Comprehensive preventive treatments for episodic migraine: a systematic review of randomized clinical trials

Background: Episodic migraine is a prevalent and disabling neurological disorder with a significant impact on quality of life and productivity. Preventive treatment aims to reduce the frequency, intensity, and disability associated with migraine attacks. However, the comparative efficacy and safety of available preventive strategies remain insufficiently addressed in the literature, especially in low- and middle-income countries.

Objective: To evaluate the efficacy and safety of pharmacological and non-pharmacological preventive treatments for episodic migraine through a systematic review and meta-analysis of randomized controlled trials (RCTs).

Methods: Following PRISMA guidelines, a comprehensive literature search was conducted across Wiley Online, BVS, MEDLINE, and OVID databases through November 2024. Eligible studies were RCTs comparing preventive treatments with placebo or active comparators in adults with episodic migraine. This review was not registered in PROSPERO due to institutional constraints at the time of project initiation. Primary outcomes included changes in monthly migraine days (MMD), monthly headache days (MHD), acute medication days (AMD), adverse events (AE) and serious adverse events (SAE). Meta-analysis was performed using fixed- or random-effects models depending on heterogeneity.

Results: Thirty-nine RCTs involving over 15,000 patients were included. Anti-CGRP monoclonal antibodies and gepants demonstrated the most consistent reduction in MMD (−3.2 to −4.4 days) with favorable tolerability. Traditional agents such as topiramate and propranolol showed modest efficacy with higher AE rates. Combination therapies offered superior MMD reductions (up to −5.1 days) but were associated with increased side effects. Non-pharmacological interventions (e.g., neuromodulation, acupuncture) showed promising results but lacked standardization. Meta-analysis of allopathic treatments revealed a significant MMD reduction vs. placebo (−1.25 days; 95% CI − 1.47 to −1.04; p < 0.001).

Conclusion: CGRP-targeted therapies and gepants are effective first-line options for episodic migraine prevention. Combinations may enhance efficacy but at the cost of tolerability. Non-pharmacological treatments represent useful adjuncts. These findings support individualized, multimodal preventive strategies, particularly in resource-limited settings. However, interpretation should consider potential publication and language bias, as well as the short follow-up duration in many included trials.

1 Introduction

Episodic migraine is a highly prevalent and disabling neurological disorder, particularly among women, affecting millions worldwide (1). It imposes a considerable socioeconomic burden, including lost workdays, decreased productivity, increased healthcare utilization with indirect costs related to caregiving, and diminished quality of life (2, 3). From a clinical standpoint, episodic migraine is characterized by recurrent attacks lasting 4–72 h and occurring on fewer than 15 days per month. These attacks are often unpredictable in onset and severity, resulting in significant physical and emotional distress (2). Effective management requires both acute treatments for symptom relief and preventive strategies aimed at reducing attack frequency and severity over time (4).

Preventive strategies, which range from pharmacological agents like antiseizure medications, beta-blockers, calcitonin gene-related peptide (CGRP) inhibitors, and (anti-CGRP) gepants to non-pharmacological approaches such as cognitive-behavioral therapy and neuromodulation, focus on decreasing the overall burden of the condition (5, 6, 7). Despite significant advances in treatment options, there remains considerable variability in individual responses, highlighting the need for personalized treatment regimens (8).

Although many studies have assessed individual acute and preventive treatments for episodic migraine (4), comprehensive analyses comparing efficacy and safety across multiple pharmacological and non-pharmacological modalities are still lacking, especially in underserved populations (9). Furthermore, global treatment guidelines remain fragmented and inconsistent regarding the integration of emerging therapies, particularly non-pharmacological approaches. This highlights the need for updated evidence-based recommendations applicable across both high- and low-resource healthcare systems. The present study aims to systematically evaluate the efficacy and safety of preventive treatments for episodic migraine in adults, using randomized controlled trials (RCTs) comparing pharmacological or non-pharmacological interventions with placebo or active comparators. A pairwise meta-analysis was performed following PRISMA guidelines, focusing on key outcomes such as monthly migraine days (MMD), monthly headache days (MHD), acute medications days (AMD), and adverse events (AE). Through this work, we aim to inform clinical decision-making and support more equitable guideline development, with a particular focus on relevance for developing countries such as Mexico.

2 Materials and methods

This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This systematic review and meta-analysis was not registered in PROSPERO due to institutional limitations at the time of project initiation. It was part of a broader systematic analysis of preventive treatments for episodic migraine available in Mexico. The study protocol was developed with input from clinical and research experts in headache management. A panel of six neurologists specializing in preventive strategies was assembled to guide protocol development.

Numerous systematic reviews have evaluated the efficacy of various pharmacological treatments, both specific (gepants or monoclonal antibodies) and non-specific (beta-blockers, anti-seizure medications, antidepressants, and others), either individually or in combination, as well as device-based therapies for the prevention of episodic migraine. A systematic review of RCTs was conducted to synthesize the existing evidence on pharmacological and non-pharmacological interventions for episodic migraine.

2.1 Data sources and searches

A systematic search was conducted across Wiley Online, BVS, MEDLINE, and OVID from their inception until November 2, 2024. Additional searches included clinical trial registries, government databases and websites, conference proceedings, patient advocacy group websites, systematic reviews/meta-analyses, and medical society websites, though these were ultimately excluded. The technical expert panel assisted in identifying relevant literature. A medical reference librarian designed and executed the search strategy, which was peer-reviewed by a second librarian and validated by coauthors MK, V-J, and I R-L.

2.2 Study selection

Eligible studies (1) included adult patients (≥18 years) with episodic migraine; (2) evaluated preventive pharmacologic and non-pharmacological treatments; (3) involved randomized clinical trials (RCTs) (phase II/phase III) comparisons of the intervention with placebo, usual care, another pharmacologic therapy, or no treatment (4) reported outcome of interest as reduction of monthly migraine days (MMD), monthly headache days (MHD) and acute medications days (AMD), (5) adverse events (AE) and serious adverse events (SAE). We excluded in vitro, phase I clinical trials, nonrandomized, open-labeled trials, studies without original data, and single-group studies. Therapies in development or intravenous administration terminated development or unavailable in the global market were excluded. Additionally, studies on patients diagnosed with tension headaches or other headache disorders and treated with NSAIDs, triptans, or ergot alkaloids therapies were excluded. Case reports, case series, reviews, post-hoc analyses, or multiple reports of the same study were excluded.

The original study definitions were retained despite evolving migraine criteria, provided they aligned with the current International Classification of Headache Disorders, Third Edition (ICHD-3) standards for episodic migraine (10), characterized by headaches occurring on ≤14 days per month in individuals with migraine. Studies were restricted to those published in English or Spanish.

2.3 Data extraction

An extraction form was developed to standardize data collection. Two reviewers independently extracted study characteristics. Inter-rater agreement was assessed using Cohen’s kappa (κ = 0.82), indicating substantial agreement. Discrepancies were resolved through consensus discussion. A third reviewer (K.V.) was consulted when necessary. Authors were contacted for clarifications when data were missing or unclear. The extracted data included the generic name of the drug or device, author, year, study design, sample size, intervention details, administration route, dose, frequency, adverse effects, efficacy and safety outcomes, time frame, and availability in Mexico. Treatments were categorized as monotherapy or combination regimens in migraine prevention.

2.4 Search strategy

A comprehensive literature search used detailed search terms and Boolean operators to identify relevant studies. The search focused on RCTs that were double-blind AND placebo-controlled interventions. The following pharmacological and non–pharmacological treatment options were included: Erenumab OR CGRP antagonist OR fremanezumab OR galcanezumab OR Eptinezumab OR gepants OR rimegepant OR atogepant OR topiramate OR propranolol OR beta-blocker OR venlafaxine OR valproate OR oxcarbazepine OR candesartan OR amitriptyline OR antiepileptics, OR antidepressants, OR melatonin OR lanepitant OR aspirin OR NSAIDs OR memantine OR neuromodulation OR nerve blockers OR vestibular treatments OR acupuncture. Additionally, the search incorporated studies involving herbal supplements, oils, and combinations using Rayyan© Software, Cambridge, MA, USA.

2.5 Outcome measures

The primary efficacy outcome included reducing MMD in the active study group compared with the placebo. The secondary efficacy outcomes were MHD and reduction of AMD, which include specific and non-specific substances. When data on reduction in days or standard deviations were not directly reported in the articles, they were estimated based on comparisons between baseline and final values, reported percentage changes, or visual inspection of figures. Standard deviations were calculated from reported standard errors or visually estimated when necessary. The primary safety outcome included the presence and frequency or percentage of adverse effects and SAE; type, and severity of adverse effects using the Common Terminology Criteria for grading from Grade 1 (mild) to Grade 5 (death), and availability in Mexico.

2.6 Risk of bias assessment

The risk of bias was evaluated using the Cochrane Risk of Bias Tool for Randomized Trials (RoB 2, v2) (11). This assessment covered five key domains: (1) bias in randomization procedures, (2) bias from deviations in intended interventions, (3) bias due to incomplete outcome data, (4) bias in outcome measurement, and (5) bias in selective reporting. Each domain was rated as “low risk,” “some concerns,” or “high risk,” with an overall bias judgment assigned per study. For this analysis, MMD were the primary outcome to determine bias. Two independent reviewers (D.S. and M.A.M.M.) conducted the assessments.

2.7 Statistical analysis

Data analysis was performed with SPSS software (v.31; IBM Corp., Armonk, NY, USA). Heterogeneity across studies was evaluated using the Chi-square test and quantified via the I² statistic. A fixed-effect model was applied for analyses with low heterogeneity (I² < 50%), while a random-effects model was used when I² ≥ 50%. No subgroup or sensitivity analyses were pre-specified due to the limited number of homogeneous studies available. Funnel plots were generated to assess publication bias for the primary efficacy comparison (allopathic pharmacological treatments vs. placebo for MMD). Egger’s test was applied and showed no evidence of publication bias (p = 0.27). Continuous outcomes were expressed as mean differences (MD) with 95% confidence intervals (CIs). Statistical significance was defined as p < 0.05. The meta-analyses conducted in this review were limited to efficacy outcomes, specifically MMD, due to heterogeneity in the reporting and classification of AE and SAE across studies.

3 Results

3.1 Characteristics of the included studies

Our search until November 30, 2024, identified 605 scientific papers through database and trial registry screening; after removing duplicates or illegible by automation tools, 202 records remained. Figure 1 shows the flowchart of the clinical studies screened and excluded, and finally, 39 RCTs were included and analyzed. All studies were published between 1987 and 2024. All studies were randomized double-blinded clinical trials classified in pharmacological treatments and non-pharmacological interventions.

Figure 1

Figure 1. Flowchart of the randomized clinical trials analyzed.

3.2 Study designs and frequencies

The included studies predominantly employed RCT designs, with the majority (27) utilizing double-blind, placebo-controlled methodologies. Additionally, 12 studies implemented double-blind RCTs with active comparators, directly comparing the efficacy and safety of different pharmacological treatments.

3.3 Sample size distribution

The included studies demonstrated considerable variability in sample sizes ranging from 28 to 1,001 participants, with a distinct trend toward larger trials (>300 participants) evaluating newer therapeutic classes such as anti-CGRP monoclonal antibodies (e.g., erenumab, fremanezumab) and gepants (e.g., rimegepant, atogepant). In contrast, smaller-scale trials were more frequently observed for established drug classes, including anti-seizure medications (e.g., topiramate, valproate) and beta-blockers (e.g., propranolol), as well as non-pharmacologic approaches such as acupuncture.

3.4 Study settings

All interventions were administered in outpatient or clinical trial environments, with routes including oral, subcutaneous (SC), intravenous (IV), transcutaneous, and topical.

3.5 Efficacy and safety of pharmacologic therapies

Table 1 summarizes the study design, sample size, interventions, clinical outcomes, adverse events profile, and availability in Mexico. This section presents a structured narrative synthesis of the efficacy and safety findings of each pharmacologic class used for episodic migraine prevention.

Table 1

Table 1. Summary of the efficacy and safety of randomized clinical trials in preventing episodic migraine.

3.5.1 Anti-CGRP monoclonal antibodies

Anti-CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) showed consistent reductions in MMD, ranging from −3.2 to −4.3 days, mostly evaluated at 12 weeks, except for galcanezumab which was assessed at 6 months. AMD was reduced between −1.1 and −3.7 days within the same timeframe. MHD was not consistently reported. AE rates ranged from 18.5 to 58%, with upper respiratory infections, injection site reactions, constipation, and fatigue being most common. SAEs occurred in 1.3–4%, including abdominal pain, asthenia, and bronchiectasis.

3.5.2 Gepants

Gepants (rimegepant and atogepant) demonstrated significant reductions in MMD (−3.6 to −4.4 days), MHD (−3.9 to −4.4 days), and AMD (−3.3 to −3.9 days), all consistently evaluated at 12 weeks. AE ranged widely (10–63.8%), mainly nausea, constipation, and fatigue. SAE occurred in 2–4.1%, including allergic reactions and fatigue.

3.5.3 Antiseizure medications

Topiramate, valproate, and oxcarbazepine showed heterogeneous evaluation periods: topiramate was assessed at 8–20 weeks, valproate at 4 weeks, and oxcarbazepine at 12 weeks. MMD reductions ranged from −1.3 to −4.2 days. Valproate showed a −1.2-day reduction in MHD at 4 weeks, and oxcarbazepine showed a −1.2-day reduction in AMD at 12 weeks. AE were frequent (60–80%), particularly paresthesia, weight loss, dizziness, and cognitive effects. SAE ranged from 2 to 15%.

3.5.4 Beta-blockers

Propranolol, metoprolol, and nebivolol showed MMD reductions from −1.2 to −4.2 days over evaluation periods ranging from 4 to 14 weeks. MHD and AMD were not reported. AE frequency varied significantly (17.9–93%), with fatigue, dizziness, and gastrointestinal issues being most common. SAE ranged from 3.5 to 7.1%.

3.5.5 Angiotensin receptor blockers

Candesartan showed a reduction in MMD (−1.8 days) and MHD (−2.9 days), both measured at 12 weeks. AMD data was not reported. AE frequency reached 50%, mainly respiratory infections, dizziness, and sleep problems. No SAE were specified.

3.5.6 Antidepressants

Amitriptyline, venlafaxine, and escitalopram were evaluated over 8–12 weeks. MMD reductions ranged from −1.0 to −7.8 days. MHD and AMD were not reported. AE incidence ranged widely (0–100%), often including drowsiness, fatigue, nausea, and weight gain. SAE ranged from 1 to 34.3%, with severe sedation and cardiovascular symptoms in some cases.

3.5.7 Hormonal therapy

Melatonin was evaluated over 8 weeks, showing an MMD reduction of −2.8 days. MHD and AMD were not reported. AE occurred in 2.8% of cases, including fatigue and dizziness. No SAE were reported.

3.5.8 NK-1 receptor antagonists

Lanepitant was evaluated over 12 weeks and showed a modest MMD reduction of −0.9 days. No data was available for MHD or AMD. AE were reported in 52.4% of participants, including headache and gastrointestinal symptoms. SAE occurred in 2.3% of participants.

3.5.9 NSAIDs

Aspirin (acetylsalicylic acid) showed a −1.3-day reduction in MMD after long-term evaluation at 36 months. MHD, AMD, AE, and SAE data were not reported.

3.5.10 NMDA antagonists

Memantine was evaluated over 12 weeks, achieving an MMD reduction of −3.5 days. AMD remained unchanged (0 days), and MHD was not reported. AE (13%) included dizziness and fatigue. SAE were not specified.

3.5.11 Herbal supplements and oils

Tanacetum, ginger, and basil oil were studied over 12 weeks. MMD reductions ranged from −0.2 to −3.2 days. Ginger also led to a reduction in MHD (−0.8 days) and AMD (−0.9 days). AE frequencies varied (8.3–35%) and included nausea, diarrhea, and skin irritation. Ginger was associated with a 7.5% SAE rate.

3.5.12 Combination therapies

Combinations such as topiramate with amitriptyline, flunarizine, or nortriptyline were evaluated between 6 and 12 weeks. MMD reductions ranged from −2.6 to −5.1 days. MHD and AMD data were mostly unavailable. AE frequency ranged from 15 to 65.9%, and SAE reached 4.3%, including sedation, weight gain, and dizziness.

Among the evaluated pharmacological groups, Gepants (Rimegepant, Atogepant) demonstrated one of the most substantial reductions in both Monthly Migraine Days (MMD) and Acute Medication Days (AMD), with MMD decreasing between −3.6 to −4.4 days and AMD showing a reduction of −3.3 to −3.9 days at 12 weeks. Similarly, anti-CGRP monoclonal antibodies (Erenumab, Fremanezumab, Galcanezumab, Eptinezumab) exhibited notable efficacy, achieving MMD reductions ranging from −3.2 to −4.3 days and AMD reductions of −1.1 to −3.7 days across various studies. Additionally, combination therapies such as Topiramate + Amitriptyline or Propranolol + Nortriptyline presented the most significant MMD reduction, with values reaching up to −5.1 days, though AMD data was not reported for this group. These findings highlight the potential of these medication classes in effectively reducing migraine frequency and medication use.

3.6 Meta-analysis of efficacy of the pharmacological treatments

3.6.1 Allopathic medications

We analyzed the RCTs that compared the intervention with placebo at the 12 weeks, using MMD as the primary outcome, as it is the most consistent measure of efficacy. To reduce heterogeneity in the timing of outcome evaluations, we excluded RCTs with different times for the assessment of the outcomes, active and heterogeneous comparators, and study arms that involved drug combinations previously mentioned in Table 1. Figure 2 of allopathic treatment showed a global −1.25 mean difference (95%, confidence interval CI −1.47, −1.04, p = 0.001) to favor the active treatments, except in some negative RCTs using eptinezumab, oxcarbazepine, candesartan, propranolol, and lanepitant. Although the pooled mean reduction in monthly migraine days (MMD) was −1.25 days, this effect should be interpreted in light of the baseline MMD observed in the placebo groups, which typically ranged from 4.5 to 7.5 days across the included trials. This corresponds to a relative reduction of approximately 17–28%, indicating a potentially meaningful clinical benefit despite the modest absolute value. Figure 3 displays the funnel plot corresponding to this meta-analysis of allopathic treatments versus placebo for MMD. Visual inspection showed no significant asymmetry, and Egger’s test did not detect publication bias. It is important to note that the quantitative meta-analysis focused exclusively on efficacy outcomes (MMD), and pooled estimates for AE or SAE were not calculated due to significant variability in reporting methods and definitions among included studies.

Figure 2

Figure 2. Forest plot of the randomized clinical trials placebo-controlled using allopathic treatments for the prevention of episodic migraine.

Figure 3

Figure 3. Funnel plot of the randomized clinical trials, placebo-controlled using allopathic treatments to prevent episodic migraine.

3.6.2 Homeopathic medications

We analyzed the RCTs that compared the intervention with placebo at 12 weeks, using MMD as the primary outcome. Figure 4 shows that homeopathic treatments had a global mean difference of −0.79 (95% confidence interval [CI]: −1.65 to 0.07, p = 0.07), which was not significant compared with the placebo. The funnel plot, shown in Figure 5 corresponds to the meta-analysis of homeopathic treatments. Visual inspection showed no major asymmetry, and Egger’s test did not indicate significant publication bias.

Figure 4

Figure 4. Forest plot of the randomized clinical trials placebo-controlled using homeopathic treatments for the prevention of episodic migraine.

Figure 5

Figure 5. Funnel plot of the randomized clinical trials placebo-controlled using homeopathic treatments for the prevention of episodic migraine.

3.7 Efficacy and safety of non-pharmacologic therapies

Table 2 summarizes a structured narrative synthesis of non-pharmacological. This section provides a structured narrative synthesis of non-pharmacological interventions for episodic migraine prevention.

Table 2

Table 2. Summary of non-pharmacological therapies.

Non-pharmacological interventions included neuromodulation techniques such as occipital nerve stimulation, caloric vestibular stimulation, and acupuncture. These modalities were assessed primarily over a 12-week period, except for occipital nerve stimulation, which reported outcomes at 1 month.

Occipital nerve stimulation showed reductions in MHD ranging from −2.0 to −5.5 days at 1 month, depending on the stimulation frequency. MMD also improved, although the data were not consistently reported across all frequency subgroups. AE were reported in up to 25% of patients and included local pain, hematoma at the stimulation site, nausea, and dizziness. SAE were not reported in these trials.

Caloric vestibular stimulation was evaluated over 12 weeks and demonstrated a reduction in both MMD and MHD of −3.9 days. The same intervention showed a reduction in AMD of −3.9 days. The most frequent AE included nausea, dizziness, ear discomfort, and tinnitus. No SAE were reported.

Acupuncture, evaluated over a 12-week period, showed a reduction of −2.5 days in MMD compared to a −1.0-day reduction in the sham acupuncture control group. MHD and AMD were not reported. AE occurred in 25% of patients and included local pain and hematoma at the puncture sites. No SAE were reported.

Although these interventions yielded promising effects in reducing migraine frequency and associated medication use, the wide variability in protocols, outcome definitions, and follow-up times hindered direct comparison and aggregation of results. Nonetheless, the generally favorable safety profile across studies supports the potential role of these non-pharmacological strategies as adjunctive treatments in individualized preventive regimens.

Unfortunately, the meta-analysis of the efficacy of the non-pharmacological treatments was not feasible for the heterogeneity of the outcome measurements used in each study.

3.8 GRADE evidence profile

A structured GRADE assessment was conducted to determine the certainty of evidence for the main pharmacological comparisons included in this review. This approach complements the narrative synthesis and meta-analysis by addressing potential limitations in risk of bias, inconsistency, indirectness, imprecision, and publication bias.

Table 3 summarizes the GRADE evidence profiles for anti-CGRP monoclonal antibodies, gepants, and combination therapies, using monthly migraine days (MMD) as the primary outcome.

Table 3

Table 3. GRADE evidence profiles.

The certainty of evidence was rated as moderate for anti-CGRP therapies due to some imprecision across trials, high for gepants based on robust and consistent findings, and low for combination treatments, mainly due to heterogeneity, indirect comparisons, and small sample sizes. These ratings provide a useful framework for interpreting the strength and applicability of the observed clinical effects.

3.9 Risk of bias

Bias was evaluated following the guidelines of the Cochrane Handbook for Systematic Reviews. The details are illustrated in Figures 6, 7. We did not find any risk of bias in the RCTs using the intention-to-treat modality. However, in the Per-protocol approach, participants were randomly assigned to groups using computer-generated random sequences through an interactive web-response system in all two studies. One trial noted that pharmacists were unblinded; however, their role was limited to drug preparation and inventory management. Another trial did not provide details on allocation concealment and blinding of outcome assessment. All two trials reported patient follow-up losses; each predefined outcome was clearly described. Studies meeting the inclusion criteria were included in this meta-analysis.

Figure 6

Figure 6. Risk of bias for the randomized clinical trials included intention-to-treat.

Figure 7

Figure 7. Risk of bias for the randomized clinical trials included per protocol.

4 Discussion

This systematic meta-analysis provides a comprehensive evaluation of the efficacy and safety of preventive interventions for episodic migraine, with a particular focus on those available in Mexico. Although the allopathic treatment analysis demonstrated an overall favorable effect for active interventions (mean difference: –1.25; 95% CI: −1.47 to −1.04; p = 0.001), several agents—including eptinezumab, oxcarbazepine, candesartan, propranolol, and lanepitant—showed non-significant effects in individual RCTs, highlighting variability in therapeutic response. The findings confirm that, despite the wide range of therapeutic options, there remains significant heterogeneity in clinical outcomes regarding reduction in MMD and treatment tolerability.

Anti-CGRP antagonists—including erenumab, fremanezumab, galcanezumab, and eptinezumab—demonstrated clinically relevant reductions in MMD with acceptable safety profiles (51). These results are consistent with international literature, where anti-CGRP monoclonal antibodies have shown superiority over traditional treatments regarding specificity and treatment adherence.

Similarly, gepants (rimegepant and atogepant), as oral CGRP receptor modulators, showed comparable efficacy to monoclonal antibodies, albeit with variability in adverse events, particularly gastrointestinal side effects (52).

Regarding conventional therapies, antiepileptic drugs and beta-blockers, despite their widespread use, showed more modest efficacy and higher rates of adverse events, limiting their applicability to specific patient profiles (53). Notably, pharmacological combinations—such as topiramate with amitriptyline or propranolol with nortriptyline—achieved the most pronounced reductions in MMD, although with lower tolerability, underscoring the need for individualized risk–benefit assessment (54, 55).

Non-pharmacological interventions, including occipital nerve stimulation, vestibular stimulation, and acupuncture, demonstrated beneficial effects on some clinical outcomes. However, the lack of uniformity in outcome measures and the limited number of controlled studies hindered their inclusion in the quantitative meta-analysis. Nevertheless, their favorable safety profile and potential utility as adjunctive therapies warrant further exploration through studies with robust methodological design (56).

In light of the limited availability of certain pharmacological agents and therapies in Mexico, it is imperative to outline strategic steps for incorporating newer evidence-based treatments into national formularies, ensuring equitable access and alignment with international standards of care.

From a methodological perspective, the risk of bias analysis using the Cochrane RoB 2 tool revealed an overall low risk of bias, particularly in studies that used intention-to-treat analysis (57). However, some limitations persisted, especially in studies with limited information on allocation concealment or blinding of outcome assessors.

The limitation of the present analysis is the exclusion of patients over 65 years of age, pregnant women, and individuals with cardiovascular or cerebrovascular conditions, which restricts the generalizability of the findings. Furthermore, variability in follow-up periods (ranging from 3 to 6 months), potential publication bias, and the lack of access to unpublished or incomplete data may have influenced the aggregate results (58).

4.1 Limitations of the meta-analysis

The present review also has some limitations. First, the present study was restricted to eligibility criteria, in which merely “Number of studies” were included in the analysis. Some unpublished and missing data from studies also influence aggregate results. Furthermore, some of the studies were completed by the same researchers, which may lead to publication bias. In addition, the double-blind period of these included studies ranged from 3 to 6 months, and the difference might result in heterogeneity. To reduce heterogeneity, only studies with 12-week follow-up were included in the final quantitative synthesis. While this approach improved comparability across trials, it also excluded a significant number of potentially relevant studies and may have limited the scope of the analysis, particularly with regard to long-term efficacy and safety outcomes.

Additionally, pharmacological treatments were grouped into broad therapeutic classes (e.g., antidepressants, anti-seizure medications), despite marked differences in their mechanisms of action and clinical profiles. For example, amitriptyline and venlafaxine, although both classified as antidepressants, have distinct pharmacodynamic properties; similarly, topiramate and valproate differ substantially in their molecular targets and tolerability. This classification may oversimplify treatment effects and obscure clinically meaningful differences between individual agents. Greater granularity, as reflected in the compound-specific data provided in Supplementary material, is likely to be more informative for guiding clinical decision making. Also, the analysis excluded older, non-specific pharmacological therapies commonly used in migraine prevention—such as other beta-blockers and certain calcium channel blockers—owing to the lack of recent or high-quality RCTs meeting inclusion criteria. Some of them are treatments that remain widely prescribed in routine practice in some countries, and their omission from the current synthesis may limit the generalizability of the findings.

In addition, non-pharmacological and nutraceutical interventions were grouped into heterogeneous categories, despite having distinct therapeutic mechanisms and varying levels of supporting evidence. This broad classification complicates interpretation and precludes firm conclusions about the relative efficacy of individual non-drug strategies.

Moreover, this review included only studies published in English or Spanish, which may have introduced language bias and limited the inclusion of potentially relevant trials from other regions. Otherwise, Meta-analyses were conducted using SPSS due to software availability at the institution. While SPSS is appropriate for basic fixed- and random-effects models, it does not offer the advanced options or flexibility of specialized platforms such as RevMan or R-based packages like meta or metafor. This may limit some statistical nuance in modeling or subgroup analysis.

Finally, due to the exclusion of patients older than 65 years, pregnant individuals, and those with significant cardiovascular or cerebrovascular comorbidities, the generalizability of the results is limited. These populations, which are frequently encountered in clinical practice, remain underrepresented in current trials. Moreover, future studies should prioritize the investigation of subgroup-specific responses to preventive treatments, including stratification by migraine frequency (e.g., high-frequency episodic vs. chronic migraine), sex, and age group. Such analyses are essential to advancing a more tailored and equitable approach to migraine management.

Furthermore, studies with longer follow-ups and larger sample sizes should be performed to identify the confirmative safety profile of gepants and monoclonal antibodies and determine the duration of its therapeutic effects.

Taken together, these limitations highlight the need for further high-quality, head-to-head trials of both pharmacological (e.g., gepants vs. monoclonal antibodies) and non-pharmacological treatments, with mechanistic specificity, standardized outcomes, and longer follow-up durations, and evaluations of cost-effects of the treatment to better inform personalized approaches to migraine prevention.

4.2 Bullet points

• Preventive therapy for episodic migraine should be individualized.

• Combined strategies (pharmacological + non-pharmacological) are recommended.

• Decision-making should consider comorbidities, adverse effect profiles, and patient preferences.

5 Conclusion

This systematic meta-analysis highlights the efficacy and safety of preventive treatments for episodic migraine, with a focus on their applicability in Mexico. While active treatments showed an overall favorable effect (mean difference: –1.25; 95% CI: −1.47 to −1.04; p = 0.001). with a variability in response. Anti-CGRP monoclonal antibodies and gepants were associated with clinically meaningful reductions in MDD and acceptable safety, offering advantages over conventional therapies. Traditional agents, including beta-blockers and antiepileptics, showed more modest efficacy and tolerability, while pharmacological combinations, though effective, were limited by side effects. Non-pharmacological strategies showed promise but lacked consistent evidence.

The limited availability of newer therapies in Mexico highlights the need for national strategies to expand formulary access and align with international treatment standards. Methodological limitations—including the exclusion of older adults and pregnant individuals, short follow-up periods, and variability in drugs. Future research should prioritize inclusive, long-term, and head-to-head trials to better inform personalized, evidence-based migraine prevention.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding author.

Author contributions

M-KV-J: Funding acquisition, Validation, Writing – review & editing. AM-M: Data curation, Writing – review & editing. IR-L: Project administration, Resources, Validation, Writing – review & editing. MMe: Data curation, Writing – review & editing. MR-Á: Data curation, Writing – review & editing. JP-G: Data curation, Writing – review & editing. RV-G: Data curation, Writing – review & editing. DS: Conceptualization, Methodology, Supervision, Writing – original draft. MP-P: Methodology, Writing – review & editing. EG: Data curation, Formal analysis, Software, Writing – review & editing. MMo: Data curation, Formal analysis, Software, Writing – review & editing. CT: Formal analysis, Software, Writing – review & editing. MG: Writing – review & editing.

Funding

The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by Pfizer Mexico. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The authors declare that no Gen AI was used in the creation of this manuscript.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2025.1611303/full#supplementary-material

References

1. Ahmad, SR, and Rosendale, N. Sex and gender considerations in episodic migraine. Curr Pain Headache Rep. (2022) 26:505–16. doi: 10.1007/s11916-022-01052-8

PubMed Abstract | Crossref Full Text | Google Scholar

2. Riggins, N, and Ehrlich, A. Episodic migraine and older adults. Curr Pain Headache Rep. (2022) 26:331–5. doi: 10.1007/s11916-022-01029-7

PubMed Abstract | Crossref Full Text | Google Scholar

3. Lanteri-Minet, M. Economic burden and costs of chronic migraine. Curr Pain Headache Rep. (2014) 18:385. doi: 10.1007/s11916-013-0385-0

PubMed Abstract | Crossref Full Text | Google Scholar

4. Orlova, YY, Mehla, S, and Chua, AL. Drug safety in episodic migraine management in adults part 1: acute treatments. Curr Pain Headache Rep. (2022) 26:481–92. doi: 10.1007/s11916-022-01057-3

PubMed Abstract | Crossref Full Text | Google Scholar

5. Hubig, LT, Smith, T, Chua, GN, Lloyd, AJ, Powell, L, Johnston, K, et al. A stated preference survey to explore patient preferences for novel preventive migraine treatments. Headache. (2022) 62:1187–97. doi: 10.1111/head.14386

PubMed Abstract | Crossref Full Text | Google Scholar

6. Raggi, A, Leonardi, M, Arruda, M, Caponnetto, V, Castaldo, M, Coppola, G, et al. Hallmarks of primary headache: part 1 – migraine. J Headache Pain. (2024) 25:189. doi: 10.1186/s10194-024-01889-x

PubMed Abstract | Crossref Full Text | Google Scholar

7. Pellesi, L, Do, TP, and Hougaard, A. Pharmacological management of migraine: current strategies and future directions. Expert Opin Pharmacother. (2024) 25:673–83. doi: 10.1080/14656566.2024.2349791

PubMed Abstract | Crossref Full Text | Google Scholar

8. Thorlund, K, Toor, K, Wu, P, Chan, K, Druyts, E, Ramos, E, et al. Comparative tolerability of treatments for acute migraine: a network meta-analysis. Cephalalgia. (2016) 37:965–78. doi: 10.1177/0333102416660552

PubMed Abstract | Crossref Full Text | Google Scholar

9. Lampl, C, MaassenVanDenBrink, A, Deligianni, CI, Gil-Gouveia, R, Jassal, T, Sanchez-Del-Rio, M, et al. The comparative effectiveness of migraine preventive drugs: a systematic review and network meta-analysis. J Headache Pain. (2023) 24:56. doi: 10.1186/s10194-023-01594-1

PubMed Abstract | Crossref Full Text | Google Scholar

10. Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edition. Cephalalgia. (2018) 38:1–211. doi: 10.1177/0333102417738202

Crossref Full Text | Google Scholar

11. Higgins, JP, Altman, DG, Gøtzsche, PC, Juni, P, Moher, D, Oxman, AD, et al. The Cochrane collaboration's tool for assessing risk of bias in randomised trials. BMJ. (2011) 343:1–9. doi: 10.1136/bmj.d5928

Crossref Full Text | Google Scholar

12. Goadsby, PJ, Reuter, U, Hallström, Y, Broessner, G, Bonner, JH, Zhang, F, et al. A controlled trial of Erenumab for episodic migraine. N Engl J Med. (2017) 377:2123–32. doi: 10.1056/NEJMoa1705848

PubMed Abstract | Crossref Full Text | Google Scholar

13. Dodick, DW, Silberstein, SD, Bigal, ME, Yeung, PP, Goadsby, PJ, Blankenbiller, T, et al. Effect of Fremanezumab compared with placebo for prevention of episodic migraine: a randomized clinical trial. JAMA. (2018) 319:1999–2008. doi: 10.1001/jama.2018.4853

PubMed Abstract | Crossref Full Text | Google Scholar

14. Skljarevski, V, Matharu, M, Millen, BA, Ossipov, MH, Kim, B-K, and Yang, JY. Efficacy and safety of galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 phase 3 randomized controlled clinical trial. Cephalalgia. (2018) 38:1442–54. doi: 10.1177/0333102418779543

PubMed Abstract | Crossref Full Text | Google Scholar

15. Smith, TR, Janelidze, M, Chakhava, G, Cady, R, Hirman, J, Allan, B, et al. Corrigendum to "Eptinezumab for the prevention of episodic migraine: sustained effect through 1 year of treatment in the PROMISE-1 study" [Clin Therapeut 42 (12) (2020) 2254-65]. Clin Ther. (2021) 43:791. doi: 10.1016/j.clinthera.2021.01.019

Crossref Full Text | Google Scholar

16. Croop, R, Lipton, RB, Kudrow, D, Stock, DA, Kamen, L, Conway, CM, et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet. (2021) 397:51–60. doi: 10.1016/S0140-6736(20)32544-7

PubMed Abstract | Crossref Full Text | Google Scholar

17. Goadsby, PJ, Dodick, DW, Ailani, J, Trugman, JM, Finnegan, M, Lu, K, et al. Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial. Lancet Neurol. (2020) 19:727–37. doi: 10.1016/S1474-4422(20)30234-9

PubMed Abstract | Crossref Full Text | Google Scholar

18. Ailani, J, Lipton, RB, Goadsby, PJ, Guo, H, Miceli, R, Severt, L, et al. Atogepant for the preventive treatment of migraine. N Engl J Med. (2021) 385:695–706. doi: 10.1056/NEJMoa2035908

PubMed Abstract | Crossref Full Text | Google Scholar

19. Tassorelli, C, Nagy, K, Pozo-Rosich, P, Lanteri-Minet, M, Sacco, S, Nežádal, T, et al. Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): a randomised, placebo-controlled, phase 3b trial. Lancet Neurol. (2024) 23:382–92. doi: 10.1016/S1474-4422(24)00025-5

PubMed Abstract | Crossref Full Text | Google Scholar

20. Schwedt, TJ, Lipton, RB, Ailani, J, Silberstein, SD, Tassorelli, C, Guo, H, et al. Time course of efficacy of atogepant for the preventive treatment of migraine: results from the randomized, double-blind ADVANCE trial. Cephalalgia. (2022) 42:3–11. doi: 10.1177/03331024211042385

PubMed Abstract | Crossref Full Text | Google Scholar

21. Ashtari, F, Shaygannejad, V, and Akbari, M. A double-blind, randomized trial of low-dose topiramate vs propranolol in migraine prophylaxis. Acta Neurol Scand. (2008) 118:301–5. doi: 10.1111/j.1600-0404.2008.01087.x

PubMed Abstract | Crossref Full Text | Google Scholar

22. Freitag, FG, Collins, SD, Carlson, HA, Goldstein, J, Saper, J, Silberstein, S, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. (2002) 58:1652–9. doi: 10.1212/WNL.58.11.1652

PubMed Abstract | Crossref Full Text | Google Scholar

23. Silberstein, S, Saper, J, Berenson, F, Somogyi, M, McCague, K, and D'Souza, J. Oxcarbazepine in migraine headache: a double-blind, randomized, placebo-controlled study. Neurology. (2008) 70:548–55. doi: 10.1212/01.wnl.0000297551.27191.70

PubMed Abstract | Crossref Full Text | Google Scholar

24. Storey, JR, Calder, CS, Hart, DE, and Potter, DL. Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache. (2001) 41:968–75. doi: 10.1046/j.1526-4610.2001.01190.x

PubMed Abstract | Crossref Full Text | Google Scholar

25. Pradalier, A, Serratrice, G, Collard, M, Hirsch, E, Feve, J, Masson, M, et al. Long-acting propranolol in migraine prophylaxis: results of a double-blind, placebo-controlled study. Cephalalgia. (1989) 9:247–53. doi: 10.1046/j.1468-2982.1989.904247.x

PubMed Abstract | Crossref Full Text | Google Scholar

26. Millán-Guerrero, RO, Isais-Millán, R, Guzmán-Chávez, B, and Castillo-Varela, G. N alpha methyl histamine versus propranolol in migraine prophylaxis. Can J Neurol Sci. (2014) 41:233–8. doi: 10.1017/s0317167100016632

PubMed Abstract | Crossref Full Text | Google Scholar

27. Steiner, TJ, Joseph, R, Hedman, C, and Rose, FC. Metoprolol in the prophylaxis of migraine: parallel-groups comparison with placebo and dose-ranging follow-up. Headache. (1988) 28:15–23. doi: 10.1111/j.1365-2524.1988.hed2801015.x

PubMed Abstract | Crossref Full Text | Google Scholar

28. Kangasniemi, P, Andersen, AR, Andersson, PG, Gilhus, NE, Hedman, C, Hultgren, M, et al. Classic migraine: effective prophylaxis with metoprolol. Cephalalgia. (1987) 7:231–8. doi: 10.1046/j.1468-2982.1987.0704231.x

PubMed Abstract | Crossref Full Text | Google Scholar

29. Olsson, JE, Behring, HC, Forssman, B, Hedman, C, Hedman, G, Johansson, F, et al. Metoprolol and propranolol in migraine prophylaxis: a double-blind multicentre study. Acta Neurol Scand. (1984) 70:160–8. doi: 10.1111/j.1600-0404.1984.tb00815.x

PubMed Abstract | Crossref Full Text | Google Scholar

30. Schellenberg, R, Lichtenthal, A, Wöhling, H, Graf, C, and Brixius, K. Nebivolol and metoprolol for treating migraine: an advance on beta-blocker treatment? Headache. (2008) 48:118–25. doi: 10.1111/j.1526-4610.2007.00785.x

PubMed Abstract | Crossref Full Text | Google Scholar

31. Stovner, LJ, Linde, M, Gravdahl, GB, Tronvik, E, Aamodt, AH, Sand, T, et al. A comparative study of candesartan versus propranolol for migraine prophylaxis: a randomised, triple-blind, placebo-controlled, double cross-over study. Cephalalgia. (2014) 34:523–32. doi: 10.1177/0333102413515348

PubMed Abstract | Crossref Full Text | Google Scholar

32. Kalita, J, Bhoi, SK, and Misra, UK. Amitriptyline vs divalproate in migraine prophylaxis: a randomized controlled trial. Acta Neurol Scand. (2013) 128:65–72. doi: 10.1111/ane.12081

PubMed Abstract | Crossref Full Text | Google Scholar

33. Lampl, C, Huber, G, Adl, J, Luthringshausen, G, Franz, G, Marecek, S, et al. Two different doses of amitriptyline ER in the prophylaxis of migraine: long-term results and predictive factors. Eur J Neurol. (2009) 16:943–8. doi: 10.1111/j.1468-1331.2009.02631.x

PubMed Abstract | Crossref Full Text | Google Scholar

34. Ozyalcin, SN, Talu, GK, Kiziltan, E, Yucel, B, Ertas, M, and Disci, R. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache. (2005) 45:144–52. doi: 10.1111/j.1526-4610.2005.05029.x

PubMed Abstract | Crossref Full Text | Google Scholar

35. Tarlaci, S. Escitalopram and venlafaxine for the prophylaxis of migraine headache without mood disorders. Clin Neuropharmacol. (2009) 32:254–8. doi: 10.1097/WNF.0b013e3181a8c84f

PubMed Abstract | Crossref Full Text | Google Scholar

36. Bulut, S, Berilgen, MS, Baran, A, Tekatas, A, Atmaca, M, and Mungen, B. Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg. (2004) 107:44–8. doi: 10.1016/j.clineuro.2004.03.004

PubMed Abstract | Crossref Full Text | Google Scholar

37. Alstadhaug, KB, Odeh, F, Salvesen, R, and Bekkelund, SI. Prophylaxis of migraine with melatonin: a randomized controlled trial. Neurology. (2010) 75:1527–32. doi: 10.1212/WNL.0b013e3181f9618c

PubMed Abstract | Crossref Full Text | Google Scholar

38. Goldstein, DJ, Offen, WW, Klein, EG, Phebus, LA, Hipskind, P, Johnson, KW, et al. Lanepitant, an NK-1 antagonist, in migraine prevention. Cephalalgia. (2001) 21:102–6. doi: 10.1046/j.1468-2982.2001.00161.x

PubMed Abstract | Crossref Full Text | Google Scholar

39. Benseñor, IM, Cook, NR, Lee, IM, Chown, MJ, Hennekens, CH, and Buring, JE. Low-dose aspirin for migraine prophylaxis in women. Cephalalgia. (2001) 21:175–83. doi: 10.1046/j.0333-1024.2001.00194.x

PubMed Abstract | Crossref Full Text | Google Scholar

40. Noruzzadeh, R, Modabbernia, A, Aghamollaii, V, Ghaffarpour, M, Harirchian, MH, Salahi, S, et al. Memantine for prophylactic treatment of migraine without aura: a randomized double-blind placebo-controlled study. Headache. (2016) 56:95–103. doi: 10.1111/head.12732

PubMed Abstract | Crossref Full Text | Google Scholar

41. Liu, Y, Dong, Z, Wang, R, Ao, R, Han, X, Tang, W, et al. Migraine prevention using different frequencies of transcutaneous occipital nerve stimulation: a randomized controlled trial. J Pain. (2017) 18:1006–15. doi: 10.1016/j.jpain.2017.03.012

PubMed Abstract | Crossref Full Text | Google Scholar

42. Wilkinson, D, Ade, KK, Rogers, LL, Attix, DK, Kuchibhatla, M, Slade, MD, et al. Preventing episodic migraine with caloric vestibular stimulation: a randomized controlled trial. Headache. (2017) 57:1065–87. doi: 10.1111/head.13120

PubMed Abstract | Crossref Full Text | Google Scholar

43. Alecrim-Andrade, J, Maciel-Júnior, JA, Cladellas, XC, Correa-Filho, HR, and Machado, HC. Acupuncture in migraine prophylaxis: a randomized sham-controlled trial. Cephalalgia. (2006) 26:520–9. doi: 10.1111/j.1468-2982.2006.01062.x

PubMed Abstract | Crossref Full Text | Google Scholar

44. Pfaffenrath, V, Diener, HC, Fischer, M, Friede, M, and von Henneicke- Zepelin, HHInvestigators. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis--a double-blind, multicentre, randomized placebo-controlled dose-response study. Cephalalgia. (2002) 22:523–32. doi: 10.1046/j.1468-2982.2002.00396.x

PubMed Abstract | Crossref Full Text | Google Scholar

45. Martins, LB, Rodrigues, AMDS, Monteze, NM, Tibaes, JRB, Amaral, MHA, Gomez, RS, et al. Double-blind placebo-controlled randomized clinical trial of ginger (Zingiber officinale Rosc.) in the prophylactic treatment of migraine. Cephalalgia. (2020) 40:88–95. doi: 10.1177/0333102419869319

PubMed Abstract | Crossref Full Text | Google Scholar

46. Ahmadifard, M, Yarahmadi, S, Ardalan, A, Ebrahimzadeh, F, Bahrami, P, and Sheikhi, E. The efficacy of topical basil essential oil on relieving migraine headaches: a randomized triple-blind study. Complement Med Res. (2020) 27:310–8. doi: 10.1159/000506349

PubMed Abstract | Crossref Full Text | Google Scholar

47. Keskinbora, K, and Aydinli, I. A double-blind randomized controlled trial of topiramate and amitriptyline either alone or in combination for the prevention of migraine. Clin Neurol Neurosurg. (2008) 110:979–84. doi: 10.1016/j.clineuro.2008.05.025

PubMed Abstract | Crossref Full Text | Google Scholar

48. Luo, N, Di, W, Zhang, A, Wang, Y, Ding, M, Qi, W, et al. A randomized, one-year clinical trial comparing the efficacy of topiramate, flunarizine, and a combination of flunarizine and topiramate in migraine prophylaxis. Pain Med. (2012) 13:80–6. doi: 10.1111/j.1526-4637.2011.01295.x

PubMed Abstract | Crossref Full Text | Google Scholar

49. Krymchantowski, AV, da Cunha Jevoux, C, and Bigal, ME. Topiramate plus nortriptyline in the preventive treatment of migraine: a controlled study for nonresponders. J Headache Pain. (2012) 13:53–9. doi: 10.1007/s10194-011-0395-4

PubMed Abstract | Crossref Full Text | Google Scholar

50. Domingues, RB, Silva, AL, Domingues, SA, Aquino, CC, and Kuster, GW. A double-blind randomized controlled trial of low doses of propranolol, nortriptyline, and the combination of propranolol and nortriptyline for the preventive treatment of migraine. Arq Neuropsiquiatr. (2009) 67:973–7. doi: 10.1590/s0004-282x2009000600002

PubMed Abstract | Crossref Full Text | Google Scholar

51. Soni, P, and Chawla, E. Efficacy and safety of anti-calcitonin gene-related peptide monoclonal antibodies for treatment of chronic migraine: a systematic review and network meta-analysis. Clin Neurol Neurosurg. (2021) 209:106893. doi: 10.1016/j.clineuro.2021.106893

PubMed Abstract | Crossref Full Text | Google Scholar

52. Silvestro, M, Orologio, I, Siciliano, M, Trojsi, F, Tessitore, A, Tedeschi, G, et al. Emerging drugs for the preventive treatment of migraine: a review of CGRP monoclonal antibodies and gepants trials. Expert Opin Emerg Drugs. (2023) 28:79–96. doi: 10.1080/14728214.2023.2207819

PubMed Abstract | Crossref Full Text | Google Scholar

53. Rushendran, R, and Vellapandian, C. Advances in migraine treatment: a comprehensive clinical review. Curr Protein Pept Sci. (2025) 26:422–35. doi: 10.2174/0113892037329429241123095325

PubMed Abstract | Crossref Full Text | Google Scholar

54. Chowdhury, D, Bansal, L, Duggal, A, Datta, D, Mundra, A, Krishnan, A, et al. TOP-PRO study: a randomized double-blind controlled trial of topiramate versus propranolol for prevention of chronic migraine. Cephalalgia. (2022) 42:396–408. doi: 10.1177/03331024211047454

PubMed Abstract | Crossref Full Text | Google Scholar

55. Alex, A, and Armand, CE. Rational polypharmacy for migraine. Pract Neurol. (2022):30–4

Google Scholar

56. Han, X, and Yu, S. Non-pharmacological treatment for chronic migraine. Curr Pain Headache Rep. (2023) 27:663–72. doi: 10.1007/s11916-023-01162-x

PubMed Abstract | Crossref Full Text | Google Scholar

57. Nejadghaderi, SA, Balibegloo, M, and Rezaei, N. The Cochrane risk of bias assessment tool 2 (RoB 2) versus the original RoB: a perspective on the pros and cons. Health Sci Rep. (2024) 7:e2165. doi: 10.1002/hsr2.2165

PubMed Abstract | Crossref Full Text | Google Scholar

58. Cho, L, Vest, AR, O’Donoghue, ML, Ogunniyi, MO, Sarma, AA, Denby, KJ, et al. Increasing participation of women in cardiovascular trials: JACC council perspectives. J Am Coll Cardiol. (2021) 78:737–51. doi: 10.1016/j.jacc.2021.06.022

Crossref Full Text | Google Scholar