{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T01:15:22Z","timestamp":1783473322729,"version":"3.55.0"},"reference-count":56,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T00:00:00Z","timestamp":1620864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Headache is the most common pain complaint in the pediatric population, with tension type headache (TTH) having a prevalence of 10\u201315% in children. Up to 70% of pediatric patients with chronic headache also experience sleep disruption, with a likely bidirectional relationship between headache and poor sleep. Treatment options include specific pharmacological approaches as well as non-pharmacological alternatives; nutraceuticals have the advantage of a relative lack of side effects. Exogenous melatonin has been shown to be useful and safe in improving sleep-wake cycles and quality of sleep in children, helping to regulate the circadian rhythm, with a secondary positive impact on headache. Supplementation with other nutraceutical ingredients, such as tryptophan, magnesium, and B vitamins, can have significant additional effects in children with primary headache, with or without sleep disorders. Tryptophan may reduce night awakenings and improve the efficiency of sleep. Primary headache has been related to low amounts of magnesium in serum, and integration with magnesium appears to be effective in reducing headache attacks without adverse effects. There are different observational reports and uncontrolled studies suggesting a possible synergistic effect for these nutraceuticals, but there is now a need for high-quality randomized controlled trials in order to confirm these positive preliminary findings.<\/jats:p>","DOI":"10.3390\/nu13051631","type":"journal-article","created":{"date-parts":[[2021,5,13]],"date-time":"2021-05-13T03:08:12Z","timestamp":1620875292000},"page":"1631","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Use of Nutraceutical Ingredient Combinations in the Management of Tension-Type Headaches with or without Sleep Disorders"],"prefix":"10.3390","volume":"13","author":[{"given":"Paolo","family":"Curatolo","sequence":"first","affiliation":[{"name":"Child Neurology and Psychiatry Medicine, Systems Medicine Department, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6200-060X","authenticated-orcid":false,"given":"Romina","family":"Moavero","sequence":"additional","affiliation":[{"name":"Child Neurology and Psychiatry Medicine, Systems Medicine Department, Tor Vergata University of Rome, Via Montpellier 1, 00133 Rome, Italy"},{"name":"Child Neurology Unit, Neuroscience Department, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"678","DOI":"10.3399\/bjgp09X454142","article-title":"Impact of headache on young people in a school population","volume":"59","author":"Kernick","year":"2009","journal-title":"Br. J. Gen. Pr."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Leonardi, M., Grazzi, L., D\u2019Amico, D., Martelletti, P., Guastafierro, E., Toppo, C., and Raggi, A. (2020). Global Burden of Headache Disorders in Children and Adolescents 2007\u20132017. Int. J. Environ. Res. Public Heal., 18.","DOI":"10.3390\/ijerph18010250"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1111\/j.1469-8749.2010.03793.x","article-title":"Prevalence of headache and migraine in children and adolescents: A systematic review of population-based studies","volume":"52","author":"Razak","year":"2010","journal-title":"Dev. Med. Child Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/0333102417738202","article-title":"Headache Classification Committee of the International Headache Society (IHS) The International Classification of Headache Disorders, 3rd edition","volume":"38","author":"Olesen","year":"2018","journal-title":"Cephalalgia"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Genizi, J., Bugdnoskya, V., Aboud, A., Segal, I., Assaf, N., Srugo, I., and Kerem, N.C. (2021). Migraine and Tension-Type Headache Among Children and Adolescents: Application of International Headache Society Criteria in a Clinical Setting. J. Child Neurol., 883073820988417.","DOI":"10.1177\/0883073820988417"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ashina, S., Buse, D.C., Bjorner, J.B., Bendtsen, L., Lyngberg, A.C., Jensen, R.H., and Lipton, R.B. (2021). Health-related quality of life in tension-type headache: A population-based study. Scand. J. Pain.","DOI":"10.1515\/sjpain-2020-0166"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1016\/j.clinph.2010.12.061","article-title":"The contribution of clinical neurophysiology to the comprehension of the tension-type headache mechanisms","volume":"122","author":"Rossi","year":"2011","journal-title":"Clin. Neurophysiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1007\/s11916-009-0078-x","article-title":"Advances in the pathophysiology of tension-type headache: From stress to central sensitization","volume":"13","author":"Chen","year":"2009","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0306-4522(99)00028-7","article-title":"Central serotonin depletion modulates the behavioural, endocrine and physiological responses to repeated social stress and subsequent c-fos expression in the brains of male rats","volume":"92","author":"Chung","year":"1999","journal-title":"Neuroscience"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1136\/jnnp.52.2.182","article-title":"Plasma serotonin in patients with chronic tension headaches","volume":"52","author":"Anthony","year":"1989","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s10072-015-2131-3","article-title":"Biochemistry of primary headaches: Role of tyrosine and tryptophan metabolism","volume":"36","author":"Cevoli","year":"2015","journal-title":"Neurol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1007\/s10072-014-1867-5","article-title":"Tryptamine levels are low in plasma of chronic migraine and chronic tension-type headache","volume":"35","author":"Bussone","year":"2014","journal-title":"Neurol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1111\/head.13207","article-title":"Pediatric Headache and Sleep Disturbance: A Comparison of Diagnostic Groups","volume":"58","author":"Rabner","year":"2017","journal-title":"Headache J. Head Face Pain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1111\/j.1526-4610.2007.00885.x","article-title":"Primary Headache and Sleep Disturbances in Adolescents","volume":"47","author":"Gilman","year":"2007","journal-title":"Headache J. Head Face Pain"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.pediatrneurol.2006.11.006","article-title":"Prevalence of Headache and its Association with Sleep Disorders in Children","volume":"36","author":"Isik","year":"2007","journal-title":"Pediatr. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/s10194-011-0397-2","article-title":"The prevalence of triggers in paediatric migraine: A questionnaire study in 102 children and adolescents","volume":"13","author":"Neut","year":"2011","journal-title":"J. Headache Pain"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S1087-0792(03)00044-3","article-title":"How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literatur?","volume":"8","author":"Smith","year":"2004","journal-title":"Sleep Med. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.3389\/fneur.2018.01009","article-title":"Non-pharmacological Approaches for Headaches in Young Age: An Updated Review","volume":"9","author":"Andrasik","year":"2018","journal-title":"Front. Neurol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/S0387-7604(00)00120-0","article-title":"The therapeutics of melatonin: A paediatric perspective","volume":"22","author":"Gordon","year":"2000","journal-title":"Brain Dev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1046\/j.1365-2869.1998.00102.x","article-title":"Delayed sleep phase syndrome: A placebo-controlled cross-over study on the effects of melatonin administered five hours before the individual dim light melatonin onset","volume":"7","author":"Nagtegaal","year":"1998","journal-title":"J. Sleep Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1046\/j.1365-2869.1996.d01-69.x","article-title":"Melatonin: Nature\u2019s soporific?","volume":"5","author":"Armstrong","year":"1996","journal-title":"J. Sleep Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1152\/physiol.00011.2014","article-title":"Melatonin: Exceeding Expectations","volume":"29","author":"Reiter","year":"2014","journal-title":"Physiology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.ejpn.2014.12.007","article-title":"Current role of melatonin in pediatric neurology: Clinical recommendations","volume":"19","author":"Bruni","year":"2015","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/biof.1690","article-title":"Ischemic stroke, obesity, and the anti-inflammatory role of melatonin","volume":"47","author":"Yawoot","year":"2021","journal-title":"BioFactors"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.brainresbull.2009.12.001","article-title":"Potential use of melatonergic drugs in analgesia: Mechanisms of action","volume":"81","author":"Srinivasan","year":"2010","journal-title":"Brain Res. Bull."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1007\/s40122-020-00207-y","article-title":"Safety and Efficacy of Melatonin in Chronic Tension-Type Headache: A Post-Marketing Real-World Surveillance Program","volume":"9","author":"Danilov","year":"2020","journal-title":"Pain Ther."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Stefani, L.C., Muller, S., Torres, I.L.S., Razzolini, B., Rozisky, J.R., Fregni, F., Markus, R., and Caumo, W. (2013). A Phase II, Randomized, Double-Blind, Placebo Controlled, Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0074107"},{"key":"ref_28","first-page":"1298","article-title":"Melatonin reduces the need for sedation in ICU patients: A randomized controlled trial","volume":"81","author":"Mistraletti","year":"2015","journal-title":"Minerva Anestesiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/head.12217","article-title":"Headache and Sleep: Also Assess Circadian Rhythm Sleep Disorders","volume":"54","author":"Rovers","year":"2014","journal-title":"Headache J. Head Face Pain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s10072-019-03837-z","article-title":"Sleep disorder-related headaches","volume":"40","author":"Galbiati","year":"2019","journal-title":"Neurol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1111\/head.13828","article-title":"Endogenous Melatonin Levels and Therapeutic Use of Exogenous Melatonin in Migraine: Systematic Review and Meta-Analysis","volume":"60","author":"Liampas","year":"2020","journal-title":"Headache J. Head Face Pain"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1111\/head.12862","article-title":"The Role of Melatonin in the Treatment of Primary Headache Disorders","volume":"56","author":"Gelfand","year":"2016","journal-title":"Headache"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s10072-008-0983-5","article-title":"Melatonin to prevent migraine or tension-type headache in children","volume":"29","author":"Miano","year":"2008","journal-title":"Neurol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1007\/s40263-019-00680-w","article-title":"Adverse Events Associated with Melatonin for the Treatment of Primary or Secondary Sleep Disorders: A Systematic Review","volume":"33","author":"Besag","year":"2019","journal-title":"CNS Drugs"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1178646918802282","DOI":"10.1177\/1178646918802282","article-title":"Analysis, Nutrition, and Health Benefits of Tryptophan","volume":"11","author":"Friedman","year":"2018","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s10194-016-0711-0","article-title":"Genetic and biochemical changes of the serotonergic system in migraine pathobiology","volume":"18","author":"Gasparini","year":"2017","journal-title":"J. Headache Pain"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"45","DOI":"10.4137\/IJTR.S2129","article-title":"L-Tryptophan: Basic Metabolic Functions, Behavioral Research and Therapeutic Indications","volume":"2","author":"Richard","year":"2009","journal-title":"Int. J. Tryptophan Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1038\/nrn3257","article-title":"Kynurenines in the mammalian brain: When physiology meets pathology","volume":"13","author":"Schwarcz","year":"2012","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"173","DOI":"10.5664\/jcsm.26314","article-title":"Oral nonprescription treatment for insomnia: An evaluation of products with limited evidence","volume":"1","author":"Meolie","year":"2005","journal-title":"J. Clin. Sleep Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1111\/jcpp.12812","article-title":"Practitioner Review: Treatment of chronic insomnia in children and adolescents with neurodevelopmental disabilities","volume":"59","author":"Bruni","year":"2017","journal-title":"J. Child Psychol. Psychiatry"},{"key":"ref_41","first-page":"271","article-title":"5-Hydroxytryptophan: A clinically-effective serotonin precursor","volume":"3","author":"Birdsall","year":"1998","journal-title":"Altern. Med. Rev. J. Clin. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Esposito, D., Belli, A., Ferri, R., and Bruni, O. (2020). Sleeping without Prescription: Management of Sleep Disorders in Children with Autism with Non-Pharmacological Interventions and Over-the-Counter Treatments. Brain Sci., 10.","DOI":"10.3390\/brainsci10070441"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1046\/j.1526-4610.2000.00067.x","article-title":"L-5-Hydroxytryptophan in the prophylaxis of chronic tension-type headache: A double-blind, randomized, placebo-controlled study. For the Portuguese Head Society","volume":"40","author":"Ribeiro","year":"2000","journal-title":"Headache J. Head Face Pain"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1111\/j.1468-2982.2006.01212.x","article-title":"Tryptophan Depletion Increases Nausea, Headache and Photophobia in Migraine Sufferers","volume":"26","author":"Drummond","year":"2006","journal-title":"Cephalalgia"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1111\/j.1526-4610.2011.01847.x","article-title":"Nutraceuticals and Headache: The Biological Basis","volume":"51","author":"Taylor","year":"2011","journal-title":"Headache J. Head Face Pain"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Maier, J.A., Pickering, G., Giacomoni, E., Cazzaniga, A., and Pellegrino, P. (2020). Headaches and Magnesium: Mechanisms, Bioavailability, Therapeutic Efficacy and Potential Advantage of Magnesium Pidolate. Nutrients, 12.","DOI":"10.3390\/nu12092660"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1111\/j.1526-4610.1989.hed2909590.x","article-title":"Low brain magnesium in migraine","volume":"29","author":"Ramadan","year":"1989","journal-title":"Headache"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1111\/j.1526-4610.1995.hed3510597.x","article-title":"Intravenous Magnesium Sulfate Relieves Cluster Headaches in Patients With Low Serum Ionized Magnesium Levels","volume":"35","author":"Mauskop","year":"1995","journal-title":"Headache J. Head Face Pain"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1097\/YIC.0000000000000130","article-title":"Serum concentration of magnesium as an independent risk factor in migraine attacks: A matched case-control study and review of the literature","volume":"31","author":"Assarzadegan","year":"2016","journal-title":"Int. Clin. Psychopharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1111\/head.14065","article-title":"Dietary magnesium and migraine in adults: A cross-sectional analysis of the National Health and Nutrition Examination Survey 2001\u20132004","volume":"61","author":"Slavin","year":"2021","journal-title":"Headache J. Head Face Pain"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Kennedy, D.O. (2016). B Vitamins and the Brain: Mechanisms, Dose and Efficacy\u2014A Review. Nutrients, 8.","DOI":"10.3390\/nu8020068"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1111\/ane.13251","article-title":"Pyridoxine, folate and cobalamin for migraine: A systematic review","volume":"142","author":"Liampas","year":"2020","journal-title":"Acta Neurol. Scand."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1007\/s10072-018-3286-5","article-title":"The association between serum vitamin B12 deficiency and tension-type headache in Turkish children","volume":"39","author":"Calik","year":"2018","journal-title":"Neurol. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1177\/0333102410365106","article-title":"Medium-dose riboflavin as a prophylactic agent in children with migraine: A preliminary placebo-controlled, randomised, double-blind, cross-over trial","volume":"30","author":"Bruijn","year":"2010","journal-title":"Cephalalgia"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3101","DOI":"10.3889\/oamjms.2019.771","article-title":"The Effects of Magnesium\u2014 Melatonin\u2014Vit B Complex Supplementation in Treatment of Insomnia","volume":"7","author":"Djokic","year":"2019","journal-title":"Open Access Maced. J. Med Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"30","DOI":"10.23736\/S0026-4946.19.05533-6","article-title":"Use of nutritional supplements based on melatonin, tryptophan and vitamin B6 (Melamil Tripto(R)) in children with primary chronic headache, with or without sleep disorders: A pilot study","volume":"72","author":"Bravaccio","year":"2020","journal-title":"Minerva Pediatr."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/5\/1631\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:00:01Z","timestamp":1760162401000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/13\/5\/1631"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,13]]},"references-count":56,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["nu13051631"],"URL":"https:\/\/doi.org\/10.3390\/nu13051631","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,13]]}}}