Managing Migraine Headaches in Children and Adolescents

Transcription

1 Expert Review of Clinical Pharmacology ISSN: (Print) (Online) Journal homepage: Managing Migraine Headaches in Children and Adolescents Antoinette Green, Marielle A. Kabbouche MD, Joanne Kacperski MD, Andrew D. Hershey MD & Hope L. O Brien MD To cite this article: Antoinette Green, Marielle A. Kabbouche MD, Joanne Kacperski MD, Andrew D. Hershey MD & Hope L. O Brien MD (2015): Managing Migraine Headaches in Children and Adolescents, Expert Review of Clinical Pharmacology, DOI: / To link to this article: Accepted author version posted online: 19 Dec Submit your article to this journal Article views: 5 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at Download by: [Cincinnati Childrens Hospital], [Hope O'Brien] Date: 05 January 2016, At: 10:51

2 Publisher: Taylor & Francis Journal: Expert Review of Clinical Pharmacology DOI: / Managing Migraine Headaches in Children and Adolescents Authors: Antoinette Green 1 Marielle A. Kabbouche, MD 1,2 Joanne Kacperski, MD 1,2 Andrew D. Hershey, MD 1,2 *Hope L. O Brien, MD 1,2 Address and Affiliations 1 Cincinnati Children s Hospital Medical Center 3333 Burnet Avenue MLC 2015 Cincinnati, Ohio Ph: Fax: *Corresponding author 2 University of Cincinnati College of Medicine Summary The diagnosis and management of migraine headaches can be challenging in children and adolescents. The description of migraine in this population may include symptoms that are not typically described in adults. Treatment options for pediatric migraine is increasing, however remain limited. This article will go through the key components to diagnosing migraine in pediatric patients as well as give options for short and long-term management. Keywords Migraine, Headache, Children, Adolescents, Acute treatment, Prevention, Nutraceuticals

3 Introduction and Background Migraine headaches affect millions of Americans. According to the US National for Health Statistics the prevalence of migraineurs are estimated at 1 out of and 7 Americans specifically [(1)]. Ten to twenty eight percent are adolescents ages 7 to 17 years old [(2)]. The International Classification of Headache Disorders IIIβ (ICHD-IIIβ) defines migraine is a recurring headache that is moderate to severe in pain intensity and can interfere with daily activities [(3)]. The pain can be described as throbbing, stabbing, and/or pulsating like sensations and is accompanied with nausea and/orvomiting, or photophobia and phonophobia[(2)]. The specific diagnostic criteria for migraine in children are similar to those used to diagnose migraine in adults with recognition that there are unique aspects to interviewing a child with headaches in order to meet the standardized criteria. Some of these fundamental differences include the duration of attack, which is often far shorter than in an adult, and the location of the attack, which may be bilateral in many children. Some of the difficulties encountered when making a diagnosis of migraine in the pediatric and adolescent age groups include that gastrointestinal complaints which are more prominent, such as abdominal pain, nausea and vomiting; and that the associated symptoms may need to be inferred by the parents by observation. Children also tend to experience headaches which are often shorter in duration, with attacks lasting from 2 to 72 hours[(2)]. The location is more likely to be bilateral, and is often described as frontal or bitemporal, as opposed to the more common unilateral headaches seen in adult

4 migraineurs. However, this unilaterality may emerge in adolescence. Because younger children may have difficulty understanding and describing the concepts of photophobia and phonophobia, these signs may need to be inferred by the parents on the basis of the child s actions. Chronic migraines are estimated to effect 3-14% of children and adolescents with migraines[(2)]. Chronic migraines are defined as headaches which occur on 15 or more days per month for at least 3 consecutive months[(4)]. Migrainosus features must be present on at least 8 of those headache days[(5)]. It is also very common for a child who experiences migraines to develop behavioral changes such as anxiety and mood fluctuations[(2)]. Diagnosing children with migraines can be a challenge, especially as their ability to describe their symptoms and the symptoms themselves may evolve through their adolescent years. One should aim to obtain a very detailed description of the headache. This should include the location of the pain, quality of the pain, severity of the pain and any associated symptoms. Quality of pain may be difficult to describe, especially for the younger patient. This may also be true when describing the severity of the pain. A variety of tools are available to assess severity and the most appropriate scale should be used based on the patient s developmental stage. Some may be able to describe the pain as mild, moderate or severe, or use a numerical scale of 0 to 10. Younger patients may find using the Wong-Baker FACES Pain Rating Scale more helpful when describing their pain [(6)]. It is a simple tool that allows a child to point to the face that reflects close to how they re feeling. Although it is essential for practitioners to involve parents in the decision making process due to their role in observing and advocating for their children s care plan, it must

5 be kept in mind that the child is the patient and should be the best source of descriptive information and agreeable to both acute and preventive treatment. A headache calendar or diary is a great way to track the number of headaches a patient is having and enable the practitioner to see any patterns and determine what types of headaches the child is experiencing. When asking about associated symptoms, the clinician should not just focus upon the classic symptoms of migraine including nausea, vomiting and light and sound sensitivities, as symptoms of other headache disorders or secondary headaches may be missed[(7)]. There are other symptoms that a child may complain of in addition to the migraine pain which includes dizziness, lightheadedness, or aura like symptoms which are simply warning signs before the onset of the migraine, difficulty concentrating and interference with daily activities whether academic or extracurricular[(8)]. An otherwise normal medical history, physical, neurological and headache examination will assist the physician to rule out any serious cognitive issues or disorders and make a determination if whether additional testing, including neuroimaging is warranted[(2)]. Imaging is not necessary if the medical history as well as physical examination fit the criteria for migraine[(9)]. Migraine is a genetic disorder and when parents are surveyed, up to 90% of children have at least one family member within 2 generations of having a history of headaches[(9)]. There are also hormonal influences with 50% of boys appearing to outgrow migraines in their early adult years[(9)]. Of the 25% of children who will no longer report migraines by the age of 25, boys are amongst those who have a greater chance of having their migraines subside[(9)]. Stress and environmental factors typically

6 cause the initiation of gene activation which leads to the manifestation of migraine headaches. So, it is very common for practitioners to see an increase in children with headaches during the school year. There are some recent studies that support school as being one of the most noted triggers for children who experience migraines[(9),(10)]. Acute Treatments The common problem with treating and managing children with headaches is the time period that elapses before seeing a headache specialist. The longer headaches go untreated, the more difficult they become to manage. When treating children, again it has to be a combined effort between patient, parent, and the health care professionals regarding the child s care plan. Management of migraine headaches requires a tailored regimen of pharmacological and behavioral measures that consider both the child s headache burden and their level of disability. As published by the American Academy of Neurology(AAN) practice parameter, abortive therapy should work fast and consistently and without headache recurrence and the need to use rescue medications, restore an individual s ability to function and care for themselves without the need to utilize other resources, be cost-effective and have minimal side effects[(11)]. Acute treatment should also effectively stop all features of migraine, including the associated symptoms. Over-the-counter NSAIDs or nonsteroidal anti-inflammatory agents such as ibuprofen and naproxen sodium are good abortive treatments at the initial onset of the headache[(7)]. NSAIDS are effective pain relievers by inhibiting the enzyme cyclooxygenase (COX) and thus the synthesis of prostaglandins[(12)]. These prostaglandins play a pivotal role in the inflammatory cascade within the central nervous system[(12)]. The migraine pain manifests when brain cells stimulate the release of chemicals causing the blood vessels to dilate and become inflamed[(9)]. Ibuprofen is prescribed and administered to children at a dose of 7.5 to 10 milligrams per kilogram of body weight (mg/kg)[(7)]. Thus, it is very important that the dosing is appropriate for both the age and weight of the child to be the most efficacious. Some of the common side effects associated with NSAIDS such as ibuprofen are gastro-intestinal(gi) symptoms such as diarrhea and constipation, and skin

7 reactions[(13)]. Acetaminophen is an analgesic with subtle anti-inflammatory effects, thus, it can be a minimally effective treatment in children and adolescents with migraine. However, acetaminophen is typically prescribed when patients have allergies and/or sensitivities to other NSAIDS such as ibuprofen[(14)]. The recommended dose of 15mg/kg is considered safe and efficacious[(14)]. There is a serious risk for hepatoxicity when acetaminophen is used in excess[(14)]. It is important that children under 12 not intake more than 75 mg/kg in a 24 hour period[(14)]. Aspirin or acetylsalicylic acid is primarily reserved for use in the adolescent and young adult population [(14)]. This is primarily due to the risk of Reyes Syndrome in children less than age 16[(14)]. Another problem when treating headaches is avoiding medication over-use. Any of the analgesics should not be used more than three days in a week to avoid an increase in headaches as a result of a rebound effect[(7)]. There are several drugs known as 5-hydroxytryptamine 1(5-HT 1 ) agonists or Triptans, rizatriptan benzoate, almotriptan malate, sumatriptan/naproxen sodium that are FDA approved for children ages 12 to 17 with migraines[(15)]. Intranasal zolmitriptan has been approved for children as young as age 6[(16)]. Triptans are safe and effective for those children who don t have sufficient relief with NSAIDs alone and can also be prescribed for a combined synergistic effect. Rizatriptan, which is available in both tablet and orally disintegrating tablets, is generally prescribed at 5mg when the child is 39kg or less and 10mg in children that are over 40kg.[(7), (14), (15)]. If headache relief is not achieved, a second dose can be administered 2 hours later, but one should not exceed 30mg in a 24 hour period[(15)]. Although side effects are uncommon, one may experience nausea, drowsiness, and dry mouth[(7)]. Preventative Treatments

8 Preventive medications should be considered for those children whose headaches occur with sufficient frequency (>= 1 headache per week) or disability (PedMIDAS > 10) to warrant daily treatment. The goal of therapy should be directed at reducing headache frequency and decreasing disability. Most clinicians require a minimum of 1 headache per week or 3 to 4 headaches per month to justify placing a child on a daily medication. For patients who report intensive and prolonged headaches (lasting > 48 hours), preventive medications should also be considered. Several classes of medications are used for preventive therapy and include antidepressants, antiepileptics, antihistamines and antihypertensives. Although a drug specifically designed to prevent migraine headaches has yet to be found, many drugs have been proven to be highly effective[(10)]. Currently, drugs that are used to treat depression, seizures, and hypertension are amongst those widely prescribed for migraine prevention. Amitriptyline, a tricyclic anti-depressant (TCA), has been used to prevent migraines in children since the early 80s[(10)]. Although the mechanism of action is not fully understood, it is thought that TCAs are effective in preventing migraines by their selectivity to diminish the inhibition of neurotransmission reuptake[(7)]. An effective dose for amitriptyline is reported to be 1mg/kg from an open-label study in children[(10)]. Some of the side effects that are commonly associated are lethargy, lightheadedness, dry mouth and dry eyes[(7)]. The patient may experience adverse effects if the dose is not properly titrated up over the course of a two month period. The dose should be gradually increased by 0.25 mg/kg/day every 2 weeks until the target dose is reached[(7)].

9 The antiepileptic agents, divalproex sodium and topiramate, have been both approved for adult use to prevent migraines[(7)]. Additionally, topiramate became the first drug approved for migraine prevention in children ages 12 and over. Topiramate is considered a first-line option for migraine prevention in adults. The effective dose in the pediatric population is not known, but a dose of 2-4mg/kg/day appears to be effective in children. Their ability to prevent migraine has been rather difficult to pinpoint, however it is thought that they clinically inhibit the excessive firing of neurons in the brain that are associated with migraine[(16)]. Appropriate dosing for topiramate in children is supported in a double-blind, placebo-controlled study at 2mg/kg/d to 3mg/kg/d, but not more than 200mg daily[(7)]. Some of the side effects commonly seen with topiramate are weight loss, tingling in the hands and feet, and lack of mental clarity and focus[(16)]. Divalproex is given at a dose of 500mg to 1000mg to primarily children in their adolescent years[(7)]. Patients that are using divalproex should be closely monitored because there s a chance it can adversely affect both the liver and/or pancreas. Commonly described side effects include dizziness, drowsiness, alopecia, weight gain, thrombocytopenia, lymphopenia, hyperammonemia and elevated pancreatic enzymes. Laboratory surveillance every 3 to 6 months is thus critical[(7)]. Cyproheptadine, an antihistamine is also commonly prescribed for migraine prophylaxis in children[(7)]. It s capability to chemically inhibit serotonin receptors is potentially why it s successful with preventing migraines[(7)]. It is important to note that cyproheptadine is generally prescribed in younger children, because it has the capability to promote increased appetite and weight gain[(7)]. Cyproheptadine has been shown effective at a dose between 0.2 mg/kg/d to 0.4 mg/kg/day[(7)]. It comes in both tablet and a liquid

10 formulation for younger patients who may have difficulty swallowing pills. The most commonly reported side effects include sedation and increased appetite. Propranolol beta-blocker used to treat hypertension is also prescribed for prevention of migraines[(9)]. Studies show variations in support of propranolol as an effective drug in migraine prevention in pediatrics[(10)]. Although it may not be as widely prescribed in children today, children and adolescent patients should be closely monitored because propranolol may exacerbate both clinical depression and asthma related symptoms[(10)]. In 2010, Onabotulinum Toxin A received US FDA approval for the treatment of chronic migraines in adults[(16)]. Treatment in children and adolescents is used off-label and is typically offered as an alternative option if conventional treatments are ineffective or not tolerated. Observational studies in pediatric migraine have suggest Onabotulinum toxin A may be effective in reducing headache days and improvement of disability scores with minimal side effects [(17)]. Nutraceuticals and dietary supplements Nutraceuticals have become a popular option for treatment of headaches, especially in cases where families may prefer a more natural option. Riboflavin (Vitamin B2) is a cofactor in energy production in the mitochondria and depletion of energy stores has been linked to migraine[(18)]. Riboflavin has been the most studied dietary supplement in children and adolescents with headache. Clinical implications remain unclear as reports on efficacy have been inconsistent and dosing remains in question [(19), (20)]. Coenzyme Q10 (CoQ10) is another co-factor involved in energy metabolism and clinical studies have shown that increased levels may be effective in pediatric migraine [(21), (18)]. However, more studies need to be done to continue the support of pain perception and various vitamin deficiencies.

11 Magnesium levels are also thought to be deficient in the migraine population. Some evidence may the benefit of magnesium in adults. There is a substantial lack of evidence in support of recommending the use of magnesium in the prevention of migraine in children and adolescents. Specifically, the few studies performed on children where small and failed to capture differences between those treated with magnesium and placebo[(22)]. Vitamin D has gained a lot of attention due to increasing awareness of vitamin D deficiency and its link to chronic pain conditions [(23)]. Clinical studies suggest a possible correlation between higher levels of Vitamin D and its ability to decrease inflammation and thus pain perception[(23)]. Inflammation of blood vessels and over stimulated nerves that surround those vessels are believed to be the underlying cause for migraine and patients with low levels of Vitamin D experience greater pain frequency[(23)]. Few studies have examined the link between low vitamin D and headache and whether there is an association remains unclear[(24, 25)]. Further studies are needed to determine whether supplementation to those who are deficient would be effective in migraine prevention. Non-pharmacological management Behavioral modifications and biofeedback relaxation practices should be integrated into the treatment plan and considered just as important as pharmacotherapy, if not more so, when managing migraines[(10)]. Migraine can be debilitating and leads to frequent school absences and missed activities with negative consequences. Some studies suggest school as being one of the most common triggers for children who experience migraines[(9),(8)]. Stress and environmental factors may be a role in the cortical activation leading to the manifestation of migraine headaches and may be one reason why

12 practitioners see an increase in children with headaches during the school year. Biofeedback relaxation techniques include a series of tests that requires active participation of the child or adolescent[(18)]. During the process, the therapists will connect small sensory indicators to the child and keep track of any physical changes in blood pressure, muscle tension, and/or heart rate[(18)]. After the therapist is able to analyze the changes, they can introduce tools that the child can use to relax. Participation in cognitive behavioral therapy (CBT) and biofeedback sessions allow patients to feel more confident in their ability to manage stress as they learn tools to better cope with pain. (CBT) has proven to be highly effective when combined with pharmcotherapy for migraineurs. In a randomized trial performed at the Cincinnati Children s Hospital Headache Center, individuals were given amitriptyline + CBT, and 86% of the subjects experienced headache improvement or at least a 50% reduction in headache days at their 12 month follow-up visit [(26)]. This is in comparison to the 69% improvement rate amongst those who had amiptriptyline + headache education [(26)]. There was also an improvement in the Pediatric Migraine Disability Assessment Score (PedMIDAS), where the group receiving amitriptyline + CBT decreased their PedMIDAS by 52.7 points [(26)]. The amitriptyline + headache education group also decreased their average PedMIDAS score by 38.6 points [(26)]. Patients should also be educated on the importance of maintaining a well-balanced diet rich in green vegetables and protein, adequate hydration, regular aerobic exercise and maintaining good sleep hygiene as it relates to improvement of pain as well as overall health and wellness[(18)]. Healthy sleep patterns consists of 8 to 10 hours of sleep each

13 night[(25)]. Although there is a slight margin for bedtime and time to rise on the weekends vs weekdays, it really is important to have a consistent sleep regimen [(27)]. Triggers are an important part in the management of migraine in both children and adults. In a retrospective study done at the Lille University Hospital Center in Lille, France, 102 children and adolescents (with parent assistance) were presented with a questionnaire that contained various triggers[(28)]. The study showed 75.7% of patients self-reported stress as a trigger, 69.6% reported sleep deprivation as a trigger, interesting enough 68.6% reported warm climate and 64.7% reported video games[(28)]. As with many factors that affect migraine, there s a lack of studies to support the most common triggers on a large scale. Children with underlying behavioral issues and psychiatric disorders such as specific phobia, Attention Deficit Hyperactivity Disorder (ADHD), and Generalized Anxiety Disorder (GAD) are increasingly difficult to treat due to the challenge of determining whether the psychiatric disorder is exacerbating the migraines or if the migraines are complicating the management of the psychiatric disorder[(8)]. Referral to psychology and/or psychiatry may be warranted in severe cases. In Conclusion, migraines particularly in children are a debilitating condition that can be diagnosed, managed, and prevented successfully. With the changes in today s health care system, primarily due to bills including the Affordable Health Care Act, the focus has shifted to a more patient centered care plan that includes both pharmacotherapies and behavioral modifications. The continual strides to make treatments safe and effective in children will

14 continue to be a priority. An integral part of this is to continually conduct much needed clinical studies for children with various conditions. Expert commentary Migraine is common but remains under-recognized in children and adolescents. Published guidelines have led to the increase in diagnosis and have led to increased awareness and education in treating pediatric headache. The goals for successful management should focus on headache reduction, minimizing disability and improvement of quality of life. Analgesics and NSAIDS are generally recommended for mild to moderate pain, while triptan reserved for moderate to severe pain. Preventative medication, both pharmaceutical and dietary supplements, may be considered in cases where headaches are frequent causing significant disability. Non-pharmacologic interventions such as cognitive behavioral therapy and biofeedback are shown to be beneficial in migraine patients and should be recommended either alone or as an adjunct to pharmacological therapies. Finally, healthy lifestyle modification is important to establish as these patients develop, which could lead to improved outcomes into adulthood. Five-year view Over the years, the diagnosis of pediatric migraine is expected to be more defined as more clinicians are able to recognized the disorder as outlined in the ICHD-IIIβ. Although there are abortive medications that are USFDA approved for pediatric migraine, further options are expected to become available as those approved in adult medications are studied and deemed safe and effective for children and adolescents. NSAIDS and non-steroidal over the counter medications will continue to be considered first-line as they are easily available and cost-effective, with triptans reserved for moderate to severe headache pain. Preventative medications will continue to be considered for

15 those with frequent, disabling headaches, although choice of medication will likely remain limited due to the lack of positive pediatric migraine prevention studies. Choice of medication will mostly depend on side effect profile, comorbidities and extrapolation studies in adults. Biobehavioral management and as well as a discussion on healthy habits should always be part of the treatment plan. Patients and families should understand that improvement may take time and an early discussion on goals and expectations is important to successful management. There is hope that as this population continues to become more recognized, future research funding will focus on ways to improve clinical outcomes in children and adolescents and overall quality of life. Key issues Migraine is common in children and adolescents. Correct diagnosis of pediatric migraine is important to proper management. NSAIDS and over the counter analgesics continue to remain first line options for acute migraine. There have been several triptans including almotriptan, rizatriptan, sumatriptan/naproxen sodium and intranasal zolmitriptan, that have been FDA approved for intractable migraine. Topiramate is the only US FDA approved medication for pediatric migraine preventative. Biobehavioral management and life-style modification should be included in the migraine treatment plan. Future studies are needed as treatment options remain limited in this population. Financial and competing interests disclosure H O Brien is a part of the Labry Pharmaceuticals Research Clinical Trial. M Kabbouche is a part of the CHAMP Research Clinical Trial for NIH and Chronic Migraine Research Study for Allergan. A Hershey is receiving consulting fees for the following companies Allergan, Amgen, and Lilly. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

16 References 1. Burch RC, Loder S, Loder E, Smitherman TA. The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies. Headache. 2015;55(1): Spiri Daniele RV, Titomanlio Luigi. Pediatric migraine and episodic syndromes that may be associated with migraine. Ital J Pediatr. 2015;40(92). 3. International Classification of Headache Disorders, Cephalagia (9): Hershey AD, Kabbouche MA, Powers SW. Chronic daily headaches in children. Curr Pain Headache Rep 2006;10(5): Marmura M, Silberstein S. Headache and Sinonasal Disease. In: Chang CC, Incaudo G, Gershwin ME, editors. Diseases of the sinuses : a comprehensive textbook of diagnosis and treatment. Second edition. ed. New York 2014: Springer; p. xviii, 601 pages. 6. Miro J, Castarlenas E, de la Vega R, Sole E, Tome-Pires C, Jensen MP, et al. Validity of three rating scales for measuring pain intensity in youths with physical disabilities. European journal of pain Hershey AD, Winner PK. Pediatric migraine: recognition and treatment. J Am Osteopath Assoc. 2005;105(4 Suppl 2):2S-8S. 8. Slater SK, Kashikar-Zuck SM, Allen JR, LeCates SL, Kabbouche MA, O'Brien HL, et al. Psychiatric comorbidity in pediatric chronic daily headache. Cephalalgia : an international journal of headache. 2012;32(15): Fenichel GM. Headache. Clinical Pediatric Neurology: A Signs and Symptoms Approach. Saunder's. 3rd ed. Philadelphia: Philadephia; p Hershey AD, Kabbouche MA, Powers SW. Treatment of pediatric and adolescent migraine. Pediatr Ann. 2010;39(7): Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, Silberstein S. Practice Parameter: Pharmacological treatment of migraine headache in children and adolescents: Report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology. 2004;63(12): Pardutz A. SJ. NSAIDs in the Acute Treatment of Migraine: A Review of Clinical and Experimental Data. Pharmaceuticals. 2010;3: Kowalski ML, Makowska JS. Seven Steps to the Diagnosis of NSAIDs Hypersensitivity: How to Apply a New Classification in Real Practice? Allergy, asthma & immunology research O'Brien H, Kabbouche M, Kacperski J, Hershey A. Treating of Pediatric Migraine. Curr Treat Options Neurol. 2015;17(1). 15. Kacperski J OBH. Triptan use in pediatric migraine: focus on rizatriptan. Future Neurology. 2012;7(4): Micromedex Solutions Web Application access. Date it 9/1/ Rothrock JF. Topiramate for migraine prevention: an update. Headache. 2012;52(5): Kabbouche M, O'Brien H, Hershey AD. OnabotulinumtoxinA in pediatric chronic daily headache. Curr Neurol Neurosci Rep. 2012;12(2): Orr S, Venkateswaran S. Nutraceuticals in prophylaxis of pediatric migraine: Evidence-based review and recommendations. Cephalalgia : an international journal of headache 2014;34(8) Condo M, Posar A, Arbizzani A, Parmeggiani A. Riboflavin prophylaxis in pediatric and adolescent migraine. J Headache Pain. 2009;10(5): Bruijin J, Duivenvoorden H, Passchier J, Locher H, Dijkstra N, Arts WF. Medium-dose riboflavin as a prophylacic agent in children with migraine: a preliminar placebo-controlles, randomised, double-

17 blind, cross-over trial. Cephalalgia 2010;30(12): Slater SK, Nelson TD, Kabbouche MA, LeCates SL, Horn P et al. A randomized, double-blinded, placbo-controlled, crossover, add-on study of Coenzyme Q10 in prevention of pediatric and adolescent migraine. Cephalalgia. 2011;31(8): Wang F, Van Den Eeden SK, Ackerson LM, et al. Oral magnesium oxide prophylaxis of frequent migrainous headache in children: a randomized, double-blind, placebo-controlled trial. Headache 2012;52(S2): Prakash S, Mehta NC, Dabhi AS, Lakhani O, Khilari M, Shah ND. The prevalence of headache may be related with the latitude: a possible role of Vitamin D insufficiency. The journal of headache and pain. 2010;11(4): Mauskop A. Nonmedication, alternative, and complementary treatments for migraine. Continuum. 2012;18(4): Kjaergaard M, Eggen AE, Mathiesen EB, Jorde R. Association between headache and serum 25- Hydroxyvitamin d; the tromso study: trumso 6. Headache 2012;52: Powers SW, Kashikar-Zuck S, Allen J, LeCates S, Slater S, Zafar M, et al. Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: a randomized clinical trial. JAMA. 2013;310(24): Hershey AD, Powers SW, Winner P, Kabbouche MA. Pediatric headache in clinical practice. First edition 2009: John Wiley and Sons; p , 223 pages. 29. Neut D, Fily A, Cuvellier JC, Vallée L. The prevalence of triggers in paediatric migraine: a questionnaire study in 102 children and adolescents. J Headache Pain 2012;13(1):61-65.