Pharmacological management of migraine: current strategies and future directions

ABSTRACT

Introduction

Migraine is a complex neurological disorder that affects a significant portion of the global population. As traditional pharmacological approaches often fall short in alleviating symptoms, the development of innovative therapies has garnered significant interest. This text aims to summarize the current pharmacological options for managing migraine and to explore the potential impact of novel therapies.

Areas covered

We focused on conventional treatments, emerging therapies, and novel compounds in 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 ClinicalTrials.gov 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.

KEYWORDS:

• CGRP
• gepant
• headache
• pain
• trigeminovascular system

1. Introduction

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

2. Methods

We searched English peer-reviewed articles with no date limits in PubMed, Scopus, and ClinicalTrials.gov electronic databases. We used the term ‘migraine’ combined with ‘acute treatment,’ ‘acute therapy,’ ‘preventive treatment’ or ‘preventive therapy’ and the results were screened for relevance to the review topic. Additionally, articles were added based on the authors’ knowledge of the topic.

3. Acute treatment

Acute pharmacological migraine therapy aims to abort the headache phase of migraine. As a general principle, treatment 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 therapies. A stepwise approach is recommended to achieve the most effective, safest, and least expensive therapy [6]. Acute treatments are commonly classified as first-line, second-line, and third-line therapies. First-line therapies include weak analgesics and antiemetics, second-line therapies are triptans, and third-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.

Table 1. Acute migraine therapies. Therapeutic gain (TG), i.e. The difference between the active drug and placebo, for pain freedom at 2 hours is reported.

Therapy	TG	Reference
Simple analgesics
Paracetamol 1,000 mg	8%	[73]
Aspirin 1,000 mg	13%	[7]
Diclofenac potassium 50 mg	14%	[10]
Ibuprofen 400 mg	14%	[8]
Naproxen 500 mg or 825 mg	9%	[9]
Oral triptans
Almotriptan 12.5 mg	22%	[16]
Eletriptan 40 mg	27%	[16]
Frovatriptan 2.5 mg	11%	[16]
Naratriptan 2.5 mg	13%	[16]
Rizatriptan 10 mg	35%	[16]
Sumatriptan 50 mg	16%	[16]
Sumatriptan 100 mg	21%	[16]
Zolmitriptan 2.5 mg	20%	[16]
Zolmitriptan 5 mg	21%	[16]
Combination
Oral sumatriptan 85 mg + naproxen 500 mg	20%	[16]
Nasal triptans
Sumatriptan 20 mg	21%	[16]
Zolmitriptan 5 mg	25%	[16]
Subcutaneous triptans
Sumatriptan 6 mg	44% (34% for 1 h pain free)	[16]
Ditans
Lasmiditan 50 mg	7%	[16]
Lasmiditan 100 mg	12%	[16]
Lasmiditan 200 mg	17%	[16]
Gepants
Rimegepant 75 mg tablet	8%	[16]
Rimegepant 75 mg orally disintegrating tablet	11%	[16]
Ubrogepant 25 mg	6%	[16]
Ubrogepant 50 mg	8%	[16]
Ubrogepant 100 mg	9%	[16]
Zavegepant 10 mg	8%	[74]

3.1. Simple analgesics

The efficacy of paracetamol (acetaminophen), aspirin and various NSAIDs for the treatment of migraine attacks has been demonstrated in several clinical trials. Paracetamol is less efficient and is primarily useful in patients who do not tolerate NSAIDs [9]. A Cochrane review of aspirin for acute migraine headache concluded that aspirin 1000 mg has an efficacy comparable to that of sumatriptan 50 mg or 100 mg [10]. Therapeutic gain (TG), i.e. the difference between the active drug and placebo, for pain freedom at 2 hours compared to placebo was 13%. Ibuprofen has shown efficacy compared to placebo in all doses between 200 mg and 600 mg for pain freedom at two hours and sustained pain relief at 24 hours [11]. Similarly, naproxen and diclofenac potassium are effective acute migraine therapies [12,13]. In addition to headache, aspirin, ibuprofen, naproxen, and diclofenac sodium relieve migraine-associated symptoms of nausea, photophobia, phonophobia. Intravenous ketorolac is probably effective but there is inadequate evidence for intravenous paracetamol [14]. Regarding intranasal formulations, there is insufficient evidence for ketorolac nasal spray and inhaled corticosteroids [14].

3.2. Triptans

Triptans, 5-HT_1B/1D receptor agonists, are used as second-line therapies if simple analgesics do not provide sufficient headache relief. The mechanism of action of triptans involves constriction of cranial arteries and inhibition of neuropeptide release, thus contributing to pain relief. All triptans have well-documented efficacy, but availability vary between countries. If a triptan is not effective in an individual patient, other triptans might still show efficacy [15]. Sumatriptan is the first marketed and most widely available triptan. In a major Cochrane review, the TG of oral sumatriptan 50 mg and 100 mg for pain freedom at 2 hours was 16% and 21%, respectively [16]. The subcutaneous route is the most effective in terms of pain relief at two hours from moderate to severe baseline pain, with a TG of 44% for a 6 mg dose. Intranasal sumatriptan is also effective for pain free at two hours (TG = 21%). An intranasal formulation of sumatriptan that include absorption enhancers has been marketed recently. In one trial intranasal sumatriptan 10 mg with this formulation had a TG of 21% [17]. There are clinically relevant differences between the seven oral triptans in terms of efficacy and side effects (Table 1). There is no evidence that the effect of orally disintegrating tablets or rapidly soluble tablets is faster than that of standard tablets. Combination of sumatriptan 85 mg with naproxen 500 mg is more effective than treatment with each drug alone (TG = 20% 2 h pain free) [18]. Common side effects of triptans include a sensation of pressure on the chest, nausea, distal paresthesia, and fatigue. Triptans remain contraindicated in patients with a previous history of stroke, uncontrolled hypertension, ischemic heart disease, and peripheral vascular disease due to concerns of an increased risk of vascular events, although the risk of such events for the individual triptan user appears to be very low [19].

3.3. Antiemetics

For migraine-associated nausea, simple analgesics or triptans can be combined with antiemetics to treat nausea and vomiting, but there is no evidence that antiemetics improve the absorption of anti-migraine drugs [20]. Metoclopramide 10 mg or domperidone 10 mg are commonly used for such combinations. The antiemetics prochlorperazine, droperidol, chlorpromazine, and metoclopramide may be effective for acute treatment of migraine headache but the evidence in support of this is limited [14].

3.4. Other acute treatment options

Ditans are 5-HT_1F receptor agonists that, as opposed to triptans, have no effect on the vasculature. Lasmiditan is approved for the acute treatment of migraine but is limited by a lower efficacy than triptans (TG = 7%, 12%, and 17% for lasmiditan 50 mg, 100 mg, and 200 mg, respectively, for 2 h pain freedom, and central nervous system adverse events (including impaired ability to drive a car for 8 h) [21]. Oral ergot alkaloids have poor efficacy and are associated with a high risk of serious adverse effects [22]. A new intranasal formulation that delivers a low dose (0.725 mg per spray) of dihydroergotamine mesylate to the upper nasal space has been recently approved for the treatment of acute migraine attacks [23]. Due to the pharmacokinetic properties of dihydroergotamine, nasally and orally inhaled formulations likely do not exert a fast clinical effect despite a quick absorption [24]. Opioids and barbiturates have dubious efficacy and substantial side effects as well as risk of dependency [25]. For these reasons, oral ergot alkaloids, opioids, and barbiturates should be avoided for the acute treatment of migraine.

4. Preventive treatment

Preventive pharmacological migraine therapy should be offered to patients experiencing impaired quality of life due to migraine, despite optimized acute therapy. Eligibility for such treatment includes patients enduring at least four migraine days per month [26]. Clinicians must evaluate attack severity and duration and consider whether acute treatment can be optimized before initiating preventive medication. Preventive treatment aims to reduce attack frequency or severity, with a successful outcome defined as a 50% reduction in migraine frequency or severity without significant side effects. Selection of preventive medication should be evidence-based, considering efficacy, side effects, and coexisting disorders. Slow titration is advised to minimize side effects, and a headache diary is recommended for documenting treatment effects. Efficacy often emerges over weeks or months. Early treatment discontinuation due to perceived inefficacy should be discouraged. If an oral preventive medication proves ineffective after 2–3 months, alternative options should be explored. Non-responsiveness to one preventive class does not preclude success with others, barring issues of adherence. Periodic reassessment of the need and effectiveness of preventive medication is crucial. Clinical practice suggests pausing successful preventive medications after 6–12 months to evaluate the necessity of continued treatment, thereby reducing unnecessary drug exposure. As for acute medications, preventive treatments are categorized as first-, second-, and third-line therapies (see Table 2) under the influence of local guidelines, availability, costs, and reimbursement policies. First-line therapies include β-blockers, topiramate, and candesartan. Second-line therapies are flunarizine, amitriptyline, and sodium valproate (with contraindications for women of childbearing potential). Third-line therapies comprise CGRP monoclonal antibodies (see section on ‘Current anti-CGRP pharmacological therapies’).

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 every 3 months	Infection at injection site
Calcitonin gene-related peptide monoclonal antibodies	Erenumab	70 or 140 mg subcutaneous once monthly	Not recommended in patients with a history of stroke, subarachnoid hemorrhage, coronary heart disease, inflammatory bowel disease, chronic obstructive pulmonary disease or impaired wound healing.
	Fremanezumab	225 mg subcutaneous once monthly or 675 mg subcutaneous once quarterly
	Galcanezumab	240 mg subcutaneous, then 120 mg subcutaneous once monthly
	Eptinezumab	100 or 300 mg intravenous quarterly
Small molecule calcitonin gene-related peptide receptor antagonists (gepants)	Atogepant Rimegepant	10 mg, 30 mg, or 60 mg once daily 75 mg every other day	Liver disease, concomitant use with strong CYP3A4 inhibitors

*Efficacy tested in less than three clinical trials.

4.1. Antihypertensive drugs

Several β-blockers have shown efficacy against placebo in clinical trials. These trials were mainly conducted in the 1980’s and results are limited by low methodological quality, short duration, and risk of publication bias [27]. Propranolol and metoprolol are best supported by evidence and the most used options. In clinical practice, the typical dosage for metoprolol is 50 mg once daily for 1 week followed by a gradual increase of dosage to 50–100 mg twice daily. Typical dosage for propranolol is 40 mg twice daily increased to 80–160 mg oral once or twice daily in slow-release formulations [28]. Data are supporting the use of bisoprolol, timolol and atenolol as well [29]. There is no evidence for one β-blocker being more effective in migraine prevention than another among those with proven efficacy. If patients experience side effects from one β-blocker, change to another could be attempted [27]. The most common side effects are fatigue, cold extremities, and dizziness. The angiotensin II receptor antagonist candesartan has shown efficacy in two relatively small clinical trials [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 inhibitors but efficacy of lisinopril compared to placebo for reduction of migraine days was reported in one study [32].

4.2. Antiepileptic drugs

Topiramate and valproate have documented efficacy comparable to that of β-blockers but are associated with more adverse effects. A Cochrane review included a pooled analysis of nine RCTs (1,700 patients) comparing topiramate 100 mg to placebo [33]. The meta-analysis reported that the use of topiramate resulted in twice as 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 headache per 28 days and an improvement in quality-of-life outcomes. A similar Cochrane review of valproate for episodic migraine prevention found that valproate (dosages ranging from 400–1500 mg daily) was superior to placebo for ≥ 50% headache frequency reduction over eight to twelve weeks (RR 2.83, 95% CI: 1.27–6.31; NNT = 3, 95% CI: 2–9), while sodium valproate 500 mg was not as effective as topiramate 400 mg [34]. In clinical practice, the use of topiramate is often limited by side effects that include paresthesia, sedation, dizziness, weight loss, kidney stones and cognitive dysfunction. Typical adverse effects of valproate include dyspepsia, hand tremor, weight gain, liver disease, and thrombocytopenia. Valproate should not be prescribed in women of childbearing age.

4.3. Antidepressants

One tricyclic antidepressant drug, amitriptyline, is commonly used for migraine prevention. It is considered suitable in patients who also suffer from frequent tension-type headache [28]. A meta-analysis found that amitriptyline (100 mg) was more effective than placebo in achieving a ≥ 50% reduction in headache frequency, but the evidence is of low quality [35]. Typical dosage is 10 mg daily, 1 h before bedtime, and increased by 10 mg at one-week intervals to 10–100 mg daily. Clomipramine and opipramol are other tricyclic antidepressants that showed a significant advance over placebo in preventing migraine [36]. The level of evidence for selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) is low due to a low number of trials with limited sample size [37].

4.4. Calcium channel blockers

A meta-analysis of seven trials of flunarizine at a dose of 10 mg daily reported a moderate benefit in patients with episodic migraine compared to placebo at eight and twelve weeks [38]. The study populations of trials included in the meta-analysis were small. Flunarizine has a comparable effect to beta blockers, but is associated with more side effects, including drowsiness, fatigue, weight increase, and depression.

4.5. Botulinum toxin A

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 episodes from baseline compared to placebo was negative. However, there was a significant reduction in headache days (−7.8 vs. −6.4; p = 0.006) and migraine days (−7.6 vs. −6.1) [39]. In PREEMPT 2, the primary endpoint was changed (prior to completion of the trial and before analysis) to reduction in headache days. The new endpoint was considered a better measure than headache episodes due to the prolonged, continuous nature of migraine headaches. There was a significant reduction in both headache days versus placebo (−9.0 vs. −6.7) and migraine days (−8.7 vs. −6.3) compared with baseline [40]. There was also a significant reduction in headache episodes (−5.3 vs. −4.6). A recent trial evaluated the effects of BTA according to the PREEMPT procedure in chronic migraine patients with medication overuse headache. Following withdrawal from acute migraine medications, BTA did not reduce monthly headache days compared to placebo (−26.9% vs. −20.5%; 95% CI: −15.2 to 2.4) [41]. A meta-analysis of studies conducted in patients with episodic migraine or tension-type headache found no difference in efficacy compared to placebo [42]. Collectively, there is evidence supporting efficacy of BTA for the treatment of chronic migraine. Medication overuse should be treated before initiating BTA.

5. Current anti-CGRP pharmacological therapies

In the initial proof-of-concept trial, 126 individuals with migraine received a 2.5 mg intravenous infusion of olcegepant, a small molecule CGRP receptor antagonist, during an acute migraine attack [43]. A significantly higher percentage of participants achieved pain freedom within two hours after olcegepant intervention compared to placebo (44% vs. 2%). Despite these promising outcomes, olcegepant encountered hindrances that prevented its commercialization, particularly the suboptimal absorption of its oral formulation. The development of further CGRP receptor antagonists faced premature termination of clinical trials for various reasons, with hepatotoxicity risk being a notable concern [44]. Nevertheless, these findings underscored the effectiveness of targeting CGRP signaling in treating migraine. Both monoclonal antibodies targeting CGRP signaling and gepants have been recently introduced to the market, catering to both preventive and, in the case of gepants, acute management. Recent recommendations suggest that anti-CGRP preventive therapies should be a first-line preventive treatment option [4,45].

5.1. Monoclonal antibodies

Four monoclonal antibodies targeting CGRP (eptinezumab, fremanezumab, and galcanezumab) or its receptor (erenumab) have received regulatory approval for migraine prevention, following positive clinical trials in individuals with both episodic and chronic migraine [46]. All these compounds have demonstrated efficacy even in patients who had previously experienced treatment failure with other drug classes [47]. Erenumab, fremanezumab, and galcanezumab are administered via subcutaneous injection either monthly or quarterly (with fremanezumab being the exception), depending on the chosen compound and treatment strategy. Eptinezumab is administered as quarterly intravenous infusion. Despite indirect comparisons suggesting equivalent efficacy among these compounds, direct comparative trial data of these compounds are currently unavailable. Monoclonal antibody therapy exhibits higher tolerability compared to non-CGRP oral therapies, with injection site reactions being the most common adverse events [48,49].

A head-to-head trial (HER-MES) comparing the tolerability and efficacy of erenumab with topiramate revealed that erenumab had a better tolerability profile in patients with both episodic and chronic migraine [50]. Moreover, a higher proportion in the erenumab group achieved a > 50% reduction in monthly migraine days from baseline compared to topiramate (55.4% vs. 31.2%), indicating superior efficacy. Open-label extension trials demonstrated sustained efficacy and tolerability of long-term erenumab treatment for up to five years [51], with similar results for long-term treatment with eptinezumab, fremanezumab, and galcanezumab [52–54]. Emerging real-world data, which encompass far more heterogeneous populations than those seen in clinical trials, confirm that these compounds are efficacious and well-tolerated [55].

However, it is crucial to emphasize that monoclonal antibodies targeting CGRP or its receptor are not a panacea. Discontinuation of treatment in individuals experiencing sustained efficacy has been linked to a resurgence of frequent migraine attacks [56]. Furthermore, there is an absence of long-term safety data regarding the use of monoclonal antibodies against CGRP or its receptor in special populations, including children, adolescents, pregnant or lactating women, and older adults.

5.2. Gepants

Two phase 3 clinical trials (ACHIEVE I-II) demonstrated the superiority of two different doses of oral ubrogepant over placebo in individuals with migraine [57,58]. In 2019, ubrogepant received approval for the acute treatment of migraine. Subsequently, regulatory approval for another oral gepant for acute treatment, rimegepant, was granted in early 2020. In 2021, the FDA approved rimegepant every other day for migraine prevention after a phase 2/3 clinical trial [59]. Notably, rimegepant stands out as the first CGRP-targeting medication available for both acute and preventive migraine treatment. Later, atogepant received approval for migraine 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) and tolerable for the acute treatment of migraine [61].

The ELEVATE trial, a phase 3 study investigating the effectiveness of oral atogepant 60 mg once daily for preventing migraine in individuals with episodic migraine who had previously failed two to four conventional oral medications, reported that this compound reduced the number of monthly migraine days by 2.4 across 12 weeks with few adverse events [62]. Similarly, the phase 3 PROGRESS trial, which involved individuals with chronic migraine, demonstrated reduction compared to placebo in monthly migraine days with oral atogepant dosages of 30 mg twice daily (2.4 days) or 60 mg once daily (1.8 days) [63]. The phase 3 PRODROME trial randomized individuals experiencing two to eight migraine attacks per month to receive either ubrogepant 100 mg or a placebo during the prodromal phase preceding a migraine attack [64]. The study found a TG of 10% for absence of any headache within 24 h compared to placebo. This marks the first crossover trial assessing the efficacy of acute treatment during the migraine prodrome and indicates the feasibility of administering treatment during the earliest phase of a migraine attack. Further investigation is required to determine if this holds true for other compounds. Nevertheless, a recent meta-analysis suggests that additional data are necessary to elucidate the true role of the prodromal phase [65].

The observation that gepants have the potential to be used as a preventive medication suggests that regular use, unlike other acute migraine treatments such as NSAIDs and triptans, may not be linked to the development of medication-overuse headache (MOH). Additionally, animal data have demonstrated that ubrogepant does not trigger cutaneous allodynia and latent sensitization, which are surrogate markers of MOH [66]. Gepants might be particularly advisable for patients at risk of MOH. However, the therapeutic benefits of these compounds for acute treatment are generally modest, so while they offer an alternative, they are not necessarily superior to older generation compounds. Additionally, it is essential to exercise caution with these compounds, as they are metabolized through the CYP3A4 pathway, and potential drug interactions should be considered. The general recommendation is to use gepants for acute migraine treatment only if triptans prove ineffective or are not well-tolerated. Gepants do not seem to provide a higher therapeutic gain (see Table 1), and, akin to monoclonal antibodies and other newer generation drugs, their accessibility and availability are more limited.

A head-to-head trial comparing galcanezumab and rimegepant for the prevention of episodic migraine does not suggest any difference in efficacy between these compounds [67]. Of note, the combined use of gepants and monoclonal antibodies targeting CGRP signaling appears to be safe, as indicated by phase 1b drug interaction trial data [68].

6. Future directions of pharmacological management of migraine

Several promising therapies are in development, including trigeminovascular therapies, cannabis-based therapies, hormonal and metabolic therapies and other ones (Table 3) [69].

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.

6.1. Trigeminovascular therapies

Neuropeptides and G protein-coupled receptors modulating the trigeminovascular activities are therapeutic targets for reducing neurogenic inflammation, vasodilation, and pain transmission associated with migraine. Activation of sensory fibers within the trigeminal nerve leads to the release of various peptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), which contribute to neurogenic inflammation and pain sensitization [70]. Meningeal mast cells (MCs) are closely associated with trigeminal nerve endings in the dura and release histamine that activates nociceptors, which in turn release neuropeptides that further activate and degranulate MCs, generating a positive-feedback loop [71]. Lu AG09222 is a monoclonal antibody specifically designed to target and inhibit PACAP. A proof-of-mechanism study conducted in healthy volunteers found that Lu AG09222 prevented PACAP38-induced cephalic vasodilation, increased heart rate and headache, providing support for the utility of Lu AG09222 in migraine prevention [72]. A proof-of-concept phase 2a trial was recently completed assessing efficacy, safety, and tolerability of Lu AG09222 in the prevention of migraine (NCT05133323). Lu AG09222 was well tolerated and significantly reduced the number of monthly migraine days from baseline to weeks 1 to 4 of treatment in 237 individuals with migraine with a history of unsuccessful prior preventive treatments [73]. LY3451838 is a second monoclonal antibody designed to target the PACAP peptide that has been tested in a phase II trial (NCT04498910) conducted in individuals with migraine with a history of lack of treatment response to two to four prophylactic migraine medications. Histamine is an efficient inducer of migraine in individuals with migraine by a mechanism that most likely involves H₁ and H₃ receptor subtypes [74]. AGX-201 is a histamine receptor modulator that acts as an antagonist at 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-inflammatory neuropeptides from trigeminal nerve endings. Subcutaneous AGX-201 is currently tested in a phase II trial (NCT02021474) enrolling subjects with migraine requiring prophylactic treatment. Further research will elucidate the precise mechanisms through which Lu AG09222, LY3451838 and AGX-201 exert their antimigraine effects.

6.2. Cannabis-based therapies

Patient-reported relief of migraine has increased scientific interest in the use of cannabis-based therapies in both acute and prophylactic settings. Cannabinoid receptors, primarily CB₁ and CB₂, are widely distributed throughout the central and peripheral nervous systems. They play a crucial role in regulating pain transmission, inflammation, and vascular functions, all of which are implicated in migraine pathogenesis. Cannabinoids, the active compounds found in cannabis plants, interact with these receptors and modulate their activity. The activation of CB₁ receptors in the central nervous system exhibits antinociceptive effects, reducing pain signaling [75], while the activation of CB₂ receptors on immune cells attenuates inflammation associated with migraine [76]. Data from a randomized, double-blind, placebo-controlled, crossover trial showed that four puffs of vaporized delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) mix was effective for acute migraine treatment (NCT04360044). Prior to this research, most of the studies on cannabis for the treatment of migraine were relatively small, retrospective, with no placebo control involved. Data were presented at the 2023 American Headache Society (AHS) Annual Meeting held in Austin, Texas. In addition to acute symptom management, the effects of cannabigerol (CBG) + CBD + THC up to 66/133/4 mg daily are currently being investigated in chronic migraine patients under preventive treatment at a stable dose for at least 3 months (NCT04989413). The study is a single-center, randomized, double-blind, placebo-controlled trial conducted in individuals of both sexes, between 25 and 65 years old, who have not previously used CBD and/or THC as a migraine treatment. A newer randomized, double-blind, placebo-controlled trial investigate the efficacy and safety of cannabidiol (high and low dose) for the treatment of chronic migraine headaches (NCT03972124). The study is sponsored by the University of Calgary (Canada) and will start in 2024. Given the evolving landscape of cannabis legislation and societal attitudes, long-term safety profiles, risk of dependence, psychotropic effects, and legal issues underscore the necessity for further rigorous research.

6.3. Hormonal and metabolic therapies

Emerging research suggests that hormonal and metabolic pathways play a role in migraine pathophysiology, presenting novel targets for therapeutic interventions. Oxytocin is a neuropeptide hormone associated with childbirth and lactation that is increasingly recognized for its role in pain modulation. Oxytocin levels fluctuate during migraine attacks and dysregulation in its release may contribute to migraine pathophysiology [77]. An open label multisite study conducted in 16 chronic and 25 high frequency episodic migraineurs demonstrated a clear decrease in headache frequency and severity after administration of 30 IU of intranasal oxytocin for 28 days [78]. A randomized, double-blind, placebo-controlled, three arm parallel study is currently evaluating the efficacy and safety of two different dosages (30 IU daily and 60 IU daily) of intranasal oxytocin in individuals with chronic migraine (NCT05679908). Sepranolone, also known as isopregnanolone, is a neuroactive steroid that acts as a negative allosteric modulator of the GABA_A receptor. Emerging evidence suggests that neurosteroids regulate nociceptive and neuropathic pain [79]. A proof-of-concept study has evaluated the efficacy and safety of two doses of subcutaneous sepranolone in preventing menstrual migraine attacks in adult women with migraine (NCT04102995). The study has been conducted in three European Countries (Denmark, Finland and Sweden) and the results have been recently submitted to ClinicalTrials.gov. Tricaprilin is a glyceride synthesized from medium-chain triglycerides that induces ketosis when orally ingested. Ketones represent an important energy source to improve mitochondrial metabolism in neuronal cells [80]. Tricaprilin is currently being tested for Alzheimer’s disease and infantile spasms. A phase 2 study investigating the efficacy and safety of daily administration of tricaprilin for the reduction of migraine episodes has been recently completed in participants with frequent migraine (NCT04437199).

6.4. Other therapies

The acute treatment of migraine revolves around the usage of analgesics to alleviate pain and related symptoms. However, the effectiveness of a single analgesic agent may be suboptimal, necessitating the exploration and development of new formulations that combine multiple analgesics. AXS-07 is an oral, investigational therapy consisting of meloxicam and rizatriptan that is formulated to provide an enhanced rate of absorption of meloxicam. AXS-07 tablets are being developed for the acute treatment of migraine with or without aura in adults. Three trials have been completed (NCT04068051, NCT04163185 and NCT03896009), with some results being published on ClinicalTrials.gov. A further open-label trial is currently evaluating the efficacy and safety of AXS-07 for the acute treatment of migraine in subjects with a prior inadequate response to oral CGRP inhibitors (NCT05550207). Additional treatment options may emerge from variants of therapies which are already approved for the treatment of migraine. Prabotulinumtoxin A, abobotulinumtoxin A and incobotulinumtoxin A are distinct variations of onabotulinumtoxin A, each possessing unique biochemical properties and structural characteristics. These differences might contribute to variations 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 enhanced diffusion properties, potentially allowing for a broader distribution within the target area. The expanded distribution pattern might result in improved effectiveness for specific migraine types that involve multiple head regions. Prabotulinumtoxin A is currently investigated for migraine prevention in adults who suffer from six or more migraine days per month (NCT04845178 and NCT05016661). Abobotulinumtoxin A is manufactured differently than onabotulinumtoxin A with potential differences in their duration or onset of effect. Most studies have used a ratio of 2.5:1, meaning 25 units of abobotulinumtoxin A have approximately the same action as 10 units of onabotulinumtoxin A. Abobotulinumtoxin A is currently investigated for the prevention of episodic migraine (NCT06047457) and chronic migraine (NCT06047444) in adults. Incobotulinumtoxin A is a neurotoxin that, unlike onabotulinumtoxin A, does not require refrigeration and is an effective off-label alternative for the treatment of migraine. Incobotulinumtoxin A and onabotulinumtoxin A are comparable in strength, with a conversion rate of 1:1. A single-center study is currently evaluating the effects of incobotulinumtoxin A vs. onabotulinumtoxin A in adults with chronic migraine (NCT05598723).

7. Conclusion

The pharmacological management of migraine continues to evolve over the years, moving from a predominantly symptomatic approach to a more targeted strategy. Triptans, NSAIDs, and oral preventive medications remain key options for acute and preventive management. However, there is still a significant unmet need for individualized treatment approaches. Many patients with migraine do not achieve adequate relief with current therapies or are unable to pay for monoclonal antibodies or gepants with their own money, which underscores the need for further research and development in this field. Several promising therapies are in clinical development and hold great potential for improving migraine management. As these novel treatments progress through clinical trials, their potential to revolutionize the management of migraine becomes increasingly evident. This review sets the stage for further research and exploration of these treatments.

8. Expert opinion

Treatment options in migraine are evolving rapidly. The recent advent of anti-CGRP drugs has markedly improved migraine therapy, especially in terms of migraine prevention. The overall efficacy of currently available gepants for acute 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 and acute therapies binding to the CGRP ligand or its receptor 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 benefits due to the functional antagonism of a pool of CGRP receptors that are more readily available to small molecules (<1 kDa) than monoclonal antibodies (≈150 kDa) [83]. Conversely, it is harder to predict a benefit when one gepant utilized for migraine prophylaxis is combined with a second gepant utilized for acute therapy in the same individual. Long-term studies in large patient populations are warranted to define the risk of CGRP-related adverse events when two anti-CGRP treatments are combined.

Migraine treatment may improve further with emerging, innovative pharmacological therapies. The manipulation of G protein-coupled receptor signaling pathways in the trigeminovascular system holds potential for efficacy in individuals with migraine who do not respond to currently available therapies. However, the costs associated with drug development, distribution, and accessibility can significantly impact their positioning in the management of migraine. The price of a monthly treatment with anti-CGRP therapies is significantly higher than a monthly treatment with non-anti-CGRP therapies. The approximate cost of anti-CGRP mAbs in Denmark amounts to €3,562 per patient per year [84]. When the additional outpatient visits associated with the treatment are considered, the expense rises to €4,131 per patient per year. Recent cost-effective analyses showed substantial socioeconomic gains associated with treatment with CGRP-mAbs, suggesting that these therapies reduce healthcare costs compared to conventional oral prophylactic therapies [85,86]. Further cost-benefit analyses are necessary to evaluate the potential reduction of healthcare costs when headaches are controlled in the long run and to ensure the greatest access and affordability of these innovative therapies.

Currently, cannabis-based therapies and hormonal and metabolic interventions are being explored. Gene therapies, although in their infancy, offer a further glimpse of personalized treatments targeting specific migraine-related genetic mutations. By implementing personalized treatment strategies based on individual´s clinical features, healthcare professionals can significantly improve the quality of life for individuals with migraine. Advances in genomics and molecular diagnostics have offered new insights into the complex biology of migraine and its subtypes [87]. These genetic markers could be used to personalize treatment and predict response to specific pharmacologic agents. Additionally, novel biomarkers could guide treatment decisions and monitor treatment response [88]. Incorporating genetic and biological markers into clinical practice would allow for an individualized and targeted approach to migraine management, increasing the likelihood of treatment success and minimizing unnecessary trial-and-error approaches. Continued research, rigorous clinical trials, and the accumulation of robust evidence are necessary steps in advancing innovative therapeutic options and improving the quality of life for individuals suffering from migraine.

Article highlights

• Therapies targeting the CGRP signaling pathway, such as monoclonal antibodies and gepants, have shown efficacy in reducing migraine frequency and improving patient outcomes.

• Acute migraine therapy targeting 5-HT receptors, triptans and ditans, show variability in efficacy and side effects, with subcutaneous sumatriptan being the most effective for pain relief.

• Lu AG09222, a monoclonal antibody targeting and inhibiting PACAP, showed promise in preventing PACAP38-induced cephalic vasodilation and headache in a proof-of-mechanism study. A phase 2a trial demonstrated its efficacy in reducing the number of monthly migraine days in individuals with a history of unsuccessful prior preventive treatments.

• The manipulation of trigeminovascular system signaling pathways offers hope for new targeted therapies aimed at those patients who do not benefit from current treatments.

Declaration of interest

L Pellesi has been employed by Lundbeck for the past two years. T Phu Do reports personal fees from Teva, outside of the submitted work. A Hougaard reports receiving personal fees from AbbVie, Eli Lilly, Lundbeck, Novartis, Teva and Pfizer. AH also serves as an associate editor of Headache.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have received institutional support for serving as an investigator from Teva, Abbvie; consultant fees from Salvia, Abbvie, Pfizer, and Cerenovus; and royalties from Cambridge University Press and MedLink, within the past two years.

Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.