrieved from any of the performed clinical trials. Timolol also has a level A evidence for the treatment of EM according to the AAN guideline, but not in the EFNS guideline. Since its evidence is considered to be less convincing compared to propranolol and metoprolol , and the fact that oral timolol is not available in several European countries, it was not included in the final analysis. As such, the following drugs were selected: propranolol, metoprolol, onabotulinumtoxinA, topiramate, valproate, candesartan and amitriptyline.
For the currently used prophylactic agents, potential clinical trials were identified by searching the PubMed and Cochrane Library databases (until the 1st of September, 2021). In addition, reference lists of included studies and relevant reviews or meta-analyses were manually screened to identify additional studies that were not found by the computerized search. As for the CGRP mAb, an additional database search on clinicaltrials.gov was performed using the following terms: TEV-48125 or fremanezumab, LY2951742 or galcanezumab, ALD403 or eptinezumab and AMG334 or erenumab. The study search was performed by FVDV, in case of doubt consensus was sought between JV and FVDV.
Clinical trial selection
Only trials in adults with a randomized (parallel group or cross-over) double-blinded placebo-controlled design studying the efficacy of an agent in monotherapy, of which the full article was available in English, with at least 10 patients in each treatment arm and reporting of the administered dosages were considered. Studies were selected based on title and abstract but deemed suitable for inclusion only after a full-text review.
The mean reduction of monthly migraine days (MMD) versus placebo was selected as the efficacy endpoint of choice, since it was the primary endpoint in most of the CGRP mAb trials and could be extracted from at least one clinical trial for every other prophylactic agent under study. Moreover, this endpoint was put forward by the International Headache Society (IHS) as one of the primary efficacy measures of choice in drug trials for migraine prophylaxis . If the MMD was calculated at different time points in a trial, only the latest reported was used unless the primary endpoint was set at a different time point.
Results from all 4 CGRP mAb were lumped, considering their comparable mechanism of action and the fact that so far no clear difference in efficacy appears from clinical trials although no head-to-head trials have been performed. Trials with CGRP mAb including patients with difficult to treat migraine were not included in the MMD reduction analysis since no comparable trials are available with the classic prophylactic drugs used for migraine. Since different dosages and dosing regimens were used for every agent, only one dosage was selected per agent for the MMD calculation in order to be consistent. As such, the following dosages were chosen: eptinezumab 300 mg, erenumab 140 mg, fremanezumab 225 mg monthly (with or without loading dose), and galcanezumab 120 mg monthly with a 240 mg loading dose (indicated in bold in Table 1 and 2).
For the standard prophylactics, if efficacy results from different dosages were available, only those from dosages commonly used in clinical practice were included. As such, efficacy results from the following daily dosages were used for the MMD calculation: propranolol 80-160 mg, metoprolol 100-200 mg, topiramate 100 mg for EM and 50-200 mg for CM, valproate 250-1500 mg, candesartan 8-16 mg, amitriptyline 25 mg and onabotulinumtoxinA at the injection sites and dosing according to the PREEMPT trials . Since there is not enough evidence that propranolol and metoprolol have a different efficacy profile, both agents were lumped in the final analysis (further referred to as beta-blockers).
The reduction in MMD versus placebo for every agent was calculated by averaging and weighing the MMD reduction according to the total number of patients in the respective trials (so larger trials contributed more to the final average MMD reduction). Only patients who entered the placebo-controlled phase of the study were counted, as such excluding screen failures during the screening or baseline phase.
For each clinical trial, dropout rates for both the active treatment and placebo arm were calculated, if available. Dropout rates were calculated as follows: the number of patients who discontinued the clinical trial due to side-effects between randomization and the time the primary endpoint was reached, divided by the total number of subjects who were randomized in the same treatment arm. The dropout rate for every prophylactic agent was calculated by summing all dropout rates across every trial (so larger trials contributed more to the final dropout rate).
The respective data extraction was independently performed by at least two authors (LVD, AVD and FV for the standard prophylactic drugs and JV and FV for the CGRP mAb). Any unclarities or disagreements were resolved by consensus between FV and JV.
Monoclonal antibodies targeting the CGRP pathway
The first phase 2 trials with CGRP mAb were published in 2014 (eptinezumab and galcanezumab) [8, 16]. To date, results from six phase 2 and eight phase 3 trials are available for EM [8,9,10,11,12,13,14,15,16,17,18,19,20,21] next to three phase 2 and four phase 3 trials for CM [14, 22,23,24,25,26,27] (Table 1and 2). The average reductions in MMD for CGRP mAb versus placebo in EM and CM, were respectively 1,9 and 2,2 days. None of the trials performed did not reach its primary endpoint, moreover each trial included a large number of patients.
In addition, the efficacy of CGRP mAb was specifically studied in patients with difficult-to-treat migraine, implicating a failure in terms of efficacy and/or tolerability of two to four preventive treatments, in four randomized placebo-controlled trials [35,36,37,38] (Table 3). In three out of four studies patients with both EM and CM were included [35, 36, 38]. Worth noting is the fact that in two out of three already completed trials, the MMD reduction versus placebo was relatively high. The remarkably low placebo response in these trials could have contributed to this [35,36,37].
Currently used prophylactic agents
An overview of all included clinical trials for every prophylactic agent and their core results are presented in the Supplementary material. Below we give an overview of every prophylactic agent studied and highlight particular findings.
Two trials compared candesartan 8-16 mg with placebo for the treatment of migraine. The first  was published in 2003 and included 60 EM patients. The second  admitted patients with both EM and CM, but no separate subanalysis was made. The weighted average MMD reduction compared to placebo was 0,9 days.
Topiramate is a frequently used prophylactic agent in both EM and CM worldwide. Eight placebo-controlled trials for the treatment of EM [41,42,43,44,45,46,47,48] and three for the treatment of CM [49,50,51] were included. Dosages varied between 50 and 200 mg. One EM trial did not reach its primary efficacy endpoint . In this trial a daily dose of 200 mg was studied. For EM the MMD reduction versus placebo was 1,2 days and for CM 1,8 days. Strikingly, in nearly all trials a relatively high dropout rate (all causes) among topiramate (range 13 to 62%) but even placebo (range 10 to 48%) treated patients was found. Looking only at dropouts due to side-effects the difference was 14% compared to placebo.
Six placebo-controlled trials including in total 436 EM valproate treated subjects were withheld [52,53,54,55,56,57]. The MMD reduction compared to placebo was 1,7 days. Dropout rates among patients treated with valproate varied between 3 and 19%, compared to 0 and 9% in the placebo group.
For propranolol the first trial was conducted in 1972, for metoprolol in 1983. Results from 18 randomized, placebo-controlled trials with propranolol [40, 41, 56, 58,59,60,61,62,63,64,65,66,67,68,69,70,71,72] and 4 with metoprolol for the preventive treatment of EM were included [73,74,75,76]. A total number of 1035 patients were treated with beta-blockers, 886 with propranolol and 149 with metoprolol. The MMD reduction compared to placebo was 0,7 days for propranolol (based on two studies) and 1,6 days for metoprolol (based on two studies), yielding an averaged and weighted MMD reduction of 0,9 days for beta-blockers.
Dropout rates varied between 0 and 20% for propranolol (compared to 0–10% for placebo) and between 0 and 4% for metoprolol (compared to 0–3% for placebo).
Three randomized placebo-controlled trials were included [32, 77, 78], studying a total number of 308 amitriptyline treated patients (dosage of 25 to 100 mg). In one study both EM and chronic daily headache patients were included . The results of this 20-week trial were considered negative since a significant reduction in headache frequency compared to placebo could only be observed at 8 weeks, but not at 12, 16, or 20 weeks. Overall dropout rates (all causes) were strikingly high for both amitriptyline and placebo, up to 48% for amitriptyline and 54% for placebo. Looking only at dropouts due to side-effects the difference was 5% compared to placebo. In only one trial a MMD change was used as an endpoint, resulting in a MMD reduction of 1,1 days in the amitriptyline treated patients (n = 59) compared to placebo.
Two large, randomized controlled trials including 688 patients treated with onabotulinumtoxinA (155-195 U) for the treatment of CM (following a fixed site injection protocol) were published in 2010 being the PREEMPT 1 and 2 trial [79, 80]. The PREEMPT 1 trial did not reach its primary endpoint, the PREEMPT 2 did and the pooled analysis also resulted in significant improvements compared with placebo in multiple headache symptom measures . Dropout rates were 3% in the treatment arm versus 1% in the placebo arm. The MMD reduction compared to placebo was 2,0 days.
Figures 1 and 2 illustrate, for EM and CM respectively, per agent the number of patients that were treated in clinical trials, the dropouts due to side-effects compared to placebo and their calculated weighted average MMD reduction compared to placebo.
Table 4 gives an overview of the obtained results for both EM and CM.
MMD reductions of all assessed prophylactic drugs in EM and CM compared to placebo varied between 0,9 and 2,2 days. When looking at EM and CM separately, the values range between 0,9 and 1,8 days for EM, and 1,9 and 2,2 days for CM. In both EM and CM, the highest MMD reduction was found for the CGRP mAb. The true clinical efficacy of CGRP mAb might even be higher since overall a high placebo response was reached in most of the trials probably related to their more invasive route of administration . However, whether this small difference reflects a clinically meaningful difference remains unclear, since a head-to-head statistical comparison of the studied prophylactic agents is limited by several factors.
First, there is an enormous variation in trial design. As such, the chosen efficacy parameter, MMD reduction, could not be retrieved in all trials of the currently used prophylactic drugs. In mainly the older trials, other efficacy parameters were used (for example migraine attacks). Indeed, MMD was only proposed in 1985 as an alternative efficacy endpoint for the number of migraine attacks . This heterogeneity of outcome measures is a well-known problem among drug trials dealing with migraine prophylaxis, rendering a formal quantitative meta-analysis not feasible.
Second, large differences in both the number of patients treated with the preventive agent and the number of trials performed were seen. The studied sample size ranged for example between 132 patients for candesartan and 3191 (CM) or 4632 (EM) for CGRP mAb. As for the number of trials performed, this ranged between only two (both onabotulinumtoxinA for CM and candesartan) and 22 for beta-blockers. This also limits a formal statistical comparison of prophylactic agents.
Third, a huge variation in methodological quality of included studies of the currently used prophylactic agents has been demonstrated [83,84,85,86]. As such, only valproate, metoprolol, propranolol and topiramate have a level A recommendation for the treatment of EM [29, 30]. However, even for those 4 prophylactic agents several possible biases were identified by previous meta-analyses [83,84,85,86]. Recent meta-analyses evaluating the efficacy of CGRP mAb on the other hand showed that the trial quality assessment was consistently more homogeneous with an overall low risk of bias [87,88,89,90,91].
Efficacy results from all CGRP mAb were lumped. One should however be aware of the important differences across trials, concerning amongst others the required and maximum number of headache days at baseline, the allowance of medication overuse, the number of previously failed or currently preventive agents allowed, study duration (varying between three and six months), the chosen primary endpoint and the way this was calculated, the definition of a migraine day, all this combined with different dosing schemes.
Among the currently used prophylactics, the highest dropout rates compared to placebo were seen in patients treated with amitriptyline, valproate or topiramate. These high dropout rates seem to be consistent with both clinical practice and with data about migraine prophylaxis adherence, in which a substantial higher rate of discontinuation was seen among patients treated with topiramate and amitriptyline compared to propranolol . One has to be aware however that the overall tolerability and safety story is not fully reflected by ‘dropouts due to side-effects’ in a clinical trial. As for the oral prophylactic drugs, side effects like depressive mood, weight changes or nephrolithiasis might not be completely captured during a clinical trial. Even so, the real-world side effect profile of CGRP mAb is an evolving area of research where for example the development of hypertension or worsening of preexisting hypertension due to erenumab needs to be further elucidated in the near future. Finally, the concurrent high overall dropout rates in the amitriptyline and topiramate trials is remarkable, and might reflect a lower trial quality although no firm conclusions can be drawn.
CGRP mAb have an efficacy which is at least comparable to the efficacy of the currently used preventive drugs where the robustness of this efficacy signal is substantiated by several randomized clinical trials each containing large numbers of patients. Because of their excellent tolerability and ease of use, the major added value of CGRP mAb, compared to the classical preventive anti-migraine drugs, seems therefore to be their unprecedented high efficacy over adverse effect profile. The high cost of CGRP mAb urges further research both exploring their cost-effectiveness and subgroups of patients who are likely to benefit most. Combining all this information with additional data concerning long term safety, can be of particular use to health policy makers in order to be able to provide guidelines on how to implement this new class of drugs in the prevention of EM and CM.
Availability of data and materials
All data generated or analysed during this study are included in this published article and its supplementary information files.
American Academy of Neurology
European Medicines Agency
European Federation of Neurological Societies
Food and Drug Administration
International Headache Society.
Calcitonin gene-related peptide
Monthly migraine day
Randomized controlled trial
Hepp Z, Bloudek LM, Varon SF (2014) Systematic review of migraine prophylaxis adherence and persistence. J Manag Care Pharm 20(1):22–33. https://doi.org/10.18553/jmcp.2014.20.1.22
Blumenfeld AM, Bloudek LM, Becker WJ, Buse DC, Varon SF, Maglinte GA, Wilcox TK, Kawata AK, Lipton RB (2013) Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache. 53(4):644–655. https://doi.org/10.1111/head.12055
Hepp Z, Dodick DW, Varon SF, Chia J, Matthew N, Gillard P, et al (2017) Persistence and switching patterns of oral migraine prophylactic medications among patients with chronic migraine: A retrospective claims analysis. Cephalalgia 37(5):470-85. https://doi.org/10.1177/0333102416678382.
Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB (2015) Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 35(6):478–488. https://doi.org/10.1177/0333102414547138
Vécsei L, Majláth Z, Szok D, Csáti A, Tajti J (2015) Drug safety and tolerability in prophylactic migraine treatment. Expert Opin Drug Saf 14(5):667–681. https://doi.org/10.1517/14740338.2015.1014797
Reuter U (2018) A review of monoclonal antibody therapies and other preventative treatments in migraine. Headache. 58(Suppl 1):48–59. https://doi.org/10.1111/head.13302
Edvinsson L, Haanes KA, Warfvinge K, DiN K (2018) CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol 14(6):338–350. https://doi.org/10.1038/s41582-018-0003-1
Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M et al (2014) Safety and efficacy of ALD403 , an antibody to calcitonin gene-related peptide , for the prevention of frequent episodic migraine : a randomised, double-blind , placebo-controlled, exploratory phase 2 trial. Lancet Neurol 13:1100–1107
Ashina M, Saper J, Cady R, Schaeffler BA, Biondi DM, Hirman J, Pederson S, Allan B, Smith J (2020) Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia. 40(3):241–254. https://doi.org/10.1177/0333102420905132
Goadsby PJ, Uwe R, Hallstrom Y, Gregor B, Bonner JH, Zhang F et al (2017) A controlled trial of erenumab for episodic migraine. N Engl J Med 377(22):2123–2132. https://doi.org/10.1056/NEJMoa1705848
Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-minet M, Osipova V et al (2018) ARISE : A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia 38:1026–1037
Wang S-J, Roxas AA, Saravia B, Kim B-K, Chowdhury D, Riachi N et al (2021) 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 25:033310242110241. https://doi.org/10.1177/03331024211024160
Sakai F, Suzuki N, Kim BK, Tatsuoka Y, Imai N, Ning X, Ishida M, Nagano K, Iba K, Kondo H, Koga N (2021) Efficacy and safety of fremanezumab for episodic migraine prevention: multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients. Headache. 61(7):1102–1111. https://doi.org/10.1111/head.14178
Bigal ME, Edvinsson L, Rapoport AM, Lipton RB, Spierings ELH, Diener HC, Burstein R, Loupe PS, Ma Y, Yang R, Silberstein SD (2015) 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 14(11):1091–1100. https://doi.org/10.1016/S1474-4422(15)00245-8
Dodick DW, Silberstein SD, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang R, Ma Y, Aycardi E (2018) Effect of Fremanezumab compared with placebo for prevention of episodic migraine a randomized clinical trial. JAMA - J Am Med Assoc 319(19):1999–2008. https://doi.org/10.1001/jama.2018.4853
Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS (2014) Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 13(9):885–892. https://doi.org/10.1016/S1474-4422(14)70128-0
Skljarevski V, Oakes TM, Zhang Q, Ferguson MB, Martinez J, Camporeale A, Johnson KW, Shan Q, Carter J, Schacht A, Goadsby PJ, Dodick DW (2018) Effect of Different Doses of Galcanezumab vs Placebo for Episodic Migraine PreventionA Randomized Clinical Trial. JAMA Neurol 85259(2):187–193. https://doi.org/10.1001/jamaneurol.2017.3859
Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR (2018) Evaluation of galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical trial. JAMA Neurol 75(9):1080–1088. https://doi.org/10.1001/jamaneurol.2018.1212
Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY (2018) Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalalgia. 38(8):1442–1454. https://doi.org/10.1177/0333102418779543
Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, Saper J, Cady R, Chon Y, Dietrich J, Lenz R (2016) Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 15(4):382–390. https://doi.org/10.1016/S1474-4422(16)00019-3
Sakai F, Takeshima T, Tatsuoka Y, Hirata K, Lenz R, Wang Y, Cheng S, Hirama T, Mikol DD (2019) A randomized phase 2 study of Erenumab for the prevention of episodic migraine in Japanese adults. Headache. 59(10):1731–1742. https://doi.org/10.1111/head.13652
Dodick DW, Lipton RB, Silberstein S, Goadsby PJ, Biondi D, Hirman J, Cady R, Smith J (2019) Eptinezumab for prevention of chronic migraine: a randomized phase 2b clinical trial. Cephalalgia. 39(9):1075–1085. https://doi.org/10.1177/0333102419858355
Lipton RB, Goadsby PJ, Smith J, Schaeffler BA, Biondi DM, Hirman J, Pederson S, Allan B, Cady R (2020) Efficacy and safety of eptinezumab in patients with chronic migraine. Neurology. 94(13):1–14. https://doi.org/10.1212/WNL.0000000000009169
Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang R, Ma Y, Aycardi E (2017) Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 377(22):2113–2122. https://doi.org/10.1056/nejmoa1709038
Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic migraine Neurology2018;0:2211–2221, 91, 24, DOI: https://doi.org/10.1212/WNL.0000000000006640
Tepper S, Ashina M, Reuter U, Brandes JL, Doležil D, Silberstein S, Winner P, Leonardi D, Mikol D, Lenz R (2017) Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 16(6):425–434. https://doi.org/10.1016/S1474-4422(17)30083-2
Sakai F, Suzuki N, Kim BK, Igarashi H, Hirata K, Takeshima T, Ning X, Shima T, Ishida M, Iba K, Kondo H, Koga N (2021) Efficacy and safety of fremanezumab for chronic migraine prevention: multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients. Headache. 61(7):1092–1101. https://doi.org/10.1111/head.14169
Schoenen J, Manise M, Nonis R, Gérard P, Timmermans G (2020) Monoclonal antibodies blocking CGRP transmission: An update on their added value in migraine prevention. Rev Neurol (Paris) 176:788–803
Evers S, Áfra J, Frese A, Goadsby PJ, Linde M, May A et al (2009) EFNS guideline on the drug treatment of migraine - revised report of an EFNS task force. Eur J Neurol 16(9):968–981. https://doi.org/10.1111/j.1468-1331.2009.02748.x
Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E (2012) Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults. Neurology. 78(17):1337–1345. https://doi.org/10.1212/WNL.0b013e3182535d20
Mulleners WM, Haan J, Dekker F, Jko T, Wbo H, Tqfdjgjfl B et al (2010) Preventieve behandeling van migraine. Ned Tijdschr Geneeskd 154:1–9
Gonçalves AL, Martini Ferreira A, Ribeiro RT, Zukerman E, Cipolla-Neto J, Peres MFP (2016) Randomised clinical trial comparing melatonin 3 mg, amitriptyline 25 mg and placebo for migraine prevention. J Neurol Neurosurg Psychiatry 87(10):1127–1132. https://doi.org/10.1136/jnnp-2016-313458
Tfelt-Hansen P, Pascual J, Ramadan N, Dahlöf C, D’Amico D, Diener HC et al (2012) Guidelines for controlled trials of drugs in migraine: third edition. A guide for investigators. Cephalalgia. 32(1):6–38. https://doi.org/10.1177/0333102411417901
Dodick DW, Turkel CC, Degryse RE, Aurora SK, Silberstein SD, Lipton RB et al (2010) OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 50(6):921–936. https://doi.org/10.1111/j.1526-4610.2010.01678.x
Mulleners WM, Kim BK, Láinez MJA, Lanteri-Minet M, Pozo-Rosich P, Wang S, Tockhorn-Heidenreich A, Aurora SK, Nichols RM, Yunes-Medina L, Detke HC (2020) 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 19(10):814–825. https://doi.org/10.1016/S1474-4422(20)30279-9
Ferrari MD, Diener HC, Ning X, Galic M, Cohen JM, Yang R, Mueller M, Ahn AH, Schwartz YC, Grozinski-Wolff M, Janka L, Ashina M (2019) 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. 394(10203):1030–1040. https://doi.org/10.1016/S0140-6736(19)31946-4
Reuter U, Goadsby PJ, Lanteri-minet M, Wen S, Hours-zesiger P, Ferrari MD et al (2018) 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. 392(10161):2280–2287. https://doi.org/10.1016/S0140-6736(18)32534-0
A Study to Evaluate the Efficacy and Safety of Eptinezumab for the Prevention of Migraine in Patients That Are Not Helped by Previous Preventive Treatments (DELIVER). https://clinicaltrials.gov/ct2/show/NCT04418765
Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G (2003) Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA. 289(1):65–69. https://doi.org/10.1001/jama.289.1.65
Stovner LJ, Linde M, Gravdahl GB, Tronvik E, Aamodt AH, Sand T, Hagen K (2014) A comparative study of candesartan versus propranolol for migraine prophylaxis: a randomised, triple-blind, placebo-controlled, double cross-over study. Cephalalgia. 34(7):523–532. https://doi.org/10.1177/0333102413515348
Diener HC, Tfelt-Hansen P, Dahlöf C, Láinez MJA, Sandrini G, Wang SJ, Neto W, Vijapurkar U, Doyle A, Jacobs D, MIGR-003 Study Group (2004) Topiramate in migraine prophylaxis: results from a placebo-controlled trial with propranolol as an active control. J Neurol 251(8):943–950. https://doi.org/10.1007/s00415-004-0464-6
Lipton RB, Silberstein S, Dodick D, Cady R, Freitag F, Mathew N, Biondi DM, Ascher S, Olson WH, Hulihan J (2011) Topiramate intervention to prevent transformation of episodic migraine: the topiramate INTREPID study. Cephalalgia. 31(1):18–30. https://doi.org/10.1177/0333102410372427
Mei D, Capuano A, Vollono C, Evangelista M, Ferraro D, Tonali P, di Trapani G (2004) Topiramate in migraine prophylaxis: a randomised double-blind versus placebo study. Neurol Sci 25(5):245–250. https://doi.org/10.1007/s10072-004-0350-0
Storey JR, Calder CS, DLP DEH (2001) Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache J Head Face Pain 41(10):968–975. https://doi.org/10.1046/j.1526-4610.2001.01190.x
Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, Neto W, S. Schwabe DJ. (2004) Topiramate for migraine prevention: a randomized controlled trial. JAMA. 291(8):965–972. https://doi.org/10.1001/jama.291.8.965
de Tommaso M, Guido M, Sardaro M, Serpino C, Vecchio E, De Stefano G et al (2008) Effects of topiramate and levetiracetam vs placebo on habituation of contingent negative variation in migraine patients. Neurosci Lett 442(2):81–85. https://doi.org/10.1016/j.neulet.2008.06.076
Silberstein SD, Hulihan J, Rezaul Karim M, Wu SC, Jordan D, Karvois D et al (2006) Efficacy and tolerability of topiramate 200 mg/d in the prevention of migraine with/without aura in adults: a randomized, placebo-controlled, double-blind, 12-week pilot study. Clin Ther 28(7):1002–1011. https://doi.org/10.1016/j.clinthera.2006.07.003
Stephen D, Silberstein MD, Walter Neto MD, Jennifer Schmitt MS, Jacobs D, M for the M-001 SG (2004) Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol 61(4):490–495. https://doi.org/10.1001/archneur.61.4.490
Silvestrini M, Bartolini M, Coccia M, Baruffaldi R, Taffi R, Provinciali L (2003) Topiramate in the treatment of chronic migraine. Cephalalgia 23(8):820–824
Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ (2007) Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia. 27(7):814–823. https://doi.org/10.1111/j.1468-2982.2007.01326.x
Silberstein SD, Lipton RB, Dodick DW, Freitag FG, Ramadan N, Mathew N, Brandes JL, Bigal M, Saper J, Ascher S, Jordan DM, Greenberg SJ, Hulihan J, Topiramate Chronic Migraine Study Group (2007) Efficacy and safety of Topiramate for the treatment of chronic migraine: a randomized, double-blind, Placebo-Controlled Trial. Headache 47(2):170–180. https://doi.org/10.1111/j.1526-4610.2006.00684.x
Klapper J (1997) Divalproex Sodium in Migraine Prophylaxis. Cephalalgia 17(2):103–108. https://doi.org/10.1046/j.1468-2982.1997.1702103.x
Jensen R, Brinck T, Olesen J (1994) Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology. 44(4):647–651. https://doi.org/10.1212/WNL.44.4.647
Hering R, Kuritzky A (1992) Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia. 12(2):81–84. https://doi.org/10.1046/j.1468-2982.1992.1202081.x
Freitag FG, Collins SD, Carlson HA, Goldstein J, Saper J, Silberstein S, Mathew N, Winner PK, Deaton R, Sommerville K, Depakote ER Migraine Study Group (2002) A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 58(11):1652–1659. https://doi.org/10.1212/WNL.58.11.1652
Kaniecki RG (1997) A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura. Arch Neurol 54(9):1141–1145. https://doi.org/10.1001/archneur.1997.00550210071015
Mathew NT, Saper JR, Silberstein SD, Rankin L, Markley HG, Solomon S, Rapoport AM, Silber CJ, Deaton RL (1995) Migraine prophylaxis with divalproex. Arch Neurol 52(3):281–286. https://doi.org/10.1001/archneur.1995.00540270077022
Ahuja GK, Verma AK (1985) Propranolol in prophylaxis of migraine. Indian J Med Res 82:263–265
Johnson RH, Hornabrook RW, Lambie DG (1986) Comparison of mefenamic acid and propranolol with placebo in migraine prophylaxis. Acta Neurol Scand 73(5):490–492. https://doi.org/10.1111/j.1600-0404.1986.tb04591.x
Mikkelsen B, Pedersen KK, Christiansen LV (1986) Prophylactic treatment of migraine with tolfenamic acid, propranolol and placebo. Acta Neurol Scand 73(4):423–427. https://doi.org/10.1111/j.1600-0404.1986.tb03299.x
Nadelmann JW, Phil M, Stevens J, Saper JR (1986) Propranolol in the prophylaxis of migraine. Headache. 26(4):175–182. https://doi.org/10.1111/j.1526-4610.1986.hed2604175.x
Solomon GDSA (1986) Verapamil and propranolol in migraine prophylaxis: a double-blind, cross over study. Headache. 26:325
Kuritzky A, Hering R (1987) Prophylactic Treatment Of Migraine With Long Acting Propranolol - A Comparison With Placebo. Cephalalgia 7(6_suppl):457–458
Pradalier A, Serratrice G, Collard M, Hirsch E, Feve J, Masson M, Masson C, Dry J, Koulikovsky G, Nguyen G, Schbath J, Carpentier M (1989) Long-acting propranolol in migraine prophylaxis: results of a double-blind, Placebo-Controlled Study. Cephalalgia 9(4):247–253. https://doi.org/10.1046/j.1468-2982.1989.904247.x
Diener HC, Föh M, Iaccarino C, Wessely P, Isler H, Strenge H et al (1996) Cyclandelate in the prophylaxis of migraine: a randomized, parallel, double-blind study in comparison with placebo and propranolol. The Study group. Cephalalgia 16(6):441–447. https://doi.org/10.1046/j.1468-2982.1996.1606441.x
Weber RB, Reinmuth OM (1972) The treatment of migraine with propranolol. Neurology. 22(4):366–369. https://doi.org/10.1212/WNL.22.4.366
Borgesen SE (1976) Treatment of migraine with propranolol. Postgrad Med J 52(Suppl 4):163–165
Wideroe TE, Vigander T (1974) Propranolol in the treatment of migraine. Br Med J 2(5921):699–701. https://doi.org/10.1136/bmj.2.5921.699
Diamond S, Medina JL (1976) Double blind study of propranolol for migraine prophylaxis. Headache. 16(1):24–27. https://doi.org/10.1111/j.1526-4610.1976.hed1601024.x
Forssman B, Henriksson KG, Johannsson V, Lindvall L, Lundin H (1976) Propranolol for migraine prophylaxis. Headache. 16(5):238–245. https://doi.org/10.1111/j.1526-4610.1976.hed1605238.x
Stensrud P (1976) Short-term clinical trial of propranolol in racemic form, D-propranolol and placebo. Acta Neurol Scand Suppl 53(3):229–232. https://doi.org/10.1111/j.1600-0404.1976.tb04342.x
Tfelt-Hansen P, Standnes B, Kangasneimi P, Hakkarainen H, Olesen J (1984) Timolol vs propranolol vs placebo in common migraine prophylaxis: a double-blind multicenter trial. Acta Neurol Scand 69(1):1–8. https://doi.org/10.1111/j.1600-0404.1984.tb07772.x
Andersson PG, Dahl S, Hansen JH, Hansen PE, Hedman C, Kristensen TN, Olivarius BF (1983) Prophylactic treatment of classical and non-classical migraine with metoprolol—a comparison with placebo. Cephalalgia. 3(4):207–212. https://doi.org/10.1046/j.1468-2982.1983.0304207.x
Steiner TJ, Joseph R, Hedman C, Rose FC (1988) Metoprolol in the prophylaxis of migraine: parallel-groups comparison with placebo and dose-ranging follow-up. Headache. 28(1):15–23. https://doi.org/10.1111/j.1365-2524.1988.hed2801015.x
Kangasniemi P, Andersen A, Andersson P, Gilhus N, Hedman C, Hultgren M, Vilming S, Olesen J (1987) Classic migraine: effective prophylaxis with metoprolol. Cephalalgia. 7(4):231–238. https://doi.org/10.1046/j.1468-2982.1987.0704231.x
Siniatchkin M, Andrasik F, Kropp P, Niederberger U, Strenge H, Averkina N, Lindner V, Stephani U, Gerber WD (2007) Central mechanisms of controlled-release metoprolol in migraine: a double-blind, Placebo-Controlled Study. Cephalalgia 27(9):1024–1032. https://doi.org/10.1111/j.1468-2982.2007.01377.x
Couch JR, Hassanein RS (1979) Amitriptyline in migraine prophylaxis. Arch Neurol 36(11):695–699. https://doi.org/10.1001/archneur.1979.00500470065013
Couch JR (2011) Amitriptyline versus placebo study group. Amitriptyline in the prophylactic treatment of migraine and chronic daily headache. Headache J Head Face Pain. 51(1):33–51. https://doi.org/10.1111/j.1526-4610.2010.01800.x
Diener HC, Dodick DW, Aurora SK, Turkel CC, Degryse RE, Lipton RB et al (2010) OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia. 30(7):804–814. https://doi.org/10.1177/0333102410364677
Aurora SK, Dodick DW, Turkel CC, Degryse RE, Silberstein SD, Lipton RB et al (2010) OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia. 30(7):793–803. https://doi.org/10.1177/0333102410364676
Evans K, Romero H, Spierings ELH, Katz N (2021) The relation between the placebo response, observed treatment effect, and failure to meet primary endpoint: a systematic review of clinical trials of preventative pharmacological migraine treatments. Cephalalgia. 41(2):247–255. https://doi.org/10.1177/0333102420960020
Tfelt-Hansen POJ (1985) Methodological aspects of drug trials in migraine. Neuroepidemiology. 4(4):204–226. https://doi.org/10.1159/000110232
Linde M, Mulleners WM, MD CEP (2013) Topiramate for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev 2013(6):CD010610
Jackson JL, Cogbill E, Santana-Davila R, Eldredge C, Collier W, Gradall A et al (2015) A comparative effectiveness meta-analysis of drugs for the prophylaxis of migraine headache. PLoS One 10:1–60
Mulleners WM, McCrory ML DC (2014) Antiepileptics in Migraine Prophylaxis: An Updated Cochrane Review. Cephalalgia 35(1):51–62. https://doi.org/10.1177/0333102414534325
Linde M, Mulleners WM, Chronicle EP, McCrory DC (2013) Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults (review). Cochrane Database Syst Rev (6):CD010611
Sacco S, Bendtsen L, Ashina M, Reuter U, Terwindt G, Mitsikostas DD et al (2019) Correction to: European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention. J Headache Pain 20:6. https://doi.org/10.1186/s10194-018-0955-y J Headache Pain. 2019;20
Alasad YW, Asha MZ (2020) Monoclonal antibodies as a preventive therapy for migraine: a meta-analysis. Clin Neurol Neurosurg 195:105900. https://doi.org/10.1016/j.clineuro.2020.105900
Zhu Y, Liu Y, Zhao J, Han Q, Liu L, Shen X (2018) The efficacy and safety of calcitonin gene-related peptide monoclonal antibody for episodic migraine: a meta-analysis. Neurol Sci 39(12):2097–2106. https://doi.org/10.1007/s10072-018-3547-3
Han L, Liu Y, Xiong H, Hong P (2019) CGRP monoclonal antibody for preventive treatment of chronic migraine: an update of meta-analysis. Brain Behav 9(2):1–6. https://doi.org/10.1002/brb3.1215
Forbes RB, McCarron M, Cardwell CR (2020) Efficacy and contextual (placebo) effects of CGRP antibodies for migraine: systematic review and Meta-analysis. Headache. 60(8):1542–1557. https://doi.org/10.1111/head.13907
Ethics approval and consent to participate
Consent for publication
KP has received personal compensation from Allergan, Amgen/Novartis, Eli Lilly, Lundbeck and Teva for consulting, serving on a scientific advisory board, and/or speaking and is a clinical trial investigator for Amgen/Novartis (erenumab), Eli Lilly (galcanezumab), and Autonomic Technologies Inc. (sphenopalatine ganglion stimulation). UR received consulting fees, speaking/teaching fees, and/or research grants from Allergan, Amgen, Autonomic Technologies, CoLucid, ElectroCore, Eli Lilly, Medscape, Novartis, StreamMedUp and Teva Pharmaceuticals. JS has received personal compensation from Allergan, Amgen/Novartis, Eli Lilly, Lundbeck,Teva, Cefaly Technology, Autonomic Technologies Inc. and Man & Science for consulting, serving on a scientific advisory board, and/or speaking and is an investigator for Eli Lilly, Novartis, Lundbeck and Teva. JV received personal fees and nonfinancial support from Teva, personal fees from Novartis and Lundbeck, and grants and nonfinancial support from Allergan.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Vandervorst, F., Van Deun, L., Van Dycke, A. et al. CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs. J Headache Pain 22, 128 (2021). https://doi.org/10.1186/s10194-021-01335-2
- Episodic migraine
- Chronic migraine
- Calcitonin gene-related peptide
- Monoclonal antibody
- Preventive treatment