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Abstract

Background

Few migraine preventive agents have been assessed in a pediatric population. We evaluated the safety and efficacy of cinnarizine and sodium valproate for migraine prophylaxis in children and adolescents.

Methods

We carried out a randomized double-blind placebo-controlled trial in the Children’s Medical Center and Sina hospital, Tehran, Iran. Eligible participants were randomly assigned in 1:1:1 ratio via interactive web response system to receive either cinnarizine, sodium valproate, or placebo. The primary endpoints were the mean change in frequency and intensity of migraine attacks from baseline to the last 4 weeks of trial. The secondary endpoint was the efficacy of each drug in the prevention of migraine. The drug was considered effective if it decreased migraine frequency by more than 50% in the double-blind phase compared with the baseline. Safety endpoint was adverse effects that were reported by children or their parents.

Results

A total of 158 children participated. The frequency of migraine attacks significantly reduced compared to baseline in cinnarizine (difference: −8.0; 95% confidence interval (CI): −9.3 to −6.6), sodium valproate (difference: −8.3; 95% confidence interval: −9.3 to −7.2), and placebo (difference: −4.4; 95% confidence interval: −5.4 to −3.4) arms. The decrease was statistically greater in cinnarizine (difference: −3.6; 95% confidence interval: −5.5 to −1.6) and sodium valproate (difference: −3.9; 95% confidence interval: −5.8 to −1.9) arms, compared to placebo group. Children in all groups had significant reduction in intensity of episodes compared to baseline (cinnarizine: −4.6; 95% confidence interval: −5.2 to −4.0; sodium valproate: −4.0; 95% confidence interval: −4.8 to −3.3; placebo: −2.6; 95% confidence interval: −3.4 to −1.8). The decrease was statistically greater in cinnarizine (difference: −2.0; 95% confidence interval: −3.2 to −0.8) and sodium valproate (difference: −1.5; 95% confidence interval: −2.7 to −0.3) arms, compared to the placebo group. Seventy-one percent of individuals in the cinnarizine group, 66% of cases in the sodium valproate group, and 42% of people in the placebo arm reported more than 50% reduction in episodes at the end of the trial. The odds ratio for >50% responder rate was 3.5 (98.3% confidence interval: 1.3 to 9.3) for cinnarizine versus placebo and 2.7 (98.3% confidence interval: 1.0 to 6.9) for sodium valproate versus placebo. Nine individuals reported adverse effects (three in cinnarizine, five in sodium valproate, and one in the placebo group) and one case in the sodium valproate group discontinued the therapy due to severe sedation.

Conclusion

Cinnarizine and sodium valproate could be useful in migraine prophylaxis in children and adolescents.

Trial registration: IRCT201206306907N4.

Keywords

Calcium channel blocker anti-seizure medication headache children

Introduction

Migraine is prevalent among children and adolescents, affecting about 8% of this population (1). Migraine has an important adverse impact on the child and the family. About half of pediatric population with migraine continue to experience it into adulthood (2,3), leading to remarkable disability and a substantial social and financial burden to the patient and society. Early diagnosis and interventions, therefore, can mitigate the burden of the condition.

The prevention of disease-related disability is the ultimate goal of successful migraine treatment. To prevent analgesic overuse and to help children to continue their normal daily activity, preventive pharmacologic treatment should be administered when the frequency of headaches exceeds four episodes per 4 weeks or when the quality of life, school attendance or daily activities are restricted (4,5). Preventive drugs can also be considered if frequent, long, or uncomfortable auras occur (6). It was shown that migraine prophylaxis has the potential to decrease the global burden of migraine on individuals and society (7). Although various preventive medications have been used for adult migraine, few have been suggested for pediatric migraine. Currently, topiramate is the only FDA-approved preventive agent for migraine in children aged 12–17 years old. A recent phase 3, multicenter, double-blind, placebo-controlled trial, however, suggested that topiramate was not different from placebo in the reduction of events in children and adolescents (8).

Calcium channel blockers such as flunarizine are considered as safe and effective medications in migraine prophylaxis of adults (9,10). Cinnarizine is an L-type calcium antagonist that may be useful in migraine prophylaxis. Anti-seizure medications (ASMs) have been tested for migraine prevention since 1970, with carbamazepine as the first drug of this group (11). The efficacy of sodium valproate in migraine prophylaxis was further described in 1988 (12). Few studies have investigated the safety and efficacy of the above-mentioned medications in the prevention of pediatric migraine. Herein, we aimed to assess the efficacy and tolerability of cinnarizine and sodium valproate in the prevention of migraine in a pediatric population. We hypothesized that cinnarizine and sodium valproate could significantly reduce the frequency and intensity of migraine attacks compared to placebo (superiority).

Methods

Study design

A randomized double-blind placebo-controlled trial was conducted in the Childrens’ Medical Center and Sina Hospital, two major Tehran referral hospitals. The study was divided into three phases: 1) initial screening phase (2 weeks); 2) baseline phase (4 weeks); and 3) double-blind treatment phase (12 weeks). Migraine preventive agents were prohibited during the study and 8 weeks before the start of the baseline phase (Supplemental material, p.1).

Inclusion and exclusion criteria

Males and females aged 6–17 years were eligible to enter the study if they fulfilled the criteria, which included: a) Diagnostic criteria for pediatric migraine (with or without aura) defined by the International Headache Society (IHS) (13); b) having had at least four headaches per 28 days or severe disabling or intolerable headache. Patients were excluded from the study if they had at least one of the following: a) a history of cluster headache, hemiplegic migraine, or chronic daily headaches; b) headaches related to structural brain lesions; c) focal neurologic deficit; d) no therapeutic response after adequate use of three preventive agents of migraine; e) a history of sensitivity (mild to severe) to cinnarizine or sodium valproate; f) pregnancy; g) systemic co-morbidity, including hepatic or cardiovascular diseases.

The trial was conducted according to the original protocol (presented in the Supplemental material, pp.6–8). The ethics committee of the Tehran University of Medical Sciences approved the final protocol of the study (Number: 35461). The method was explained to all parents and children. Written informed consent was obtained from the parents of all participants. The study was registered with the Iranian Registry of Clinical Trials, IRCT.ir, number: IRCT201206306907N4.

Randomization and blinding

Eligible outpatients were randomly assigned in a 1:1:1 ratio via an interactive web response system to receive either cinnarizine, sodium valproate, or placebo. The responsible statistician was not aware of the clinical data of participants. The study medications were coded and administered by a nurse from our medical center who was not informed about the clinical characteristics of cases. Investigators, study personnel, participants, and their parents were all masked during the course of the study until the code was broken at the end of the trial or if a serious complication occurred during the study period. Cinnarizine, sodium valproate, and placebo were provided as identical tablets regarding color (white), shape (round), and size (9 mm) in neutral containers.

Procedures

Phase 1 and 2

All children had full physical and neurological examinations. Screening in all individuals included blood count (hemoglobin, white blood cells, and platelets), serum chemistry, and electrocardiography. Neuroimaging and urine pregnancy test were performed if clinically indicated (phase 1). After providing a headache diary for each individual, the parent who had greater contact with the participant was responsible for recording events in the diary. We asked each responsible parent to fill the diary every day and not retrospectively. A simple form of migraine diagnostic criteria (including criteria B-D) (13) translated into the Farsi language was also provided and explained to the responsible parent so that only migraineous episodes were reported. Parents entered the migraine characteristics, including attack frequency and severity, in the headache diary 4 weeks before the initiation of treatment (phase 2).

Phase 3

The given dosage of cinnarizine and sodium valproate was based on the age and weight of participants. This was 37.5 mg/day cinnarizine in children aged 6–12 years and 50 mg/day in children aged 12–17 years, divided into two doses. Sodium valproate was given at a dose of 15 mg/kg/day divided in two doses. The responsible parent had to record the headache frequency and intensity daily. The first follow-up visit was 1 week after initiation of the treatment phase to confirm if the medications had been used at the correct times and doses and if any adverse effects had occurred in the beginning days. The next follow-up visits were at 4, 8, and 12 weeks. Investigators collected the data from the headache diary at the end of each 4-week interval during the treatment phase. The study could be discontinued for a patient in the case of a) any adverse event that, in the opinion of the investigator, required termination of medication; b) progression of migraine attacks; c) pregnancy; or d) withdrawal of consent.

Outcomes

The primary endpoint was the mean change in attack frequency and intensity of migraine headaches from the baseline phase to the last 4 weeks of phase 3. Migraine frequency was defined as the number of attacks that fulfilled the IHS criteria for migraine with or without aura (13). In each arm, we obtained the mean number of these episodes every 4 weeks after initiation of treatment.

Migraine intensity was defined as the severity of migraine attacks. To report this ordinal qualitative variable as a quantitative one, the visual analogue scale (VAS) was used. This scale consists of a 10 cm line that is divided into 10 parts, which are numbered 0 (no pain) to 10 (most extreme pain). In each group, we obtained the mean of migraine intensity every 4 weeks after initiation of treatment.

The secondary endpoint was > 50% responder rate, which shows the efficacy of cinnarizine and sodium valproate in the prevention of migraine. In fact, the drug was effective if it could decrease the headache frequency by more than 50% in the double-blind phase compared with the baseline frequency.

Safety endpoint was the adverse events. At each follow-up session, the patients and their parents were asked to report any adverse events from the medications that were experienced in phase 3 of the study. A phone number was also provided so adverse events could be reported. Participants and their parents were asked to visit the emergency department if serious complication occurred.

Statistical analysis

Based on previous studies, we assumed that mean change in migraine frequency would be 7 (from 10 to 3) in each active treatment arm and 5 (from 10 to 5) in the placebo group at the end of the trial. By assuming the standard deviation (SD) of mean change in migraine frequency within each group to be 3.33 and considering two-sided α (the probability of type I error) as 0.05, and β (the probability of type II error) as 0.20, a total sample size of 126 (42 in each group) was estimated to provide at least 80% power to detect a statistical significant difference in the primary endpoint. After considering a 15% dropout rate, the required sample size was estimated to be 48 per treatment group. G*Power software was used for sample size calculation (Supplemental material, p.2).

The statistician was blinded to the study arms. The Shapiro-Wilk test and quantile-quantile plot (Q-Q plot) were used to assess the normal distribution (Supplemental material, p.3). Continuous variables were presented as mean with SD, standard error of mean (SEM) or 95% confidence interval (CI). Categorical variables were described using numbers and percentages. Between-group differences were analyzed according to the intention to treat (ITT) approach. For safety and efficacy analyses, we included all participants who received at least one dose of the assigned drug. Missing data were handled by the multiple imputation method using the SPSS V.25.0 (Markov chain Monte Carlo method). Variables included in the model as predictors were age, gender, assigned medication, migraine frequency (baseline, week 4, week 8, and week 12), and migraine intensity (baseline, week 4, week 8, and week 12). Five datasets were imputed and pooled data were reported for primary outcome analyses. One-way analysis of variance (ANOVA) test was used for primary outcome analysis. Tukey method was used for multiplicity adjustment. To more rigorously assess the robustness of the treatment effect, analysis of covariance (ANCOVA) models with adjustment for covariates including age, gender, and baseline migraine frequency or intensity was performed as a supplemental analysis. For > 50% responder rate comparisons, as a secondary outcome, odds ratios (OR) and 98.3% CI were obtained from a logistic regression analysis. All statistical analyses were performed using the SPSS V.25 and GraphPad Prism version 7.04. Two-sided significance testing was conducted, and p-values < 0.05 were considered statistically significant.

Results

Participants

Initial screening started on 18 February 2015. The double-blind phase was from 23 March 2015, when the first patient was assigned, to 17 November 2017. One hundred and ninety-six patients were screened for eligibility and 158 were randomly allocated. Of the initial 158 cases, two participants were lost to follow-up; three were not compliant, and three withdrew their consent without providing any reason. One participant discontinued the therapy due to adverse effect. Overall, 149 participants (49 in the cinnarizine, 51 in the sodium valproate, and 49 in the placebo group) completed the trial (Figure 1). All the baseline demographic and headache characteristics of participants are included in Table 1.

Figure 1.

CONSORT flow diagram.

Table 1.

Baseline characteristics of the participants.

Characteristic	Cinnarizine (n = 53)	Sodium valproate (n = 53)	Placebo (n = 52)
Age (years), (Mean ± SD)	10.4 ± 2.8	11.2 ± 2.9	11.2 ± 3.1
Male, n (%)	30 (56.6)	33 (62.3)	27 (51.9)
Migraine with aura, n (%)	12 (22.6)	8 (15.1)	14 (26.9)
Prior preventive treatment failure, n (%)
None	41 (77.4)	47 (88.7)	44 (84.6)
One medication	9 (17.0)	4 (7.5)	6 (11.5)
Two medications	3 (5.7)	2 (3.8)	2 (3.8)
Rescue medication, n (%)
None	3 (5.7)	1 (1.9)	5 (9.6)
Analgesics	22 (41.5)	31 (58.5)	26 (50.0)
Triptan	18 (34.0)	16 (30.2)	17 (32.7)
Ergotamine	4 (7.5)	1 (1.9)	1 (1.9)
Combination	6 (11.3)	4 (7.5)	3 (5.8)
Migraine frequency¹, (Mean ± SD)	11.1 ± 5.4	12.1 ± 5.0	10.7 ± 4.7
Migraine intensity², (Mean ± SD)	7.0 ± 1.8	6.2 ± 2.2	6.3 ± 1.9

¹Mean migraine frequency per 4 weeks.

²Mean migraine intensity per 4 weeks measured by visual analogue scale.

Four participants were included in the study due to the presence of severe migraine attacks and the remainder had at least four migraine episodes per 4 weeks. Over 80% of cases had no history of previous preventive treatment for migraine and the rest failed at least one preventive medication (Supplemental Table 1). Full doses of medications were initiated at day one.

Primary endpoint

Migraine attack frequency

All 158 cases were included in the analysis. The mean frequency of migraine attacks at each visit is shown in Figure 2. Cinnarizine and sodium valproate were superior to placebo (Table 2). When cinnarizine was compared with sodium valproate for migraine frequency outcome, no significant difference was found (mean difference [95% CI]: 0.3 [−1.6 to 2.2]; p = 0.926). The analysis of individuals who completed the trial (149 individuals) is presented in Supplemental Table 2.

Figure 2.

Migraine attack frequency (Mean (SD)) during the study period.

Table 2.

Primary and secondary endpoints.

Outcome	Cinnarizine (n = 53)	Sodium valproate (n = 53)	Placebo (n = 52)
Primary outcome
Migraine frequency
Week 9–12¹	3.2 (0.4)	3.9 (0.5)	6.3 (0.7)
Mean difference from baseline (95% CI)	−8.0 (−9.3 to −6.6)	−8.3 (−9.3 to −7.2)	−4.4 (−5.4 to −3.4)
Difference vs. placebo (95% CI)	−3.6 (−5.5 to −1.6)	−3.9 (−5.8 to −1.9)	−
Migraine intensity (VAS score)
Week 9–12¹	2.4 (0.3)	2.2 (0.2)	3.8 (0.3)
Mean difference from baseline (95% CI)	−4.6 (−5.2 to −4.0)	−4.0 (−4.8 to −3.3)	−2.6 (−3.4 to −1.8)
Difference vs. placebo (95% CI)	−2.0 (−3.2 to −0.8)	−1.5 (−2.7 to −0.3)	−
Secondary outcome
>50% responder rate, n (%)	38 (71.7)	35 (66.0)	22 (42.3)

¹Mean (SEM) are shown.

CI: confidence interval; SEM: standard error of mean; VAS: visual analogue scale.

Similar results were found when migraine attack frequency outcome was compared among the groups using ANCOVA analysis: cinnarizine versus placebo (mean difference [95% CI]: −3.4 [−4.9 to −1.9]; p < 0.001); sodium valproate versus placebo (mean difference [95% CI]: −3.1 [−4.6 to −1.6]; p < 0.001); and cinnarizine versus sodium valproate (mean difference [95% CI]: −0.3 [−1.8 to 1.1]; p = 0.854).

Migraine attack intensity

The mean intensity of migraine attacks at each visit is demonstrated in Figure 3.

Figure 3.

Migraine attack intensity (Mean (SD)) during the study period.

In each of the three groups, the intensity of migraine episodes in the last 4-week period of the trial was significantly reduced compared with the baseline period. Migraine attack intensity was decreased prominently in the cinnarizine and sodium valproate groups compared with placebo (Table 2). No statistical significant difference was found between cinnarizine and sodium valproate regarding the migraine intensity outcome (mean difference [95% CI]: −0.5 [−1.7 to 0.7]; p = 0.537).

When ANCOVA analysis was performed for comparing the change in migraine attack intensity among the groups, the following results were achieved: Cinnarizine versus placebo (mean difference [95% CI]: −1.5 [−2.4 to −0.6]; p < 0.001); sodium valproate versus placebo (mean difference [95% CI]: −1.6 [−2.5 to −0.7]; p < 0.001); and cinnarizine versus sodium valproate (mean difference [95% CI]: 0.1 [−0.8 to 1.0]; p = 0.960).

Secondary endpoint

The percentage of >50% responder rate was 71.7% (38/53) in the cinnarizine group, 66.0% (35/53) in the sodium valproate group, and 42.3% (22/52) in the placebo group (Table 2). The odds ratio for >50% responder rate was 3.5 (98.3% CI: 1.3 to 9.3) for cinnarizine versus placebo and 2.7 (98.3% CI: 1.0 to 6.9) for sodium valproate versus placebo. There was no significant difference in >50% responder rate when cinnarizine was compared with sodium valproate (OR [98.3% CI]: 1.3 [0.5 to 3.6]).

Safety endpoint

A total of five adverse events were reported by nine patients, three patients (3/53 [5.7%]) in the cinnarizine group, five patients (5/53 [9.4%]) in the sodium valproate group, and one patient (1/52 [1.9%]) in the placebo group (Table 3). Sedation was the most common adverse event and was the reason for discontinuation in one subject in the sodium valproate group.

Table 3.

Frequency of adverse events in cinnarizine, sodium valproate and placebo groups.

Adverse event	Cinnarizine (n = 53)	Sodium valproate (n = 53)	Placebo (n = 52)
Sedation	2 (3.8)	2 (3.8)	0 (0)
Nausea or vomiting	0 (0)	1 (1.9)	1 (1.9)
Anorexia	0 (0)	1 (1.9)	0 (0)
Dizziness	0 (0)	1 (1.9)	0 (0)
Tremor	1 (1.9)	0 (0)	0 (0)

Number (%) are shown.

Discussion

Summary of results

We demonstrated that all medications were able to significantly decrease the frequency and severity of migraine episodes compared to the baseline but the decrease was significantly greater in the cinnarizine and sodium valproate groups compared to placebo. About two thirds of subjects in the sodium valproate group and three quarters of individuals in the cinnarizine arm had more than 50% reduction in baseline migraine frequency. No significant difference was observed in mean change of headache frequency and intensity when cinnarizine and sodium valproate were compared to each other. The medications were well tolerated and only one case in sodium valproate arm discontinued the study due to severe sedation.

Previous studies

Previous studies which assessed the efficacy of cinnarizine and sodium valproate in prevention of pediatric migraine are listed in Table 4 (14–22). No life-threatening side effects were reported and no discontinuations attributable to adverse events were observed in studies investigating the safety of cinnarizine in a pediatric population. In line with this trial, mild daytime sedation was the most frequent side effect. Weight gain (14), irritability (15), and decreased appetite (17) were seen in a few cases in other studies.

The safety and efficacy of cinnarizine in prevention of adult migraine was also assessed. It was shown that the frequency and severity of migraine attacks considerably decreased in adults using this medication (23–25). A double-blind trial indicated that sodium valproate was more effective than cinnarizine in improving headache in adults (24). However, another trial showed no difference between groups (25).

Table 4.

Studies evaluating the efficacy of cinnarizine and sodium valproate in prevention of pediatric migraine.

Study	Medications	Number of cases (controls)	Age range (years)	Study duration	Measured outcomes of headaches	Results
Ashrafi et al. (14)	Cinnarizine vs. placebo	34 (34)	5–17	16 weeks (4 weeks pre-randomization phase; 12 weeks treatment phase)	Frequency Intensity Duration	- Cinnarizine decreased headache frequency, intensity, and duration significantly greater than placebo
Togha et al. (15)	Cinnarizine vs. propranolol	57 (56)	6–17	16 weeks (4 weeks baseline phase; 12 weeks treatment phase)	Frequency Intensity Duration >50% responders	- Both medications significantly reduced headache frequency, intensity and duration - No difference was observed between two groups
Alebrahim et al. (16)	Cinnarizine vs. propranolol	28 (28)	6–14	2 months	Frequency Intensity	- Cinnarizine and propranolol were both effective in pediatric migraine prophylaxis - Propranolol was significantly more effective in reducing the number of mild and moderate headaches - Cinnarizine was significantly more effective in reducing the number of severe headaches
Ashrafi et al. (17)	Cinnarizine vs. topiramate	20 (20)	4–15	16 weeks (4 weeks baseline phase; 12 weeks treatment phase)	Frequency Intensity > 50% responders	- Both drugs were effective to improve headache characteristics of participants
- No significant difference was observed between groups
Serdaroglu et al. (18)	Sodium valproate	10	9–17	At least 12 weeks	Frequency Intensity Duration	- All outcomes reduced significantly compared to the baseline
Caruso et al. (19)	Divalproex sodium	42	7–16	4 months	Frequency Need for abortive headache medications	- Headache characteristics improved significantly due to the therapy
Ashrafi et al. (20)	Sodium valproate vs. propranolol	57 (58)	3–15	At least 3 months (4 weeks baseline period; at least 2 months of treatment)	> 50% responders Intensity	- Both medications significantly improved headache characteristics - No difference was observed between the two groups
Bidabadi and Mashouf (21)	Sodium valproate vs. propranolol	31 (32)	5–15	4–6 months	Frequency Intensity Duration > 50% responders	- All headache outcomes improved due to therapy by both drugs - No difference was observed between the two groups
Unalp et al. (22)	Sodium valproate vs. topiramate	20 (28)	Mean age (sodium valproate): 10.3; (topiramate): 11	4–6 months	Frequency Intensity Duration Disability	- Both medications significantly decreased headache outcomes compared to baseline - No difference was observed between arms

Recent studies have described that intravenous sodium valproate was useful as an abortive therapy for migraine in children and adolescents (26). Sodium valproate was tolerable in most studied cases but adverse events including somnolence, weight gain, dizziness, alopecia, and tremor were reported in trials.

Mechanisms of action

Calcium channel blockers

The underlying pathophysiology of migraine is only partly understood and the exact mechanisms by which medications prevent headache occurrence are unclear. Flunarizine (like cinnarizine) is a calcium antagonist commonly used as a preventive agent for migraine and is the best studied compound and licensed for this indication in numerous countries (27). It has been shown that flunarizine was able to block the voltage-gated sodium channel, which may decrease neuronal excitability and prohibit cortical hyperexcitability (28). A similar mechanism was also described in cinnarizine (29). This mechanism may somewhat lead to migraine prevention. Further human and animal studies are needed to resolve our various ambiguities.

Anti-seizure medications

Randomized controlled trials assessed the efficacy of 15 ASMs (e.g. sodium valproate) in migraine prevention in an adult population (30). We recently showed that levetiracetam was effective in reducing the frequency and intensity of migraine episodes in a pediatric population (31). The pathophysiologic link between epilepsy and migraine may be the key to realizing how these medications act against migraine. The high prevalence of migraine among individuals with epilepsy as well that of epilepsy in people with migraine (32) showed the possible shared pathophysiology between these conditions. Similarities in clinical features of epilepsy and migraine such as the presence of premonition, aura, and post-ictal phases may also suggest elements of pathophysiologic link (33). Enhancement of gamma aminobutyric acid (GABA)-A inhibition and concurrent blocks of excitatory ion channels by sodium valproate were assumed to play a role in migraine prevention (34).

Strengths, limitations and future directions

Randomization and masking were major strengths of our trial. Furthermore, the prospective population-based approach with two study sites could enhance the external validity of our results. The small rate of withdrawal from the study (9/158, 5%) as well as reported adverse events in treatment groups (8/106, 7%) could indicate the applicability of these medications in the pediatric population. Small sample size and short period of follow-up were the major weaknesses of this trial. Misdiagnosis and misclassification of migraine in the pediatric population are other limitations. As migraine can not be objectively assessed, the outcomes of the study relied on reports from individuals or their parents, which could lead to information bias. Headache/migraine days were not estimated in our participants and this is another limitation. Future trials are needed to suggest the most effective preventive medications in pediatric migraine and also recognize subgroups that may have the most benefits from calcium channel blockers and ASMs. Trying to understand the pathophysiologic links between migraine and its co-morbidities may also help in finding new treatments for migraine.

Conclusion

Cinnarizine and sodium valproate may be effective as preventive treatments for migraine in children and adolescents. Both drugs are safe and well tolerated, but cinnarizine could be considered as a new preventive option especially for long-term treatment of pediatric migraine, particularly in females.

Clinical implications

Cinnarizine may be useful for migraine prophylaxis in a pediatric population.

Sodium valproate may be useful for migraine prophylaxis in a pediatric population.

Cinnarizine and sodium valproate are safe for children and adolescents.

Supplemental Material

CEP888485 Supplemental material - Supplemental material for Cinnarizine and sodium valproate as the preventive agents of pediatric migraine: A randomized double-blind placebo-controlled trial

Supplemental material, CEP888485 Supplemental material for Cinnarizine and sodium valproate as the preventive agents of pediatric migraine: A randomized double-blind placebo-controlled trial by Man Amanat, Mansoureh Togha, Elmira Agah, Mahtab Ramezani, Ali Reza Tavasoli, Reza Azizi Malamiri, Fariba Fashandaky, Morteza Heidari, Mona Salehi, Hamid Eshaghi and Mahmoud Reza Ashrafi in Cephalalgia

Footnotes

Acknowledgements

The authors are grateful to all parents and patients for their participation in this study. Our special thanks to Mrs Leila Forotan, who administered medications to the participants.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Research Deputy of Tehran University of Medical Sciences provided ﬁnancial and logistic support for this trial but had no role in study design, the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.

References

Abu-Arafeh

Razak

Sivaraman

, et al. Prevalence of headache and migraine in children and adolescents: A systematic review of population-based studies. Dev Med Child Neurol 2010; 52: 1088–1097.

Bille

. A 40-year follow-up of school children with migraine. Cephalalgia 1997; 17: 488–491.

Virtanen

Aromaa

Rautava

, et al. Changing headache from preschool age to puberty. A controlled study. Cephalalgia 2007; 27: 294–303.

Lewis

. Pediatric migraine. Neurol Clin 2009; 27: 481–501.

Damen

Bruijn

Verhagen

, et al. Prophylactic treatment of migraine in children. Part 2. A systematic review of pharmacological trials. Cephalalgia 2006; 26: 497–505.

Evers

Afra

Frese

, et al. EFNS guideline on the drug treatment of migraine – revised report of an EFNS task force. Eur J Neurol 2009; 16: 968–981.

D'amico

Solari

Usai

, et al. on behalf of the Progetto Cefalee Lombardia Group. Improvement in quality of life and activity limitations in migraine patients after prophylaxis. A prospective longitudinal multicentre study. Cephalalgia 2006; 26: 691–696.

Powers

Coffey

Chamberlin

, et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Eng J Med 2017; 376: 115–124.

Karsan

Palethorpe

Rattanawong

, et al. Flunarizine in migraine-related headache prevention: Results from 200 patients treated in the UK. Eur J Neurol 2018; 25: 811–817.

10.

Jackson

Cogbill

Santana-Davila

, et al. A comparative effectiveness meta-analysis of drugs for the prophylaxis of migraine headache. PloS One 2015; 10: e0130733–e0130733.

11.

Rompel

Bauermeister

. Aetiology of migraine and prevention with carbamazepine (Tegretol): Result of a double-blind, cross-over study. S Afr Med J 1970; 44: 75–80.

12.

Sorensen

. Valproate: A new drug in migraine prophylaxis. Acta Neurol Scand 1988; 78: 346–348.

13.

Olesen

. Headache Classification Sub-Committee of the International Headache Society. The International Classification of Headache Disorders, 2nd edn. Cephalagia 2004; 24: 1–160.

14.

Ashrafi

Salehi

Malamiri

, et al. Efficacy and safety of cinnarizine in the prophylaxis of migraine in children: A double-blind placebo-controlled randomized trial. Pediatr Neurol 2014; 51: 503–508.

15.

Togha

Malamiri

Rashidi-Ranjbar

, et al. Efficacy and safety of cinnarizine in the prophylaxis of migraine headaches in children: An open, randomized comparative trial with propranolol. Acta Neurol Belg 2012; 112: 51–55.

16.

Alebrahim

Moayedi

Nazemi

, et al. Prophylactic efficacy of cinnarizine versus propranolol in the treatment of childhood migraine: A single-blind randomized clinical trial. Int J Pediatr 2019; 7: 8907–8913.

17.

Ashrafi

Najafi

Shafiei

, et al. Cinnarizine versus topiramate in prophylaxis of migraines among children and adolescents: A randomized, double-blind clinical trial. Iran J Child Neurol 2014; 8: 18–27.

18.

Serdaroglu

Erhan

Tekgul

, et al. Sodium valproate prophylaxis in childhood migraine. Headache 2002; 42: 819–822.

19.

Caruso

Brown

Exil

, et al. The efficacy of divalproex sodium in the prophylactic treatment of children with migraine. Headache 2000; 40: 672–676.

20.

Ashrafi

Shabanian

Zamani

, et al. Sodium valproate versus propranolol in paediatric migraine prophylaxis. Eur J Paediatr Neurol 2005; 9: 333–338.

21.

Bidabadi

Mashouf

. A randomized trial of propranolol versus sodium valproate for the prophylaxis of migraine in pediatric patients. Pediatr Drugs 2010; 12: 269–275.

22.

Ünalp

Uran

Öztürk

. Comparison of the effectiveness of topiramate and sodium valproate in pediatric migraine. J Child Neurol 2008; 23: 1377–1381.

23.

Togha

Ashrafian

Tajik

. Open-label trial of cinnarizine in migraine prophylaxis. Headache 2006; 46: 498–502.

24.

Bostani

Rajabi

Moradian

, et al. The effects of cinnarizine versus sodium valproate in migraine prophylaxis. Int J Neurosci 2013; 123: 487–493.

25.

Mansoureh

Jirde

Nilavari

, et al. Cinnarizine in refractory migraine prophylaxis: Efficacy and tolerability. A comparison with sodium valproate. J Headache Pain 2008; 9: 77–82.

26.

Sheridan

Sun

O’Brien

, et al. Intravenous sodium valproate for acute pediatric headache. J Emerg Med 2015; 49: 541–545.

27.

Sprenger

Viana

Tassorelli

. Current prophylactic medications for migraine and their potential mechanisms of action. Neurotherapeutics 2018; 15: 313–323.

28.

Yan

Xue

, et al. Flunarizine blocks voltage-gated Na(+) and Ca(2+) currents in cultured rat cortical neurons: A possible locus of action in the prevention of migraine. Neurosci Lett 2011; 487: 394–399.

29.

Brahmane

Wanmali

Pathak

, et al. Role of cinnarizine and nifedipine on anticonvulsant effect of sodium valproate and carbamazepine in maximal electroshock and pentylenetetrazole model of seizures in mice. J Pharmacol Pharmacother 2010; 1: 78–81.

30.

Mulleners

McCrory

Linde

. Antiepileptics in migraine prophylaxis: An updated Cochrane review. Cephalalgia 2015; 35: 51–62.

31.

Montazerlotfelahi

Amanat

Tavasoli

, et al. Levetiracetam for prophylactic treatment of pediatric migraine: A randomized double-blind placebo-controlled trial. Cephalalgia 2019; 39: 1509–1517.

32.

Keezer

Sisodiya

Sander

. Comorbidities of epilepsy: Current concepts and future perspectives. Lancet Neurol 2016; 15: 106–115.

33.

Nye

Thadani

. Migraine and epilepsy: Review of the literature. Headache 2015; 55: 359–380.

34.

Cutrer

. Antiepileptic drugs: How they work in headache. Headache 2001; 41: S3–S10.

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