Efficacy of prophylactic sodium valproate in pediatric migraines: a systematic review of randomized clinical studies

Introduction

Migraine is a prevalent neurological issue that is frequently encountered in primary healthcare. Recent data from the Global Burden Disease study reveal that migraine remains the second most common cause of disability globally and is the primary cause among young women (1). Migraine is a common disorder that affects approximately 18% of women and 6% of men. Chronic migraine, a more severe form of the condition, affects around 2% of the worldwide population. This condition is associated with a significant burden for patients, their families, and society (2).

Migraine is a neurological disorder that is chronic and presents with episodes of paroxysmal features consisting of multiphase attacks of head pain, along with other symptoms related to neurological dysfunction such as sensitivity to movement, photophobia, phonophobia, nausea, and vomiting. The migraine attack is divided into three distinct phases: the premonitory (prodrome) phase, the headache phase, and the postdrome phase, each with unique and often disabling symptoms. Additionally, about 20–25% of individuals with migraine experience a fourth phase known as aura (3).

Migraine is a prevalent condition in the pediatric population, with an estimated overall prevalence of 7.7% (4). The incidence of migraine increases during childhood and adolescence, with rates ranging from 5% among children aged 5 to 10 years to approximately 15% among teenagers (5). Chronic migraine, which is defined as experiencing headaches at least 15 days per month, affects 0.8% to 1.8% of children aged 12 to 17 years (5,6). While both boys and girls are equally affected by migraine in childhood and early adolescence, the prevalence of migraine is higher in girls during late adolescence, with a ratio similar to that seen in adults (4). Migraine can cause significant disability in children and adolescents, leading to school absenteeism, impaired academic performance, and missed extracurricular activities (7).

Primary headaches are diagnosed based on the International Classification of Headache Disorders, 3rd edition (ICHD-3) diagnostic criteria (8). While migraines in adults typically last between 4 to 72 hours, pediatric patients may experience shorter attacks lasting as little as 2 hours (8,9). In contrast to the unilateral location of migraine in adults, more than 80% of children and adolescents with migraine experience bilateral symptoms (9). With the availability of more migraine-specific therapeutic interventions for children, recognizing and diagnosing migraine is becoming increasingly important. For most children, acute migraine treatments, along with behavioral and lifestyle modifications, are effective for preventing headaches and do not necessitate further pharmacologic or biobehavioral preventive treatment (10). However, when headaches occur frequently and with significant severity, resulting in disability related to migraine, additional prevention strategies may be considered.

In the United States, the only Food and Drug Administration (FDA) approved medications for the preventive treatment of migraine are valproate semisodium, topiramate, propranolol, and timolol (11). Sodium valproate is an FDA-approved antiseizure drug used for the prevention of migraine (12). The antimigraine action of sodium valproate in patients has been attributed to various functions. Still, its exact mechanism is not yet fully understood due to the complex nature of migraine pathophysiology and the multiple biochemical effects of the drug migraines (13-15). However, the FDA has not yet approved sodium valproate for pediatric migraines. Therefore, this systematic review aims to assess the efficacy of sodium valproate as a prophylaxis treatment for pediatric migraines. We present this article in accordance with the PRISMA reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-279/rc) (16).

Methods

Protocol and registry

The protocol of this study was registered with PROSPERO (CRD42023454491). However, a meta-analysis was not performed due to high heterogeneity in the included studies. An electronic search was conducted of indexed databases PubMed, Embase, Scopus, Web of Science, and Cochrane without time restriction up to May 2024. Two authors screened the titles and abstracts of studies identified with the abovementioned protocol, and the full texts of relevant studies were read independently. The reference lists of pertinent original studies and review articles were also hand-searched to identify studies that might have been missed in the previous step. Disagreements were resolved through discussion and consultation with a third researcher.

Eligibility criteria

The current systematic review incorporated randomized controlled clinical trials that compared the effectiveness of sodium valproate as a prophylactic treatment for pediatric migraine with other commonly used migraine prophylactic medications. The primary research question aimed to determine the efficacy of sodium valproate as a preventive treatment for pediatric migraine compared to other frequently used drugs for pediatric migraine prevention. This comparison was based on the following Participants-Interventions-Comparisons-Outcome-Study design (PICOS) approach. (P): pediatric and adolescent patients with migraine; (I): sodium valproate; (C): other migraine prophylactic medications; (O): migraine prophylaxis parameters: migraine frequency, intensity, duration, complete cessation of attacks, Pediatric Migraine Disability Assessment (PedMIDAS); (S): randomized controlled clinical trials. The current study excluded case reports, case series, letters to the editor, commentaries, reviews, retrospective, experimental, non-randomized, and cross-sectional studies.

Study selection, data collection, and risk of bias (RoB)

The articles underwent independent review by two investigators (G.A. and O.A.), who screened the titles and abstracts of the identified studies. Any irrelevant articles, duplicates, or studies not addressing the focused question were excluded. In cases of disagreement, the reviewers resolved the issues through mutual discussion. If a consensus could not be reached through discussion, a third reviewer (M.A.) and a fourth reviewer (J.K.) were engaged to provide input. All the information from the included studies was synthesized by tabulating the data according to (I) study design; (II) migraine classification, frequency, intensity, duration, and PedMIDAS score; (III) sodium valproate and control medication dosages, frequency, and route of administration; (IV) duration and interval of the follow-up treatment; and (V) study outcomes of the efficacy of sodium valproate versus other medications on pediatric patients with migraine. Furthermore, a quality assessment was carried out. Two authors (G.A. and O.A.) assessed the RoB in the included studies using the Cochrane Collaboration’s RoB tool for randomized controlled trials (RCTs) (17). Any disagreements in the RoB assessment were addressed as stated previously.

Results

Search strategy

An electronic search was performed without time restrictions up to and including May 2024. Search database engines, including PubMed, Embase, Web of Science, and Cochrane, revealed 984 articles. After removing duplicates, 478 studies were left. Additionally, three articles were identified through manual searching of the references in relevant articles and were added for further screening. Following the review of titles and abstracts, 43 articles underwent a comprehensive full-text assessment for eligibility, excluding 38 articles. The current systematic review included five RCTs (Figure 1).

Figure 1 PRISMA flow chart.

General characteristics of included studies

Four RCTs followed a parallel group design (18-21). They consisted of an intervention group receiving sodium valproate and a control group receiving other medications commonly used for pediatric migraine prevention. Among the four RCTs with a parallel group design, three had their control group using propranolol (18-20), while one RCT had its control group utilizing topiramate (21). The fifth RCT (22) included in this systematic review adopted a parallel group design with three groups in a 1:1:1 ratio (22). The intervention group received sodium valproate, and the two control groups received cinnarizine and placebo, respectively.

The included RCTs had a participant range of 63 to 158, and the mean ages of the participants ranged from 5 to 16 years. Both male and female patients were included in all the RCTs. Variability was observed among the included RCTs concerning the allowance of rescue medications during the study period. In this systematic review, two randomized controlled RCTs provided information on the rescue medications permitted for patients (21,22). In contrast, three RCTs did not specify whether patients could use rescue medications during the study (18-20). The studies’ duration ranged from 6 weeks to 4 months, as reported in all RCTs (18-22) (Table 1).

General characteristics of sodium valproate

Among the five RCTs, four specifically enrolled patients diagnosed with pediatric migraine without aura (18-21). However, in one of the randomized RCTs, the patient cohort consisted of individuals diagnosed with pediatric migraine, encompassing both those with and without aura (22). Four of the five RCTs in the review provided data on migraine frequency and standard deviation before treatment (18,20-22). At the same time, one RCT did not report this information (19). Regarding migraine intensity, two RCTs reported it (21,22), while the remaining three RCTs did not include this data. Additionally, only one RCT presented the duration of migraine attacks along with the standard deviation and the PedMIDAS score (21). The medications were administered orally in this systematic review’s RCTs (18-22). Moreover, all RCTs provided information on the dosage of the drugs; however, there were variations in the dosages among the studies. Amanat et al. administered sodium valproate at 15 mg/kg/day, divided equally into two daily doses (22). For patients aged between 6 and 12 years, cinnarizine was given at a daily dose of 37.5 mg divided into two equal doses per day. For patients between 12 and 17 years, the daily dose of cinnarizine was 50 mg, similarly administered in two equally divided daily doses. Gajbhiye et al. (20) and Ashrafi et al. (18) employed comparable dosages in their studies for sodium valproate, starting at 10 mg/kg/day and gradually escalating to 40 mg/kg/day (18,20). The administration was divided into two equally divided doses per day. Moreover, both studies employed propranolol in the control group, with a dosage range of 1–3 mg/kg/day, also given in two equally divided daily doses. On the other hand, Yadav et al. employed a dosage range of 10–20 mg/kg/day for sodium valproate and 1–2 mg/kg/day for topiramate (21). However, the frequency of medication administration was not specified in their study. Bidabadi et al. administered sodium valproate at a dosage of 15 mg/kg/day and propranolol at a dosage of 2 mg/kg/day in children weighing less than 35 kg, with both medications given in two equally divided doses per day (19) (Table 2).

General characteristics of outcome variables

All RCTs in this study used assessments by patients’ parents to evaluate the outcomes. The RCTs had variations in the specific aspects they measured. In all the included RCTs, migraine frequency was evaluated as one of the parameters (18-22). Among these RCTs, four also measured migraine duration (18-21). Three RCTs (18-20) assessed migraine severity (18-20). Amanat et al. (22) and Yadav et al. (21) examined migraine intensity and the rate of patients who experienced a 50% reduction in symptoms using the PedMIDAS score. Additionally, Bidabadi et al. evaluated complete cessation of migraine attacks (19), while Ashrafi et al. reported the response to rescue medication (18).

The included RCTs displayed variation in the timing of their follow-up intervals. In Amanat et al.’s study, patients were monitored 1, 4, 8, and 12 weeks after receiving the medication (22). Yadav et al. conducted follow-ups at 4-, 8-, and 12-week marks after medication administration (21). Bidabadi et al. conducted monthly follow-ups for 4 months post-medication (19). Ashrafi et al. performed two follow-ups, one at 4 weeks and another at 3 months post-medication (18). However, Gajbhiye et al. did not specify the intervals they used for following up with patients to evaluate outcome measures (20). Only three of the RCTs included provided information about the rate at which patients discontinued their participation in the studies, specifically Amanat et al. (22) recorded a dropout rate of 5% (22), Bidabadi et al. noted a dropout rate of 4.7% (19), and Ashrafi et al. observed a dropout rate of 4.1% (18). However, Yadav et al. and Gajbhiye et al. did not present data on patient dropout rates in their respective studies (20,21).

All the RCTs consistently reported that there were no statistically significant differences in the effectiveness of sodium valproate as a prophylactic treatment for pediatric migraine compared to other medications. Amanat et al. reported no notable statistical distinction between sodium valproate and cinnarizine when employed as prophylaxis for pediatric migraine (22). They concluded sodium valproate might be an effective preventive measure for migraine in children and adolescents. Similarly, Yadav et al. found no significant difference in efficacy between sodium valproate and topiramate as prophylactic treatments for pediatric migraine (21). They concluded that sodium valproate effectively prevents migraine headaches in this age group. Gajbhiye et al., did not provide specific p-values or detailed statistical analyses for migraine severity and duration (20). Still, they did report no statistically significant difference in migraine frequency between sodium valproate and propranolol for pediatric migraine prevention. They concluded sodium valproate exhibited greater efficacy and safety in migraine prevention than propranolol. Bidabadi et al. reported no statistically significant difference between sodium valproate and propranolol in terms of their effectiveness for pediatric migraine prevention according to IHS criteria (19). Lastly, Ashrafi et al. reported sodium valproate and propranolol significantly improved headache frequency, severity, duration, and response to rescue medication (18). They concluded that there were no statistically significant differences between the two treatments. All these RCTs collectively suggest that sodium valproate holds promise as an effective prophylactic treatment for pediatric migraine, with no significant differences observed compared to other commonly used medications (18-22) (Table 3).

RoB within studies

Among the five RCTs incorporated into this study, two of them exhibited a generally low RoB (19,22). In contrast, the remaining RCTs (18,20,21) demonstrated a high risk for bias (18,20,21) (Table 4, Figures 2,3).

Figure 2 RoB of included studies. RoB, risk of bias.

Figure 3 Traffic plot (RoB). RoB, risk of bias.

Discussion

On a global scale, migraine is the second leading contributor to the loss of disability-adjusted life-years (DALYs) due to neurological conditions, accounting for 16.3% of the DALYs attributed to such disorders (23). The prevalence of migraine, standardized for age on a global level, saw an increase of 1.7% (ranging from 0.7% to 2.8%) between 1990 and 2019. In 2019, there were an estimated 1.1 billion prevalent cases of migraine (with a range of 0.98 to 1.3 billion) and a calculated 525.5 years lived with disability (YLDs) per 100,000 population (24). In the United States, individuals afflicted by migraine bore a significantly more significant economic burden compared to those without the condition (25). Among both males and females, the age bracket of 10 to 14 years witnessed the highest occurrence rate and the most significant count of newly occurring cases of migraine (24). In the year 2019, although the count of YLDs began to rise from birth, it reached its highest point within the 30 to 34 years age categories, subsequently showing a gradual decrease for both genders (24). In the context of pharmacotherapy, the available treatment choices for children and adolescents have primarily relied on findings from studies conducted on adults. Out of the antiseizure medications, only sodium valproate and topiramate have received approval from the FDA for preventing adult migraine. More recently, topiramate gained approval for pediatric migraine, whereas sodium valproate did not. Nevertheless, the off-label utilization of these drugs for pediatric migraine is widespread (26).

Earlier research assessing the effectiveness of sodium valproate in migraine treatment has shown encouraging outcomes, although these studies have predominantly centered on adult patients rather than pediatric or adolescent populations. Hering and Kuritzky reported sodium valproate effectively prevented migraine or reduced their frequency, severity, and duration in 86.2% of patients during 8 weeks (27). Mathew et al. reported that 48% of individuals treated with divalproex experienced a 50% or more reduction in migraine frequency compared to their baseline over a 12-week duration (28). Furthermore, Shaygannejad et al. indicated treatment with sodium valproate significantly reduced migraine duration, monthly frequency, and intensity after 8 weeks (29). Takeshima et al. reported that the efficacy of sodium valproate was measured at 59.7% 2 months after the commencement of treatment (30).

All RCTs in this review have concluded that sodium valproate is an effective preventive treatment for pediatric migraine (18-22). Nevertheless, there exists a disparity in the criteria employed to evaluate sodium valproate’s effectiveness. Due to the participants’ age range, spanning from 5 to 16 years, the parents reported a subjective assessment of study outcome parameters. Furthermore, variability was observed in the dosage and frequency of sodium valproate administration. This is due to the absence of a definitive consensus on the most effective dosage. Gajbhiye et al. (20) and Ashrafi et al. (18) initiated sodium valproate at 10 mg/kg/day and gradually increased it to 40 mg/kg/day (18,20). Conversely, Amanat et al. (22) and Bidabadi et al. (19) reported utilizing a 15 mg/kg/day dosage, while Yadav et al. (21) adopted a dosage of 10 mg/kg/day. Amanat et al. included patients diagnosed with pediatric migraine, with and without aura (22), whereas the remaining RCTs enrolled patients diagnosed with pediatric migraine without aura (18-21). There were slight variations in the study duration, which was relatively short for an adequate evaluation of migraine prophylactic treatments, ranging from 6 weeks to 4 months—notably, only Amanat et al. provided details about the types of rescue medications allowed during the study and reported the number of patients who utilized such rescue medications (22). The remaining RCTs did not disclose whether rescue medications were permitted during their studies or specify the type and frequency of such medications (18-21). This absence of information could potentially introduce bias when assessing the efficacy of sodium valproate as a prophylactic treatment for pediatric migraine.

Yurekli et al. investigated the effectiveness of sodium valproate in managing daily headaches; they identified common adverse effects such as drowsiness, tremors, impotence, and hair loss (31). Amanat et al. reported that sodium valproate was linked to adverse events like sedation, nausea/vomiting, anorexia, and dizziness (22). In the study by Yadav et al. mild tiredness, weight gain, and abdominal pain were reported as side effects associated with sodium valproate (21). Bidabadi et al. reported abdominal pain, slight drowsiness, and minor weight gain as possible side effects (19). However, Gajbhiye et al. and Ashrafi et al. did not provide information about the associated side effects of sodium valproate (18,20).

In children and adolescents, primary headache disorders, mainly migraine, have been reported to be associated with several comorbid conditions that include psychiatric and neurological comorbidities (32). Literature reports have revealed the association of an emotional component with headache, a bidirectional relationship between psychological comorbidities and migraine, and these psychological factors have a contributory role in headache persistence or reactivity (33). Studies have found an increased risk of anxiety disorder in children and adolescents with migraine, and anxiety could predict the persistence of migraine and headache-related disability (32,33). Pastorino et al., in a cross-sectional observational study, reported the bidirectional link between migraine and epilepsy in children, as both these conditions share common substrates, such as alterations in neuronal transmission or genetic basis, and have similar triggers comprising sleep deprivation, stress, and bright flashing lights. The prevalence of depressive symptoms was observed to be higher in pediatric patients with comorbid headache and epilepsy compared to epilepsy alone (33). Furthermore, there is evidence that sleep deprivation in children could result in the onset of headache and nocturnal migraine attacks (32). Therefore, it is essential to recognize the presence of comorbid conditions in children with of migraines to develop more effective treatment strategies. In addition, it could contribute to better treatment outcomes and improve the patient’s overall well-being and quality of life. However, the relationship between migraine, depression, epilepsy, and other comorbid conditions, such as sleep disorders in the pediatric population, needs to be further investigated.

This study has certain limitations. The findings are derived from a limited number of clinical trials (five RCTs), each with a relatively small sample size ranging from 63 to 158 patients. This limited scope reduces the applicability of the study’s outcomes to a broader population. Furthermore, only two RCTs within this study were assessed as having a low RoB (19,22), while the other three RCTs were identified as having a high RoB (18,20,21). The primary sources of bias stemmed from inadequate reporting related to participant randomization across different study groups, the concealment of allocation to various study groups, lack of blinding in outcome assessment, and selective reporting of outcome results. The heightened RoB across the included RCTs makes it challenging to place complete confidence in the conclusions drawn from this systematic review. Lastly, all the RCTs incorporated participants diagnosed with pediatric migraine without an aura, except for the study conducted by Amanat et al., which included patients with pediatric migraine both with and without an aura, introducing heterogeneity in this systematic review.

Conclusions

Based on the findings derived from the RCTs included in this study, it can be concluded that sodium valproate may serve as an effective prophylactic measure for treating pediatric migraine. Notably, no significant differences were identified compared to other frequently employed medications. Sodium valproate was shown to significantly enhance various migraine-related aspects, including frequency, intensity, severity, duration, and response to rescue medication. It is essential for future research to incorporate improved methodological standards and ensure uniform treatments in RCTs. This will enable a comprehensive assessment of the effectiveness of sodium valproate in comparison to other commonly prescribed medications for migraine prophylaxis in pediatric patients. Furthermore, future studies should adhere to a consistent protocol framework and implement blinding techniques across outcome evaluation, participants, and researchers. These measures are crucial in reducing potential biases.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-279/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-279/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-279/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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