Clinical predictors of propranolol responsiveness in pediatric migraine: a prospective observational study

Background: This study aimed to evaluate the comparative effectiveness of propranolol therapy and structured behavioral interventions in reducing headache severity in pediatric patients and to identify predictors of treatment response. Methods: In this prospective, single-center study, 178 pediatric patients diagnosed with migraine based on the International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria were enrolled. Participants were allocated into two groups according to baseline Pediatric Migraine Disability Assessment Scale (PedMIDAS) scores: Group 1 (PedMIDAS <15, n = 88) received standardized behavioral therapy, while Group 2 (PedMIDAS ≥15, n = 90) received propranolol (1–3 mg/kg/day) for 12 weeks. Primary outcomes were predefined as changes in monthly migraine attack frequency, PedMIDAS scores, and Visual Analog Scale (VAS)-measured headache intensity. Vitamin D deficiency and vitamin B12 deficiency were evaluated as biochemical predictors, and adherence was monitored bi-weekly. Results: Both groups showed significant improvement at week 12. Monthly migraine attacks declined from 3.5± 1.6 to 2.1 ± 1.2 in Group 1 and from 6.4 ± 2.1 to 3.1 ± 1.7 in Group 2. PedMIDAS scores decreased from 8.60 ± 3.25 to 5.75 ± 2.52 and 24.40 ± 9.65 to 16.11 ± 7.72, respectively (p < 0.001 both). VAS scores also improved in both groups with no significant between-group difference in percentage reduction. A ≥50%reduction in attack frequency plus ≥1-grade PedMIDAS improvement defined treatment response. In the propranolol group, response was independently associated with benign paroxysmal vertigo and essential tremor, while vitamin D and vitamin B12 deficiency predicted poorer outcomes. Conclusions: Both propranolol and structured behavioral therapy effectively reduce migraine-related disability and pain in pediatric patients, yielding comparable proportional improvements. The identification of key clinical and biochemical predictors supports a personalized treatment approach, integrating comorbidity screening and nutritional assessment to optimize outcomes. Clinical Trial Registration: ClinicalTrials.gov/NCT07180043, retrospectively registered.

Pediatric migraine; Propranolol; Behavioral therapy; PedMIDAS; Personalized treatment

[1] Onofri A, Pensato U, Rosignoli C, Wells-Gatnik W, Stanyer E, Ornello R, et al. Primary headache epidemiology in children and adolescents: a systematic review and meta-analysis. The Journal of Headache and Pain. 2023; 24: 8.

[2] Szperka CL. Headache in children and adolescents. Continuum: Lifelong Learning in Neurology. 2021; 27: 703–731.

[3] Headache classification committee of the international headache society (IHS). The international classification of headache disorders, 3rd edition. Cephalalgia. 2018; 38: 1–211.

[4] Abu-Arafeh I, Razak S, Sivaraman B, Graham C. Prevalence of headache and migraine in children and adolescents: a systematic review of population-based studies. Developmental Medicine & Child Neurology. 2010; 52: 1088–1097.

[5] Orr SL, Kabbouche MA, O’Brien HL, Kacperski J, Powers SW, Hershey AD. Paediatric migraine: evidence-based management and future directions. Nature Reviews Neurology. 2018; 14: 515–527.

[6] Headache classification committee of the international headache society (IHS). The International Classification of headache disorders, beta version. Cephalalgia. 2013; 33: 629–808.

[7] Khan A, Liu S, Tao F. Current trends in pediatric migraine: clinical insights and therapeutic strategies. Brain Sciences. 2025; 15: 280.

[8] Kroon Van Diest AM, Powers SW. Cognitive behavioral therapy for pediatric headache and migraine: why to prescribe and what new research is critical for advancing integrated biobehavioral care. Headache. 2019; 59: 289–297.

[9] Puledda F, Silva EM, Suwanlaong K, Goadsby PJ. Migraine: from pathophysiology to treatment. Journal of Neurology. 2023; 270: 3654–3666.

[10] Chowdhury D, Bansal L, Duggal A, Datta D, Mundra A, Krishnan A, et al. TOP-PRO study: a randomized double-blind controlled trial of topiramate versus propranolol for prevention of chronic migraine. Cephalalgia. 2022; 42: 396–408.

[11] Peng J, Liu L, Li Q, Liu M, Zhou R, Chen L, et al. Efficacy and safety of levetiracetam for migraine prophylaxis in children: a systematic review and meta-analysis. Frontiers in Pharmacology. 2024; 15: 1407897.

[12] Keerthana D, Mishra D, Chauhan MK, Juneja M. Effect of propranolol prophylaxis on headache frequency in children with migraine without aura: a randomized, double-blind, placebo-controlled trial. Indian Journal of Pediatrics. 2023; 90: 880–885.

[13] Pelzer N, de Boer I, van den Maagdenberg AM, Terwindt GM. Neurological and psychiatric comorbidities of migraine: concepts and future perspectives. Cephalalgia. 2023; 43: 03331024231180564.

[14] Altamura C, Corbelli I, De Tommaso M, Di Lorenzo C, Di Lorenzo G, Di Renzo A, et al. Pathophysiological bases of comorbidity in migraine. Frontiers in Human Neuroscience. 2021; 15: 640574.

[15] Saniasiaya J, Salim R. Characteristics and diagnostic approach of vestibular migraine in children and adolescents: a systematic review. Auris Nasus Larynx. 2023; 50: 218–227.

[16] Hao S, Qian R, Chen Y, Liu J, Xu X, Guan Y. Association between serum vitamin D and severe headache or migraine: a population-based analysis. PLOS ONE. 2025; 20: e0313082.

[17] Aydin H, Bucak IH, Geyik M. Vitamin B12 and folic acid levels in pediatric migraine patients. Acta Neurologica Belgica. 2021; 121: 1741–1744.

[18] Ghorbani Z, Togha M, Rafiee P, Ahmadi ZS, Rasekh Magham R, Haghighi S, et al. Vitamin D in migraine headache: a comprehensive review on literature. Neurological Sciences. 2019; 40: 2459–2477.

[19] Sadeghvand S, Barzegar M, Shiva S, Tarmahi V, Hamed H, Khamaneh ER, et al. The effects of vitamin B-complex supplementation on serum homocysteine levels and migraine severity in children: a randomized controlled trial. Iranian Journal of Child Neurology. 2023; 17: 143.

[20] Rastogi RG, Arnold TL, Borrero-Mejias C, Hastriter EV, Hickman C, Karnik KT, et al. Non-pharmacologic and mindful-based approaches for pediatric headache disorders: a review. Current Pain and Headache Reports. 2021; 25: 78.

[21] Locher C, Kossowsky J, Koechlin H, Lam TL, Barthel J, Berde CB, et al. Efficacy, safety, and acceptability of pharmacologic treatments for pediatric migraine prophylaxis: a systematic review and network meta-analysis. JAMA Pediatrics. 2020; 174: 341–349.

[22] Noser AE, Gibler RC, Ramsey RR, Wells RE, Seng EK, Hommel KA. Digital headache self-management interventions for patients with a primary headache disorder: a systematic review of randomized controlled trials. Headache. 2022; 62: 1105–1119.

[23] Zhang J, Guo Y, Su J, Wang M, Zhang G, Zhou H, et al. Clinical features of benign paroxysmal positional vertigo in children. Journal of Clinical Otorhinolaryngology Head and Neck Surgery. 2025; 39: 243–249.

[24] Zhang J, Yan R, Cui Y, Su D, Feng T. Treatment for essential tremor: a systematic review and Bayesian model-based network meta-analysis of RCTs. EClinicalMedicine. 2024; 77: 102037.

[25] Szeleszczuk Ł, Frączkowski D. Propranolol versus other selected drugs in the treatment of various types of anxiety or stress, with particular reference to stage fright and post-traumatic stress disorder. International Journal of Molecular Sciences. 2022; 23: 10099.

[26] Ioannidou E, Tsakiris C, Goulis DG, Christoforidis A, Zafeiriou D. The association of serum vitamin D concentrations in paediatric migraine. European Journal of Paediatric Neurology. 2023; 47: 60–66.

[27] Boyce TG, Ballone NT, Certa KM, Becker MA. The use of β-adrenergic receptor antagonists in psychiatry: a review. Journal of the Academy of Consultation-Liaison Psychiatry. 2021; 62: 404–412.

[28] Nematgorgani S, Razeghi-Jahromi S, Jafari E, Togha M, Rafiee P, Ghorbani Z, et al. B vitamins and their combination could reduce migraine headaches: a randomized double-blind controlled trial. Current Journal of Neurology. 2022; 21: 105.

[29] Suliman O, Abutwaimah J, Abutwaimah A, Alhusayni M, Albader D, Abd Elmagid A, et al. Recommendations for the management of migraine in paediatric patients: a systemic review. Journal of Advances in Medicine and Medical Research. 2025; 37: 275–288.

[30] Liampas I, Siokas V, Bakirtzis C, Dardiotis E. Vitamin B12, folate, and migraine. In Smith JA, Brown LM (eds.) Vitamins and minerals in neurological disorders (pp. 309–322). Oxford University Press: Oxford. 2023.

[31] Maiese K. Migraine disorders, neurovascular disease, and the underlying role of oxidative stress. Current Neurovascular Research. 2024; 21: 111–115.

[32] Blumenfeld A, McVige J, Knievel K. Post-traumatic headache: Pathophysiology and management—a review. Journal of Concussion. 2022; 6: 1–10.

[33] Godley F III, Meitzen J, Nahman-Averbuch H, O’Neal MA, Yeomans D, Santoro N, et al. How sex hormones affect migraine: an interdisciplinary preclinical research panel review. Journal of Personalized Medicine. 2024; 14: 184.