Abstract
The confirmed involvement of the neuropeptide calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine has led to the development of treatments, which for the first time are specific to migraine and mechanism based, in contrast to repurposed traditional prophylactic anti-migraine medications. Thus, in the last 5 years, the European Medicines Agency (EMA) approved four monoclonal antibodies that target either the CGRP ligand (eptinezumab, fremanezumab, and galcanezumab) or the CGRP receptor (erenumab). These anti-CGRP therapies are indicated for use in people with migraine who have more than 4 migraine days per month. In this consensus article, the Hellenic Headache Society highlights the indications and treatment protocols of these novel anti-migraine therapies, aiming to assist Greek neurologists in the optimal management of people with migraine. The recommendations are based on data from phase 3 randomized-controlled clinical trials, the recent European Headache Federation (EHF) recommendations, a consensus article under the auspices of both the EHF and the European Academy of Neurology (EAN), recent real-world evidence studies, and the authors’ acquired clinical experience.
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Introduction
The calcitonin gene-related peptide (CGRP) belongs to a family of peptides that include adrenomedullin, amylin, and calcitonin with a variety of biological functions in the body and central nervous system (CNS) [1]. CGRP is the strongest vasodilator peptide on the human body, but in addition to the smooth muscle fibers of the vessel wall, CGRP mRNA is also detected in the endings of the C and Aδ sensory nerve fibers of the trigeminovascular system [2]. Extensive studies from different laboratories around the world, both in animals and humans, demonstrated the involvement of CGRP in the pathophysiology of migraine [3]. Increased levels of CGRP alone but not any other neuropeptides, e.g., the neuropeptide Y and substance P, were initially documented during a migraine attack in humans [4]. Subsequently, animal studies showed that the symptomatic anti-migraine drugs triptans, which are selective 5-HT1B/1D receptor agonists, are associated with inhibition of CGRP [5, 6]. Later, it was observed that intravenous administration of CGRP to migraineurs induces migraine without aura, which relieves with sumatriptan [7]. In addition, inhibitors of the CGRP receptor relieve migraine [8]. These findings led to the development of monoclonal antibodies against CGRP, which after a large clinical program of studies have demonstrated good efficacy and excellent tolerance, when administered to migraineurs for the prophylaxis of episodic and chronic migraine [9, 10]. Three biological agents (monoclonal antibodies) against the ligand CGRP (eptinezumab, fremanezumab, and galcanezumab) and one against the CGRP receptor (erenumab) have already been approved by the European Medicines Agency (EMA) for use in the prophylactic treatment of migraine in the European Union [11,12,13,14]. Three of them are currently marketed in Greece (erenumab, fremanezumab, and galcanezumab), licensed for people with more than 4 monthly days with migraine. All three biologic agents are 100% reimbursed, but only through an Electronic Prior Authorization System (ePAS) and only if at least three traditional migraine medications have failed or are contraindicated and only if there is headache diary documentation of more than 8 migraine days/month. Hundreds of people with migraine have already started prophylactic treatment with anti-CGRP biological agents through ePAS, as well as through participation in phase 3 randomized-controlled clinical trials (RCTs). Many people also have private insurance that covers the cost of treatment, while others cover the purchase of the drug at their own expenses. The Hellenic Headache Society (HHS) has published a consensus statement proposing ways to use anti-CGRP biological agents [15] based on the guidelines of the European Headache Federation (EHF) [16]. Following the acquisition of relevant clinical experience and the publication of real-world observational studies, EHF has recently updated the 2019 recommendations [17]. For the same reasons, the HHS also decided to update the 2019 guidelines for the use of anti-CGRP monoclonal antibodies (anti-CGRP mAbs), as it was stated in the original text. The consensus article under the auspices of the EHF and the European Academy of Neurology (EAN) [18], the recent guidelines of EHF for the use of anti-CGRP mAbs [17], the real-world studies of anti-CGRP mAbs [19], and the personal experience of the panelists were the basic elements for the update aiming at improving decision-making in daily clinical practice in Greece.
Monoclonal Antibodies Targeting the CGRP Pathway for the Prophylactic Treatment of Episodic and Chronic Migraine
Biological agents or monoclonal antibodies (mAbs) are homogeneous populations of immunoglobulins derived from a single plasmacyte with a predetermined specificity towards an antigenic epitope and potential for in vitro worm production [20]. Due to their high molecular weight, they do not to cross the blood–brain barrier and their site of action is peripheral, within the trigeminal-vascular system. The half-life of all mAbs is long, and all of them that are currently marketed in Greece (with the exception of eptinezumab) are administered subcutaneously once a month (or once every 3 months for the case of 625 mg of fremanezumab) [9, 10]. In summary, the key characteristics of the four EMA-approved biological agents for migraine prophylaxis are presented in Table 1. The phase 3 RCTs documenting the efficacy of each anti-CGRP mAb are summarized in Table 2 for episodic migraine and Table 3 for chronic migraine. These studies showed that the efficacy of anti-CGRP mAbs in the prophylaxis of episodic and chronic migraine is superior to placebo. There is only one randomized phase 3B RCT that compared erenumab (70 or 140 mg/month) with topiramate (50 to 100 mg/day), a traditional anti-migraine synthetic drug, in the prophylaxis of episodic migraine, the HERMES study [34]. The primary endpoint was the treatment discontinuation due to adverse events, and the predetermined secondary endpoint was the proportion of patients with a 50% reduction in migraine days/month. This study was carried out in Germany exclusively. In the intention to treat analysis, it was found that 10.6% of the participants treated with erenumab discontinued treatment due to AEs compared to 38.9% in the topiramate group (odds ratio, 0.19; 95% confidence intervals: 0.13–0.27; p < 0.001). In addition, more participants achieved a ≥ 50% reduction in monthly migraine days with erenumab treatment than with topiramate (55.4% vs. 31.2%, odds ratio 2.76, 95% confidence intervals: 2.06–3.71, p < 0.001). No relevant safety concerns of erenumab were observed [34]. In indirect comparisons, the anti-CGRP mAbs had similar efficacy to propranolol and topiramate in episodic migraine and to topiramate and onabotulinumtoxinA in the prophylaxis of chronic migraine, but the risk–benefit ratio (e.g., the likelihood to help versus to harm) was in favor of anti-CGRP mAbs [35], making these agents protagonists in migraine therapeutics.
The most common adverse events (AEs) in the phase 3 RCTs of anti-CGRP mAbs in migraine prevention were mostly mild to moderate in severity with similar incidence rates between the study drug group and the placebo group. Adverse events leading to treatment discontinuation were reported in very low rates (1–4%) and were mainly related to constipation and fatigue intolerance, but these rates were similar in the placebo group. Adverse events with a frequency of > 2% were upper respiratory tract infections, nausea, sinusitis, pharyngitis, urinary tract infection, arthralgias, muscle spasms, and dizziness. There was no hepatotoxicity, an increase in blood pressure, or an increased risk for any heart disease or vascular event. It should also be emphasized that the anti-CGRP mAbs used in migraine do not target the immune system, and in this point, they differ considerably from the biological therapies used in other diseases such as multiple sclerosis, cancer, or systemic inflammatory diseases [20]. Data from the RCTs with anti-CGRP mAbs in migraine have shown the development of neutralizing antibodies in a very small percentage of cases, from 0 to 3.1%. Thus, it is not considered necessary to measure neutralizing antibodies in daily clinical practice [21,22,23,24,25,26,27,28,29,30,31,32,33]. Also, routine measurement of neutralizing antibodies is not recommended by the EHF, the EAN, and any other scientific society.
The prospective, observational, real-world studies that have since been published (Table 4) add a lot of important information mainly on the safety of anti-CGRP mAbs, given that they extend over a period of more than 6 months [36,37,38,39,40,41]. Overall, real-world studies showed significant efficacy in treating episodic and chronic migraine with response rates comparable to the numbers reported in phase 3 RCTs, or even higher. However, it should be noted that in some studies, the percentages of AEs were much higher than those reported in phase 3 RCTs [36, 42]. Arterial hypertension and constipation were recorded as expected AEs of erenumab and are now listed in the SPC of this agent [36, 43].
Recommendations for the Use of Anti-CGRP mAbs in Episodic and Chronic Migraine
Recommendations are categorized into strong and weak according to the documentation and experience of the authors. Documentation of a recommendation is considered good when it is based on at least 2, placebo-controlled RCTs. Moderate documentation corresponds to data from only one placebo-controlled RCT. Poor documentation is based on data from observational studies only.
-
1.
We recommend to carefully educate people with migraine on the correct use of symptomatic medications and the avoidance of known triggers, before suggesting any prophylactic pharmacological treatment [44]. (Strong recommendation, poor documentation)
-
2.
We recommend the anti-CGRP mAbs as first-line pharmacological treatment for the prevention of migraine in people older than18 years with 4 or more days with migraine/month, along with the traditional anti-migraine therapies (e.g., anti-hypertensives, anti-depressants, anti-epileptics, anti-vertigo medicines, and onabotulinumtoxinA for the case of chronic migraine only). The choice of the best optimum treatment depends on the comorbidity and the preferences of the patient. Therefore, the therapeutic decision is recommended to be individualized from the outset and not be stratified. This recommendation is presumed from the data presented in Tables 2 and 3, the head-to-head comparative study of erenumab and topiramate [34], the indirect comparative study of anti-CGRP mAbs with traditional anti-migraine pharmacological treatments [35], and the data from the real-world studies (Table 4). Additionally, anti-CGRP mAbs have also been proved to be financially beneficial in a cost–benefit analysis study adapted to the Greek economy [45]. Notably, there is good documentation for the use of anti-CGRP biological agents in people with migraine who are older than 65 years [46,47,48]. (Strong recommendation, good documentation)
-
3.
We recommend the headache diary as the primary instrument for assessing treatment outcomes. Alternatively, other scales can be used (e.g., MIDAS or HIT-6), which are also standardized in Greek individuals [49, 50]. The headache diary was the tool for monitoring the primary endpoints in all phase 3 RCTs while the MIDAS and HIT-6 scales were used for secondary outcomes (Tables 2 and 3). (Strong recommendation, good documentation)
-
4.
We recommend treatment with anti-CGRP mAbs for more than 3 months initially. If there is no greater than 50% reduction in headache days/month compared to the pre-treatment period, and/or the person under treatment remains unsatisfied, we recommend discontinuing treatment and switching to another preventative medication. There are studies indicating that a significant number of people with migraine respond to treatment after 3 months of treatment [36; 51–54] like in the case of onabotulinumtoxinA [55]. Thus, the first evaluation is recommended to be done at least after 3 months of treatment. (Strong recommendation, moderate documentation)
-
5.
We recommend prophylactic treatment with anti-CGRP mAbs in people with migraine and overuse of symptomatic anti-migraine medications, because post hoc analyses of the phase 3 studies for all four anti-CGRP mAbs showed significant efficacy over placebo in this group of people [56,57,58,59,60]. However, there are no placebo-controlled RCTs with anti-CGRP mAbs in people with migraine and medication overuse exclusively. (Strong recommendation, poor documentation)
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6.
When treatment with anti-CGRP mAbs is successful in the first assessment (reduction ≥ 50% of headache days/month and/or treated person satisfied), we recommend that it should be continued for at least 12 additional months, for a second assessment. Pause of treatment may be suggested to evaluate potential migraine relapse, lasting 1 to 2 months. In case of a relapse, re-administration of the initial treatment is recommended. There is poor documentation for this recommendation, which is based on two observational studies that found a clear relapse of migraines to discontinuation of treatment before the completion of 1 year [61, 62]. (Strong recommendation, poor documentation)
-
7.
We recommend avoiding anti-CGRP mAbs in pregnant or lactating women because there is no relevant safety documentation. We recommend caution and individual decision to administer an anti-CGRP mAb to individuals with vascular disease or to individuals with risk factors for vascular disease, or to individuals with Raynaud’s phenomenon. In addition, particular caution is advised in the use of erenumab in people with migraine and a history of severe constipation [36] and/or arterial hypertension [63]. (Strong recommendation, moderate documentation)
-
8.
When the response to an anti-CGRP mAb is inadequate, administration of another anti-CGRP mAb may be attempted, especially when the target of the new treatment is different (e.g., CGRP ligand or CGRP receptor). There is poor scientific evidence for this recommendation with two observational studies in which 30% of patients who did not respond to an anti-CGRP mAb had a clear improvement after initiation of treatment with another anti-CGRP mAb [64, 65]. Moreover, this recommendation is in line with the framework of daily medical practice. (Weak recommendation, poor documentation)
-
9.
There is insufficient evidence to make recommendations on a possible combination of anti-CGRP biological agents with other prophylactic anti-migraine pharmacological treatments. In clinical practice, this is certainly the case, and in the case of chronic migraine, there is a recent study of coadministration of onabotulinumtoxinA with an anti-CGRP mAb providing favorable results [66]. (Weak recommendation, poor documentation)
-
10.
A neurologist with appropriate training or dedicated headache centers should guide initiation, monitoring, and discontinuation of anti-CGRP mAb therapy, because knowledge is required not only of pain neurotransmission but also of the broader CNS neurovascular environment, since CGRP has a strong vasodilator effect [1]. Thus, only a neurologist or other physicians with special training may effectively manage the use of anti-CGRP mAbs in people with migraine and other potential comorbidities, in the event that the number of neurologists is sufficient to treat migraine patients. (Weak recommendation, undocumented)
These recommendations do not cover all the questions arising from the use of anti-CGRP mAbs in clinical practice. The specific clinical features of migraines or other biomarkers predicting the efficacy for an anti-CGRP mAb have not been studied. The same applies to the class of drugs against CGRP versus the other classes of anti-migraine drugs. Erenumab and fremanezumab have two different dosing regimens, which have been accepted as being of equal efficacy and safety. Therefore, no recommendation has been issued with regard to the use of any dose at the beginning of treatment. In two phase 3 RCTs, erenumab 140 mg had better efficacy compared to the 70 mg dose [21, 23], but the difference had marginal statistical significance. Dose increase from 70 to 140 mg did not affect the 50% migraine attack reduction efficacy criterion in an observational study, but more patients achieved the 30% reduction in migraine attacks/month with the higher erenumab dose [36].
Anti-CGRP Biological Agents in Cluster Headache
Based on clinical data claiming that during a spontaneous cluster headache (CH) attack, external jugular vein blood levels of CGRP are raised and reduced after successful treatment with sumatriptan or oxygen [67] and that infusion of CGRP may trigger a CH attack in the vast majority of people with CH within a bout [68], clinical studies with anti-CGRP mAbs as prophylactic treatment of CH were designed. Galcanezumab was tested in a placebo-controlled RCT in 106 individuals with episodic CH [69]. Although the study ended prematurely due to a low rate of participant enrolment, a significant reduction in the weekly frequency of CH attacks was observed after administration of only one dose of 300 mg galcanezumab (minus 8.7 attacks), compared to placebo (minus 5.2 attacks) for a total of 3 weeks. The adverse events of galcanezumab were similar to placebo, except from the pain at the site of administration that was reported by 8% of participants receiving galcanezumab. Another multicenter, placebo-controlled RCT of galcanezumab (300 mg) in 237 participants with chronic CH did not reach the primary endpoint (significant reduction in weekly frequency of CH attacks relative to baseline frequency) [70]. Fremanezumab (a single intravenous administration of 225–900 mg) was tested in two multicenter placebo-controlled RCTs, one in chronic CH (https://clinicaltrials.gov/ct2/show/NCT02945046) and the other in episodic CH (https://clinicaltrials.gov/ct2/show/NCT02964338), which unfortunately ended prematurely, because the planned interim analysis showed futile results. These studies did not provide any new safety data. Ongoing trials are testing the efficacy of eptinezumab in episodic CH and erenumab in chronic CH (NCT04688775 and NCT04970355, respectively). The existing evidence, therefore, may support for efficacy of galcanezumab as a prophylactic treatment for episodic CH [71], licensed by the Food and Drug Administration (FDA), but not by the EMA. Its administration could, however, be tested on refractory cases of CH at doses of 240–360 mg/month, as several observational studies substantiate [72,73,74].
Emerging Treatments for Migraine
In addition to the biological agents targeted at CGRP pathway, there are also synthetic molecules, administered orally, that inhibit the binding of CGRP to its receptor. These medications mostly do not cross the blood–brain barrier and do not cause vasoconstriction and form another anti-migraine drug class, the gepants [75]. The likelihood of headache from gepant withdrawal is theoretically lower because these medications compete with the CGRP receptor, unlike other anti-migraine drugs that activate receptor systems (e.g., triptans that are selective agonists for the 5-HT1B and 5-HT1D receptors) [76]. Therefore, the gepants are symptomatic anti-migraine medications with possible prophylactic anti-migraine action. Indeed, rimegepant has demonstrated in phase 3 RCT efficacy in both symptomatic [77] and prophylactic treatment for episodic migraine [78] and has been approved by the FDA and EMA for both uses at a dose of 75 mg (for prophylaxis on every other day administration 75 mg and for symptomatic treatment 75 mg one-off). A second synthetic anti-CGRP molecule of the gepant class, atogepant, is under evaluation by the EMA for use exclusively in the preventive treatment of episodic and chronic migraine [79] ( https://clinicaltrials.gov/ct2/results?term=NCT03855137&draw=2&rank=1#rowId0).
Conclusions
A number of innovative therapies targeting CGRP or its receptor have recently become available in Europe. Prescribing through electronic pre-approval by the authorities with full reimbursement, three anti-CGRP biological agents, erenumab, fremanezumab, and galcanezumab, are currently marketed in Greece and eptinezumab is expected soon. As with any new treatment, integration into clinical practice is essential to provide the best possible care to those who need it, taking into account the safety, tolerance, and effectiveness of the novel treatments [80, 81]. The aforementioned recommendations (Table 5) express the detailed opinion of the Hellenic Headache Society, after evaluating the recent available data. Needless to say that they will have to be re-evaluated in the near future, especially when newer data emerge that may challenge the present recommendations. Other anti-CGRP prophylactic treatments for migraine are imminent. Gepant is a novel anti-migraine drug-class consisting of oral, synthetic drugs that antagonize the CGRP receptor. Rimegepant and atogepant are representatives of gepants. Rimegepant is the only pharmacological agent so far with an indication for both symptomatic and prophylactic treatments of migraine approved by both FDA and EMA, while atogepant has an indication for the prophylaxis of migraine by FDA and is under evaluation by the EMA. Currently, therefore, for the pharmacological prophylaxis of episodic migraine (monthly days with migraine < 15), the treating physician has to choose a medication for episodic migraine from 5 drug classes (anti-CGRP mAbs, anti-depressants, anti-epileptics, anti-hypertensives, and Ca-blockers). For the prophylaxis of chronic migraine (monthly days with migraine ≥ 15), the list of proposed evidence-based treatments includes only 5 medicines (3 anti-CGRP mAbs, onabotulinumtoxinA, and topiramate). It should be noted however that the documentation of the efficacy and the safety and tolerance of topiramate in the prevention of chronic migraine clearly fall short of the anti-CGRP mAbs and onabotulinumtoxinA, moving topiramate at the second line of treatment [34, 80,81,82]. The same applies to medication for episodic migraine prophylaxis. Traditional repurposed anti-migraine drugs lack the documentation of anti-CGRP mAbs, and only topiramate shares a comparable clinical program to test efficacy in the prevention of episodic migraine, which unfortunately suffer from low adherence and tolerance. Nevertheless, the list of preventive anti-migraine medications will soon be expanded in Greece with an anti-CGRP mAb, eptinezumab, and two gepants. From all these treatments, one should be selected for each individual with migraine. The decision process should be individualized from the outset, depending on the comorbidity, previous therapeutic efforts, and patient’s personal preferences and lifestyle choices. Educating the patient to avoid known migraine triggers and to use symptomatic medications properly is essential, while the possibility of using non-pharmacological therapies should always be discussed [80, 81]. Often the patient expects migraine elimination or at other times considers the migraine incurable, so he or she should be informed about the goals and effectiveness of the proposed treatment in detail. Whatever the consensual treatment choice by the doctor-patient dyad, re-evaluation should include, in addition to efficacy and adverse effects, compliance with medication adherence, and agreed-upon behavioral changes by the patient.
Data Availability
There are no original data.
Code Availability
Not applicable.
References
Russell FA, King R, Smillie SJ, Kodji X, Brain SD. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014;94(4):1099–142. https://doi.org/10.1152/physrev.00034.2013.
Uddman R, Edvinsson L, Ekman R, Kingman T, McCulloch J. Innervation of the feline cerebral vasculature by nerve fibers containing calcitonin gene-related peptide: trigeminal origin and co-existence with substance P. Neurosci Lett. 1985;62(1):131–6. https://doi.org/10.1016/0304-3940(85)90296-4.
Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):338–50. https://doi.org/10.1038/s41582-018-0003-1.
Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive peptides in the extracerebral circulation of humans and the cat during activation of the trigeminovascular system. Ann Neurol. 1988;23(2):193–6. https://doi.org/10.1002/ana.410230214.
Buzzi MG, Carter WB, Shimizu T, Heath H 3rd, Moskowitz MA. Dihydroergotamine and sumatriptan attenuate levels of CGRP in plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion. Neuropharmacology. 1991;30(11):1193–200. https://doi.org/10.1016/0028-3908(91)90165-8.
Durham PL, Sharma RV, Russo AF. Repression of the calcitonin gene-related peptide promoter by 5-HT1 receptor activation. J Neurosci. 1997;17(24):9545–53. https://doi.org/10.1523/JNEUROSCI.17-24-09545.1997.
Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia. 2010;30(10):1179–86. https://doi.org/10.1177/0333102410368444.
Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM, BIBN 4096 BS Clinical Proof of Concept Study Group. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004;350(11):1104–10. https://doi.org/10.1056/NEJMoa030505.
Charles A, Pozo-Rosich P. Targeting calcitonin gene-related peptide: a new era in migraine therapy. Lancet. 2019;394(10210):1765–74. https://doi.org/10.1016/S0140-6736(19)32504-8.
Ashina M, Buse DC, Ashina H, Pozo-Rosich P, Peres MFP, Lee MJ, Terwindt GM, Halker Singh R, Tassorelli C, Do TP, Mitsikostas DD, Dodick DW. Migraine: integrated approaches to clinical management and emerging treatments. Lancet. 2021;397(10283):1505–18. https://doi.org/10.1016/S0140-6736(20)32342-4.
https://www.ema.europa.eu/en/medicines/human/EPAR/aimovig, accessed online on 02–10–2022
https://www.ema.europa.eu/en/medicines/human/EPAR/emgality, accessed online on 02–10–2022
https://www.ema.europa.eu/en/medicines/human/EPAR/ajovy, accessed online on 02–10–2022
https://www.ema.europa.eu/en/medicines/human/EPAR/vyepti, accessed online on 02–10–2022
Kouremenos E, Arvaniti C, Constantinidis TS, Giannouli E, Fakas N, Kalamatas T, Kararizou E, Naoumis D, Mitsikostas DD, Hellenic Headache Society. Consensus of the Hellenic Headache Society on the diagnosis and treatment of migraine. J Headache Pain. 2019;20(1):113. https://doi.org/10.1186/s10194-019-1060-6.
Sacco S, Bendtsen L, Ashina M, Reuter U, Terwindt G, Mitsikostas DD, Martelletti P. 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. 2019;20(1):6. https://doi.org/10.1186/s10194-018-0955-y. (Erratum in: J Headache Pain. 2019 May 23;20(1):58).
Sacco S, Amin FM, Ashina M, Bendtsen L, Deligianni CI, Gil-Gouveia R, Katsarava Z, MaassenVanDenBrink A, Martelletti P, Mitsikostas DD, Ornello R, Reuter U, Sanchez-Del-Rio M, Sinclair AJ, Terwindt G, Uluduz D, Versijpt J, Lampl C. European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention - 2022 update. J Headache Pain. 2022;23(1):67. https://doi.org/10.1186/s10194-022-01431-x.
Eigenbrodt AK, Ashina H, Khan S, Diener HC, Mitsikostas DD, Sinclair AJ, Pozo-Rosich P, Martelletti P, Ducros A, Lantéri-Minet M, Braschinsky M, Del Rio MS, Daniel O, Özge A, Mammadbayli A, Arons M, Skorobogatykh K, Romanenko V, Terwindt GM, Paemeleire K, Sacco S, Reuter U, Lampl C, Schytz HW, Katsarava Z, Steiner TJ, Ashina M. Diagnosis and management of migraine in ten steps. Nat Rev Neurol. 2021;17(8):501–14. https://doi.org/10.1038/s41582-021-00509-5.
Wang YF, Wang SJ. CGRP targeting therapy for chronic migraine-evidence from clinical trials and real-world studies. Curr Pain Headache Rep. 2022;26(7):543–54. https://doi.org/10.1007/s11916-022-01056-4.
Gklinos P, Papadopoulou M, Stanulovic V, Mitsikostas DD, Papadopoulos D. Monoclonal antibodies as neurological therapeutics. Pharmaceuticals (Basel). 2021;14(2):92. https://doi.org/10.3390/ph14020092.
Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377(22):2123–32. https://doi.org/10.1056/NEJMoa1705848.
Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-Minet M, Osipova V, Palmer K, Picard H, Mikol DD, Lenz RA. ARISE: a phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018;38(6):1026–37. https://doi.org/10.1177/0333102418759786.
Wang SJ, Roxas AA Jr, Saravia B, Kim BK, Chowdhury D, Riachi N, Tai MS, Tanprawate S, Ngoc TT, Zhao YJ, Mikol DD, Pandhi S, Wen S, Mondal S, Tenenbaum N, Hours-Zesiger P. 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(13):1285–97. https://doi.org/10.1177/03331024211024160.
Reuter U, Goadsby PJ, Lanteri-Minet M, Wen S, Hours-Zesiger P, Ferrari MD, Klatt J. 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(10161):2280–7. https://doi.org/10.1016/S0140-6736(18)32534-0.
Ashina M, Saper J, Cady R, Schaeffler BA, Biondi DM, Hirman J, Pederson S, Allan B, Smith J. Eptinezumab in episodic migraine: a randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia. 2020;40(3):241–54. https://doi.org/10.1177/0333102420905132.
Dodick DW, Silberstein SD, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T, Grozinski-Wolff M, Yang R, Ma Y, Aycardi E. Effect of fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. 2018;319(19):1999–2008. https://doi.org/10.1001/jama.2018.4853.
Sakai F, Suzuki N, Kim BK, Tatsuoka Y, Imai N, Ning X, Ishida M, Nagano K, Iba K, Kondo H, Koga N. 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(7):1102–11. https://doi.org/10.1111/head.14178.
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(9):1080–8. https://doi.org/10.1001/jamaneurol.2018.1212. (Erratum in: JAMA Neurol. 2019 Jul 1;76(7):872).
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(8):1442–54. https://doi.org/10.1177/0333102418779543.
Tepper S, Ashina M, Reuter U, Brandes JL, Doležil D, Silberstein S, Winner P, Leonardi D, Mikol D, Lenz R. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16(6):425–34. https://doi.org/10.1016/S1474-4422(17)30083-2.
Lipton RB, Goadsby PJ, Smith J, Schaeffler BA, Biondi DM, Hirman J, Pederson S, Allan B, Cady R. Efficacy and safety of eptinezumab in patients with chronic migraine: PROMISE-2. Neurology. 2020;94(13):e1365–77. 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. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med. 2017;377(22):2113–22. https://doi.org/10.1056/NEJMoa1709038.
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(24):e2211–21. https://doi.org/10.1212/WNL.0000000000006640.
Reuter U, Ehrlich M, Gendolla A, Heinze A, Klatt J, Wen S, Hours-Zesiger P, Nickisch J, Sieder C, Hentschke C, Maier-Peuschel M. Erenumab versus topiramate for the prevention of migraine - a randomised, double-blind, active-controlled phase 4 trial. Cephalalgia. 2022;42(2):108–18. https://doi.org/10.1177/03331024211053571.
Drellia K, Kokoti L, Deligianni CI, Papadopoulos D, Mitsikostas DD. Anti-CGRP monoclonal antibodies for migraine prevention: a systematic review and likelihood to help or harm analysis. Cephalalgia. 2021;41(7):851–864. https://doi.org/10.1177/0333102421989601. Epub 2021 Feb 10. Erratum in: Cephalalgia. 2022 Jan;42(1):90.
Lambru G, Hill B, Murphy M, Tylova I, Andreou AP. A prospective real-world analysis of erenumab in refractory chronic migraine. J Headache Pain. 2020;21(1):61. https://doi.org/10.1186/s10194-020-01127-0.
Andreou AP, Fuccaro M, Hill B, Murphy M, Caponnetto V, Kilner R, Lambru G. Two-year effectiveness of erenumab in resistant chronic migraine: a prospective real-world analysis. J Headache Pain. 2022;23(1):139. https://doi.org/10.1186/s10194-022-01507-8.
Torres-Ferrús M, Gallardo VJ, Alpuente A, Caronna E, Gine-Cipres E, Pozo-Rosich P. The impact of anti-CGRP monoclonal antibodies in resistant migraine patients: a real-world evidence observational study. J Neurol. 2021;268(10):3789–98. https://doi.org/10.1007/s00415-021-10523-8.
Cullum CK, Do TP, Ashina M, Bendtsen L, Hugger SS, Iljazi A, Gusatovic J, Snellman J, Lopez-Lopez C, Ashina H, Amin FM. Real-world long-term efficacy and safety of erenumab in adults with chronic migraine: a 52-week, single-center, prospective, observational study. J Headache Pain. 2022;23(1):61. https://doi.org/10.1186/s10194-022-01433-9.
Barbanti P, Egeo G, Aurilia C, d'Onofrio F, Albanese M, Cetta I, Di Fiore P, Zucco M, Filippi M, Bono F, Altamura C, Proietti S, Bonassi S, Vernieri F; FRIEND-Study Group. Fremanezumab in the prevention of high-frequency episodic and chronic migraine: a 12-week, multicenter, real-life, cohort study (the FRIEND study). J Headache Pain. 2022 Apr 9;23(1):46. https://doi.org/10.1186/s10194-022-01396-x. Erratum in: J Headache Pain. 2022 Apr 28;23(1):51. Erratum in: J Headache Pain. 2022 Jun 7;23(1):64.
Vernieri F, Altamura C, Brunelli N, Costa CM, Aurilia C, Egeo G, Fofi L, Favoni V, Pierangeli G, Lovati C, Aguggia M, d'Onofrio F, Doretti A, Di Fiore P, Finocchi C, Rao R, Bono F, Ranieri A, Albanese M, Cevoli S, Barbanti P; GARLIT Study Group. Galcanezumab for the prevention of high frequency episodic and chronic migraine in real life in Italy: a multicenter prospective cohort study (the GARLIT study). J Headache Pain. 2021;22(1):35. https://doi.org/10.1186/s10194-021-01247-1.
Murray AM, Stern JI, Robertson CE, Chiang CC. Real-world patient experience of CGRP-targeting therapy for migraine: a narrative review. Curr Pain Headache Rep. 2022. https://doi.org/10.1007/s11916-022-01077-z.
Saely S, Croteau D, Jawidzik L, Brinker A, Kortepeter C. Hypertension: a new safety risk for patients treated with erenumab. Headache. 2021;61(1):202–8. https://doi.org/10.1111/head.14051.
Owens C, Pugmire B, Owens K. A migraine prophylaxis educational intervention in a Medicaid population. Headache. 2008;48(2):267–71. https://doi.org/10.1111/j.1526-4610.2007.01012.x.
Giannouchos TV, Mitsikostas DD, Ohsfeldt RL, Vozikis A, Koufopoulou P. Cost-effectiveness analysis of erenumab versus onabotulinumtoxinA for patients with chronic migraine attacks in Greece. Clin Drug Investig. 2019;39(10):979–90. https://doi.org/10.1007/s40261-019-00827-z.
Lampl C, Kraus V, Lehner K, Loop B, Chehrenama M, Maczynska Z, Ritter S, Klatt J, Snellman J. Safety and tolerability of erenumab in individuals with episodic or chronic migraine across age groups: a pooled analysis of placebo-controlled trials. J Headache Pain. 2022;23(1):104. https://doi.org/10.1186/s10194-022-01470-4.
Nahas SJ, Naegel S, Cohen JM, Ning X, Janka L, Campos VR, Krasenbaum LJ, Holle-Lee D, Kudrow D, Lampl C. Efficacy and safety of fremanezumab in clinical trial participants aged ≥60 years with episodic or chronic migraine: pooled results from 3 randomized, double-blind, placebo-controlled phase 3 studies. J Headache Pain. 2021;22(1):141. https://doi.org/10.1186/s10194-021-01351-2.Erratum.In:JHeadachePain.2022May17;23(1):57.
Stauffer VL, Turner I, Kemmer P, Kielbasa W, Day K, Port M, Quinlan T, Camporeale A. Effect of age on pharmacokinetics, efficacy, and safety of galcanezumab treatment in adult patients with migraine: results from six phase 2 and phase 3 randomized clinical trials. J Headache Pain. 2020;21(1):79. https://doi.org/10.1186/s10194-020-01148-9.
Martin M, Blaisdell B, Kwong JW, Bjorner JB. The short-form headache impact test (HIT-6) was psychometrically equivalent in nine languages. J ClinEpidemiol. 2004;57(12):1271–8. https://doi.org/10.1016/j.jclinepi.2004.05.004.
Oikonomidi T, Vikelis M, Artemiadis A, Chrousos GP, Darviri C. Reliability and validity of the Greek migraine disability assessment (MIDAS) questionnaire. Pharmacoecon Open. 2018;2(1):77–85. https://doi.org/10.1007/s41669-017-0034-3.
Russo A, Silvestro M, Scotto di Clemente F, Trojsi F, Bisecco A, Bonavita S, Tessitore A, Tedeschi G. Multidimensional assessment of the effects of erenumab in chronic migraine patients with previous unsuccessful preventive treatments: a comprehensive real-world experience. J Headache Pain. 2020;21(1):69. https://doi.org/10.1186/s10194-020-01143-0.
Goadsby PJ, Dodick DW, Martinez JM, Ferguson MB, Oakes TM, Zhang Q, Skljarevski V, Aurora SK. Onset of efficacy and duration of response of galcanezumab for the prevention of episodic migraine: a post-hoc analysis. J Neurol Neurosurg Psychiatry. 2019;90(8):939–44. https://doi.org/10.1136/jnnp-2018-320242.
McAllister PJ, Turner I, Reuter U, Wang A, Scanlon J, Klatt J, Chou DE, Paiva da Silva Lima G. Timing and durability of response to erenumab in patients with episodic migraine. Headache. 2021;61(10):1553–1561. https://doi.org/10.1111/head.14233.
Kuruppu DK, North JM, Kovacik AJ, Dong Y, Pearlman EM, Hutchinson SL. Onset, maintenance, and cessation of effect of galcanezumab for prevention of migraine: a narrative review of three randomized placebo-controlled trials. Adv Ther. 2021;38(3):1614–26. https://doi.org/10.1007/s12325-021-01632-x.
Silberstein SD, Dodick DW, Aurora SK, Diener HC, DeGryse RE, Lipton RB, Turkel CC. Per cent of patients with chronic migraine who responded per onabotulinumtoxinA treatment cycle: PREEMPT. J Neurol Neurosurg Psychiatry. 2015;86(9):996–1001. https://doi.org/10.1136/jnnp-2013-307149.
Tepper SJ, Ashina M, Reuter U, Hallström Y, Broessner G, Bonner JH, Picard H, Cheng S, Chou DE, Zhang F, Klatt J, Mikol DD. Reduction in acute migraine-specific and non-specific medication use in patients treated with erenumab: post-hoc analyses of episodic and chronic migraine clinical trials. J Headache Pain. 2021;22(1):81. https://doi.org/10.1186/s10194-021-01292-w.
Silberstein SD, Cohen JM, Seminerio MJ, Yang R, Ashina S, Katsarava Z. The impact of fremanezumab on medication overuse in patients with chronic migraine: subgroup analysis of the HALO CM study. J HeadachePain. 2020;21(1):114. https://doi.org/10.1186/s10194-020-01173-8.
Dodick DW, Doty EG, Aurora SK, Ruff DD, Stauffer VL, Jedynak J, Dong Y, Pearlman EM. Medication overuse in a subgroup analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine. Cephalalgia. 2021;41(3):340–52. https://doi.org/10.1177/0333102420966658.
Diener HC, Marmura MJ, Tepper SJ, Cowan R, Starling AJ, Diamond ML, Hirman J, Mehta L, Brevig T, Sperling B, Cady R. Efficacy, tolerability, and safety of eptinezumab in patients with a dual diagnosis of chronic migraine and medication-overuse headache: Subgroup analysis of PROMISE-2. Headache. 2021;61(1):125–36. https://doi.org/10.1111/head.14036.
Koumprentziotis IA, Mitsikostas DD. Therapies targeting CGRP signaling for medication overuse headache. CurrOpinNeurol. 2022;35(3):353–9. https://doi.org/10.1097/WCO.0000000000001061.
Gantenbein AR, Agosti R, Gobbi C, Flügel D, Schankin CJ, Viceic D, Zecca C, Pohl H. Impact on monthly migraine days of discontinuing anti-CGRP antibodies after one year of treatment - a real-life cohort study. Cephalalgia. 2021;41(11–12):1181–6. https://doi.org/10.1177/03331024211014616.
Nsaka M, Scheffler A, Wurthmann S, Schenk H, Kleinschnitz C, Glas M, Holle D. Real-world evidence following a mandatory treatment break after a 1-year prophylactic treatment with calcitonin gene-related peptide (pathway) monoclonal antibodies. Brain Behav. 2022;12(7):e2662. https://doi.org/10.1002/brb3.2662.
de Vries LS, van der Arend BWH, MaassenVanDenBrink A, Terwindt GM. Blood pressure in patients with migraine treated with monoclonal anti-CGRP (receptor) antibodies: a prospective follow-up study. Neurology. 2022;99(17):e1897–904. https://doi.org/10.1212/WNL.0000000000201008.
Schankin CJ, Broessner G, C. Gaul C, Kraya T, Hamann X, Haertel B, L. Neeb L, Straube A. Response to fremanezumab in migraine patients with and without prior anti-CGRP mAbs – preliminary data from the FINESSE study. Nervenheilkunde 2022; 41(05): 353. https://doi.org/10.1055/s-0042-1745703
Overeem LH, Peikert A, Hofacker MD, Kamm K, Ruscheweyh R, Gendolla A, Raffaelli B, Reuter U, Neeb L. Effect of antibody switch in non-responders to a CGRP receptor antibody treatment in migraine: a multi-center retrospective cohort study. Cephalalgia. 2022;42(4–5):291–301. https://doi.org/10.1177/03331024211048765.
Scuteri D, Tonin P, Nicotera P, Vulnera M, Altieri GC, Tarsitano A, Bagetta G, Corasaniti MT. Pooled analysis of real-world evidence supports anti-CGRP mAbs and onabotulinumtoxinA combined trial in chronic migraine. Toxins (Basel). 2022;14(8):529. https://doi.org/10.3390/toxins14080529.
Goadsby PJ, Edvinsson L. Human in vivo evidence for trigeminovascular activation in cluster headache. Neuropeptide changes and effects of acute attacks therapies. Brain. 1994;117( Pt 3):427–34. https://doi.org/10.1093/brain/117.3.427.
Vollesen ALH, Snoer A, Beske RP, Guo S, Hoffmann J, Jensen RH, Ashina M. Effect of infusion of calcitonin gene-related peptide on cluster headache attacks: a randomized clinical trial. JAMA Neurol. 2018;75(10):1187–97. https://doi.org/10.1001/jamaneurol.2018.1675.
Goadsby PJ, Dodick DW, Leone M, Bardos JN, Oakes TM, Millen BA, Zhou C, Dowsett SA, Aurora SK, Ahn AH, Yang JY, Conley RR, Martinez JM. Trial of galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019;381(2):132–41. https://doi.org/10.1056/NEJMoa1813440.
Dodick DW, Goadsby PJ, Lucas C, et al. Phase 3 randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: results from 3-month double-blind treatment. Cephalalgia. 2020;40:935–48.
Argyriou AA, Vikelis M, Mantovani et al. Recently available and emerging therapeutic strategies for the acute and prophylactic management of cluster headache: a systematic review and expert opinion. Expert Rev Neurother. 2021;21(2):235–248.
Membrilla JA, Torres-Ferrus M, Alpuente A, Caronna E, Pozo-Rosich P. Efficacy and safety of galcanezumab as a treatment of refractory episodic and chronic cluster headache: case series and narrative review. Headache. 2022. https://doi.org/10.1111/head.14404.
Riesenberg R, Gaul C, Stroud CE, Dong Y, Bangs ME, Wenzel R, Martinez JM, Oakes TM. Long-term open-label safety study of galcanezumab in patients with episodic or chronic cluster headache. Cephalalgia. 2022;42(11–12):1225–35. https://doi.org/10.1177/03331024221103509.
Mo H, Kim BK, Moon HS, Cho SJ. Real-world experience with 240 mg of galcanezumab for the preventive treatment of cluster headache. J Headache Pain. 2022;23(1):132. https://doi.org/10.1186/s10194-022-01505-w.
Argyriou AA, Mantovani E, Mitsikostas DD, Vikelis M, Tamburin S. A systematic review with expert opinion on the role of gepants for the preventive and abortive treatment of migraine. Expert Rev Neurother. 2022;22(6):469–88. https://doi.org/10.1080/14737175.2022.2091435.
Mitsikostas DD, Sanchez del Rio M. Receptor systems mediating c-fos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Brain Res Rev. 2001;35(1):20–35. https://doi.org/10.1016/s0165-0173(00)00048-5.
Croop R, Goadsby PJ, Stock DA, Conway CM, Forshaw M, Stock EG, Coric V, Lipton RB. Efficacy, safety, and tolerability of rimegepant orally disintegrating tablet for the acute treatment of migraine: a randomised, phase 3, double-blind, placebo-controlled trial. Lancet. 2019;394(10200):737–45. https://doi.org/10.1016/S0140-6736(19)31606-X.
Croop R, Lipton RB, Kudrow D, Stock DA, Kamen L, Conway CM, Stock EG, Coric V, Goadsby PJ. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. 2021;397(10268):51–60. https://doi.org/10.1016/S0140-6736(20)32544-7.
Ailani J, Lipton RB, Goadsby PJ, Guo H, Miceli R, Severt L, Finnegan M, Trugman JM; ADVANCE Study Group. Atogepant for the preventive treatment of migraine. N Engl J Med. 2021;385(8):695–706. https://doi.org/10.1056/NEJMoa2035908.
Bentivegna E, Onan D, Martelletti P. Unmet needs in preventive treatment of migraine. Neurol Ther. 2023. https://doi.org/10.1007/s40120-023-00438-z.
Ambat FDF, Bentivegna E, Martelletti P. Novel migraine therapies may reduce public and personal disadvantages for people with migraine. BioDrugs. 2022;36(3):337–9. https://doi.org/10.1007/s40259-022-00532-y.
Rothrock JF, Adams AM, Lipton RB, Silberstein SD, Jo E, Zhao X, Blumenfeld AM; FORWARD Study investigative group. FORWARD study: evaluating the comparative effectiveness of onabotulinumtoxinA and topiramate for headache prevention in adults with chronic migraine. Headache. 2019;59(10):1700–1713. https://doi.org/10.1111/head.13653.
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DDM led the consensus process and drafted the manuscript. All other authors participated in the development of the expert consensus statements, and all revised the manuscript and approved the statements for content.
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Conflict of Interest
Dimos D. Mitsikostas has received fees for lectures, travel, and research from AbbVie/Allergan, Amgen, Genesis Pharma, Eli Lilly, Lundbeck, Merz, Merck Serono, Novartis, Sanofi, and Teva. He has participated in clinical studies for migraine of Amgen, Eli Lilly, electroCore, Lundbeck, Novartis, and Teva. He is the president of the Hellenic Headache Society and co-chairman of the Headache Panel of the European Academy of Neurology.
Chrysa Arvaniti has received fees for lectures, travel, and research from Eli Lilly, Novartis, and Teva.
Athanasia Alexoudi has received fees for lectures, travel, and research from AbbVie/Allergan, Abbott, Eli Lilly, Teva, and Alzheimer’s Association.
Ermioni Giannouli has received fees for lectures, travel, and advisory board participation from AbbVie/Allergan, Genesis Pharma, Eli Lilly, Merck Serono, Novartis, Sanofi, and Teva.
Evangelos Kouremenos has received fees for lectures, travel, and research from AbbVie/Allergan, Genesis Pharma, Medicare, Merck, Novartis, Sanofi, Teva, and Viatris.
Theodoros S. Constantinidis has received fees as honoraria for lectures, advisory boards, research and clinical trials, congress registration, and travel from Teva-Specifar, Novartis, Allergan-AbbVie, Elpen, UCB, Genesis Pharma-Biogen, Merck Serono, Sanofi-Genzyme, Bayer, Pharmathen, Arriani, Brain Therapeutics, and C.A. Papaellinas.
Nikolaos Fakas has received speech honoraria, travel expenses, and consultation fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Elpen, Genesis Pharma, Merck Serono, Novartis, Roche, Sanofi, and Teva. He has participated in clinical trials of Actelion, Amgen, Biogen, Celgene, Eli Lilly, Janssen, Merck, Novartis, Receptos, Roche, Sanofi, and Teva and received research support from Roche Diagnostics.
Christina Deligianni has received the International Headache Society research fellowship grant for the year 2021, and she is a member of the European Headache Federation Board of Directors.
Theodoros Karapanayiotides received fees for lectures, travel, research, and advisory boards from Bayer, Eli Lilly, Innovis, IPSEN, Novartis, Pfizer, and Teva.
Efthimios Dardiotis has received fees for lectures, travel, and research from AbbVie/Allergan, Bayer, Genesis Pharma, Lundbeck, Merck Serono, Novartis, Sanofi, UCB, Teva, and Tikun.
Stylianos Gatzonis has received fees as honoraria for lectures, advisory boards, research and clinical trials, congress registration, and travel from UCB, Tikun, Novartis, Sanofi, Lilly Pharmaserv, Pfizer, Genesis Pharma-Biogen, Glaxo-Wellcome, Sanofi-Genzyme, Ariani, Janssen-Cilag, Bayern, Merck Serono, Εlpen, Pharmathen, Teva-Specifar, Cyberonics, and Cormed.
Spyros Konitsiotis has received fees for lectures, travel, consultation, and research from AbbVie, BMS, Genesis Pharma, Medison, Medtronic, Merck, Novartis, Teva, and UCB.
Georgios Tsivgoulis is the president of the Hellenic Neurological Society and general secretary of the Hellenic Society of Cerebrovascular Diseases. He also serves as the vice-president of European Stroke Organization. He has received no funding or fees relevant to this publication.
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Mitsikostas, D.D., Alexoudi, A., Arvaniti, C. et al. Hellenic Headache Society Recommendations for the Use of Monoclonal Antibodies Targeting the Calcitonin Gene-Related Peptide Pathway for the Prevention of Migraine and Cluster Headache—2023 Update. SN Compr. Clin. Med. 5, 118 (2023). https://doi.org/10.1007/s42399-023-01452-w
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DOI: https://doi.org/10.1007/s42399-023-01452-w