Iatrogenic harm in paediatric and adolescent populations of patients with migraine: A systematic review with meta-analysis

Abstract

Background

Migraine is a common condition that causes a high burden of disability even at a young age, significantly affecting various aspects of quality of life. Despite this significant burden, the pharmacological treatment of migraine is still a subject of debate, with controversial results that do not provide sufficient evidence of its effectiveness. Furthermore, the safety profile in this inherently fragile population leaves some doubts about pharmacological prophylaxis use. This study aims to provide an overview of the safety profile of the main drugs used in populations of children and adolescents with migraine, analysing the type and frequency of the main side effects reported.

Methods

PubMed and Scopus were systematically searched for papers reporting adverse events (AEs) of pharmacological prophylaxis of migraine in children and adolescents, and all eligible original articles were included. A meta-analysis was carried out to define the pooled proportion of the summary safety information (i.e. the number of subjects reporting at least one AE) with 95% confidence intervals for those compounds present in at least two samples, regardless of dosage.

Results

In total, 40 studies were included, accounting for 62 subsamples and 2742 patients (55% females). The most used compounds were topiramate (22 subsamples), propranolol and sodium valproate (six subsamples). Overall, 30% of patients reported at least one AE. Erenumab showed the highest rate of AEs, most likely due to the higher-precision detection typical of a randomized controlled trial, and cinnarizine the lowest. In total, 53 different AEs were reported, most frequently drowsiness, anorexia, fatigue and paraesthesia.

Conclusions

In accordance with the results of this systematic review with a meta-analysis, clinicians should consider that 30% of the paediatric patients with migraine will report some AEs from prevention treatment. The information on the safety profile is essential for clinicians in evaluating the choice of a specific therapy, making a better risk/benefit ratio evaluation for each single patient, which is crucial in consideration of the inconsistent efficacy profiles of preventive medications, with the exception of topiramate, in this population.

Keywords

adolescents adverse event children migraine prophylaxis safety

Introduction

Primary headaches are common neurological disorder, even affecting children and adolescents, and are often underdiagnosed and undertreated.^1–3 A recent meta-analysis reveals that the prevalence of primary headache disorders in populations of children and adolescents is 62%, with 17% for tension-type headache (TTH), 11% for migraine and no large data available for trigeminal autonomic cephalalgias (TACs).⁴ While prevalence is equally distributed between boys and girls during childhood and early adolescence, a higher tendency is observed in girls during late adolescence, which persists in adulthood.⁵ Migraine and TTH together account for a significant proportion of all-cause disability, representing 6.1% and 7.6% of all-cause years lived with disability (YLDs) in the age groups 10–14 years and 15–19 years, respectively.^6,7

Migraine in children presents distinct clinical features compared to adult migraine, notably in its duration, location and sometimes symptoms, such that nausea, vomiting and loss of appetite, commonly mistaken for gastrointestinal disorders, are much represented. Generally, attacks in children are shorter, even less than 4 h, and pain is often bilateral.⁸ These different features seem to be tied with brain development and myelination of neurons, in the growing and development phases of childhood and adolescence.⁹

In recent years, there has been growing interest in the burden of these disabling pain syndromes affecting many areas of life such as school performances, relationships, sport and social activities, resulting in a lower quality of life.¹⁰ Indeed, different studies highlight how headaches can result in impaired school attendance and missing social and physical activities, even in young people.^11–13

Despite this non-negligible burden, prevention treatment is still a matter of discussion in this fragile population. Indeed, three network meta-analyses did not provide sufficient confidence in suggesting pharmacological treatment for prevention in this age cohort, with prophylactic pharmacologic treatments not showing evidence of efficacy profiles compared to placebo in a consistent way.^14–16 The only compound for which efficacy against placebo was consistently found is topiramate, whereas trazodone, propranolol, pregabalin, flunarizine, levetiracetam, cinnarizine and amitriptyline showed efficacy only in one of the three meta-analyses.

Regarding the safety profile, these therapies provide concerns in this population, as reported in a recent network meta-analysis where treatment discontinuation due to adverse events (AEs) was more common, with an overall lower acceptability.¹⁴ For example, as reported in the CHAMP study, both topiramate and amitriptyline were associated with higher rates of AEs compared to placebo, and lacked any clear efficacy benefit¹⁷; moreover, despite slightly supporting evidence, antiepileptic drugs (e.g. topiramate and valproic acid) offer serious additional safety issue as ‘class X’ drugs with respect to their teratogenic effects.¹⁸

Based on such evidence, even the American Academy of Neurology and the American Headache Society, in their joint practice guideline for migraine prevention in populations of children and adolescents with migraine, recommend that clinicians engage in shared decision-making, carefully weighing the limited efficacy and notable tolerability concerns of pharmacologic agents.¹⁹

In sum, to date, prophylactic pharmacologic treatments have inconsistent efficacy profiles compared to placebo (except for topiramate), with some concerns about possible AEs. However, a systematic analysis that examines each drug evaluating its safety profiles is lacking. This review aims to provide a summary of the safety profile of preventive medications used in children and adolescents with migraine, describing the type and frequency of the main AEs reported in literature.

Methods

We conducted a literature review with meta-analysis and reported results according to the ‘Preferred Reporting Items for Systematic Reviews and Meta-Analyses’ (PRISMA).²⁰

Search strategy

Search terms had to combine information of three main terms: migraine, child/adolescent (with possible variations) and a set of compounds used for migraine prophylaxis. PubMed and SCOPUS were searched for the terms, using database-specific variations, in the period between 2000 and 2025 (dated 30 May). The full search strategy by database is reported in the Supplementary material (File S1).

Retrieved references were exported as .csv files and imported to Rayyan QRCI (http://rayyan.qcri.org) for duplicate checking. The set of records was then exported to Excel (Microsoft Corp.) for study selection and data extraction.

Study selection

Retrieved references were equally and randomly assigned to two of the reviewers (AP and GG) for titles and abstracts screening. A double check on titles and abstracts eligibility was randomly performed on 30% of selected references: AM performed the double check on abstracts.

To be eligible and be evaluated in full texts, records had to refer to repeated-measures design studies (i.e. RCTs or cohort studies) on pharmacological prophylaxis for migraine in children and adolescents with migraine. We excluded records at abstract check if they: (a) were published before 2000; (b) did not have an abstract; (c) were not in English; (d) were letters, editorials, conference material, book chapters, case reports, literature reviews or meta-analyses; and (e) were not RCTs or cohort studies on pharmacological prophylaxis for children and adolescents with migraine.

The agreement among reviewers (i.e. the inter-rater reliability) was calculated using Krippendorff's alpha coefficient (α), which ranges between 0 (total disagreement) and 1 (total agreement). In case of disagreement, the record was considered as selected and retained for full-text evaluation. In case α was below 0.70, a second 20% set of reference was submitted to double check.

Eligible references were equally and randomly assigned to the same reviewers who screened abstracts before (AP and GG), but employing a ‘shuffle procedure’, so that the reviewers did not check those papers that they previously revised. For full texts evaluation, studies were excluded if they: (a) could not be retrieved; (b) were not in English; (c) were not RCTs or cohort studies on pharmacological prophylaxis for children and adolescents with migraine (including conference material or book chapters); (d) did not report safety data; and (e) reported insufficient data (i.e. not linkable to experimental or group, with no mention of follow-up duration, or no information on drug dosage).

The double check was performed by a single reviewer (AR) on 30% of the full texts regarding their eligibility and Krippendorff's α was calculated; in case of disagreement, a third opinion was sought (AM). In case Krippendorff's α was below 0.70, a second 30% set of reference was submitted to double check.

Data extraction

Data extraction was performed through an ad hoc electronic spreadsheet in Excel (Microsoft Corp.). Included studies were equally and randomly assigned to AP and GG who had to extract the following information: (a) compound name; (b) compound dosage as reported (i.e. as mg/day or as mg/kg/day); (c) observation duration in weeks; (d) number of children and adolescents with migraine and, if available, number of patients with episodic migraine (EM) or chronic migraine (CM); (e) number of females out of the total; (f) mean, median, standard deviation, 95% confidence interval (CI) or interquartile range for patients’ age; (g) summary safety information (i.e. number of subjects reporting at least one AE); and (h) specific safety information (i.e. number of subjects reporting specific Aes).

Extracted information were referred to a single compound. Therefore, for studies contrasting different compounds (e.g. flunarizine vs. topiramate), or the same compound at different dosages (e.g. topiramate at 50 mg/day vs. 100 mg/day), the information was extracted separately in two different rows. This did not apply when dosage was referred with ranges with no better specification (e.g. topiramate between 15 and 100 mg/day), or when combined treatment was proposed (i.e. topiramate added to vitamin D3).

A comprehensive list of possible AEs was prepared derived from a set of well-known trials to provide a scheme for AEs extraction, and reviewers were allowed to add other columns when needed. As a final control measure, a senior reviewer (AR) made a cross-check on 30% of the finally included papers.

Statistical analysis

Studies’ descriptive statistics are reported as the mean, SD, median, interquartile range (IQR) and N for quantitative data, and as frequencies and percentages for categorical data. Data were reported at the level of samples: for studies comparing different compounds or the same compounds at different dosages, sub-samples were described.

Meta-analysis

A pooled proportion of AEs with 95% CIs was obtained through meta-analysis for those compounds present in at least two samples, regardless of dosage. The variable of interest was the summary safety information, i.e., the number of subjects reporting at least one AE. Random-effects inverse-variance models were applied. To obtain narrower confidence intervals, lower heterogeneity and more stable pooled estimates, Freeman–Tukey double arcsine square-root transformation was adopted.²¹

Heterogeneity between the studies was quantified by the Cochran's Q test (significance level at p < 0.1) and the I2 statistic (with a value higher than 75% considered large).²²

All analyses were carried out using STATANow/SE 19.5 (StataCorp LLC).

Results

Out of 649 records retrieved in PubMed and SCOPUS, we selected 40 papers^17,23–61 with 62 subsamples, that fulfilled the inclusion criteria of the corresponding RCTs or cohort studies (for PRISMA diagram, see Figure 1). The agreement rate was 86% at abstract check and 93% at full-text selection. Out of the selected 40 papers, 62 sub-samples were identified and used for the analyses.

Figure 1.

Flowchart of selected studies.

In total, 2742 patients were enrolled, of whom 1520 (55%) were females. In most cases (32/62 subsamples), no distinction between EM and CM was reported; 21/62 subsamples included patients with CM only, eight of 62 included patients with EM only, and one subsample included patients with both EM and CM. The sub-samples were composed of a minimum of four to a maximum of 150 subjects, with the median number of patients per sample being 32. Patients’ age was comprised between 8 and 16.5 years, with mean age 12.5 years (95% CI = 12.0–13.0). Table 1 reports demographic information for selected studies. Table 2 reports the random-effects model meta-analysis.

Table 1.

Demographics, comorbidities, initial migraine characteristics and oral preventive treatments.

Compound name	62 sub-samples							46 sub-samples
Compound name	n sub-samples	n pts	n EM	n CM	n anyMIG	n female	Age median	n sub-samples	n pts	n EM	n CM	n anyMIG	n females	Age median
Topiramate	22	1143	208	512	423	663	11	17	938	63	512	363	549	11
Sodium valproate	6	214	31	39	144	103	10,6	5	183	0	39	144	94	10,9
Propranolol	6	215	32	107	76	81	9,8	4	127	0	107	20	52	9905
OnabotulinumtoxinA	5	195	0	193	2	160	15,1	5	195	0	193	2	160	15,1
Flunarizine	5	279	72	0	207	169	13	5	279	72	0	207	169	13
Erenumab	4	53	0	0	53	31	12,7	4	53	0	0	53	31	12,7
Cinnarizine	4	160	0	20	140	64	10,1	2	73	0	20	53	31	9,85
Pregabalin	2	77	0	46	31	27	10,6	2	77	0	46	31	27	10,6
Amitriptyline	2	174	0	144	30	106	11,9	2	174	0	144	30	106	11,9
Alpha-lipoic acid (ALA) + flunarizine	1	30	0	0	30	16	16,1	–	–	–	–	–	–	–
Fremanezumab	1	15	0	0	15	7	9,3	–	–	–	–	–	–	–
Levetiracetam	1	30	0	0	30	14	10,6	–	–	–	–	–	–	–
Topiramate + vitamin D3	1	29	0	29	0	15	10,33	–	–	–	–	–	–	–
Topiramate and ferrous sulfate	1	98	0	98	0	46	9,72	–	–	–	–	–	–	–
vitamin D3 supplementation	1	30	0	0	30	18	10,12	–	–	–	–	–	–	–

Note. The left side of the table reports sociodemographic information for all included studies, and on the right side for the subsamples submitted to meta-analysis.

CM: chronic migraine; EM: episodic migraine; MIG: migraine.

Table 2.

Random-effects model meta-analysis

				Homogeneity statistics
Compound name	Proportion	N substudy	N subjects	Q	P	I² (%)	H	tau²
Amitriptyline	0.484	2	174	33.64	< 0.001	97.0%	5.80	0.6480
Amitriptyline	(0.032–0.954)	2	174	33.64	< 0.001	97.0%	5.80	0.6480
Cinnarizine	0.106	2	73	2.97	0.085	66.4%	1.724	0.0665
Cinnarizine	(0.005–0.283	2	73	2.97	0.085	66.4%	1.724	0.0665
Erenumab	0.787	4	53	4.10	0.251	26.8%	1.169	0.0339
Erenumab	(0.611–0.928)	4	53	4.10	0.251	26.8%	1.169	0.0339
Flunarizine	0.182	5	279	25.08	< 0.001	84.1%	2.504	0.1022
Flunarizine	(0.075–0.320)	5	279	25.08	< 0.001	84.1%	2.504	0.1022
OnabotulinumtoxinA	0.348	5	195	29.96	< 0.001	86.7%	2.737	0.1655
OnabotulinumtoxinA	(0.176–0.543)	5	195	29.96	< 0.001	86.7%	2.737	0.1655
Pregabalin	0.159	2	77	6.78	0.009	85.2%	2.603	0.1538
Pregabalin	(0.006–0.429)	2	77	6.78	0.009	85.2%	2.603	0.1538
Propranolol	0.161	4	127	5.71	0.127	47.4%	1.379	0.0305
Propranolol	(0.074–0.270)	4	127	5.71	0.127	47.4%	1.379	0.0305
Sodium valproate	0.154	5	183	10.33	0.035	61.3%	1.607	0.0438
Sodium valproate	(0.074–0.253)	5	183	10.33	0.035	61.3%	1.607	0.0438
Topiramate	0.319	17	938	287.21	< 0.001	94.4%	4.237	0.3172
Topiramate	(0.193–0.459)	17	938	287.21	< 0.001	94.4%	4.237	0.3172

The most used compound in our dataset was topiramate (used in 22 sub-samples as monotherapy, and in a further three associated with vitamin D3 or ferrous sulfate), propranolol and sodium valproate (used in six subsamples each). Summary safety information (i.e. number of subjects reporting at least one AE) was reported in 52/62 subsamples, and varied between 3.3% and 87.5%. The average percentage of patients with AEs, considering the entire set of studies and compounds, was 30.0% (SD = 23.8%); range (3.33–87.5%). With regard to specific safety information, a total of 53 different AEs were described: the most reported were drowsiness (26 occasions), anorexia (20 occasions), fatigue and paraesthesia (15 occasions). No life-threatening AEs were reported. Figure 2 provides an overview of the most common AEs for each compound. The entire set of reported AEs from each included study is provided in the Supplementary material (File S2).

Figure 2.

Overview of adverse events by compound. AE: adverse event.

An additional selection process was performed to enable a meta-analysis of the reported AEs associated with each drug on 46 subgroups. Many were excluded: six single-arm subgroups because it was not possible to compare AEs between groups, 10 due to missing safety data (i.e. these studies did not report the number of patients reporting at least one AE). In total, 2099 patients were included in the meta-analysis: 1219 (58%) were female and the median age was 11 years (95% CI = 8–16.5), 668 patients reported at least one AE.

Topiramate

Sixteen studies^{17,42,45,46,49–56}^,58–61 evaluating seventeen groups of patients treated with topiramate were included. In total, 938 patients were enrolled, of whom 549 (59%) were females. The median age was 11 years [IQR = 8–14.2 years]. The observation period ranged from 8 to 113 weeks, with a drug dosage between 1 and 200 mg/kg per day. Among all subjects, 325 patients experienced at least one AE, corresponding to an overall estimated proportion of 32% (95% CI = 19–46%; median: 24%; IQR: 7–77%).

In total, 34 AEs were reported; the most common across sub-samples were anorexia (reported in 12/17 sub-samples, IQR = 3–23%), paraesthesia (reported in 9/17 sub-samples, IQR = 3–31%), drowsiness (reported in 8/17 sub-samples, IQR = 3–8%) and cognitive AEs (reported in 7/17 sub-samples, IQR = 4–18%). There was marked heterogeneity between studies (I² = 94.4%).

Sodium valproate

Five studies^{39,42,45,48,57} evaluating five groups of patients treated with sodium valproate were included. In total, 183 patients were enrolled, of whom 94 (51%) were females. The median age was 10.9 years [IQR = 10.18–15.4 years]. The observation period ranged from 0.5 to 24 weeks, with a drug dosage between 10 and 75 mg/kg per day. Among all subjects, 28 patients experienced at least one AE, corresponding to an overall estimated proportion of 15% (95% CI = 7–25%; median: 11%; IQR = 9–40%).

In total, 11 AEs were reported; the most common across sub-samples were drowsiness (reported in 3/5 sub-samples, IQR = 5–12%) and dizziness (reported in 3/5 sub-samples, IQR = 2–8%). These were followed by weight increased (reported in 2/5 sub-samples, IQR = 7–12%) and nausea (reported in 2/5 sub-samples, IQR = 2–4%). The data show substantial heterogeneity (I² = 61.3%).

Propranolol

Four studies^24,30,36,52 evaluating four groups of patients treated with propranolol were included. In total, 127 patients were enrolled, of whom 52 (41%) were females. The median age is 9.9 years [IQR = 9.6–10.7 years]. The observation period ranged from 8 to 12 weeks, with a drug dosage between 1 and 20 mg/kg per day. Among all subjects, 20 patients experienced at least one AE, corresponding to an overall estimated proportion of 61% (95% CI = 7–27%; median: 15%; IQR = 10–35%).

In total, nine AEs were reported; the most common across sub-sample was drowsiness (reported in 2/4 sub-samples, IQR = 4–15%). Other AEs reported in ¼ sub-samples included: nausea (estimated proportion: 20%), vomiting (estimated proportion: 20%), fatigue (estimated proportion: 15%), dizziness (estimated proportion: 8%), behavioural abnormalities (estimated proportion: 8%), mild hypotension (estimated proportion: 6%), constipation (estimated proportion: 4%) and muscle contraction/stiffness (estimated proportion: 2%). There was moderate heterogeneity between studies (I² = 47.4%).

OnabotulinumtoxinA

Four studies^23,28,31,38 evaluating five groups of patients treated with onabotulinumtoxinA were included. In total, 195 patients with chronic migraine were enrolled, of whom 160 (82%) were females. The median age was 15.1 years [IQR = 14.7–16.5 years]. The observation period ranged from 12 to 96 weeks, with a drug dosage between 74 U and 195 U. Among all subjects, 75 patients experienced at least one AE, corresponding to an overall estimated proportion of 35% (95% CI = 18–54%; median: 32%; IQR = 3–51%).

In total, 14 AEs were reported; the most common across sub-samples were musculoskeletal pain (reported in 3/5 sub-samples, IQR = 9–34%), migraine/migraine worsening (reported in 2/5 sub-samples, IQR = 2–7%) dizziness (reported in 2/5 sub-samples, IQR = 3–7%), nausea (reported in 2/5 sub-samples, IQR = 3–6%) and ear/nose/throat reactions (reported in 2/5 sub-samples, IQR = 4%). There was marked heterogeneity between studies (I² = 86.7%).

Pregabalin

Two studies^36,39 evaluating two groups of patients treated with pregabalin were included. In total, 77 patients were enrolled, of whom 27 (35%) were females. The median age was 10.6 years [IQR = 9.95–11.25 years]. The observation period ranged from 8 to 16 weeks with a drug dosage between 50 and 75 mg per day. Among all subjects, 12 patients experienced at least one AE, corresponding to an overall estimated proportion of 16% (95% CI = 1–43%; median: 18%; IQR = 6–29%).

In total, five AEs were reported; the most common across sub-samples was drowsiness (reported in 2/2 subsamples, range 4–13%). Other AEs reported in 1/2 sub-samples included: migraine/migraine worsening (estimated proportion: 10%), dizziness (estimated proportion: 6%), depressive symptomatology (estimated proportion: 3%) and increased appetite (estimated proportion: 2%). There was marked heterogeneity between studies (I² = 85.2%).

Flunarizine

Five studies^{24,26,27,32,51} evaluating five groups of patients treated with flunarizine were included. In total, 279 patients were enrolled, of whom 169 (61%) were females. The median age was 13 years [IQR = 10.2–15.3 years]. The observation period ranged from 12 to 48 weeks with a drug dosage between 2.5 and 10 mg per day. Among all subjects, 44 patients experienced at least one AE, corresponding to an overall estimated proportion of 18% (95% CI = 7–32% median: 21%; IQR = 5–45%).

In total, 12 AEs were reported; the most common across sub-samples were weight increased (reported in 4/5 sub-samples, IQR = 2–7%), fatigue (reported in 3/5 sub-samples, IQR = 2–40%), drowsiness (reported in 2/5 sub-samples, IQR = 4–40%), sedation (reported in 2/5 sub-samples, IQR = 4–9%), depressive symptoms (reported in 2/5 sub-samples, IQR = 4–8%) and vomiting (reported in 2/5 sub-samples, IQR = 4–5%). The heterogeneity analysis indicated a high level of variability among studies (I² = 84.1%).

Cinnarizine

Two studies^56,57 evaluating two groups of patients treated with cinnarizine were included. In total, 73 patients were enrolled, of whom 31 (42%) were females. The median age was 9.85 years [IQR = 9.3–10.4 years]. The observation period was 12 weeks, with a drug dosage of 37.5 mg per day or 50 mg per day for patients aged 4–12 years and > 12 years, respectively. Among all subjects, seven patients experienced at least one AE, corresponding to an overall estimated proportion of 11% (95% CI = 1–28%; median: 13%; IQR = 5–20%).

In total, two AEs were reported: sedation (reported in 2/2 sub-samples, IQR = 4–20%) and tremor (reported in 1/2 sub-samples, estimated proportion: 2%). The heterogeneity analysis shows a moderate-to-high variability across studies (I² = 66.4%).

Erenumab

One study³³ evaluating four groups of patients treated with erenumab was included. In total, 53 patients were enrolled, of whom 31 (59%) were females. The median age was 12.7 years [IQR = 10.4–15.4 years]. The observation period was 12 weeks, with a drug dosage of 35 or 70 mg for patients ≤ 40 kg, and 70 or 140 mg for those ≥ 40 kg. Among all subjects, 42 patients experienced at least one AE, corresponding to an overall estimated proportion of 79% (95% CI = 61–93%; median: 71%; IQR = 50–88%).

In total, nine AEs were reported; the most common across sub-samples were vomiting (reported in 3/4 sub-samples, IQR = 11–38%), ear–nose–throat reactions (reported in 3/4 sub-samples, IQR = 11–25%), migraine or migraine worsening (reported in 3/4 sub-samples, IQR = 11–25%), epistaxis (reported in 3/4 sub-samples, IQR = 3–22%), abdominal pain (reported in 2/4 sub-samples, IQR = 25–31%), upper respiratory tract infection (reported in 2/4 sub-samples, estimated proportion: 25%) and nausea (reported in 2/4 sub-samples, IQR = 11–13%). These side effects are not presented in the lowest dose subgroup, except for abdominal pain. In this study, 42 patients reported a treatment emerged adverse event (TEAE) counting for the 79.2% of the entire sample. Only four (7.5%) were serious AEs, with two leading to discontinuation of treatment. The heterogeneity analysis showed a low level of variability among studies (I² = 26.8%).

Amitriptyline

Two studies^17,41 evaluating two groups of patients treated with amitriptyline were included. In total, 174 patients were enrolled, of whom 106 (61%) were females. The median age was 11.9 years [IQR = 9.6–14.2 years]. The observation period ranged from 12 to 24 weeks, with a drug dosage between 0.25 and 1.0 mg/kg per day. Among all subjects, 115 patients experienced at least one AE, corresponding to an overall estimated proportion of 48% (95% CI = 3–95%; median: 48%; IQR = 20–76%).

In total, 15 AEs were reported. Each AE was observed exclusively in one of the two subsamples, and the most common were: fatigue (estimated proportion: 30%), dry mouth (estimated proportion: 25%), drowsiness (estimated proportion: 20%), depressive symptoms (estimated proportion: 10%), cognitive AEs (estimated proportion: 10%) and upper respiratory tract infection (estimated proportion: 10%). The heterogeneity analysis showed a high level of variability among studies (I² = 97%).

Other studies not included in the meta-analysis

Six single-sample compounds studies were not included in the meta-analysis.

One study³⁵ evaluating patients treated with fremanezumab was included. In total, 15 patients were enrolled, of whom 7 (47%) were females. The median age was 9.3 years [IQR: 6–11 years]. The observation period was 4 weeks, with a drug dosage of 75 mg. Among all subjects, seven patients experienced at least one AE, corresponding to an overall estimated proportion of 47%. In total, five AEs were reported: injection site reactions (estimated proportion: 40%), prolonged prothrombin time (estimated proportion: 13%), abdominal pain (estimated proportion: 7%), injuries (estimated proportion: 7%) and neutrophil count decreased (estimated proportion: 7%).

One study⁴¹ evaluating patients treated with levetiracetam was included. In total, 30 patients were enrolled, of whom 14 (47%) were females. The median age was 10.6 years [IQR = 5–15 years]. The observation period was 12 weeks, with a drug dosage between 2.5 and 10 mg/kg per day. Among all subjects, five patients experienced at least one AE corresponding to an overall estimated proportion of 17%, and the only reported AE was depressive symptomatology.

One study²⁶ evaluating patients treated with alpha-lipoic acid (ALA) + flunarizine was included. In total, 30 patients were enrolled, of whom 16 (53%) were females. The median age was 16.1 years [IQR = 10–19 years]. The observation period was 12 weeks, with a drug dosage of 300 mg for ALA and 5 mg for flunarizine per day. Among all subjects, two patients experienced at least one AE corresponding to an overall estimated proportion of 7%. In total, three AEs were reported: sedation (estimated proportion: 7%), weight increased (estimated proportion: 7%) and fatigue (estimated proportion: 3%).

One study⁵⁹ evaluating patients treated with topiramate + vitamin D3 was included. In total, 29 patients were enrolled, of whom 15 (52%) were females. The median age was 10.3 years [IQR: 5–15 years]. The observation period was 8 weeks, with a drug dosage of 500,000 U of vitamin D3 and 2 mg/kg of topiramate per day. Among all subjects, five patients experienced at least one AE, corresponding to an overall estimated proportion of 17%. In total, three AEs were reported: constipation (estimated proportion: 7%), drowsiness (estimated proportion: 7%) and anorexia (estimated proportion: 3%).

One study³⁴ evaluating patients treated with topiramate + ferrous sulphate was included. In total, 98 patients were enrolled, of whom 46 (47%) were females. The median age was 9.7 years [IQR = 5–15 years]. The observation period was 12 weeks, with a drug dosage of 2 mg/kg of topiramate and 4 mg/kg of ferrous sulphate per day. Among all subjects, six patients experienced at least one AE, corresponding to an overall estimated proportion of 6%. In total, four AEs were reported: vomiting (estimated proportion: 2%), nausea (estimated proportion: 2%), drowsiness (estimated proportion: 2%) constipation (estimated proportion: 1%) and heartburn (estimated proportion: 1%).

One study²⁹ evaluating patients treated with vitamin D3 supplementation was included. In total, 30 patients were enrolled, of whom 18 (60%) were females. The median age was 10.1 years [IQR = 5–14 years]. The observation period was 16 weeks, with a drug dosage of 500,000 U per day. Among all subjects, four patients experienced at least one AE corresponding to an overall estimated proportion of 13%. In total, three AEs were reported: abdominal pain (estimated proportion: 7%), nausea (estimated proportion: 3%) and anorexia (estimated proportion: 3%).

Discussion

This systematic review with meta-analysis investigated the AEs associated with the main drugs used in migraine prophylaxis for children and adolescents. We included a total of 40 studies (2742 patients, 55% female, with a mean age of 12.5 years), with safety information reported in 62 different subsamples: overall, 30% of patients reported at least one AE. The most frequents AEs reported in different subsamples were drowsiness, anorexia, fatigue and paraesthesia. The worst overall safety proportions were reported for erenumab (79%), amitriptyline (48%), onabotulinumtoxinA and topiramate (35% and 32%, respectively). Globally, no life-threatening AEs were reported across the sub-samples, but a punctual stratification of severity of AEs was not provided for most of them.

The highest proportion of AEs were reported for erenumab, which could likely be explained by the rigorous setting of a RCT from which the four subsamples were derived,³³ and in which a systematic collection of AEs with evaluation of their severity was performed as part of a research protocol. This sheds light on a possible bias with which we faced off in this work (i.e. the considerable variability on AEs collection procedure across the studies). On the other hand, the rigours approach of erenumab's reports was likely also associated with an acceptable level of homogeneity (I² = 26.8%) compared to the other compounds, which, in contrast, showed higher levels of heterogeneity. For erenumab, the most frequent AEs were abdominal pain and ear–nose–throat reactions: those could be related to widely expression of CGRP receptors in the gastrointestinal tract and upper respiratory mucosa, where CGRP plays a role in gastrointestinal motility and mucosal integrity; the antagonist action exerted by erenumab could knowingly lead to symptoms as abdominal pain and, more frequently constipation; moreover, nasopharyngitis and upper respiratory tract infections, are also frequently observed, likely related to immune modulation CGRP-mediated.^62,63

The second drug in terms of AEs proportion was amitriptyline with 48%, a proportion arising from two sub-samples analysis.^17,64 For amitriptyline, the most frequent AEs were fatigue and dry mouth: the tricyclic antidepressant class, among other actions, exerts a significant antihistamine effect, particularly H1 receptor antagonism, which is known to cause dose-dependent fatigue; the second AE, relying on the antihistamine role, is a result of reduced salivary secretion.⁶⁵

For topiramate, the most frequent AEs were fatigue and paraesthesia: both could be explained by its GABAergic activity and the antagonizing of AMPA/kainate glutamate receptors, leading to symptoms such as paraesthesia and fatigue, similar to several antiepileptic drugs.⁶⁶ For onabotulinumtoxinA, the most frequent AEs was musculoskeletal pain. This AE is likely the result of two mechanisms: for the first, blocking the release of acetylcholine in the neuromuscular junction may interfere with normal muscle function; the second is tied to the procedure itself, which could provoke pain near the injection site.⁶⁷ For flunarizine, the most frequent AEs were fatigue and weight increase: these effects are due to its action as a non-selective calcium channel blocker with antihistaminic and antidopaminergic properties; antagonism of H1 receptors and D2 receptors leads to increased appetite and sedation with a dose-dependent effect.^68,69 For sodium valproate, the most frequent AEs was drowsiness. Indeed, because it is a CNS depressor, enhancing GABA levels and modulation of neuronal firing, this leads to a reduced neuronal excitability and sedation.⁷⁰ For propranolol, the most frequent AEs were drowsiness. Propranolol is a non-selective lipophilic β-blocker, crossing the blood–brain barrier, which exerts a CNS depressant effect, leading to this AE.⁷¹

Our results show consistency with those of a previous network meta-analysis,¹⁵ in which many drugs reported a higher incidence of side effects (e.g. those observed for topiramate and amitriptyline). This, in consideration of the modest efficacy profiles compared to placebo, with modest improvement of headache frequency and little or no enhancement of quality-of-life measures, should lead to a serious reconsideration of the choice of preventive pharmacological approach to migraine in populations of children and adolescents. These conflicting results should not lead to underestimate the migraine question in children and adolescent. Indeed, longitudinal evaluations showed that poor management and under treatment of migraine in young people lead to a high rate of chronification and possibility the development of psychiatric comorbidity in adults; moreover, adults who experienced untreated headaches in childhood reported lower life satisfaction and increased use of health services.^72,73

Our results revealed that these drugs exhibited different safety profiles, both in terms of frequency of AEs and the types of reported symptoms. Caution when using preventive therapy in paediatric migraine is needed: although these compounds were not associated with severe or life-threatening AEs, a comprehensive cost/benefit balance is essential, given the inconsistent efficacy profiles compared to placebo (except for topiramate) as reported in previous reviews.^14–16 In these populations, a multimodal approach that integrates behavioural and educational components along with pharmacological support, when needed, might be preferable.⁷⁴

Limitations

Caution is needed in interpreting these results because of selected paper differences with regard to overall quality, definitions of AEs and the diversity of the populations studied, and so the following limitations have to be acknowledged. First, heterogeneity between studies was generally high. Only the analysis of erenumab showed heterogeneity below 30%, suggesting greater consistency among the included subgroups and more reliable results. Second, the quality and availability of the data reported in the included studies varies due to differences in AE collection methods, follow-up duration, observation time, drug doses and diagnostic criteria. In almost all of the included studies, no severity stratification of AEs was available, making it impossible to produce information on this aspect: what can be stated is that no life-threating effects were reported. The dosage and duration of observation periods were often not comparable, even within studies involving the same drug. Variable duration of the follow-up period may lead to underestimation or overestimation of AEs. Third, the lack of a comparison group limits our ability to generalize the results.

Conclusions

In conclusion, the results of this systematic review with a meta-analysis showed that 30% of the paediatric patients with migraine are expected to experience some kind of AEs, with drowsiness, anorexia, fatigue and paraesthesia being the most frequently observed. Important differences were also observed across molecules, with erenumab showing the highest rate of AEs, most likely due to the higher-precision detection typical of a RCT, and cinnarizine the lowest.

The information on the safety profile for the molecules that can be used in the prophylaxis of migraine in cohorts of children and adolescents is essential for clinicians when evaluating the choice of a specific therapy, used alone or in combination with non-pharmacological approaches. Such information will make it possible to accurately assess of the risk/benefit ratio for the patient, which is crucial in consideration of the inconsistent efficacy profiles of pharmacological prophylaxis (except for topiramate) in this population.

Public health relevance

Migraine in children causes significant disability, yet preventive drug efficacy and safety remain a matter of debate.

Meta-analysis of 40 studies (2742 patients) found that 30% experienced adverse effects, mainly drowsiness, anorexia, fatigue and paraesthesia.

Safety data is crucial for clinicians to weigh risk/benefit, given the low efficacy of current prophylactic treatments.

Supplemental Material

sj-docx-1-cep-10.1177_03331024261441586 - Supplemental material for Iatrogenic harm in paediatric and adolescent populations of patients with migraine: A systematic review with meta-analysis

Supplemental material, sj-docx-1-cep-10.1177_03331024261441586 for Iatrogenic harm in paediatric and adolescent populations of patients with migraine: A systematic review with meta-analysis by Danilo Antonio Montisano, Gandini Giulia, Marcassoli Alessia, Corso Barbara, Grazzi Licia, Raggi Alberto and Parisi Alessandra in Cephalalgia

Supplemental Material

sj-xlsx-2-cep-10.1177_03331024261441586 - Supplemental material for Iatrogenic harm in paediatric and adolescent populations of patients with migraine: A systematic review with meta-analysis

Supplemental material, sj-xlsx-2-cep-10.1177_03331024261441586 for Iatrogenic harm in paediatric and adolescent populations of patients with migraine: A systematic review with meta-analysis by Danilo Antonio Montisano, Gandini Giulia, Marcassoli Alessia, Corso Barbara, Grazzi Licia, Raggi Alberto and Parisi Alessandra in Cephalalgia

Footnotes

Acknowledgements

AR and AM are supported by Italian Ministry of Health (RRC).

ORCID iDs

Danilo Antonio Montisano

Grazzi Licia

Raggi Alberto

Author contributions

DAM, AP, LG and AR conceptualized the study; AR, AM, GG and AP were responsible for checking the literature and selecting articles. BC was responsible for statistical analysis. DAM and AP were responsible for the main draft of the paper. All authors critically revised the paper.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

Declaration of conflicting interests

The author declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: DAM has received personal fee as speaker and travel grant from: AbbVie, Lundbeck, Pfizer and TEVA Pharm Ind. LG has received consultancy and advisory fees from: Abbvie, EliLilly, Lundbeck, Organon, Pfizer and TEVA Pharm Ind.

Data availability statement

The data used for this article may be obtained from the authors with a reasonable request.

Supplemental material

Supplemental material for this article is available online.

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