Viewpoint/Perspective

Cephalalgia
2024, Vol. 44(3) 1–8
New migraine drugs: A critical appraisal ! International Headache Society 2024
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DOI: 10.1177/03331024241228605
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an adequate medication

Hans Christoph Diener1 and Arne May2

Abstract
The last three decades have produced several novel and efficient medications to treat migraine attacks and reduce attack
frequency. Additionally, promising approaches for the development of acute therapy and migraine prophylaxis continue to
be pursued. At the same time as we witness the development of better and more efficient medications with continuously
fewer side effects, we also realise that the high cost of such therapies means that only a minority of migraine patients
who could benefit from these medications can afford them. Furthermore, information on cost-effectiveness is still
lacking. Here, we compare availiable data, highlight open questions and suggest trials to close knowledge gaps. With
good reason, our medicine is evidence-based. However, if this evidence is not collected, our decisions will continue to
be based on marketing and assumptions. At the moment, we are not doing justice to our patients.

Keywords
Gepant, migraine, migraine attack, migraine prevention, monoclonal antibody against CGRP or the CGRP receptor, oral
medication, triptan
Date received: 10 October 2023; revised: 9 January 2024; accepted: 9 January 2024

RCTs are available to all, or at least the majority of

Introduction all migraine patients.
Recent years have seen the emergence of a number of
new and effective drugs for the treatment of migraine
and very promising approaches to the development of A critical appraisal: therapy of the acute
acute therapy and migraine prophylaxis continue to be migraine attack
pursued. This unprecedented success story of the last
30 years obscures our neglect that, as a result of the Until recently, acute migraine attacks were treated with
high costs, these new medications are only available to analgesics and non-steroidal anti-inflammatory drugs
a very small fraction of migraine patients worldwide.
At the same time, a large part of all scientific publica- 1
Department of Neuroepidemiology, Institute for Medical Informatics,
tions and main symposia of scientific congresses (and Biometry and Epidemiology (IMIBE), Faculty of Medicine, University
thus all the money spent) revolve around the innova- Duisburg-Essen, Essen, Germany
2
Department of Systems Neuroscience, University Hamburg, Hamburg,
tions, and not around medications which have been on
Germany
the market for more than 20 years. International pro-
fessional societies such as the International Headache Corresponding author:
Society (IHS) have as their declared main objective Hans Christoph Diener, Department of Neuroepidemiology, Institute for
Medical Informatics, Biometry and Epidemiology (IMIBE), Faculty of
“the benefit of people affected by headache disorders”. Medicine, University Duisburg-Essen, Hufelandstrasse 55, 45147 Essen,
We will only come closer to this goal if new and effec- Germany.
tive medications that have been investigated in valid Email: [email protected]

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2 Cephalalgia

or triptans. Triptans are very effective and have a good after the use of a triptan in the last three years in
side effect and safety profile. In a meta-analysis, suma- Germany (personal communication, German Medical
triptan had a pain free rate of 29%. Compared with Association). Because the patent protection of the trip-
sumatriptan, 10 mg of rizatriptan showed better effica- tans has expired, there will be no initiatives to change
cy and consistency, and similar tolerability; 80 mg of the SmPCs of the triptans regarding contraindications.
eletriptan showed better efficacy, similar consistency, The rationale behind the development of new drugs
but lower tolerability; 12.5 mg of almotriptan showed for the treatment of acute migraine attacks was the
a similar efficacy at two hours (but better than other patient population for whom triptans are not or not
results); 2.5 mg of naratriptan and 20 mg of eletriptan sufficiently effective and patients with actual or per-
showed lower efficacy and (the first two) better tolera- ceived contra-indications to triptans. Three calcitonin
bility; 2.5 mg and 5 mg of zolmitriptan, 40 mg of ele- gene-related peptide (CGRP) receptor antagonists, the
triptan and 5 mg of rizatriptan showed very similar so-called gepants, were developed: for the treatment of
results (1). A recent real world study including acute migraine attacks, rimegepant 75 mg, ubrogepant
4,777,524 medication-outcome pairs from 3,119,517 50 and 100 mg and zavegepant nasal spray 10 mg.
migraine attacks among 278,006 users showed a mean There are no significant differences in the efficacy of
odds ratio of 4.8 for triptans compared to ibuprofen the three gepants, and the 95% confidence intervals of
and superiority of triptan over opioids, ergots and non- the odds ratios overlap (Table 1) (9). Unfortunately,
steroidal anti-inflammatory drugs (2). The data are suf- there are no direct comparative studies between trip-
ficiently good to conclude that triptans are the drugs of tans, analgesics, non-steroidal anti-inflammatory drugs
choice in the treatment of acute migraine attacks, both and the approved gepants. It is rather likely that suma-
in terms of benefit and side-effect profile. However, triptan 100 mg and rizatriptan 10 mg are more effective
some patients are non-responders to triptans and, in than the three gepants.
many cases, the non-response is a result of application The target group for treatment of acute migraine
errors such as administering the triptan too late during attacks with a gepant are, as described above, patients
a migraine attack when the headache has already with proven ineffectiveness of triptans. It is surprising
reached its peak level. Triptans act via serotonin that there are no randomised trials with patients in
5-HT1B and 5-HT1D receptors. Initially, it was assumed whom the lack of efficacy or ineffectiveness of a triptan
that the effect of triptans was mediated by a constric- has been prospectively tested. In such a study, patients
tion of dilated dural arteries during the migraine attack would first have to be treated with a triptan in the first
(3,4). This assumption led to the contraindications in phase and only non-responders (i.e. patients who do
the original marketing authorisation, namely serious not respond to the triptan in three out of three migraine
vascular diseases. Subsequently, it was shown, howev- attacks) would then receive a gepant or a triptan in a
er, that the effect of triptans is mediated predominantly randomised study. Such studies are undoubtedly
via 5-HT1D receptors in terminal nerve endings of the expensive and the pharmaceutical industry should
trigeminal nerve, in the trigeminal ganglion, in the take its responsibility and make such studies available.
trigeminal nucleus area and in the thalamus (5). Another class of new migraine triptans are the
Consequently, further studies showed that the vasocon- ditans. Lasmiditan has shown efficacy in the treatment
strictive properties of triptans in humans are minimal of migraine attacks but has central side effects (10–12).
(6). In addition, the mechanism of stroke or myocardial Lasmiditan has no vasoconsstrictive properties and
infarction is in most cases plaque rupture and local therefore would be an alternative for patients with
thrombosis or embolism and not vasoconstriction (7). clear contraindications for triptans (13)
Vasoconstriction mainly plays a role in Prinzmetal Because gepants block the CGRP receptor and thus
angina and vasospasm after subarachnoidal haemor- probably prevent the dilation of collaterals in cases of
rhage. Despite these new findings, the package inserts ischaemia, they should also not be used in patients with
(summary of product characteristics or SmPC) for trip-
tans were never changed, such that contraindications Table 1. Two hour pain free rates and corresponding odds
such as uncontrolled hypertension, stroke, myocardial ratios (OR) and 95% confidence intervals (CI).
infarction, angina pectoris and other serious vascular
Verum Placebo OR (9) 95% CI
diseases are still mentioned. However, large observa-
tional studies have not shown an increased risk of Rimegepant 75 mg (43) 21% 11% 1.59 1.03–2.47
acute coronary syndromes and ischaemic strokes in Ubrogepant 50 mg (44) 19.2% 11.8% 1.72 1.22–2.41
patients who treat their migraine attacks with triptans Ubrogepant 100 mg (44) 21.2% 11.8% 1.97 1.27–3.07
(8). A query of the database of the Drug Commission Zavegepant 10 mg (45) 24% 15% 1.58 1.20–2.01
of the German Medical Association did not reveal a Sumatriptan 100 mg (46) 27% 10.6% 3,22 2.7–3.8
Rizatriptan 10 mg (46) 36% 10.6% 4.86 3.9–6.2
single report of a stroke or myocardial infarction
Diener and May 3

Table 2. Treating an acute migraine attack: cost per tablet in the 3. There have been no randomised trials in patients
USA and Europe, lowest prices by internet pharmacies. who cannot take triptans because of real or assumed
Cost per tablet1 USA $ Europe e contraindications.
4. There are no data on the safety of gepants in
Rimegepant 75 mg 115 31 patients with severe vascular diseases.
Ubrogepant 50 mg 95 NA 5. There are no valid cost–benefit analyses for the
Ubrogepant 100 mg 95 NA gepants so far.
Zavegepant 10 mg 177 NA 6. The proof that gepants do not lead to medication
Lasmiditan 50 or 100 mg 98 NA
overuse headache is still lacking
Sumatriptan 100 mg 1.50 5.00
Sumatriptan 50 mg 1.20 2.50*
Rizatriptan 10 mg 1.10 2.10 Clinical implications acute migraine
*Over the counter, NA, not available. medication
1
Prices from Goodrs.com. Accessed 29 September 2023 (2:00 pm
Eastern Time).
There is no doubt that the development of the gepants
is an important step in the treatment of acute migraine
attacks. The main advantage of gepants over triptans is
severe vascular disease (14). However, it would be
that thery are well tolerated. It is very likely that
extremely unlikely that a migraine patient would coin-
gepants can also be used in patients with vascular dis-
cidentally suffer an ischemic stroke in temporal relation
eases. Gepants might not lead to medication overuse
to taking a gepant.
and medication overuse headache (15). The main
obstacle for the use of gepants is the very high price.

Acute medication: cost–benefit analysis

A critical appraisal: migraine prevention
Three gepants are approved and commercially available
in the USA. Table 2 shows the cost of one tablet of each Until five years ago, migraine prophylaxis was carried
of the gepants compared with sumatriptan and rizatrip- out with substances whose efficacy for the prevention
of migraine was discovered by chance. Only methyser-
tan in the USA. For comparison, the cost of rimegepant
gide and pizotifen were developed as specific migraine
and sumatriptan and rizatriptan in Europe is also
preventive drugs but are either no longer available or
shown. These figures show the most important problem
no longer used. Beta-receptor blockers such as pro-
for the use of gepants: at current prices, there are few
pranolol (16), flunarizine (17), topiramate (18), val-
migraine patients outside the USA who can afford to proic acid (19), amitriptyline (20) and candesartan
treat migraine attacks with a gepant. This deprives mil- (21) have been shown to be effective in placebo-
lions of people with migraine who do not respond ade- controlled trials. For chronic migraine, there is evi-
quately to triptans of a potentially effective therapy. It dence of efficacy for onabotulinumtoxinA (22). The
also raises the question of the unique selling point: what problem with oral migraine prophylactics was not effi-
is the added benefit of a medication that costs 31 times cacy but tolerability. Unfortunately, many patients
(USA) or six times (Europe) as much as the triptans? discontinued migraine prophylaxis because of adverse
drug reactions (23). In addition, most of the randomised
controlled trials addressing oral drugs for migraine pre-
Acute medication: what data and vention would nowadays considered inadequate from a
information are still missing? methodological point to establish if the study drug was
superior to placebo. Therefore, there was a clear clinical
Clinical neurologists and headache specialists lack need to develop new migraine medications with proven
information to make evidence-based, valid decisions efficacy and a better side effect profile.
about the best treatment of migraimne attacks for Three monoclonal antibodies against CGRP (epti-
their patients. nezumab, fremanezumab and galcanezumab) and a
monoclonal antibody against the CGRP receptor
1. There are no randomised controlled trials that have (erenumab) were developed as specific migraine pro-
directly compared a triptan such as 50 or 100 mg of phylactics. In randomised placebo-controlled trials,
sumatriptan with an approved gepant. all monoclonal antibodies were more effective than pla-
2. There are no randomised trials to date to demon- cebo in reducing the mean number of migraine days per
strate the efficacy of gepants in patients who have month and 50% responder rates. This was true
prospectively shown that they do not benefit from for both episodic and chronic migraine patients.
triptans. In a meta-analysis, the efficacy of monoclonal
4 Cephalalgia

antibodies against CGRP or the CGRP receptor was Which patients should be treated with
comparable (24). monoclonal antibodies to CGRP or the
The tolerability and safety of monoclonal antibodies
CGRP receptor or gepants?
in migraine prophylaxis is very good (25). A dose of
240 mg of galcanezumab had the highest rates of adverse 1. Patients with chronic migraine and medication over-
drug reactions. Otherwise, there were no significant dif- use are likely to benefit most from monoclonal anti-
ferences between the individual monoclonal antibodies. bodies and gepants.
Erenumab has a slightly higher risk of constipation. 2. Patients in whom oral migraine prophylactics or
Initially, health care systems in Europe restricted the onabotulinumtoxinA for chronic migraine are inef-
prescription of monoclonal antibodies for patients who fective, not tolerated or contraindicated should be
did not respond to two to five previous oral therapies treated with a monoclonal antibodies. Data from
or onabotulinumtoxinA, valproic acid or could not tol- randomised trials for this patient population are
erate them or had contraindications (e.g. topiramate in not yet available for gepants.
women) (26). However, most health systems severely limit reimburse-
ment for the new migraine prophylactics because of the
Migraine prophylaxis with gepants high annual treatment costs.

Two of the gepants namely rimegepant 75 mg every Migraine prophylaxis: cost–benefit analysis
other day (27) and atogepant once daily (28–30) were
studied for the prophylaxis of migraine. The study of The treatment costs for the monoclonal antibodies are
rimegepant was based on the observation from open- currently still very high (Table 4). This is in partly
label, long-term studies that patients who treated their because of the high costs for the production of human-
migraine attacks with rimegepant also experienced a ised monoclonal antibodies. The costs for the gepants
reduction in the frequency of migraine days (31). are even higher. A systematic review of the economic
Table 3 shows efficacy data for CGRP antagonists, evaluation of erenumab, fremanezumab and galcanezu-
CGRP antibodies, and topiramat and propranolol. mab showed that they are not cost-effective compared
Atogepant is approved for the prophylaxis of episodic to OnabotulinumtoxinA (32). As a result of the high
and chronic migraine. Rimegepant is only approved for cost of treatment, very few patients are currently
the treatment of episodic migraine. treated with monoclonal antibodies outside the USA.
In Germany, with a population of 84 million people,
there were an estimated 35,000 patients with migraine
in 2022 who were treated with a monoclonal antibody
(personal communication,). In addition, many patients
and physicians are not aware that new options for the
prevention of migraine exist.
The high cost of the monoclonal antibodies and
gepants means that only a minimal fraction of all

Table 3. Reduction in migraine days per month compared to placebo and odds ratios (OR) and 95% confidence
intervals (CI) for the comparison of migraine preventive drugs and placebo for 50% responder rates, adapted from
Haghdoost et al. (24) and Frank et al. (47)

Reduction in monthly Odds ratio for 50%

Drug migraine days (95% CI) responder rate (95% CI)

Erenumab 70 mg 1.27 (–1.81 to –0.74) 1.83 (1.45–2.30)

Erenumab 140 mg 1.78 (–2.41 to –1.14) 2.49 (1.85–3.34)
Fremanezumab 225 mg 2.06 (–2.57 to –1.54) 3.04 (2.45–3.78)
Fremanezumab 675 mg 2.36 (–2.87 to –1.84) 3.19 (2.57–3.96)
Galcanezumab 120 mg 2.28 (–2.82 to –1.74) 2.64 (2.14–3.26)
Eptinezumab 100 mg 1.35 (–2.51 to –0.19) 1.92 (1.52–2.42)
Eptinezumab 300 mg 1.80 (–2.96 to –0.63 2.34 (1.85–2.96)
Atogepant 60 mg 1.35 (–1.85 to –0.85) 1.79 (0.71–4.52)
Rimegepant 75 mg 0.80 (–1.56 to –0.04) 1.38 (0.38–5.01)
OnabotulinumtoxinA (47) 1.28 (0.98–1.67)
Topiramate (47) 2.70 (1.97–3.69)
Propranolol (16) 1.2 (–1.8 to –0.60) 1.4 (1.1–1.8)
Diener and May 5

Table 4. Cost for one year of treatment in the USA and Europe conducting studies on how their drugs are best
discontinued.
USA/
Interval Canada $ Europe e 4. Prospective studies on the duration of therapy. In
these studies, patients should be treated with a
Eptinezumab 100, 300 mg 12 weeks 6845 3280 monoclonal antibody or a gepant for nine or
Erenumab 70, 140 mg 4 weeks 8598 3384 12 months. Then they should be randomised to con-
Fremanezumab 225 mg 4 weeks 8143 5328 tinuation of drug prophylaxis or placebo. In this
Galcanezumab 120 mg 4 weeks 7603 5880
way, it will be possible to prospectively assess the
Rimegepant 75 mg EAD 20964 NA
Atogepant 60 mg OD 12084 NA percentage of patients who need to be retreated
OnabotulinumtoxinA 12 weeks 4900 2320 with the new migraine prophylactics after a treat-
(200 units) ment pause.
Topiramate (50 mg) OD 118 133 5. Prospective randomised studies on switching thera-
py when efficacy is poor or insufficient. Patients in
Data based on information from internet pharmacies, with Prices from
Goodrs.com. Accessed 29 September 2023 (2:00 pm Eastern Time). whom a monoclonal antibody was not effective after
NA, not available; EAD, every other day; OD, once daily. three months should be randomised and treated for
a further 3 months with the previously used mono-
migraine patients who could benefit from these drugs clonal antibody or an alternative antibody or a
receive modern migraine prophylaxis. gepant.
6. Prospective randomised trials of the combination of
Prophylaxis: which data and information traditional oral migraine prophylactics or in chronic
migraine with onabotulinumtoxinA in patients who
are still missing? have had an inadequate response to a monoclonal
Clinical neurologists and headache specialists lack antibody or gepant (responder rate >30–50%).
the information they need to make evidence-based,
valid decisions about the best treatment for their
Which patients should currently receive
patients.
limited or no treatment with monoclonal
1. Head–to-head comparative studies of monoclonal antibodies against CGRP or the CGRP
antibodies are completely lacking. receptor or gepants?
2. Comparative studies of monoclonal antibodies and CGRP has numerous biological functions and is a par-
gepants with oral migraine prophylactics and in ticularly potent vasodilator in reduced perfusion and
chronic migraine with onabotulinumtoxinA are ischaemia. In addition, CGRP receptors are also
also lacking. To date, there is only one direct com- found, for example, in the intestine, in the endothelium
parison study between erenumab and topiramate of the bronchi and in the skin. For purely pathophys-
with the question of the side effect rate, in which, iological reasons, there are therefore a number of dis-
unsurprisingly, erenumab was not only better toler- eases in which both the monoclonal antibodies against
ated than topiramate, but also caused a significantly CGRP and the gepante should only be used with great
higher reduction in monthly migraine days in the restraint or caution (36,37) (Table 5). The new migraine
secondary objectives (33). Topiramate is known to drugs are currently contraindicated in pregnant
be poorly tolerated. Comparative studies should be women, children and adolescents.
conducted with propranolol, which is significantly
better tolerated than topiramate.
3. Prospective study at the end of therapy: most Clinical implications of new migraine
patients experience a rapid increase in migraine fre- preventive drugs
quency as soon as successful anti-CGRP therapy is Gepants are an important new therapeutic option for
discontinued (34,35). In future studies, successful the treatment of acute migraine attacks, particularly in
therapy with monoclonal antibodies should be ter- patients in whom triptans are ineffective, not tolerated
minated after six months in randomised and or contraindicated. Monoclonal antibodies against
placebo-controlled trials, either abruptly (as is cur- CGRP or the CGRP receptor and gepants offer an
rently common practice) or gradually (over longer effective and well-tolerated option for migraine pro-
intervals between new injections). Pharmaceutical phylaxis, particularly in patients in whom previous
companies, however, are probably not interested in oral migraine prophylactics or onabotulinumtoxinA
6 Cephalalgia

Table 5. Patients in whom monoclonal antibodies or gepants instead of the currently small minority. In some studies
should be used with care reporting on monoclonal antibodies (39,40), the
Disruption of the impression was also given that triptans are dangerous
blood–brain barrier in the treatment of acute migraine attacks. This is
(e.g. traumatic brain simply wrong (41). Moreover, given the good tolerabil-
Acute ischaemic stroke, TIA injury, meningitis) ity of CGRP antagonists and antibodies, devaluing the
gold standard for marketing reasons is unnecessary. So
Subarachnoidal haemorrhage Wound healing
Acute coronary syndrome Inflammatory bowel disease far, there has been one published study comparing
Angina pectoris COPD a monoclonal antibody with an oral migraine prophy-
Severe constipation Raynaud’s syndrome lactic. (33). The much more important question of ther-
apeutic benefit, which can be clearly answered in a
COPD, chronic obstructive pulmonary disease.
direct comparison, is being bypassed. The elephant in
the room here is the fact that most of the medical pro-
have not been effective, are not tolerated or are contra- phylactics used so far can be discontinued after about
indicated. Patients with the highest benefit from mono-
six to nine months because the migraine frequency
clonal antibodies are those with chronic migraine and
remains permanently low. The conventional prophylac-
medication overuse. All monoclonal antibodies showed
tics therefore have a positive effect on the migraine
efficacy in these patients. In the past, this had only been
biology. CGRP antibodies usually only work as long
shown for onabotulinumtoxinA. The particular advan-
as they are given and, even after a year of treatment,
tage of monoclonal antibodies and gepants is that they
the frequency of attacks rises again as soon as the ther-
are well tolerated. The subcutaneous or intravenous
apy is discontinued (42). This is not even taken into
administration of the monoclonal antibodies ensures
account when calculating the costs (Table 4). We also
high adherence. So far, there are no serious safety con-
cerns. A final conclusion on the saftey of monoclonal simply do not know how a therapy with CGRP antibod-
antibodies requires the treatment of large numbers of ies, which may be necessary for many years, will be toler-
patients including those with a hypothetical risk such ated long-term. Studies are urgently needed here. So far,
as ischaemic stroke, acute coronary syndrome, inflam- there have been no prospective studies in which non-
matory bowel disease or severe chronic obstructive pul- responders to triptans or patients with contraindications
monary disease (38) to triptans were examined. There have also been no rand-
omised trials of the new migraine prophylactics regarding
the duration of treatment, the consequences of drug inter-
Conclusions and call for action ruption, switching in case of ineffectiveness, and the effi-
At the current prices for monoclonal antibodies and cacy, tolerability and safety of combination therapy.
the gepants, only extremely few patients can benefit Our therapy decisions should be based on comprehen-
from this therapy. Professional societies and pharma- sible data. With good reason, our medicine is evidence-
ceutical companies should take their responsibility and based. However, if this evidence is not collected, our
set the goal that at least 50% of all migraine patients decisions will continue to be based on marketing and
can be treated with modern migraine medication, assumptions. We are not doing justice to our patients.

Clinical implications
• Gepants are an important new therapeutic option for the treatment of acute migraine attacks, particularly
in patients in whom triptans are ineffective, not tolerated or contraindicated.
• Monoclonal antibodies against CGRP or the CGRP receptor and gepants offer an effective and well-
tolerated option for migraine prophylaxis, particularly in patients in whom previous oral migraine pro-
phylactics or onabotulinumtoxinA have not been effective, are not tolerated or are contraindicated.
• The patient group with the highest benefit from monoclonal antibodies is patients with chronic migraine
and medication overuse.
• The particular advantage of monoclonal antibodies and gepants is that they are well tolerated.
• The subcutaneous or intravenous administration of the monoclonal antibodies ensures high adherence.
• So far, there are no serious safety concerns.
• The high costs of the new medications impede the use of these medications for the majority of migraine
patients.
Diener and May 7

Author contributions 12. Farkkila M, Diener HC, Geraud G, et al. Efficacy and
HCD and AM wrote the paper. tolerability of lasmiditan, an oral 5-HT(1F) receptor ago-
nist, for the acute treatment of migraine: a phase 2 rand-
omised, placebo-controlled, parallel-group, dose-ranging
Declaration of conflicting interests
study. Lancet Neurol 2012; 11: 405–413.
The authors declare that there are no potential conflicts of 13. Shapiro RE, Hochstetler HM, Dennehy EB, et al.
interest with respect to the research, authorship and/or pub- Lasmiditan for acute treatment of migraine in patients
lication of this article. with cardiovascular risk factors: post-hoc analysis of
pooled results from 2 randomized, double-blind,
Funding placebo-controlled, phase 3 trials. J Headache Pain
No funding was received. 2019; 20: 90.
14. Mulder IA, Li M, de Vries T, et al. Anti-migraine calci-
ORCID iDs tonin gene-related peptide receptor antagonists worsen
cerebral ischemic outcome in mice. Ann Neurol 2020;
Hans Christoph Diener https://orcid.org/0000-0002-6556-
88: 771–84.
8612
15. Koumprentziotis IA and Mitsikostas DD. Therapies tar-
Arne May https://orcid.org/0000-0002-3499-1506
geting CGRP signaling for medication overuse headache.
Curr Opin Neurol 2022; 35: 353–359.
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