European Journal of Cardiovascular Medicine

Migraine is a complex neurological disorder characterised by recurrent episodes of moderate-to-severe headache accompanied by photophobia, phonophobia, nausea, and cutaneous allodynia.  The Global Burden of Disease study ranks migraine among the top five causes of disability worldwide [1].  Historically conceptualised as a purely vascular phenomenon, migraine is now recognised as a neurovascular network disorder involving dysregulation of sensory processing, brainstem excitability, and neuropeptide release—most prominently CGRP [16].  The CGRP peptide, released from trigeminal afferents, acts on receptors within the dura and brainstem, promoting vasodilation and neurogenic inflammation leading to pain transmission [17].

Traditional preventive therapies such as propranolol, amitriptyline, valproate, and topiramate have modest efficacy and high discontinuation rates due to fatigue, cognitive effects, or teratogenic potential [17].  Triptans, the cornerstone of acute treatment since the 1990s, activate 5-HT₁B/₁D receptors to inhibit neuropeptide release, yet their vasoconstrictive mechanism limits their use in patients with cardiovascular disease [3].  The need for safe and effective migraine therapies prompted targeted exploration of CGRP signalling and trigeminal neurotransmission.

Between 2018 and 2025, the therapeutic landscape has transformed with the approval of four CGRP monoclonal antibodies—erenumab, fremanezumab, galcanezumab, and eptinezumab—and three small-molecule CGRP receptor antagonists, collectively termed gepants (ubrogepant, rimegepant, atogepant).  These agents directly inhibit the CGRP pathway, providing selective efficacy with minimal systemic toxicity [2–6,7–9].  The introduction of the first serotonin 5-HT₁F agonist, lasmiditan, offered a vasoconstriction-free acute option, broadening treatment access to patients with vascular risk factors [10,22].

Concurrently, advancements in non-pharmacological strategies—such as non-invasive vagus-nerve stimulation (nVNS), single-pulse transcranial magnetic stimulation (sTMS), cognitive-behavioural therapy (CBT), mindfulness-based stress reduction, and evidence-based nutraceuticals (magnesium, riboflavin, coenzyme Q10)—have contributed to an integrative therapeutic paradigm [11–15].  These modalities address comorbid anxiety and stress, improve adherence, and reduce medication-overuse headache, aligning with contemporary precision-medicine models [25,35,36].

The neurobiology of migraine encompasses cortical spreading depolarisation, thalamic sensory amplification, and hypothalamic–brainstem connectivity.  Recent neuroimaging studies demonstrate premonitory activation of the hypothalamus hours before pain onset, implicating neuroendocrine and circadian regulation [16].  CGRP and related peptides, including pituitary adenylate cyclase-activating peptide (PACAP-38), serve as key molecular mediators bridging trigeminovascular activation and systemic homeostatic responses [26,27].  These discoveries have catalysed the development of next-generation therapeutic targets, including dual CGRP–PACAP antibodies and orexin-modulating agents [31–33].

Given this rapid evolution, a contemporary synthesis of the pharmacological and device-based advances in migraine treatment is warranted.  The present systematic review critically evaluates high-quality studies published between 2020 and 2025, integrating evidence from RCTs, meta-analyses, and large real-world registries.  The objective is to summarise the efficacy, safety, and clinical utility of these emerging treatments and to highlight future research directions towards mechanistic precision and global accessibility in migraine cares.

Protocol and registration

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) statement [18]. The protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO). The methodology followed the Cochrane Handbook for Systematic Reviews of Interventions, ensuring transparency and reproducibility at every stage.

Eligibility criteria

Eligibility criteria were defined a priori using the PICO framework (Population, Intervention, Comparator, Outcomes).

1. Population: Adults (≥ 18 years) diagnosed with episodic or chronic migraine according to International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria.

2. Interventions: Novel pharmacological or device-based migraine treatments introduced between 2020 and 2025, including CGRP monoclonal antibodies (mAbs), gepants, ditans, neuromodulation devices, behavioural/digital therapies, and nutraceuticals.

3. Comparators: Placebo, sham stimulation, or standard preventive/acute therapy.

4. Outcomes: Efficacy endpoints—change in monthly migraine days (MMD), proportion of ≥ 50 % responders, 2-hour pain-freedom rate—and safety/tolerability outcomes.

5. Study design: Randomised controlled trials (RCTs), meta-analyses, prospective cohort studies, and large real-world observational studies (≥ 100 participants).

6. Exclusions: Case reports, animal studies, reviews, conference abstracts, non-English publications, and studies lacking clear outcome measures.

Information sources and search strategy

A comprehensive search was performed across PubMed, Scopus, and Embase databases for studies published from 1 January 2020 to 31 May 2025. The following Boolean string was adapted for each database:

(“migraine” AND (“calcitonin gene-related peptide” OR “CGRP” OR “monoclonal antibody” OR “erenumab” OR “fremanezumab” OR “galcanezumab” OR “eptinezumab” OR “gepants” OR “ubrogepant” OR “rimegepant” OR “atogepant” OR “lasmiditan” OR “5-HT1F” OR “neuromodulation” OR “vagus nerve stimulation” OR “TMS” OR “transcranial magnetic” OR “supraorbital” OR “mindfulness” OR “CBT” OR “biofeedback” OR “magnesium” OR “riboflavin” OR “CoQ10”)).

Reference lists of included articles and relevant reviews were manually screened to identify additional studies. All retrieved records were exported into EndNote v21 for citation management and duplicate removal.

Study selection process

Two independent reviewers screened titles and abstracts for relevance. Full texts of potentially eligible papers were then assessed against inclusion criteria. Discrepancies were resolved by discussion or consultation with a third reviewer. The PRISMA 2020 flow diagram (Figure 1) depicts each screening stage from identification to final inclusion.

Data extraction and synthesis

A standardised extraction form captured:

1. Study characteristics (authors, year, design, sample size, population type);

2. Intervention and comparator details (dose, route, duration);

3. Primary and secondary outcomes;

4. Adverse-event data and discontinuation rates;

5. Funding source and potential conflicts of interest.

Given heterogeneity in endpoints and populations, a qualitative narrative synthesis was undertaken rather than meta-analysis. Efficacy estimates were summarised as mean changes from baseline or responder proportions. Safety findings were expressed as percentage incidence of adverse events versus placebo.

Risk of bias and quality assessment

Quality appraisal of RCTs used the Cochrane Risk-of-Bias 2.0 (RoB 2) tool [19], evaluating randomisation, blinding, outcome assessment, incomplete data, and selective reporting. Observational studies were rated with the Newcastle–Ottawa Scale (NOS), considering selection, comparability, and outcome domains. Only studies rated moderate-to-high quality were retained. Inter-rater reliability exceeded 0.90 (Cohen’s κ).

Data handling and statistical considerations

All extracted quantitative data were cross-verified by both reviewers. Where necessary, medians were converted to means using established formulas, and 95 % confidence intervals were estimated from reported standard errors. No imputation was applied for missing data. Given heterogeneity among study populations, a descriptive analytical framework was preferred over pooled effect-size computation.

Figure 1 — PRISMA 2020 Flow Diagram

Text description (black-and-white journal layout):

1. Identification: 1 276 records retrieved (PubMed 642, Scopus 402, Embase 232); 258 duplicates removed → 1 018 unique records.

2. Screening: 1 018 titles/abstracts screened; 922 excluded as off-topic or not novel therapy.

3. Eligibility: 96 full-texts reviewed; 54 excluded (non-randomised, insufficient data).

4. Included: 42 studies incorporated into qualitative synthesis (26 RCTs, 8 meta-analyses, 8 observational).

This structured process adhered strictly to PRISMA 2020 standards, ensuring transparency and reproducibility. A schematic representation of these stages appears in Figure 1 (journal-style black-and-white version embedded in manuscript)

Study selection

The database search retrieved 1 276 unique citations: PubMed = 642, Scopus = 402, Embase = 232.

After removal of duplicates, 1 018 records underwent title–abstract screening, yielding 96 full-text papers for detailed eligibility assessment.

Ultimately, 42 studies satisfied inclusion criteria: 26 randomised controlled trials (RCTs), 8 meta-analyses, and 8 large observational registries.

The PRISMA 2020 flow diagram (Figure 1) summarises the process from identification through inclusion.

Overview of included evidence

Among the 42 included studies, 25 000 participants were represented collectively, with trial durations ranging from single-attack designs to 52-week extensions.

The interventions comprised four CGRP monoclonal antibodies (mAbs)—erenumab, fremanezumab, galcanezumab, eptinezumab—three CGRP receptor antagonists (gepants)—ubrogepant, rimegepant, atogepant—one 5-HT₁F agonist (lasmiditan), and multiple non-pharmacological modalities including nVNS, sTMS, and supraorbital stimulation devices.

Behavioural and nutraceutical studies evaluated CBT, mindfulness-based stress reduction, magnesium, riboflavin, and coenzyme Q10.

Pharmacological therapies

3.3.1 CGRP monoclonal antibodies

All four marketed mAbs demonstrated clinically meaningful efficacy and favourable tolerability compared with placebo [2–6, 20].

1. Erenumab: In pivotal RCTs (STRIVE and ARISE; n ≈ 1 600), erenumab 70 mg and 140 mg reduced monthly migraine days (MMDs) by –3.7 to –7.0 versus –1.8 with placebo at 12 weeks (p < 0.001) [2,3]. ≥ 50 % responder rates reached 43–50 % (vs 26 % placebo). Common AEs: constipation (3 %), injection-site pain (6 %).
   
   
2. Fremanezumab: Phase III HALO trials showed MMD reductions of –4.1 to –8.0, with responder rates of 47–53 % [4]. Quarterly and monthly regimens performed similarly.
   
   
3. Galcanezumab: EVOLVE 1–2 and REGAIN trials reported –4.6 MMD vs –2.1 placebo; ≥ 50 % responders ≈ 62 % [5].
   
   
4. Eptinezumab: Intravenous infusion achieved onset within 1 day, reducing MMD by –7.7 vs –3.4 placebo at 24 weeks (p < 0.001) [6].
   
   

Long-term extension studies confirm durable benefit through two years with < 5 % discontinuation. No hepatic, cardiovascular, or immunogenicity safety signals were observed [20].

Gepants (CGRP receptor antagonists)

Gepants provide both acute and preventive benefits without vasoconstriction or medication-overuse potential [7–9, 21].

• Ubrogepant: ACHIEVE I–II trials (n = 2 907) demonstrated 2-h pain freedom 21–22 % vs 12 % placebo and pain relief 61 % vs 48 % (p < 0.001) [7].
  
  
• Rimegepant: At 75 mg ODT, acute trials showed 19–21 % pain freedom and preventive use (every-other-day) reduced MMD by –4.3 vs –1.5 placebo [8].
  
  
• Atogepant: ADVANCE and PROGRESS trials (n ≈ 2 500) reported MMD change –3.7 to –4.2 days and ≥ 50 % responders ≈ 55 % vs 29 % [9].
  
  

Adverse events were mild (nausea ≤ 5 %, fatigue ≤ 3 %); no hepatotoxicity observed, contrasting earlier gepants such as telcagepant [21].

3.3.3 Ditans (5-HT₁F agonists)

Lasmiditan selectively activates 5-HT₁F receptors, inhibiting trigeminal nociception without vasoconstriction [10, 22].

In pooled SAMURAI and SPARTAN RCTs (n = 4 439), lasmiditan 200 mg achieved 2-h pain freedom 32 % vs 15 % placebo and most bothersome-symptom relief 40 % vs 30 %.

Adverse events included dizziness (16 %), somnolence (6 %), paraesthesia (3 %); transient CNS effects required post-dose driving restriction.

Non-pharmacological and adjunctive therapies

Neuromodulation

Non-invasive neuromodulation offers drug-free preventive and acute options, particularly suitable for pregnancy, polypharmacy, and cardiovascular contraindications [11, 12, 23].

• nVNS (γ-Core): PREVA trial and real-world extensions (n = 314) showed ≥ 50 % responder rate 34 % vs 14 % placebo (OR = 3.4, p < 0.01).
  
  
• Single-pulse TMS: Two multicentre RCTs in migraine with aura (n ≈ 300) demonstrated 2-h pain freedom 39 % vs 22 %; preventive use reduced monthly attacks by –2.8 days [12].
  
  
• Transcutaneous supraorbital stimulation: Head-to-head comparison with topiramate revealed equivalent preventive efficacy (≥ 50 % responders ~50 %) with fewer systemic side-effects [23].
  
  

Behavioural and digital interventions

Behavioural therapies complement pharmacologic strategies by modulating central pain networks and addressing psychiatric comorbidities [13, 25, 36].

Randomised trials of CBT and mindfulness-based stress reduction (n ≈ 600) reported MIDAS score improvement 25–35 % and attack-frequency reduction 1–2 days/month.

Biofeedback and smartphone-assisted CBT further improved adherence and reduced acute medication use by ~20 % [13].

Nutraceuticals

Nutraceuticals with the strongest evidence base include magnesium, riboflavin, and coenzyme Q10 [14, 15].

• Magnesium 400 mg/day decreased MMD by 1.3 days (95 % CI 0.8–1.8).
  
  
• Riboflavin 400 mg/day improved responder rate (≥ 50 %) in 34 % vs 19 % placebo (p = 0.02).
  
  
• Coenzyme Q10 100 mg TID reduced headache days by 1.5 per month and lowered attack intensity scores [15].
  
  

While absolute effect sizes are smaller than with pharmacological agents, tolerability and affordability justify adjunctive use.

Safety and tolerability

Across modalities, overall discontinuation due to adverse events was < 5 %.

CGRP mAbs and gepants exhibited placebo-like AE profiles, with injection-site pain, constipation, and nausea most frequent.

No cardiovascular, hepatic, or neurocognitive toxicity was identified.

Ditans produced transient CNS adverse effects but no cardiovascular risk.

Neuromodulation and behavioural interventions were essentially side-effect-free apart from mild local irritation during device use.

Summary of efficacy data

Table 1 – Mechanistic Targets and Agents

Table 2 – Key Randomised Controlled Trials (2020–2025)

Summary statement

Across pharmacological and non-pharmacological domains, contemporary migraine therapies deliver 3–8 day reductions in MMD and 30–60 % responder rates, markedly improving outcomes versus historical controls [2–15].

CGRP-pathway agents exhibit superior tolerability and adherence compared with traditional preventives [17, 20]. Integration of neuromodulation, behavioural interventions, and nutraceuticals further enhances therapeutic precision, positioning migraine management within a personalised-medicine framework [25, 35–40].

Therapeutic evolution and comparative efficacy

The approval of calcitonin gene-related peptide (CGRP) pathway modulators marks the most significant advance in migraine pharmacotherapy since the introduction of triptans in the 1990s.  Network meta-analyses and head-to-head trials consistently demonstrate that CGRP-targeted monoclonal antibodies (mAbs) achieve superior preventive efficacy, improved tolerability, and higher adherence compared with traditional agents such as propranolol, topiramate, or valproate [2-6, 17, 20].  Mean reductions of 3–8 monthly migraine days (MMD) translate to a relative risk reduction of approximately 45 % compared with placebo [20].

Gepants extend these advantages to oral administration, providing flexibility and dual utility for both acute and preventive indications [7-9, 21].  Their pharmacokinetic properties—short half-lives, hepatic metabolism via CYP3A4, and minimal blood–brain barrier penetration—support intermittent dosing without accumulation or hepatotoxicity.  In real-world registries, combination therapy with a CGRP mAb for prevention and a gepant for acute rescue achieved additive benefit with no overlapping toxicity [24, 37].  The 5-HT₁F agonist lasmiditan fills an unmet niche for patients with cardiovascular contraindications, as it lacks 5-HT₁B-mediated vasoconstriction [10, 22].  Together, these innovations represent a paradigm shift from broad neuroinhibition to mechanism-specific modulation.

Integration of non-pharmacological modalities

Non-invasive neuromodulation technologies such as nVNS, sTMS, and supraorbital stimulation have emerged as credible adjuncts to pharmacotherapy [11-13, 23].  Meta-analytic data show that nVNS yields ≥ 50 % responder rates in one-third of patients, comparable to conventional oral preventives but without systemic side-effects.  sTMS demonstrates particular efficacy in migraine with aura, possibly through cortical inhibition of spreading depolarisation [12].  Supraorbital stimulation confers preventive benefit similar to topiramate yet with superior tolerability [23].  These findings underscore a growing shift toward multi-modal therapy, where pharmacological and device-based interventions target complementary neural circuits.

Behavioural interventions, including cognitive-behavioural therapy (CBT), mindfulness-based stress reduction, and biofeedback, modulate pain-related cortical and limbic networks, reducing attack frequency and disability indices [13, 25, 36].  Their digital adaptation through smartphone applications enhances accessibility and self-management.  When implemented alongside pharmacotherapy, these strategies reduce medication-overuse headache and improve long-term adherence [36].  Nutraceuticals such as magnesium, riboflavin, and coenzyme Q10 provide modest but clinically meaningful prophylaxis with minimal risk [14, 15].

Biomarkers and precision-medicine perspectives

The move toward precision therapy requires biomarkers that predict therapeutic response and disease trajectory.  Plasma CGRP concentration correlates with attack severity and treatment response to CGRP mAbs [26].  Pituitary adenylate cyclase-activating peptide (PACAP-38) is implicated in migraine pathogenesis and is under evaluation as a secondary target [27].  Electroencephalographic (EEG) signatures and functional MRI connectivity profiles may stratify patients by cortical excitability, facilitating individualised drug selection [28].  Machine-learning algorithms using wearable and digital diary data can forecast attacks up to 24 hours in advance, enabling pre-emptive dosing of fast-acting agents [28, 39].

Genomic studies have identified variants in TRPM8, LRP1, and HTR1F genes influencing migraine susceptibility and pharmacodynamic response [39].  Integration of such multi-omic data with clinical phenotypes may refine future treatment algorithms.

Economic and accessibility considerations

Despite robust efficacy, cost remains a primary barrier to widespread adoption of CGRP mAbs and gepants, especially in low- and middle-income countries [29].  Annual treatment expenses frequently exceed those of conventional preventives by 10- to 20-fold.  Health-economic models suggest that cost-effectiveness is achieved when treatment leads to ≥ 50 % reduction in monthly headache days or restores ≥ 10 quality-adjusted life-years [30].  Strategies to enhance accessibility include tiered pricing, inclusion in national essential-medicine lists, and local manufacture of biosimilar antibodies [29, 30].  Intravenous quarterly dosing of eptinezumab may improve adherence while reducing healthcare visits.

Clinical implications

From a clinical standpoint, the therapeutic hierarchy for migraine should evolve from empiric step-therapy toward mechanism-driven precision medicine.  For patients with frequent attacks or intolerance to legacy preventives, CGRP mAbs represent first-line options.  Gepants and lasmiditan provide acute relief without vascular restriction, offering safe alternatives for those with cardiovascular risk.  Neuromodulation and behavioural interventions should be incorporated early, not merely as rescue modalities, to enhance resilience of the trigeminovascular network.  Combination therapy—pharmacological plus device-based—appears additive rather than redundant, justifying integrated care pathways [25, 35].  Clinicians must also counsel patients on realistic expectations, adherence, and recognition of medication-overuse patterns.

Future directions

The pipeline of migraine therapeutics continues to expand.  PACAP and orexin pathway modulators are under phase II–III evaluation, with preliminary evidence of efficacy in refractory cases [31-33].  Dual-target biologics combining CGRP and PACAP blockade aim to address incomplete responders.  Orexin receptor antagonists may stabilise hypothalamic arousal circuits implicated in prodromal symptoms [32].  Long-term registries are assessing safety of chronic CGRP blockade in pregnancy, adolescents, and the elderly [34].  Digital phenotyping, coupled with AI-assisted clinical decision systems, is expected to guide dose timing, identify non-responders early, and predict relapse [28, 39, 40].  Collectively, these innovations are propelling migraine care toward a biologically rational, data-driven framework.

CGRP-targeted monoclonal antibodies, gepants, and ditans have fundamentally changed the preventive and acute management of migraine.  Their high efficacy, favourable safety, and rapid onset distinguish them from traditional agents.  Complementary integration of neuromodulation, behavioural, and nutraceutical interventions promotes a multimodal, precision-based approach that addresses both neurobiological and psychosocial dimensions of migraine.  Although cost and access barriers persist, ongoing biosimilar development and digital therapeutics may democratise these advances globally.  Future research should give importance to biomarker-guided personalisation, long-term safety, and equitable distribution to fully understand the transformative potential of these therapies [35-40].

Author Declarations

Author contributions: Dr. Manoj E. Mathew ,  Dr. Aswathy P T and Dr.Akshai Saarkara conceived the review, designed the search strategy, performed literature screening and data extraction, and drafted the manuscript. All authors critically revised and approved the final version.

Funding: No external funding was received.

Conflicts of interest: The authors declare no conflicts of interest.

Ethical approval: Not required, as this study synthesises previously published data.

Acknowledgments: The authors thank colleagues and institutional librarians for technical support in literature retrieval.

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