Expert Opinion on Pharmacotherapy

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Pharmacological management of migraine:

current strategies and future directions

Lanfranco Pellesi, Thien Phu Do & Anders Hougaard

To cite this article: Lanfranco Pellesi, Thien Phu Do & Anders Hougaard (2024)
Pharmacological management of migraine: current strategies and future directions, Expert
Opinion on Pharmacotherapy, 25:6, 673-683, DOI: 10.1080/14656566.2024.2349791

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EXPERT OPINION ON PHARMACOTHERAPY
2024, VOL. 25, NO. 6, 673–683
[Link]

REVIEW

Pharmacological management of migraine: current strategies and future directions

a
Lanfranco Pellesi , Thien Phu Dob,c,d,e and Anders Hougaard b,d,e

a
Clinical Pharmacology, Pharmacy and Environmental Medicine, Department of Public Health, University of Southern Denmark, Odense, Denmark;
b
Department of Neurology, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark; cDepartment of Neurology, Danish
Knowledge Center on Headache Disorders, Glostrup, Denmark; dDepartment of Clinical Medicine, Faculty of Medical and Health Sciences,
University of Copenhagen, Copenhagen, Denmark; eDepartment of Neurology, Copenhagen University Hospital - Herlev and Gentofte, Herlev,
Denmark

ABSTRACT ARTICLE HISTORY

Introduction: Migraine is a complex neurological disorder that affects a significant portion of the global Received 22 February 2024
population. As traditional pharmacological approaches often fall short in alleviating symptoms, the Accepted 26 April 2024
development of innovative therapies has garnered significant interest. This text aims to summarize the KEYWORDS
current pharmacological options for managing migraine and to explore the potential impact of novel CGRP; gepant; headache;
therapies. pain; trigeminovascular
Areas covered: We focused on conventional treatments, emerging therapies, and novel compounds in system
clinical development, including therapies targeting the trigeminovascular system, cannabis-based
therapies, hormonal and metabolic therapies, and other options. English peer-reviewed articles were
searched in PubMed, Scopus, and [Link] electronic databases.
Expert opinion: Several novel treatment options for migraine have become available in recent years.
Emerging pharmacological therapies targeting the trigeminovascular system, cannabis-based therapies,
hormonal and metabolic interventions, and other emerging treatment modalities, may prove to be
valuable for the treatment of migraine. Further research, clinical trials, and substantiated evidence are
necessary to validate the efficacy, safety, and long-term outcomes of these therapeutic options.

1. Introduction the development of new classes of medications, including

monoclonal antibodies and gepants. Monoclonal antibodies
Migraine is a common neurological disorder that affects
blocking CGRP or its receptor have shown remarkable effi­
a considerable portion of the global population, leading to
cacy in reducing migraine frequency and improving patient
significant individual and societal burdens. It is characterized
outcomes [4]. These antibodies act by binding to CGRP or its
by recurrent episodes of moderate to severe headache often
receptor, thereby preventing its interaction with trigeminal
accompanied by various neurological and gastrointestinal
nociceptors and suppressing inflammation and pain.
symptoms. The exact pathophysiology of migraine is still
Gepants, another class of CGRP-targeted therapies, are com­
not fully understood, but it is believed to involve the activa­
petitive inhibitors of the CGRP receptor. Unlike monoclonal
tion of the trigeminovascular system, leading to the release
of vasoactive peptides, particularly calcitonin gene-related antibodies, gepants are small molecules that are orally active
peptide (CGRP) [1]. The pharmacological management of and prevent CGRP-mediated vasodilation and trigeminal
migraine has evolved over the years, with the development nerve activation, leading to pain relief [5]. One of these
of both acute and preventive treatment strategies. Acute drugs, rimegepant, can be used as both acute and preventive
therapies aim to relieve the symptoms experienced during therapies with positive results. There are several guidelines,
migraine, while preventive therapies aim to reduce the fre­ recommendations, and position papers on migraine pharma­
quency and severity of migraine episodes. Until recently, cotherapies [4,6–8]. As novel pharmacological therapies for
pharmacological management of migraine has largely been migraine emerge, there is an interest to consider their inte­
limited to triptans, nonsteroidal anti-inflammatory drugs gration in clinical practice. This review aims to provide an
(NSAIDs), and oral preventatives originally developed for overview of the current pharmacological management of
other disorders, such as antihypertensives, antidepressants, migraine, including anti-CGRP therapies. Furthermore, we
and antiepileptics [2]. Recent advances have focused on will discuss ongoing clinical trials in phases II and III, explor­
developing therapies specifically targeting the CGRP signal­ ing the future directions of pharmacological treatments for
ing pathway. CGRP, a neuropeptide involved in vasodilation, migraine. By doing so, we expect to contribute to our under­
inflammation, and pain transmission, has emerged as standing of how these treatments may potentially change
a promising target for migraine therapy [3]. This has led to the landscape of migraine management.

CONTACT Anders Hougaard ahougaard@[Link] Department of Neurology, Copenhagen University Hospital - Herlev and Gentofte, Borgmester Ib Juuls
Vej 1, Herlev DK-2730, Denmark
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ([Link]
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
674 L. PELLESI ET AL.

Table 1. Acute migraine therapies. Therapeutic gain (TG), i.e. The difference
Article highlights between the active drug and placebo, for pain freedom at 2 hours is reported.
Therapy TG Reference
● Therapies targeting the CGRP signaling pathway, such as monoclonal Simple analgesics
antibodies and gepants, have shown efficacy in reducing migraine Paracetamol 1,000 mg 8% [73]
frequency and improving patient outcomes. Aspirin 1,000 mg 13% [7]
● Acute migraine therapy targeting 5-HT receptors, triptans and ditans, Diclofenac potassium 50 mg 14% [10]
show variability in efficacy and side effects, with subcutaneous suma­ Ibuprofen 400 mg 14% [8]
triptan being the most effective for pain relief. Naproxen 500 mg or 825 mg 9% [9]
● Lu AG09222, a monoclonal antibody targeting and inhibiting PACAP, Oral triptans
showed promise in preventing PACAP38-induced cephalic vasodila­ Almotriptan 12.5 mg 22% [16]
tion and headache in a proof-of-mechanism study. A phase 2a trial Eletriptan 40 mg 27% [16]
demonstrated its efficacy in reducing the number of monthly Frovatriptan 2.5 mg 11% [16]
migraine days in individuals with a history of unsuccessful prior Naratriptan 2.5 mg 13% [16]
preventive treatments. Rizatriptan 10 mg 35% [16]
● The manipulation of trigeminovascular system signaling pathways Sumatriptan 50 mg 16% [16]
offers hope for new targeted therapies aimed at those patients Sumatriptan 100 mg 21% [16]
who do not benefit from current treatments. Zolmitriptan 2.5 mg 20% [16]
Zolmitriptan 5 mg 21% [16]
Combination
Oral sumatriptan 85 mg + naproxen 20% [16]
500 mg
2. Methods Nasal triptans
Sumatriptan 20 mg 21% [16]
We searched English peer-reviewed articles with no date limits Zolmitriptan 5 mg 25% [16]
in PubMed, Scopus, and [Link] electronic databases. Subcutaneous triptans
Sumatriptan 6 mg 44% (34% for 1 h pain [16]
We used the term ‘migraine’ combined with ‘acute treatment,’ free)
‘acute therapy,’ ‘preventive treatment’ or ‘preventive therapy’ Ditans
and the results were screened for relevance to the review Lasmiditan 50 mg 7% [16]
Lasmiditan 100 mg 12% [16]
topic. Additionally, articles were added based on the authors’ Lasmiditan 200 mg 17% [16]
knowledge of the topic. Gepants
Rimegepant 75 mg tablet 8% [16]
Rimegepant 75 mg orally disintegrating 11% [16]
tablet
3. Acute treatment Ubrogepant 25 mg 6% [16]
Ubrogepant 50 mg 8% [16]
Acute pharmacological migraine therapy aims to abort the Ubrogepant 100 mg 9% [16]
headache phase of migraine. As a general principle, treatment Zavegepant 10 mg 8% [74]
should be initiated as early as possible in the headache phase.
The response to different therapies varies considerably between
patients. Some patients benefit from a combination of thera­ aspirin, ibuprofen, naproxen, and diclofenac sodium relieve
pies. A stepwise approach is recommended to achieve the most migraine-associated symptoms of nausea, photophobia, phono­
effective, safest, and least expensive therapy [6]. Acute treat­ phobia. Intravenous ketorolac is probably effective but there is
ments are commonly classified as first-line, second-line, and inadequate evidence for intravenous paracetamol [14].
third-line therapies. First-line therapies include weak analgesics Regarding intranasal formulations, there is insufficient evidence
and antiemetics, second-line therapies are triptans, and third- for ketorolac nasal spray and inhaled corticosteroids [14].
line therapies are ditans and gepants (see section on ‘Current
anti-CGRP pharmacological therapies’). An overview of acute
migraine treatments and their efficacy is provided in Table 1. 3.2. Triptans
Triptans, 5-HT1B/1D receptor agonists, are used as second-line
therapies if simple analgesics do not provide sufficient head­
3.1. Simple analgesics
ache relief. The mechanism of action of triptans involves con­
The efficacy of paracetamol (acetaminophen), aspirin and var­ striction of cranial arteries and inhibition of neuropeptide
ious NSAIDs for the treatment of migraine attacks has been release, thus contributing to pain relief. All triptans have well-
demonstrated in several clinical trials. Paracetamol is less effi­ documented efficacy, but availability vary between countries.
cient and is primarily useful in patients who do not tolerate If a triptan is not effective in an individual patient, other
NSAIDs [9]. A Cochrane review of aspirin for acute migraine triptans might still show efficacy [15]. Sumatriptan is the first
headache concluded that aspirin 1000 mg has an efficacy com­ marketed and most widely available triptan. In a major
parable to that of sumatriptan 50 mg or 100 mg [10]. Cochrane review, the TG of oral sumatriptan 50 mg and 100
Therapeutic gain (TG), i.e. the difference between the active mg for pain freedom at 2 hours was 16% and 21%, respec­
drug and placebo, for pain freedom at 2 hours compared to tively [16]. The subcutaneous route is the most effective in
placebo was 13%. Ibuprofen has shown efficacy compared to terms of pain relief at two hours from moderate to severe
placebo in all doses between 200 mg and 600 mg for pain baseline pain, with a TG of 44% for a 6 mg dose. Intranasal
freedom at two hours and sustained pain relief at 24 hours sumatriptan is also effective for pain free at two hours (TG =
[11]. Similarly, naproxen and diclofenac potassium are effective 21%). An intranasal formulation of sumatriptan that include
acute migraine therapies [12,13]. In addition to headache, absorption enhancers has been marketed recently. In one trial
 EXPERT OPINION ON PHARMACOTHERAPY 675

intranasal sumatriptan 10 mg with this formulation had a TG Preventive treatment aims to reduce attack frequency or
of 21% [17]. There are clinically relevant differences between severity, with a successful outcome defined as a 50% reduc­
the seven oral triptans in terms of efficacy and side effects tion in migraine frequency or severity without significant side
(Table 1). There is no evidence that the effect of orally disin­ effects. Selection of preventive medication should be evi­
tegrating tablets or rapidly soluble tablets is faster than that of dence-based, considering efficacy, side effects, and coexisting
standard tablets. Combination of sumatriptan 85 mg with disorders. Slow titration is advised to minimize side effects,
naproxen 500 mg is more effective than treatment with each and a headache diary is recommended for documenting treat­
drug alone (TG = 20% 2 h pain free) [18]. Common side effects ment effects. Efficacy often emerges over weeks or months.
of triptans include a sensation of pressure on the chest, nau­ Early treatment discontinuation due to perceived inefficacy
sea, distal paresthesia, and fatigue. Triptans remain contra­ should be discouraged. If an oral preventive medication
indicated in patients with a previous history of stroke, proves ineffective after 2–3 months, alternative options should
uncontrolled hypertension, ischemic heart disease, and per­ be explored. Non-responsiveness to one preventive class does
ipheral vascular disease due to concerns of an increased risk of not preclude success with others, barring issues of adherence.
vascular events, although the risk of such events for the Periodic reassessment of the need and effectiveness of pre­
individual triptan user appears to be very low [19]. ventive medication is crucial. Clinical practice suggests paus­
ing successful preventive medications after 6–12 months to
evaluate the necessity of continued treatment, thereby redu­
3.3. Antiemetics
cing unnecessary drug exposure. As for acute medications,
For migraine-associated nausea, simple analgesics or triptans preventive treatments are categorized as first-, second-, and
can be combined with antiemetics to treat nausea and vomit­ third-line therapies (see Table 2) under the influence of local
ing, but there is no evidence that antiemetics improve the guidelines, availability, costs, and reimbursement policies.
absorption of anti-migraine drugs [20]. Metoclopramide 10 mg First-line therapies include β-blockers, topiramate, and cande­
or domperidone 10 mg are commonly used for such combina­ sartan. Second-line therapies are flunarizine, amitriptyline, and
tions. The antiemetics prochlorperazine, droperidol, chlorpro­ sodium valproate (with contraindications for women of child­
mazine, and metoclopramide may be effective for acute bearing potential). Third-line therapies comprise CGRP mono­
treatment of migraine headache but the evidence in support clonal antibodies (see section on ‘Current anti-CGRP
of this is limited [14]. pharmacological therapies’).

3.4. Other acute treatment options 4.1. Antihypertensive drugs

Ditans are 5-HT1F receptor agonists that, as opposed to trip­ Several β-blockers have shown efficacy against placebo in
tans, have no effect on the vasculature. Lasmiditan is clinical trials. These trials were mainly conducted in the
approved for the acute treatment of migraine but is limited 1980’s and results are limited by low methodological quality,
by a lower efficacy than triptans (TG = 7%, 12%, and 17% for short duration, and risk of publication bias [27]. Propranolol
lasmiditan 50 mg, 100 mg, and 200 mg, respectively, for 2 h and metoprolol are best supported by evidence and the most
pain freedom, and central nervous system adverse events used options. In clinical practice, the typical dosage for meto­
(including impaired ability to drive a car for 8 h) [21]. Oral prolol is 50 mg once daily for 1 week followed by a gradual
ergot alkaloids have poor efficacy and are associated with increase of dosage to 50–100 mg twice daily. Typical dosage
a high risk of serious adverse effects [22]. A new intranasal for propranolol is 40 mg twice daily increased to 80–160 mg
formulation that delivers a low dose (0.725 mg per spray) of oral once or twice daily in slow-release formulations [28]. Data
dihydroergotamine mesylate to the upper nasal space has are supporting the use of bisoprolol, timolol and atenolol as
been recently approved for the treatment of acute migraine well [29]. There is no evidence for one β-blocker being more
attacks [23]. Due to the pharmacokinetic properties of dihy­ effective in migraine prevention than another among those
droergotamine, nasally and orally inhaled formulations likely with proven efficacy. If patients experience side effects from
do not exert a fast clinical effect despite a quick absorption one β-blocker, change to another could be attempted [27].
[24]. Opioids and barbiturates have dubious efficacy and sub­ The most common side effects are fatigue, cold extremities,
stantial side effects as well as risk of dependency [25]. For and dizziness. The angiotensin II receptor antagonist cande­
these reasons, oral ergot alkaloids, opioids, and barbiturates sartan has shown efficacy in two relatively small clinical trials
should be avoided for the acute treatment of migraine. [30,31]. It appears to have an efficacy comparable to that of
propranolol and it is well tolerated. There is limited evidence
to support the use of angiotensin-converting enzyme inhibi­
4. Preventive treatment
tors but efficacy of lisinopril compared to placebo for reduc­
Preventive pharmacological migraine therapy should be tion of migraine days was reported in one study [32].
offered to patients experiencing impaired quality of life due
to migraine, despite optimized acute therapy. Eligibility for
4.2. Antiepileptic drugs
such treatment includes patients enduring at least four
migraine days per month [26]. Clinicians must evaluate attack Topiramate and valproate have documented efficacy comparable
severity and duration and consider whether acute treatment to that of β-blockers but are associated with more adverse effects.
can be optimized before initiating preventive medication. A Cochrane review included a pooled analysis of nine RCTs (1,700
676 L. PELLESI ET AL.

Table 2. Preventive migraine therapies. Adapted from Eigenbrodt AK et al. [6].

Drug class Drug Dosage and route Contraindications
First-line medication
Beta blockers Atenolol* 25–100 mg oral twice daily Asthma, cardiac failure, atrioventricular block
Bisoprolol* 5–10 mg oral once daily
Metoprolol 50–100 mg oral twice daily or 200 mg
modified-release oral once daily
Propranolol 80–160 mg oral once or twice daily in
long-acting formulations
Angiotension II-receptor blocker Candesartan* 16–32 mg oral per day Co-administration of aliskiren
Anti-seizure medication Topiramate 50–100 mg oral daily Neprolithiasis, pregnancy, lactation, depression,
glaucoma
Second-line medication
Tricyclic antidepressant Amitriptyline 10–100 mg oral at night Co-administration of monoamine oxidase inhibitors,
heart failure, glaucoma, atrioventricular block
Calcium antagonist Flunarizine 5–10 mg oral once daily Parkinsonism, depression
Anti-seizure medication Sodium valproate 600–1,500 mg oral once daily Liver disease, thrombocytopenia, women of
childbearing potential
Third-line medication
Botulinum toxin Onabotulinumtoxin A 155–195 units at 31–39 injection sites Infection at injection site
every 3 months
Calcitonin gene-related peptide Erenumab 70 or 140 mg subcutaneous once Not recommended in patients with a history of
monoclonal antibodies monthly stroke, subarachnoid hemorrhage, coronary heart
Fremanezumab 225 mg subcutaneous once monthly disease,
or 675 mg subcutaneous once inflammatory bowel disease, chronic obstructive
quarterly pulmonary disease or impaired wound healing.
Galcanezumab 240 mg subcutaneous, then 120 mg
subcutaneous once monthly
Eptinezumab 100 or 300 mg intravenous quarterly
Small molecule calcitonin gene-related Atogepant 10 mg, 30 mg, or 60 mg once daily Liver disease, concomitant use with strong CYP3A4
peptide receptor antagonists Rimegepant 75 mg every other day inhibitors
(gepants)
*Efficacy tested in less than three clinical trials.

patients) comparing topiramate 100 mg to placebo [33]. The meta- norepinephrine reuptake inhibitors (SNRIs) is low due to
analysis reported that the use of topiramate resulted in twice as a low number of trials with limited sample size [37].
many patients reporting a ≥ 50% reduction in headache frequency
(RR 2.02, 95% CI: 1.57–2.60; NNT = 4, 95% CI: 3–6), one less head­
ache per 28 days and an improvement in quality-of-life outcomes. 4.4. Calcium channel blockers
A similar Cochrane review of valproate for episodic migraine pre­ A meta-analysis of seven trials of flunarizine at a dose of 10 mg
vention found that valproate (dosages ranging from 400–1500 mg daily reported a moderate benefit in patients with episodic
daily) was superior to placebo for ≥ 50% headache frequency migraine compared to placebo at eight and twelve weeks [38].
reduction over eight to twelve weeks (RR 2.83, 95% CI: 1.27–6.31; The study populations of trials included in the meta-analysis
NNT = 3, 95% CI: 2–9), while sodium valproate 500 mg was not as were small. Flunarizine has a comparable effect to beta block­
effective as topiramate 400 mg [34]. In clinical practice, the use of ers, but is associated with more side effects, including drowsi­
topiramate is often limited by side effects that include paresthesia, ness, fatigue, weight increase, and depression.
sedation, dizziness, weight loss, kidney stones and cognitive dys­
function. Typical adverse effects of valproate include dyspepsia,
hand tremor, weight gain, liver disease, and thrombocytopenia. 4.5. Botulinum toxin A
Valproate should not be prescribed in women of childbearing age.
Evidence for a prophylactic effect of botulinum toxin A (BTA)
in chronic migraine originates from the two PREEMPT trials. In
PREEMPT 1, the primary endpoint of reduction in headache
4.3. Antidepressants
episodes from baseline compared to placebo was negative.
One tricyclic antidepressant drug, amitriptyline, is commonly However, there was a significant reduction in headache days
used for migraine prevention. It is considered suitable in (−7.8 vs. −6.4; p = 0.006) and migraine days (−7.6 vs. −6.1) [39].
patients who also suffer from frequent tension-type headache In PREEMPT 2, the primary endpoint was changed (prior to
[28]. A meta-analysis found that amitriptyline (100 mg) was completion of the trial and before analysis) to reduction in
more effective than placebo in achieving a ≥ 50% reduction headache days. The new endpoint was considered a better
in headache frequency, but the evidence is of low quality [35]. measure than headache episodes due to the prolonged, con­
Typical dosage is 10 mg daily, 1 h before bedtime, and tinuous nature of migraine headaches. There was a significant
increased by 10 mg at one-week intervals to 10–100 mg reduction in both headache days versus placebo (−9.0 vs.
daily. Clomipramine and opipramol are other tricyclic antide­ −6.7) and migraine days (−8.7 vs. −6.3) compared with base­
pressants that showed a significant advance over placebo in line [40]. There was also a significant reduction in headache
preventing migraine [36]. The level of evidence for selective episodes (−5.3 vs. −4.6). A recent trial evaluated the effects of
serotonin reuptake inhibitors (SSRIs) and serotonin and BTA according to the PREEMPT procedure in chronic migraine
 EXPERT OPINION ON PHARMACOTHERAPY 677

patients with medication overuse headache. Following with­ extension trials demonstrated sustained efficacy and tolerabil­
drawal from acute migraine medications, BTA did not reduce ity of long-term erenumab treatment for up to five years [51],
monthly headache days compared to placebo (−26.9% vs. with similar results for long-term treatment with eptinezumab,
−20.5%; 95% CI: −15.2 to 2.4) [41]. A meta-analysis of studies fremanezumab, and galcanezumab [52–54]. Emerging real-
conducted in patients with episodic migraine or tension-type world data, which encompass far more heterogeneous popu­
headache found no difference in efficacy compared to placebo lations than those seen in clinical trials, confirm that these
[42]. Collectively, there is evidence supporting efficacy of BTA compounds are efficacious and well-tolerated [55].
for the treatment of chronic migraine. Medication overuse However, it is crucial to emphasize that monoclonal anti­
should be treated before initiating BTA. bodies targeting CGRP or its receptor are not a panacea.
Discontinuation of treatment in individuals experiencing sus­
tained efficacy has been linked to a resurgence of frequent
5. Current anti-CGRP pharmacological therapies
migraine attacks [56]. Furthermore, there is an absence of
In the initial proof-of-concept trial, 126 individuals with long-term safety data regarding the use of monoclonal anti­
migraine received a 2.5 mg intravenous infusion of olcege­ bodies against CGRP or its receptor in special populations,
pant, a small molecule CGRP receptor antagonist, during an including children, adolescents, pregnant or lactating
acute migraine attack [43]. A significantly higher percentage of women, and older adults.
participants achieved pain freedom within two hours after
olcegepant intervention compared to placebo (44% vs. 2%).
5.2. Gepants
Despite these promising outcomes, olcegepant encountered
hindrances that prevented its commercialization, particularly Two phase 3 clinical trials (ACHIEVE I-II) demonstrated the
the suboptimal absorption of its oral formulation. The devel­ superiority of two different doses of oral ubrogepant over
opment of further CGRP receptor antagonists faced premature placebo in individuals with migraine [57,58]. In 2019, ubroge­
termination of clinical trials for various reasons, with hepato­ pant received approval for the acute treatment of migraine.
toxicity risk being a notable concern [44]. Nevertheless, these Subsequently, regulatory approval for another oral gepant for
findings underscored the effectiveness of targeting CGRP sig­ acute treatment, rimegepant, was granted in early 2020. In
naling in treating migraine. Both monoclonal antibodies tar­ 2021, the FDA approved rimegepant every other day for
geting CGRP signaling and gepants have been recently migraine prevention after a phase 2/3 clinical trial [59].
introduced to the market, catering to both preventive and, Notably, rimegepant stands out as the first CGRP-targeting
in the case of gepants, acute management. Recent recommen­ medication available for both acute and preventive migraine
dations suggest that anti-CGRP preventive therapies should be treatment. Later, atogepant received approval for migraine
a first-line preventive treatment option [4,45]. prevention following the ADVANCE trial [60]. More recently,
a phase 3 clinical trial reported that an intranasal formulation,
zavegepant, was efficacious (TG = 9% for 2 h pain freedom)
5.1. Monoclonal antibodies
and tolerable for the acute treatment of migraine [61].
Four monoclonal antibodies targeting CGRP (eptinezumab, The ELEVATE trial, a phase 3 study investigating the effec­
fremanezumab, and galcanezumab) or its receptor (erenumab) tiveness of oral atogepant 60 mg once daily for preventing
have received regulatory approval for migraine prevention, migraine in individuals with episodic migraine who had pre­
following positive clinical trials in individuals with both episo­ viously failed two to four conventional oral medications,
dic and chronic migraine [46]. All these compounds have reported that this compound reduced the number of monthly
demonstrated efficacy even in patients who had previously migraine days by 2.4 across 12 weeks with few adverse events
experienced treatment failure with other drug classes [47]. [62]. Similarly, the phase 3 PROGRESS trial, which involved
Erenumab, fremanezumab, and galcanezumab are adminis­ individuals with chronic migraine, demonstrated reduction
tered via subcutaneous injection either monthly or quarterly compared to placebo in monthly migraine days with oral
(with fremanezumab being the exception), depending on the atogepant dosages of 30 mg twice daily (2.4 days) or 60 mg
chosen compound and treatment strategy. Eptinezumab is once daily (1.8 days) [63]. The phase 3 PRODROME trial rando­
administered as quarterly intravenous infusion. Despite indir­ mized individuals experiencing two to eight migraine attacks
ect comparisons suggesting equivalent efficacy among these per month to receive either ubrogepant 100 mg or a placebo
compounds, direct comparative trial data of these compounds during the prodromal phase preceding a migraine attack [64].
are currently unavailable. Monoclonal antibody therapy exhi­ The study found a TG of 10% for absence of any headache
bits higher tolerability compared to non-CGRP oral therapies, within 24 h compared to placebo. This marks the first cross­
with injection site reactions being the most common adverse over trial assessing the efficacy of acute treatment during the
events [48,49]. migraine prodrome and indicates the feasibility of administer­
A head-to-head trial (HER-MES) comparing the tolerability ing treatment during the earliest phase of a migraine attack.
and efficacy of erenumab with topiramate revealed that ere­ Further investigation is required to determine if this holds true
numab had a better tolerability profile in patients with both for other compounds. Nevertheless, a recent meta-analysis
episodic and chronic migraine [50]. Moreover, a higher pro­ suggests that additional data are necessary to elucidate the
portion in the erenumab group achieved a > 50% reduction in true role of the prodromal phase [65].
monthly migraine days from baseline compared to topiramate The observation that gepants have the potential to be used
(55.4% vs. 31.2%), indicating superior efficacy. Open-label as a preventive medication suggests that regular use, unlike
678 L. PELLESI ET AL.

other acute migraine treatments such as NSAIDs and triptans, nociceptors, which in turn release neuropeptides that further
may not be linked to the development of medication-overuse activate and degranulate MCs, generating a positive-feedback
headache (MOH). Additionally, animal data have demon­ loop [71]. Lu AG09222 is a monoclonal antibody specifically
strated that ubrogepant does not trigger cutaneous allodynia designed to target and inhibit PACAP. A proof-of-mechanism
and latent sensitization, which are surrogate markers of MOH study conducted in healthy volunteers found that Lu
[66]. Gepants might be particularly advisable for patients at AG09222 prevented PACAP38-induced cephalic vasodilation,
risk of MOH. However, the therapeutic benefits of these com­ increased heart rate and headache, providing support for the
pounds for acute treatment are generally modest, so while utility of Lu AG09222 in migraine prevention [72]. A proof-of-
they offer an alternative, they are not necessarily superior to concept phase 2a trial was recently completed assessing
older generation compounds. Additionally, it is essential to efficacy, safety, and tolerability of Lu AG09222 in the preven­
exercise caution with these compounds, as they are metabo­ tion of migraine (NCT05133323). Lu AG09222 was well toler­
lized through the CYP3A4 pathway, and potential drug inter­ ated and significantly reduced the number of monthly
actions should be considered. The general recommendation is migraine days from baseline to weeks 1 to 4 of treatment in
to use gepants for acute migraine treatment only if triptans 237 individuals with migraine with a history of unsuccessful
prove ineffective or are not well-tolerated. Gepants do not prior preventive treatments [73]. LY3451838 is a second
seem to provide a higher therapeutic gain (see Table 1), and, monoclonal antibody designed to target the PACAP peptide
akin to monoclonal antibodies and other newer generation that has been tested in a phase II trial (NCT04498910) con­
drugs, their accessibility and availability are more limited. ducted in individuals with migraine with a history of lack of
A head-to-head trial comparing galcanezumab and rimege­ treatment response to two to four prophylactic migraine
pant for the prevention of episodic migraine does not suggest medications. Histamine is an efficient inducer of migraine in
any difference in efficacy between these compounds [67]. Of individuals with migraine by a mechanism that most likely
note, the combined use of gepants and monoclonal antibo­ involves H1 and H3 receptor subtypes [74]. AGX-201 is
dies targeting CGRP signaling appears to be safe, as indicated a histamine receptor modulator that acts as an antagonist at
by phase 1b drug interaction trial data [68]. H1 receptors and an agonist at H3 receptors. This dual
mechanism of action offer a unique approach to mitigate
migraine symptoms by reducing the release of pro-
6. Future directions of pharmacological inflammatory neuropeptides from trigeminal nerve endings.
management of migraine Subcutaneous AGX-201 is currently tested in a phase II trial
Several promising therapies are in development, including (NCT02021474) enrolling subjects with migraine requiring
trigeminovascular therapies, cannabis-based therapies, hormo­ prophylactic treatment. Further research will elucidate the
nal and metabolic therapies and other ones (Table 3) [69]. precise mechanisms through which Lu AG09222, LY3451838
and AGX-201 exert their antimigraine effects.

6.1. Trigeminovascular therapies

6.2. Cannabis-based therapies
Neuropeptides and G protein-coupled receptors modulating
the trigeminovascular activities are therapeutic targets for Patient-reported relief of migraine has increased scientific
reducing neurogenic inflammation, vasodilation, and pain interest in the use of cannabis-based therapies in both acute
transmission associated with migraine. Activation of sensory and prophylactic settings. Cannabinoid receptors, primarily
fibers within the trigeminal nerve leads to the release of CB1 and CB2, are widely distributed throughout the central
various peptides, including pituitary adenylate cyclase- and peripheral nervous systems. They play a crucial role in
activating polypeptide (PACAP), which contribute to neuro­ regulating pain transmission, inflammation, and vascular func­
genic inflammation and pain sensitization [70]. Meningeal tions, all of which are implicated in migraine pathogenesis.
mast cells (MCs) are closely associated with trigeminal nerve Cannabinoids, the active compounds found in cannabis plants,
endings in the dura and release histamine that activates interact with these receptors and modulate their activity. The

Table 3. Several pharmacological therapies that are in development for migraine.

Drug(s) Mode of action Indication Status
Lu AG09222 and LY3451838 PACAP-targeted mAbs Migraine prevention Phase 2
AGX-201 Histamine receptor modulator Migraine prevention Phase 2
Vaporized CBD and THC Modulator of the endocannabinoid system Acute migraine treatment Phase 2
Oral CBG, CBD and THC Modulator of the endocannabinoid system Migraine prevention Phase 4
Oral CBD Modulator of the endocannabinoid system Migraine prevention Phase 2
Intranasal oxytocin Oxytocin receptor agonist Migraine prevention Phase 2
Sepranolone Allosteric modulator of the GABAA receptor Menstrual migraine prevention Phase 2
Tricaprilin Inducer of ketosis Migraine prevention Phase 2
Meloxicam and rizatriptan COX2 inhibitor and 5-HT1B/1D receptor agonist Acute migraine treatment Pre-registration
Prabotulinumtoxin A Botulinum toxin Migraine prevention Phase 2
Abobotulinumtoxin A Botulinum toxin Migraine prevention Phase 3
Incobotulinumtoxin A Botulinum toxin Migraine prevention Phase 3
5-HT: serotonin; CBD: cannabidiol; CBG: cannabigerol; COX: cyclooxygenase; GABA: γ-aminobutyric acid; mAb: monoclonal antibody; THC: delta-
9-tetrahydrocannabinol.
 EXPERT OPINION ON PHARMACOTHERAPY 679

activation of CB1 receptors in the central nervous system [80]. Tricaprilin is currently being tested for Alzheimer’s disease
exhibits antinociceptive effects, reducing pain signaling [75], and infantile spasms. A phase 2 study investigating the efficacy
while the activation of CB2 receptors on immune cells attenu­ and safety of daily administration of tricaprilin for the reduction
ates inflammation associated with migraine [76]. Data from of migraine episodes has been recently completed in partici­
a randomized, double-blind, placebo-controlled, crossover trial pants with frequent migraine (NCT04437199).
showed that four puffs of vaporized delta-9-tetrahydrocanna­
binol (THC) and cannabidiol (CBD) mix was effective for acute
6.4. Other therapies
migraine treatment (NCT04360044). Prior to this research,
most of the studies on cannabis for the treatment of migraine The acute treatment of migraine revolves around the usage of
were relatively small, retrospective, with no placebo control analgesics to alleviate pain and related symptoms. However, the
involved. Data were presented at the 2023 American effectiveness of a single analgesic agent may be suboptimal,
Headache Society (AHS) Annual Meeting held in Austin, necessitating the exploration and development of new formula­
Texas. In addition to acute symptom management, the effects tions that combine multiple analgesics. AXS-07 is an oral, investi­
of cannabigerol (CBG) + CBD + THC up to 66/133/4 mg daily gational therapy consisting of meloxicam and rizatriptan that is
are currently being investigated in chronic migraine patients formulated to provide an enhanced rate of absorption of melox­
under preventive treatment at a stable dose for at least 3 icam. AXS-07 tablets are being developed for the acute treatment
months (NCT04989413). The study is a single-center, rando­ of migraine with or without aura in adults. Three trials have been
mized, double-blind, placebo-controlled trial conducted in completed (NCT04068051, NCT04163185 and NCT03896009),
individuals of both sexes, between 25 and 65 years old, who with some results being published on [Link]. A further
have not previously used CBD and/or THC as a migraine treat­ open-label trial is currently evaluating the efficacy and safety of
ment. A newer randomized, double-blind, placebo-controlled AXS-07 for the acute treatment of migraine in subjects with a prior
trial investigate the efficacy and safety of cannabidiol (high inadequate response to oral CGRP inhibitors (NCT05550207).
and low dose) for the treatment of chronic migraine head­ Additional treatment options may emerge from variants of thera­
aches (NCT03972124). The study is sponsored by the pies which are already approved for the treatment of migraine.
University of Calgary (Canada) and will start in 2024. Given Prabotulinumtoxin A, abobotulinumtoxin A and incobotulinum­
the evolving landscape of cannabis legislation and societal toxin A are distinct variations of onabotulinumtoxin A, each pos­
attitudes, long-term safety profiles, risk of dependence, psy­ sessing unique biochemical properties and structural
chotropic effects, and legal issues underscore the necessity for characteristics. These differences might contribute to variations
further rigorous research. in therapeutic effects, pharmacokinetics, and duration of action
within the context of migraine treatment. Prabotulinumtoxin
A has a higher purity level than onabotulinumtoxin A and exhibits
6.3. Hormonal and metabolic therapies
enhanced diffusion properties, potentially allowing for a broader
Emerging research suggests that hormonal and metabolic path­ distribution within the target area. The expanded distribution
ways play a role in migraine pathophysiology, presenting novel pattern might result in improved effectiveness for specific
targets for therapeutic interventions. Oxytocin is a neuropeptide migraine types that involve multiple head regions.
hormone associated with childbirth and lactation that is increas­ Prabotulinumtoxin A is currently investigated for migraine preven­
ingly recognized for its role in pain modulation. Oxytocin levels tion in adults who suffer from six or more migraine days per
fluctuate during migraine attacks and dysregulation in its release month (NCT04845178 and NCT05016661). Abobotulinumtoxin
may contribute to migraine pathophysiology [77]. An open label A is manufactured differently than onabotulinumtoxin A with
multisite study conducted in 16 chronic and 25 high frequency potential differences in their duration or onset of effect. Most
episodic migraineurs demonstrated a clear decrease in headache studies have used a ratio of 2.5:1, meaning 25 units of abobotuli­
frequency and severity after administration of 30 IU of intranasal numtoxin A have approximately the same action as 10 units of
oxytocin for 28 days [78]. A randomized, double-blind, placebo- onabotulinumtoxin A. Abobotulinumtoxin A is currently investi­
controlled, three arm parallel study is currently evaluating the gated for the prevention of episodic migraine (NCT06047457) and
efficacy and safety of two different dosages (30 IU daily and 60 IU chronic migraine (NCT06047444) in adults. Incobotulinumtoxin
daily) of intranasal oxytocin in individuals with chronic migraine A is a neurotoxin that, unlike onabotulinumtoxin A, does not
(NCT05679908). Sepranolone, also known as isopregnanolone, is require refrigeration and is an effective off-label alternative for
a neuroactive steroid that acts as a negative allosteric modulator the treatment of migraine. Incobotulinumtoxin A and onabotuli­
of the GABAA receptor. Emerging evidence suggests that neuro­ numtoxin A are comparable in strength, with a conversion rate of
steroids regulate nociceptive and neuropathic pain [79]. A proof- 1:1. A single-center study is currently evaluating the effects of
of-concept study has evaluated the efficacy and safety of two incobotulinumtoxin A vs. onabotulinumtoxin A in adults with
doses of subcutaneous sepranolone in preventing menstrual chronic migraine (NCT05598723).
migraine attacks in adult women with migraine (NCT04102995).
The study has been conducted in three European Countries
7. Conclusion
(Denmark, Finland and Sweden) and the results have been
recently submitted to [Link]. Tricaprilin is a glyceride The pharmacological management of migraine continues to
synthesized from medium-chain triglycerides that induces keto­ evolve over the years, moving from a predominantly sympto­
sis when orally ingested. Ketones represent an important energy matic approach to a more targeted strategy. Triptans,
source to improve mitochondrial metabolism in neuronal cells NSAIDs, and oral preventive medications remain key options
680 L. PELLESI ET AL.

for acute and preventive management. However, there is still Currently, cannabis-based therapies and hormonal and
a significant unmet need for individualized treatment metabolic interventions are being explored. Gene therapies,
approaches. Many patients with migraine do not achieve although in their infancy, offer a further glimpse of personalized
adequate relief with current therapies or are unable to pay treatments targeting specific migraine-related genetic muta­
for monoclonal antibodies or gepants with their own money, tions. By implementing personalized treatment strategies
which underscores the need for further research and devel­ based on individual´s clinical features, healthcare professionals
opment in this field. Several promising therapies are in clin­ can significantly improve the quality of life for individuals with
ical development and hold great potential for improving migraine. Advances in genomics and molecular diagnostics
migraine management. As these novel treatments progress have offered new insights into the complex biology of migraine
through clinical trials, their potential to revolutionize the and its subtypes [87]. These genetic markers could be used to
management of migraine becomes increasingly evident. personalize treatment and predict response to specific pharma­
This review sets the stage for further research and explora­ cologic agents. Additionally, novel biomarkers could guide
tion of these treatments. treatment decisions and monitor treatment response [88].
Incorporating genetic and biological markers into clinical prac­
tice would allow for an individualized and targeted approach to
8. Expert opinion migraine management, increasing the likelihood of treatment
success and minimizing unnecessary trial-and-error approaches.
Treatment options in migraine are evolving rapidly. The recent Continued research, rigorous clinical trials, and the accumula­
advent of anti-CGRP drugs has markedly improved migraine tion of robust evidence are necessary steps in advancing inno­
therapy, especially in terms of migraine prevention. The over­ vative therapeutic options and improving the quality of life for
all efficacy of currently available gepants for acute migraine individuals suffering from migraine.
has not been impressive in clinical trials (Table 1) but these
drugs may nonetheless benefit individuals who respond
poorly to other types of acute therapy. Of interest, preventive Funding
and acute therapies binding to the CGRP ligand or its receptor This paper was not funded.
are safely combined together [81,82]. Combining
a monoclonal antibody binding to the CGRP peptide or its
receptor with a gepant as needed may provide additive ben­ Declaration of interest
efits due to the functional antagonism of a pool of CGRP L Pellesi has been employed by Lundbeck for the past two years. T Phu Do
receptors that are more readily available to small molecules reports personal fees from Teva, outside of the submitted work. A Hougaard
(<1 kDa) than monoclonal antibodies (≈150 kDa) [83]. reports receiving personal fees from AbbVie, Eli Lilly, Lundbeck, Novartis,
Conversely, it is harder to predict a benefit when one gepant Teva and Pfizer. AH also serves as an associate editor of Headache.
The authors have no other relevant affiliations or financial involvement
utilized for migraine prophylaxis is combined with a second
with any organization or entity with a financial interest in or financial
gepant utilized for acute therapy in the same individual. Long- conflict with the subject matter or materials discussed in the manuscript
term studies in large patient populations are warranted to apart from those disclosed.
define the risk of CGRP-related adverse events when two anti-
CGRP treatments are combined.
Migraine treatment may improve further with emerging, Reviewer disclosures
innovative pharmacological therapies. The manipulation of A reviewer on this manuscript has disclosed that they have received
G protein-coupled receptor signaling pathways in the trigemi­ institutional support for serving as an investigator from Teva, Abbvie;
novascular system holds potential for efficacy in individuals consultant fees from Salvia, Abbvie, Pfizer, and Cerenovus; and royalties
with migraine who do not respond to currently available from Cambridge University Press and MedLink, within the past two years.
Peer reviewers on this manuscript have no other relevant financial
therapies. However, the costs associated with drug develop­ relationships or otherwise to disclose.
ment, distribution, and accessibility can significantly impact
their positioning in the management of migraine. The price
of a monthly treatment with anti-CGRP therapies is signifi­ ORCID
cantly higher than a monthly treatment with non-anti-CGRP Lanfranco Pellesi [Link]
therapies. The approximate cost of anti-CGRP mAbs in Anders Hougaard [Link]
Denmark amounts to €3,562 per patient per year [84]. When
the additional outpatient visits associated with the treatment
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