Headaches in children and adolescents have high incidence and prevalence rates, with consequent elevated costs to individuals and the community [1]. The prevalence of headaches varies considerably approximatively from 5.9 to 88% [2,3] depending on diagnostic criteria and age, reaching a peak at about 11–13 years of age [3] with migraine and tension-type headache as the most predominant forms. The frequency is higher in males before puberty, with an inverse relationship thereafter [4,5]. Pediatric migraine is a potentially disabling disorder that has substantial clinical differences compared to the adult form. The average prevalence of migraine ranges from 8% to 24% in school-aged children [6]; among these, 0.6 to 1.8% of adolescents and 0.6% of children have a diagnosis of chronic migraine (defined as more than 15 days with headache per month, of which there are ≥8 migraine days) [7,8]. The diagnosis of primary headaches in pediatric patients follows the criteria of the International Headache Society (IHS) [9]. Overall, these criteria could have some limitations that apply to the pediatric age, and the latest version (ICHD 3) [9] addresses some specifics of migraine in pediatric age, such as shorter duration (less than 4 h) and unilateral/bilateral localization of pain [10].

Evidence-based support for the treatment of pediatric migraine remains unsatisfactory as not many specific clinical studies on acute and preventative therapies have been carried out at present. Few clinical trials have been designed and performed in pediatric patients, and conflicting results are often reported [11,12]. Furthermore, randomized controlled trials (RCTs) in the pediatric age group studying the efficacy of preventive migraine medications have reported inconsistent results. The high impact of the placebo effect in young migraineurs [13,14], with a great reduction in both the frequency and intensity of migraine attacks in the placebo arm, is probably one of the reasons for the many discrepant RTCs [15]. The placebo effect, although useful in clinical practice, represents an unsurmountable bias in both pharmacological and non-pharmacological interventional studies [16,17]. Recently, the Childhood and Adolescent Migraine Prevention (CHAMP) trial [18] compared the effects of amitriptyline and topiramate against placebo in pediatric migraine. The trial, which was stopped early owing to futility, showed no significant differences in reductions in headache frequency or headache-related disability over a period of 24 weeks, and the active drugs showed higher rates of adverse events [18,19]. These findings could suggest that the adult model of headache treatment may not apply to pediatric patients, considering that these drugs are effective in adults as reported by clinical trials and observational studies [20].

In recent years, significant advancements have been made in the acute and preventive treatment of migraine and cluster headache. The development of small molecules (gepants) and monoclonal antibodies against the proalgesic neuropeptide, the calcitonin gene-related protein (CGRP) and its receptor [20,21], and serotonin receptor 5-HT_1F agonists (ditans) [22] has substantially changed migraine patient care. However, RTCs on these new drugs in the pediatric population are ongoing, meaning that evidence-based guidance for these patients is still unavailable.

2. Diagnosis and Current Evidence-Based Management

The ICHD has been highly successful in diagnosing children and adolescents to be enrolled in clinical trials. In the latest version, ICHD-3, notes and comments were used to distinguish the specific features of pediatric migraine, including shorter duration, frontotemporal location, and allowance for parental observation [9,10]. For children and adolescents, the duration of a migraine attack is reduced to 2–72 h, recognizing that children and adolescents may have headaches of a shorter duration. Furthermore, the characteristics of headache in children are not those typical of adults, and therefore it may be necessary to infer the symptoms from the child’s behavior during the attack itself. To establish the diagnosis, a detailed medical history and physical exam should be performed. The family and patient should be provided with an individualized treatment plan for their headaches, inclusive of medications and/or accommodations the child may need to receive at school [10,23].

Practice guidelines on acute and preventative treatments for migraine in children and adolescents have recently been published by the American Academy of Neurology (AAN) [12,24]. They systematically assessed all RCTs that evaluate acute and preventative migraine treatments in children and adolescents for assessing efficacy compared with placebo. However, they excluded non-pharmacologic therapies and nutraceuticals [25]. Outcomes such as headache pain and associated symptom reduction and freedom from headache were used for acute treatments, whereas headache frequency reduction was used for preventative treatments.

2.1. Acute Treatments

For the treatment of acute migraine, the recommendations focus on the importance of early treatment, choosing the route of administration best suited to the characteristics of the individual migraine attack and providing counselling on lifestyle factors that can exacerbate migraine, including trigger avoidance and medication overuse [24]. There is evidence to support the efficacy of the use of ibuprofen, acetaminophen (in children and adolescents), and triptans (mainly in adolescents) for the relief of migraine pain, although the evidence varies for each agent. There is high confidence that adolescents receiving oral sumatriptan/naproxen and zolmitriptan nasal spray are more likely to be headache-free at 2 h than those receiving placebo [24].

About one-third of pediatric patients with migraine remain refractory to acute therapies, and prolonged painful migraine sometimes requires emergency department (ED) management with intravenous (IV) treatments. However, the choice of therapy varies widely in different EDs and there is still no consensus regarding the use of various IV treatments in children and adolescents [26]. Common intravenous treatments for migraine in the pediatric population have recently been reviewed [4,26].

2.2. Preventative Treatments

Regarding preventative treatment, the above-mentioned CHAMP study [18,19] demonstrated that, contrary to adults, amitriptyline and topiramate do not show a favorable risk–benefit profile for use in pediatric migraine prevention over at least 24 weeks. The AAN guidelines have reported that there is insufficient evidence to determine if children and adolescents receiving divalproex, onabotulinumtoxinA, nimodipine, or flunarizine are more or less likely than those receiving placebo to have a reduction in headache frequency [12]. Children with migraine who receive propranolol could be more likely than those receiving placebo to have a reduction of at least 50% in headache frequency. Overall, those receiving topiramate and cinnarizine are probably more likely than those receiving placebo to have a decrease in headache frequency. Children with migraine receiving amitriptyline plus CBT are more likely than those receiving amitriptyline plus headache education or amitriptyline alone to have a reduction in headache frequency [12].

Although results from RCTs in children and adolescents are not yet available for antibodies or small molecules against the CGRP pathway, the American Headache Society (AHS) has proposed recommendations on the use of these drugs for pediatric headache disorders [27]. The authors suggested that the use of CGRP receptor antagonists could be considered in adolescent patients with frequent migraine attacks (≥8 headache days/month), with moderate to severe disability associated with migraine (evaluated with a PedMIDAS score of ≥30), and who have failed ≥2 preventive therapies [27]. For younger patients who are refractory to multiple preventive therapies, CGRP receptor antagonists may also be considered with proper monitoring (e.g., bone health, linear growth, weight/BMI, and infections) [17,27]. As reported below, several RTCs testing anti-CGRP antibodies and small molecules are ongoing.

3. Drugs under Development

Recently, the International Headache Society developed ad hoc guidelines to assist in the design and execution of well-controlled clinical trials of pharmaceuticals, biologics, devices, and behavioral preventative interventions in children and adolescents with migraine [28]. The recommendations include participant features, trial design, outcome measures and endpoints, statistics, and others. Considering the high placebo effect and the inconsistency of the results of several RCTs in pediatric populations [11,15,18], some recommendations are fundamental to properly design trials and perform enrolment. For instance, age at entry must assure adequate age strata, defining children as participants aged 6 to 11 years, and adolescents as participants aged 12 to 17 years. Data on participants younger than 6 years of age should be considered as observational and safety testing. A minimum 28-day prospective baseline period followed by a treatment period of at least 12 weeks is recommended. The authors defined two possible primary efficacy endpoints: change in headache frequency, as measured by headache days or migraine days, and a 50% responder rate, as measured by migraine days [28]. No guidelines for controlled trials with acute treatments have been published to date by IHS. Several clinical trials are currently ongoing in pediatric patients with migraine.

3.1. Literature Search Strategy

We searched (January 2022) MEDLINE (accessed by PubMed), the Cochrane Central Register of Controlled Trials (CENTRAL), and the US National Institute of Health Clinical Trials Registry (www.Clinicaltrials.gov [accessed on 22 January 2022]) for active, ongoing trials involving pharmacological treatments in the pediatric population (defined as patients aged <18 years) with migraine. The search terms were (migraine OR chronic migraine OR episodic migraine) AND (children OR adolescents OR pediatric). Therefore, we selected only interventional studies with active status (i.e., excluding completed, suspended, terminated, withdrawn, and unknown status studies), involving pharmacological treatments regardless of recruitment status. Non-pharmacological devices, cognitive behavioral therapy (CBT), and techniques such as acupuncture were excluded. There were no date limitations or language restrictions.

3.2. Preventative Treatments

Of 14 active clinical trials, regardless of the phase, 10 (71.4%) involve an mAbs against the CGRP pathway or gepants. Specific study features, including primary endpoint, status, and age range, are reported in Table 1. In recent years, several anti-CGRP drugs have been marketed, including gepants, small molecule CGRP receptor antagonists (i.e., rimegepant, ubrogepant, and atogepant) and CGRP-pathway-targeted mAbs (i.e., erenumab, eptinezumab, fremanezumab, and galcanezumab) [29]. Several clinical trials and real-world observational studies have consistently demonstrated their effectiveness and tolerability for the acute or preventive treatment of migraine in adults [30]. Considering the breakthrough impact of drugs acting on the CGRP pathways in adults, it is expected that the majority of ongoing RCTs in pediatrics involve small molecules or monoclonal antibodies already approved for patients > 18 years.

In particular, three studies (two phase III and one phase I) [31,32,33] are assessing erenumab in episodic and chronic migraine; two phase III studies are investigating galcanezumab in episodic and chronic migraine [34,35]; one phase III study is evaluating fremanezumab [36]; and three studies (two phase III and one phase I) are investigating eptinezumab [37,38,39]. All these studies are active with ongoing recruitment. One phase III study is assessing rimegepant as a preventative drug in episodic migraine, but recruitment has not yet started [40].

Table 1. Ongoing studies on preventative treatments in the pediatric population.

Treatments and Comparators	Status	Phase	Diagnosis	Age Range	Primary Endpoint	Planned Patients/Treatment Duration	Trial Number
1. Alpha lipoic acid 300mg 2. Flunarizine 5 mg	Recruiting	IV; open label	Chronic migraine	10 to 19 Years	Mean monthly migraine attack rate	60/12 weeks	NCT04064814 [41]
Erenumab three doses adjusted by weight	Recruiting	I; open label	Migraine with or without aura	6 to 17 Years	Serum PK parameter Cmax, tmax, AUC 0–28 days, Cthrough; treatment emergent adverse events; heart rate; body temperature; blood pressure; duration and morphology of P, QRS, and T waves in ECG; standard hematology lab assessment and chemistry; standard sensory and motor assessment of body and PNS and CNS	60/12 up to 52 weeks	NCT03499119 [31]
1. Erenumab three doses adjusted by weight 2. Placebo	Recruiting	III	Episodic migraine with or without aura	6 to 11 Years; 12 to 17 years	Change from baseline in MMDs	456/12 weeks	NCT03836040 [32]
1. Erenumab three doses adjusted by weight 2. Placebo	Recruiting	III	Chronic migraine	6 to 11 Years; 12 to 17 years	Change from baseline in MMDs	286/12 weeks	NCT03832998 [33]
Eptinezumab adjusted by weight	Recruiting	I	Migraine with or without aura	6 to 17 Years	Area under curve (AUC) (0–infinity) eptinezumab; Cmax eptinezumab	32/20 weeks	NCT04537429 [37]
Eptinezumab 100 mg IV or 300 mg IV adjusted by weight	Recruiting	III	Migraine with or without aura and chronic migraine	6 to 17 Years	Number of participants with treatment-emergent adverse events	610/44 weeks	NCT05164172 [38]
1. Eptinezumab (300 or 100 mg IV adjusted by weight) 2. Placebo	Recruiting	III	Chronic migraine	12 to 17 Years	Change from baseline in MMDs averaged over weeks 1–12	285/12 weeks	NCT04965675 [39]
Fremanezumab dose adjusted by weight	Recruiting	III; open label	Migraine with or without aura and chronic migraine	6 to 17 Years	Incidence of AEs; incidence of participants with clinically significant changes in laboratory values; incidence of abnormal ECG findings; incidence of abnormal vital signs; incidence of abnormal physical examination findings; suicidal ideation	550/56 weeks	NCT04530110 [36]
1. Galcanezumab 2. Placebo	Recruiting	III	Migraine with or without aura	6 to 17 Years	Change from baseline in the number of monthly migraine headache days	325/3 months	NCT03432286 [34]
1. Galcanezumab 2. Placebo	Recruiting	III	Chronic migraine	12 to 17 Years	Change from baseline in the number of monthly migraine headache days	300/3 months	NCT04616326 [35]
1. OnabotulinumtoxinA 2. Placebo	Active, not recruiting	II	Chronic migraine	8 to 17 Years	Pain scores (intensity); change in duration of migraine episode; frequency of migraine; PedMIDAS scoring reduction; opioid consumption	26 patients/48 weeks	NCT03055767 [42]
1. Rimegepant 75 or 50 mg 2. Placebo	Active, not yet recruiting	III	Episodic migraine with or without aura	6 to 17 Years	Change from baseline in the mean number of migraine days per month as measured over the 12-week double-blind phase	1100/12 weeks	NCT05156398 [40]
1. Topiramate ER capsules 2. Placebo	Recruiting	IV	Migraine with or without aura	6 to 11 Years	Frequency of migraine attack per 28 days during the treatment phase.	162/28 days	NCT04050293 [43]
1. Topiramate ER capsules 2. Placebo	Recruiting	IV	Migraine with or without aura	6 to 11 Years	Change from baseline (last 28 days run-in period) in the monthly number of headache days during the 8-week maintenance period based on the diary.	132/16 weeks	NCT04748601 [44]

AE, adverse events; CNS, central nervous system; ECG, electrocardiogram; ER, extended release; MMDs monthly migraine days; NA, not applicable; PedMIDAS, Pediatric Migraine Disability Assessment; PNS, peripheral nervous system.