Optimizing migraine management in young patients

Migraine in children and adolescents is a neurological disorder that impacts quality of life, school performance and psychosocial development. In pediatric neurology practice, migraine is diagnosed in 50%–88% of headache encounters.1-3 This is unsurprising, given that migraine is highly disabling and very common,4 with a global prevalence of approximately 11% in children and adolescents.5 In Canada, migraine affects approximately 10% of children before puberty, with prevalence rising sharply to as high as 20%–25% during adolescence.5Migraine in children and adolescents has unique challenges, with great variability in presentation and the need to rely on caregiver information. Pharmacists have the unique opportunity to identify and address challenges with medication use for these patients, including suboptimal dosing or drug interactions.6 Recent reviews have shown that pharmacist-led migraine interventions improve medication adherence, patient counselling outcomes and therapeutic safety profiles.7,8This review provides pharmacists with guidance on acute and preventive treatments for migraine, adapted to children and adolescents (i.e., 6–17 years), migraine severity and the patient’s individual needs.Etiology and pathophysiologyMigraine is a neurological disorder characterized by recurrent moderate–severe headaches and associated symptoms that may include nausea, vomiting, and sensitivity to light and sound.9 Contemporary models conceptualize migraine as a complex brain network disorder involving altered sensory processing, dysregulated pain modulation, some vascular involvement and activation of the trigeminovascular system,7,10 rather than a purely vascular phenomenon.7,11 The activation of the trigeminovascular system, during the pain phase of migraine attacks, causes release of vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating peptide (PACAP) from trigeminal nerve endings around the dura and meningeal blood vessels.12 These mediators promote neurogenic inflammation, central sensitization and sustained nociceptive signalling that underlies migraine pain.10,11Migraine pathophysiology supports a multimodal treatment paradigm that integrates pharmacologic and nonpharmacologic strategies.7 Acute pharmacologic therapies aim to interrupt trigeminovascular nociceptive signalling early in an attack, while preventive agents target neuronal hyperexcitability, neurotransmitter dysregulation or CGRP pathways to reduce attack frequency and severity.7,13DiagnosisIn the absence of a reliable and clinically available biomarker, the diagnosis of migraine in children and adolescents is based clinically on the International Classification of Headache Disorders (ICHD) 3rd edition criteria. ICHD criteria include at least five attacks lasting two to 72 hours, with nausea/vomiting or photophobia and phonophobia, and at least two characteristic features (unilateral or bilateral frontotemporal pain, pulsating quality, moderate to severe intensity, or activity limitation).10Once migraine is diagnosed, management should prioritize timely, evidence-based treatment of acute attacks to restore function, and appropriate use of preventive therapy. For pharmacists, this means reinforcing early use of acute therapy, adherence to preventive regimens, avoidance of medication-overuse headache (MOH), and reinforcing behavioural and self-management strategies.Therapeutic managementEffective acute migraine management in children and adolescents requires early treatment, appropriate agent selection and avoidance of medication overuse.Long-term outcome studies have shown that a higher risk of chronification is associated with limited use or a poor response to acute treatment; prolonged pain exposure reinforces central sensitization in the brain and increases the risk of higher attack frequencies and more refractory disease over time.14 Treating migraine while pain is mild is also known to significantly improve two-hour pain relief and functional recovery.13,15-17 Using the acute-treatment summaries (Figures 1, 2) and dosing guidance in Table 1, pharmacists should reinforce limits on weekly medication use, to prevent MOH.Therapy selection should be individualized based on age, tolerability, cost and capacity to swallow solid dosage forms. The route of administration should be adapted to symptoms that are present during the attack (e.g., nausea and vomiting). Migraine attacks and their response to therapy can vary from one episode to another in terms of onset, intensity of symptoms and duration. Clinicians recommend prioritizing the medication that is the most effective at aborting all types of migraine attacks versus using multiple therapies for different types of attacks. When monotherapy does not provide adequate relief, combination therapy may be appropriate, particularly when medications target different aspects of the attack (e.g., analgesic therapy for pain and antiemetics for nausea).12,15 In adolescents, combination regimens, such as triptan–nonsteroidal anti-inflammatory drug (NSAID) therapy, have demonstrated improved efficacy compared with single agents in some studies.15,17Nonspecific acute therapyNonspecific acute therapies, including NSAIDs and acetaminophen, are recommended first-line treatments for mild-to-moderate pediatric migraine attacks.13,17 NSAIDs are preferred first-line agents due to their efficacy, accessibility and favourable risk–benefit profile.13,17 NSAIDs and acetaminophen are particularly appropriate for infrequent attacks, for use in combination with a triptan, or when migraine-specific therapy is contraindicated.7 Clear counselling regarding dosing, timing and expectations (e.g., partial versus complete pain relief, need for repeat dosing, expected onset of benefit) helps optimize response and prevent MOH.13a) First-line choice: NSAIDsClinical trials have shown that ibuprofen 10 mg/kg provides meaningful two-hour pain relief compared to placebo and acetaminophen.18,19 In older children and adolescents, tablets may be used when weight-based dosing aligns with available strengths, without exceeding adult maximum single-dose limits. Early administration improves outcomes.13 Ibuprofen may be repeated every six to eight hours within daily dosing limits and should be trialed across several attacks before being deemed ineffective.7,13Lack of improvement within two hours, repeated rescue medication use or ongoing functional impairment should prompt escalation to another NSAID or migraine-specific therapy.7,13 Naproxen may be considered in adolescents for prolonged attacks due to its longer half-life than ibuprofen, although pediatric comparative data are limited.17b) Alternative nonspecific therapy: AcetaminophenAcetaminophen is a reasonable alternative when NSAIDs are contraindicated or not tolerated.7,13 Although efficacy data suggest that acetaminophen is inferior to ibuprofen, guideline-based reviews support its use when administered early.13,17 Recommended dosing is 10–15 mg/kg per dose every four to six hours as needed, within age-appropriate maximum per dose and daily limits.13 As with NSAIDs, response, frequency of use and functional outcomes should be monitored, with reassessment if relief remains inadequate, along with monitoring for MOH.7,13Migraine-specific acute and adjunctive therapyMigraine-specific therapies are evidence-based first-line options for acute migraine in children and adolescents.13,17 In practice, they are often introduced after nonspecific treatments due to cost, access, insurance coverage or family preference rather than lack of efficacy.Triptans target the serotonin receptor and have been shown to decrease CGRP levels. They are appropriate for moderate attacks, rapidly escalating pain, or when nonspecific therapy provides inadequate relief despite correct dosing and timing.13,17 Therapy selection should focus on ensuring reliable and early treatment rather than framing prescription agents as “stronger.” Acute management may require a layered approach that addresses headache pain, nausea, vomiting and barriers to timely medication use.a) Acute therapyTriptans are first-line migraine-specific agents for moderate to severe attacks or inadequate response to nonspecific monotherapy.13,17 Network meta-analyses and guidelines demonstrate consistent efficacy for rizatriptan, sumatriptan and zolmitriptan in children and adolescents, with numbers needed to treat comparable to adults and no increase in serious adverse events.15,16,20Acute migraine treatment plans often combine a nonspecific medication (e.g., NSAID) with a triptan. Selection of a triptan and whether or not to combine it with a nonspecific therapy should be individualized based on age, prior response, formulation and attack characteristics.7,13Pharmacists should counsel using monthly guardrails rather than weekly limits. For MOH prevention when using triptans, combination analgesics or opioid-containing products, limit to 10 days or less per month; for nonspecific analgesics (NSAIDs or acetaminophen), limit to 15 days or less per month. These limits apply to total days of acute medication use, not per drug class. For example, if a patient uses an NSAID on five days and a triptan on five additional days, this represents 10 total acute-treatment days in that month.9,21Gepants (rimegepant, ubrogepant) are indicated for the acute treatment of migraine in adults. Studies in children and adolescents are ongoing at the time of publication of this review. Gepants are less effective than triptans in adults, but they are better tolerated, are not vasoconstrictors, and are not associated with MOH.22,23b) Adjunctive therapyAntiemetic medications are effective in providing relief to children and adolescents with prominent nausea or vomiting associated with their acute migraine attacks. They are particularly important to add in the acute treatment plan when these symptoms interfere with the tolerability or timely administration of oral acute migraine-specific treatment, when other medications are not effective for the nausea/vomiting, or when there is early vomiting (within the first hour).13,17,21Dopamine antagonists, such as metoclopramide and prochlorperazine, have demonstrated efficacy in reducing migraine-associated nausea and may also contribute to headache relief when used adjunctively.13,17 Pharmacists should counsel on sedation and extrapyramidal symptoms, and monitor for interactions or repeated use.7Ondansetron is also frequently used as an adjunct antiemetic, particularly to facilitate early oral intake of analgesics or triptans. While ondansetron does not treat migraine pain directly, it is well tolerated and can improve treatment success by enabling timely administration of acute migraine-specific therapy (Table 1; Figures 1, 2).7,13Antiemetics do not cause MOH; however, repeated use increases the risk of sedation, extrapyramidal symptoms and other adverse effects. In practice, many clinicians counsel limiting antiemetics to 10 days or less per month, particularly when dopamine antagonists are used.Preventive pharmacotherapyPreventive therapy is a key component of migraine care in children and adolescents, particularly for patients with four migraine days per month or more, significant disability, or inadequate response to acute treatment.20,24 Pharmacists can support appropriate initiation, safe titration, and integration of preventive therapy with behavioural strategies. They should also counsel on appropriate dosing, expected time to benefit (at least 4–8 weeks at target dose for oral preventives; at least a 3-month trial for anti-CGRP monoclonal antibodies) and the importance of an adequate trial with reassessment before deciding on continuation or discontinuation.Preventive pharmacotherapy can be optimized and individualized by screening for contraindications, anticipating adverse effects and monitoring needs (Table 2), reviewing headache diaries to confirm burden, assessing adherence, and identifying acute medication overuse during follow-up (Table 3).a) Traditional oral preventive agentsAmong pharmacologic preventive options, topiramate, amitriptyline and propranolol remain the most commonly used and best-studied agents for migraine prevention in children and adolescents. Evidence indicates that benefits are modest and variable, with substantial placebo response observed across pediatric preventive trials. Amitriptyline and propranolol demonstrated small but statistically significant effects in pooled analyses, although responses were inconsistent across individual studies.20,24 However, the Childhood and Adolescent Migraine Prevention (CHAMP) trial—a large randomized controlled study—found that amitriptyline and topiramate were not superior to placebo for reducing headache frequency and were associated with higher rates of adverse events.25These findings support a structured, trial-based approach to prevention. Pharmacists should reinforce slow titration to a defined target dose and counsel families that benefit should be assessed only after six to eight weeks at the goal dose, provided the medication is tolerated. Early reassessment during titration may underestimate effectiveness.Treatment goals should focus on clinically meaningful improvement, commonly defined in trials as a substantial reduction in monthly migraine days (often 50% or more), along with improved function and reduced reliance on acute medication.20,24 Pharmacists play a key role in reinforcing adherence during this period, monitoring adverse effects and guiding reassessment before discontinuation.b) CGRP monoclonal antibodiesFremanezumab, one of the anti-CGRP monoclonal antibodies used for migraine prevention, was recently approved by Health Canada for the prevention of episodic migraine in children and adolescents weighing ≥ 45 kg. It is the first on-label migraine preventive treatment for children and adolescents in Canada and is likely to become more frequently encountered in outpatient pharmacy practice going forward.26 Fremanezumab is administered as a monthly subcutaneous (SC) injection, with autoinjector devices enhancing ease of use for adolescents. Common side effects include injection site reactions, while serious adverse events (such as allergic reactions or vascular symptoms) are uncommon.27,28Pharmacists’ scope of practice has expanded to include administration of subcutaneous medications and vaccines in many Canadian jurisdictions; however, authorization and pediatric injection training requirements vary by province. Pharmacists play an important role in patient and caregiver education on SC injection technique, site rotation, aseptic practices, adherence reinforcement, monitoring for potential side effects and appropriate sharps disposal.7,29 Access to these medications may be restricted by public or private payer criteria, and some patients may require prior authorization or enrollment in manufacturer support programs depending on provincial coverage policies.Other CGRP-targeted monoclonal antibodies (erenumab, galcanezumab) and oral CGRP receptor antagonists (“gepants”) used for prevention (e.g., atogepant) are approved for adult migraine prevention, with pediatric trials ongoing.30-33 Theoretical risks of CGRP blockade in children and adolescents include effects on bone metabolism, pubertal development and wound healing, given the role of CGRP in developmental and vascular processes.34 Pharmacists should counsel on evolving evidence and support shared decision-making when these therapies are prescribed.OTC preventive optionsOver-the-counter (OTC) supplement-based preventive options, including magnesium, riboflavin (vitamin B₂), and coenzyme Q10, are commonly used in children and adolescents with migraine because of their favourable safety profiles and accessibility.25 Evidence suggests that magnesium may reduce migraine frequency and severity, while riboflavin and coenzyme Q10 may provide benefit in selected children and adolescents with migraine.7,35-37 Pharmacists should counsel patients about potential gastrointestinal adverse events with magnesium (gastrointestinal upset, diarrhea) and coenzyme Q10 (increased eructation), and about orange discolouration of the urine with riboflavin.Self-management and behavioural InterventionsSelf-management strategies, including regular sleep routines, adequate hydration, consistent meal timing and routine physical activity, are recommended for all children and adolescents with migraine, either alone or in combination with pharmacologic preventive therapy depending on the clinical scenario and patient preferences.7,17 When reinforced through structured pharmacist counselling and follow-up, these interventions represent a core component of sustainable and effective long-term migraine prevention and management (Figures 1, 2; Table 3).SummaryMigraine is a very common yet frequently underrecognized source of disability among Canadian children and adolescents. The evidence synthesized in this review supports a proactive and multidisciplinary approach to migraine management in children and adolescents. Early and appropriate use of acute migraine therapy are key determinants of treatment success and significantly increase the likelihood of rapid pain relief and functional recovery in pediatric patients.15-17 Ineffective or delayed acute treatment may lead to prolonged exposure to pain and contribute to poorer long-term outcomes.14 For patients with higher attack frequency or migraine-related disability, preventive pharmacotherapy plays an important role in reducing migraine burden and improving functional outcomes.Alongside other healthcare providers, pharmacists play a central role in acute and preventive migraine therapies. Their contributions span four interrelated domains: early intervention, medication safety, prevention of MOH, and support for prevention; all four are grounded in high-level evidence and are known to substantially improve outcomes for children and adolescents living with this disabling chronic neurological disease.Ariane Blanc (ablanc@cheo.on.ca) is the Director of Pharmacy at the Children’s Hospital of Eastern Ontario (CHEO) in Ottawa, ON, and CHEO Research Institute research investigator. Serena L. Orr is a pediatric neurologist and clinician-scientist at the Cumming School of Medicine, University of Calgary, Alberta Children’s Hospital Research Institute and Hotchkiss Brain Institute in Calgary, AB. Alexandra Julia Faber is a pediatric neurologist, City Pediatric Specialty Group, Vancouver, BC and a member of the Faculty of Medicine, Department of Pediatrics, University of British Columbia. Elizabeth Leroux is a neurologist and national migraine expert, Montreal Neurological Clinic in Montreal, QC. Wendy Gerhart is the Executive Director of Migraine Canada. Jameason D. Cameron (jcameron@cheo.on.ca) is a pharmacy researcher and project coordinator at the Children’s Hospital of Eastern Ontario (CHEO) in Ottawa, ON and CHEO Research Institute. The authors acknowledge the assistance of CHEO pharmacy students Grace Liu, Mia Lefebvre and Ny Ako Ndrianjasoazanany.References: Curless RG. Diagnostic problems in three pediatric neurology practice plans. Pediatric Neurology 1998;19(4):272-4. doi: 10.1016/s0887-8994(98)00056-3.Raieli V, Giordano G, Spitaleri C, et al. Migraine and cranial autonomic symptoms in children and adolescents: a clinical study. J Child Neurol 2015;30(2):182-6. doi:10.1177/0883073814535494.Pedraza MI, Mulero P, Ruíz M, et al. Characteristics of the first 2000 patients registered in a specialist headache clinic. 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Optimizing migraine management in young patients

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