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ediatric Headacheara Stuart Lewis, MD

Headache is a common presenting complaint in the practice of child neurology. Themedical and social impact of headache is often very severe both for the affected child andfor his/her family. As there exist few good clinical studies to guide practitioners in choosingappropriate medications, treatments are mostly based on extrapolation of adult studyresults. Personal trial-and-error experience and specialized considerations for patients alsoinfluence choice and implementation. A careful medical history, however, can enableoptimal choices for abortive and prophylactic use in the context of a multi-disciplinaryapproach toward headache management. This article provides a pathophysiologically-based overview of a wide range of therapeutic options for children and adolescents withheadache.Semin Pediatr Neurol 17:224-229 © 2010 Elsevier Inc. All rights reserved.

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eadaches in children and adolescents are common andrepresent a significant portion of the patients seen in a

hild neurology office. Although classification of headaches is aopic that warrants an entire chapter alone, the determination ofreatment options can be made on the basis of careful distinc-ions between acute and chronic or intermittent and daily forms.here are episodic headaches, such as migraines that have inter-al-free periods, and these need treatment at the time of theeadache (ie, rescue or abortive medications). There arehronic, daily headaches with very few headache-free days inetween, and these are treated differently, usually requiring pro-hylactic medications. In both acute and chronic headaches, the

dentification and management of potential triggers is a neces-ary step, and one that can lessen the need for rescue and pro-hylactic medications. Nonmedical interventions at the time ofheadache will be touched upon briefly, but their importance asomplementary to pharmacologic treatments cannot be under-stimated.

Migraines are a type of primary headache that have beentudied for many decades, and yet the full pathophysiology re-ains elusive. Certain neuroactive transmitters and substances,

uch as serotonin (5-HT), clearly play a critical role, and many ofhe medication options are predicated on this knowledge. Theres continuing controversy as to whether the vascular componentf migraines or neurogenic inflammation is the more importantactor in the physiological headache state. Most likely, there is annitial electrical phenomenon that begins in the cerebrum, initi-

rom the Barrow Neurological Institute, St Joseph’s Hospital, Medical Cen-ter, Phoenix, AZ.

ddress reprint requests to Kara Stuart Lewis, MD, Child Neurology 500West Thomas Road, Suite 400, Phoenix, AZ 85013. E-mail: k3lewis@

dchw.edu

24 1071-9091/10/$-see front matter © 2010 Elsevier Inc. All rights reserved.doi:10.1016/j.spen.2010.10.004

ting a cascade of events that affects the vasculature with releasef biochemical substances, which then lead to neurogenic in-ammation. Pharmacologic intervention has been directed atreventing neurogenic inflammation in the meninges to de-rease neuropeptide release and therefore reduce stimulation offferent nerve fibers, preventing migraine pain. The best de-criptive term for the physiology of migraines should be “neu-ovascular,” suggesting the more integrated theory involvingoth vascular and neuronal components.1,2

Physiological mechanisms can be inferred by studying sub-tances that provoke migraine. Calcitonin gene-related peptideCGRP) is a neuropeptide that is released from activated trigem-nal sensory nerves. It acts to dilate blood vessels both intra- andxtracranially and has a central modulating effect on vascularociception. The infusion of CGRP can provoke migraine head-ches. Knowing that CGRP plays a role in the pathophysiologyf migraine led to the hypothesis that blockade of CGRP recep-ors could abort or prevent migraine.3 The effects of CGRP arelso facilitated by the adenosine A2A receptor, which is one ofhe molecular targets of caffeine. This information is being usedo aid in the search for genetic factors in migraine with aura anday explain the varying pharmacogenomics of caffeine and mi-

raine.4

reatmentor the purposes of this review, 3 areas of treatment in childrenill be discussed: (1) nonmedical interventions or general treat-ent measures, (2) rescue or abortive medications, and (3) pro-hylactic medications. The importance of preventative mea-ures (such as the maintenance of a good sleep schedule and thevoidance of known triggers, such as hypoglycemia and dehy-

ration) must be discussed at the initial visit with each child who

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Pediatric headache 225

resents with recurrent migraines and then reinforced at eachubsequent visit.

onmedical Interventionsonmedical interventions are very important, especially for theoung child. Many if not most of the medications that are de-cribed in articles on the treatment of migraine in adults are notpecifically labeled for use in the pediatric population. Parents ofoung children with migraines often are wary of “adult” medi-ations and are very interested in discussing nonmedical inter-entions. Their benefit clearly depends on the timing of thentervention with relation to the onset of the headache as well ashe severity and associated symptoms of the migraine.

As discussed previously, all patients with recurrent migraineseed to avoid the triggers that provoke their migraines, buturing a migraine attack, avoidance of these same triggers is alsossential. Placing the child in a darkened room with minimal too extraneous noise will lessen the severity of the associatedymptoms of photophobia and phonophobia. Knowing that hy-oglycemia can provoke a migraine does not, however, meanhat feeding the child during a migraine will be beneficial. Usu-lly, the anorexia experienced by children and adolescents willnsure that very little food will be consumed. Small amounts ofater or ice chips are usually helpful.The use of caffeinated beverages poses an interesting di-

emma. The use of caffeine can enhance the absorption of somebortive medications and therefore can be beneficial. Caffeinelso acts centrally as an antagonist of adenosine A2 receptorswhich are excitatory) and therefore diminishes the effect ofGRP. However, because sleep is the most clear-cut, well-de-ned treatment for migraines, the use of an alerting agent such asaffeine can be detrimental in some children who need the sleepo stop the migraine. In general, the use of caffeine as an abortivegent in the form of a beverage is more likely to work in patientsho do not regularly consume caffeinated drinks, so the recom-endation that children and adolescents avoid caffeine in gen-

ral but try it as a rescue medication (while watching for theyperalerting adverse effect in some children) is a reasonablepproach.

Temperature can be a worsening factor during a migraine forany patients. The use of cool cloths for the forehead or neck orgentle fan can be beneficial. This is more helpful early in theigraine before the onset of cutaneous allodynia that develops

n many migraineurs. In these patients, stimuli that are normallyonnoxious such as heat, cold, or pressure can become quiteainful. When this occurs, even fans or cloths can worsen ratherhan help the pain.

In young children, the stress of a migraine can be lessened byoping strategies that are used in a number of pain syndromes.reathing exercises and relaxation techniques as well as moreophisticated measures, such as biofeedback, can be beneficialn some children.

escue Medicationsor pharmacologic rescue of migraine, the options begin withimple analgesics and anti-inflammatory agents (Table 1). Anal-

esics work by interfering with the way the pain message is t

ransmitted by the nerves, leading to temporary relief from theain without treating the cause of the pain. Anti-inflammatoryrugs work by decreasing prostaglandins, which contribute toain and swelling of inflamed tissues. Many simple (ie, nonopi-id) analgesics are available over-the-counter and include aspi-in, acetaminophen, ibuprofen, Naprosyn (Roche, Basel, Swit-erland), and combination medications. Prescription analgesicsre less commonly used in the pediatric population but includeedications that contain isometheptene mucate (Midrin,araco Pharmaceuticals, Detroit, MI) or butalbital (Fiorinal andioricetR, Watson Pharmaceuticals, Inc, Corona, CA). Prescrip-ion-strength nonsteroidal anti-inflammatory medications in-lude indomethacin and ketorolac.

Some medications target nausea as a specific symptom of theigraine. By treating the nausea, vomiting, anorexia, and gen-

ral abdominal discomfort that often accompany a migraine,ome patients are able to achieve enough relief to fall asleep, andhen it is often the sleep that cures the remaining migraine. Theffect of sleep on migraine is significant, but the gastrointestinalomponent often prevents adequate sleep. Many antinauseaedications have the added benefit of sedative properties,hich can enhance this effect. In pediatric patients, prometha-

ine is often used first line because of the availability of tablet,iquid, and suppository dosage forms. In older patients whorefer to treat nausea without added sedation, the use of ondan-etron can be considered.

Ergotamines are a category of medication that acts by vaso-onstriction. The most common formulation is dihydroergota-ine (DHE 45), which is a 5-HT1 receptor agonist. It can be

iven to outpatients as a nasal spray in the form of MigranalValeant Pharmaceuticals International, Inc, Mississauga, ON,anada). The intravenous form is used in the urgent care orospital setting. The intravenous form is limited by its adverseffect of nausea, so it must be preceded by antiemetic medica-ion. The dose must be started slowly to prevent intolerance butan be increased every 6 hours by a small increment. It can beery effective at arresting a prolonged migraine event and pre-enting status migrainosus.5 Oral administration of ergotaminess limited by the potential for rebound headaches and the ad-erse effect of nausea.

Triptans are a class of medications that act on serotonin-HT1B/D receptors, likely both in nerve endings as well as inlood vessels, with a resultant decrease in the release of neu-opeptides, including CGRP and substance P. The first triptaneleased in the United States was sumatriptan in 1992. Initially,t was only available as an injection and was shown to be effec-ive in over 75% of patients within 1 hour and in over 80% ofatients within 2 hours. However, headache recurrence in the

nitial studies was as high as 30% to 40%. Adverse effects in-lude tingling, flushing, heaviness, and burning but are gener-lly transient and tolerable. Sumatriptan is contraindicated inatients with significant risk factors for coronary artery diseaser uncontrolled hypertension. The tablet forms have a longernset to efficacy, sometimes taking 1 to 2 hours. The nasal sprayormulation exerts some efficacy within 15 minutes and causesewer side effects. Many good trials have been performed using

he nasal spray form of sumatriptan, and the results are convinc-

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ng.6 Many pediatric patients, however, are extremely intolerantf the strong taste of the nasal spray.

Zolmitriptan was the second triptan released (in 1997) andas initially available only in tablet form but later also as a nasal

pray. This was followed by naratriptan and rizatriptan in 1998,lmotriptan and frovatriptan in 2001, and eletriptan in 2002. Itas become quite clear that in any individual patient, 1 triptanay be more efficacious than another, and failing 1 or 2 triptans

hould not preclude further trials with others in the same druglass. Naratriptan has been shown to have a longer time to onsetf relief, but this is offset with the potential for fewer side effects.izatriptan is available in standard and disintegrating tablet

orms. The clinical onset of relief for both naratriptan andizatriptan is similar and may be faster than for sumatriptan.

able 1 Rescue/Abortive Medications for Migraine in the Ped

MedicationClass Generic Name Brand Nam

onsteroidal anti-inflammatoryagents

IbuprofenNaproxen sodiumIndomethacin

Motrin, AdvilAleve, NaproIndocin

onspecific painreliever

Acetaminophen Tylenol, othe

ombinationmedications

Acetaminophen, 325 mg/dichloralphenazone100 mg/isometheptanemucate 65 mg

Midrin, other

riptans AlmotriptanEletriptanFrovatriptanNaratriptanRizatriptanSumatriptanSumatriptan combined

with naproxen sodiumZolmitriptan

AxertRelpaxFrovaAmergeMaxaltImitrexTreximet

Zomig

HE Dihydroergotamine nasal Migranal

ose recommendations are based on the authors’ opinion and pracconsult full, current prescribing information on any medication tas http://www.pdr.net or http://www.rxlist.com are recommende

, every; tid, 3 times a day.

izatriptan’s disintegrating form is much more palatable to c

any pediatric patients because of its pleasant taste and the lackf a need to take it with water. Almotriptan (Axert®, Ortho-cNeil Neurologics, Titusville, NJ) was the first triptan ap-

roved for pediatric use (ages 12-17) in 2009 based on compel-ing evidence in clinical trials.7 Frovatriptan has the benefit ofeing longer acting and therefore has been used as a niche med-

cation for hormonally induced migraines during the menstrualeriod. In adult females, the use of frovatriptan as “scheduledhort-term prevention” for migraines that occur exclusively inssociation with menses can be quite helpful. In pediatric pa-ients, migraines do seem to change with the onset of puberty.mong patients who have onset of migraines before the onset ofuberty, many females have an increase in severity and fre-uency of their migraines, and many males have a decrease or

Population

Dosing in Pediatrics

Special Considerationsin the Pediatric

Population

0 mg/kg q 6-8 h.5-5 mg/kg q 12 h-4 mg/kg/d divided tid

Do not exceed adultmaximum (usually 1200mg/d)

0-15 mg/kg q 4-6 h Do not exceed adultmaximum (usually 4 g/d)

-2 tablets at onset ofmoderate migraine, mayrepeat with 1 tablet in30-60 minutes if needed.Write maximum onprescription (eg, max 3tablets per 24 hours max2 d/wk).

May be difficult to find in allpharmacies

ll are dosed fairly similarlydespite different mg. Use1 tablet (generallystarting with smallestavailable dose) orally orintranasally at onset ofmoderate migraine. Mayrepeat in 2 h if needed.Write maximum onprescription (eg, max 2tablets per 24 hours max2 d/wk).

Only Axert tablets and Zomignasal spray have FDAapproval for the 12- to 17-year-old age group. Manyof the others are commonlyused in practice. Literaturesupports some (eg,sumatriptan nasal spray)down to age 8 or below.Need to use clinicaljudgment (and parentalconsent).

se 1 puff in each nostril atonset of moderatemigraine. Wait 15minutes and repeat with1 puff in each nostril.Data support the use of 1additional puff in eachnostril 15 minutes orlonger after the seconddose if needed (not FDAapproved).

No pediatric indication yetfor this medication. Hasbeen used successfully inpediatric case studies andliterature searches. Lessdisturbing taste noted bypatients (compared withsumatriptan or zolmitriptannasal sprays), which canbe a huge factor.

d are believed to be accurate; however, physicians should alwaysrm accurate dosing for age and weight in their patients. Sites such

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omplete cessation of their migraines after puberty has been

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Pediatric headache 227

eached. In females with prepubertal onset of migraines, thehances of their migraines becoming exclusively hormonallyelated are fairly minimal although hormonal influences can ben added trigger.

The most recently released triptan is a combination medica-ion containing sumatriptan and naproxen sodium and has theradename of Treximet (Glaxo-Smith-Kline, Middlesex, UK). Its approved for the abortive treatment of migraine in adults onlylthough an adolescent trial (for ages 12-17 years) has beenompleted and may lead to labeling for this age group in the nearuture. This medication makes intuitive sense, using the combi-ation triptan and nonsteroidal anti-inflammatory mechanisms.Although triptans on a whole have shown consistent efficacy

n many migraine patients, their adverse effects are not insignif-cant. Furthermore, the prevalence of nonresponders hasrompted continued research to develop additional treatmentptions. A novel class of antimigraine medications is the CGRPeceptor blockers. The first-in-class CGRP medication is tel-agepant. This substance blocks receptors for CGRP at severalites in the trigeminal and central nervous systems. The benefitf this mechanism is the lack of vasoconstriction, which is aimiting factor in triptan use. The initial study comparing tel-agepant with zolmitriptan revealed similar results and withlacebo improved results.8 Safety and tolerability have beenood although trials of the medication as a preventative choicedosed twice daily for 3 months) led to elevated liver enzymes.rospects for Food and Drug Administration (FDA) approvalre unclear at this time although the medication may be noorse for liver toxicity than existing medications for migraine,

ncluding valproate and chronic nonsteroidal anti-inflammatoryrugs.

nalgesic Rebound Headacheo discussion of migraine treatment can be complete without

he mention of an analgesic rebound headache, which is defineds the worsening of head pain in patients with a prior history ofntermittent migraines who are using “frequent and excessive”escue medications, which can include analgesics, barbiturates,piates, triptans, and ergots. The clinical parameters that inducen analgesic rebound headache (such as dosage, frequency, anduration of use of the rescue medication) remain controversial,ut the essential concept that “too much of a good thing” can beetrimental to a migraineur must be recognized by the practi-ioner. Animal studies have provided some insights into thislinical problem. De Felice et al9 showed that the repeated use ofriptans led to a latent sensitization, with the rodents sufferingreater pain from a migraine trigger even after the triptan usead been stopped.9 CGRP labeling in blood revealed activationf trigeminal dural afferents, which remained active long afterhe discontinuation of triptan exposure. This supports the hy-othesis that the use of triptans, like many analgesics, needs toe limited in frequency to prevent an increased frequency ofigraine headaches. Similar to drug addiction, there is differen-

ial susceptibility to exposure of a substance. However, in gen-ral, if an individual limits the use of any and all of these medi-ations to less than 3 times a week, the risk of a rebound

eadache is minimal. This recommendation needs to be pre- t

ented to the pediatric migraineur and the family at the initialisit and reinforced at all subsequent visits.

rophylactic Medicationsn patients who experience frequent migraine attacks, the risk ofrebound headache is quite high, and, regardless of the efficacyf the rescue medication, the need for preventive therapy arises.he general theory behind prophylactic medications in mi-raines is that the normal triggers that occur during day-to-dayife may be less likely to initiate the cascade of events that lead to

igraines if these medications are maintained at a reasonableevel. Decreasing the frequency of episodic migraine can allowor the less frequent use of rescue medication and therefore lessisk of rebound headaches. Data are also emerging to suggesthat the use of prophylactic migraine medications in chronicigraine may assist the patient in reverting to an episodic mi-

raine state.10

Preventative medications for migraines do not have a uniformharmacologic mechanism. This is clearly evident by the facthat the medication options comprise heterogeneous druglasses (Table 2). Categories include antihistamines, antidepres-ants, beta-blockers, anticonvulsants, and calcium channellockers. These will be discussed in separate pharmacologicategories. The essential principle guiding the use of prophylac-ic agents is to start at low doses and make upward dose adjust-ents very slowly and with repeated clinical assessments.

ntihistaminesne medication used in the pediatric (but rarely in the adult)igraine population is cyproheptadine, an antihistamine with

edative side effects. Although cyproheptadine as an antihista-ine has been largely replaced by nonsedating compounds, itevertheless has efficacy in preventing migraine attacks and not

ust in children whose migraines are worsened or triggered byheir underlying allergies (although in patients with dual diag-oses, it may be a good starting medication). The other mainide effect of cyproheptadine is appetite enhancement, which isot usually a problem in prepubertal children, but it can be adeal breaker” for many adolescents who are weight conscious.

ntidepressantshe medications in this class used for migraine prophylaxis in-lude the tricylics amitriptyline and nortriptyline as well as theerotonin-norepinephrine reuptake inhibitors venlafaxine anduloxetine. None of these are labeled for use in migraine pre-ention, and very few pediatric trials are available. Amitriptylines usually the first choice, and there are a number of retrospec-ive and review studies in pediatrics11,12 Generally, the initialose for children and adolescents is 10 mg and is increasedlowly if ineffective. This approach often avoids complaints ofedation that are typically seen with higher doses. Many adoles-ents with migraines have concomitant sleep issues, often in-luding sleep-initiation concerns. Amitriptyline can be useful inllowing faster sleep onset, and this confers an additional benefito these patients.

eta-Blockershe most common medication in this class is propranolol al-

hough timolol is also used. The data showing efficacy in mi-

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228 K.S. Lewis

able 2 Prophylactic/Preventative Medications for Migraine in the Pediatric Population

MedicationClass

GenericName

BrandNames Dosing in Pediatrics

Special Considerations in thePediatric Population

ntidepressants Amitriptyline Elavil Start very low (eg, 5-10 mgPO at night � 1 wk). If nosedation, increase to 20 mgorally every night. Mayslowly increase weekly,titrate to efficacy andtolerability. Usual maximum50 mg/day.

Can be very helpful in improving subtlecomorbid sleep disorders. Watch forschool-time sedation however.Generally, well tolerated. Recommendelectrocardiogram (EKG) if titrate above40 mg/day.

Nortriptyline Pamelor Start at 10 mg orally everynight. Increase slowly, up to50 mg/d.

May be better tolerated than amitriptylinefor sedation. Do not use with Midrin.

Duloxetine Cymbalta Start at 30 mg every night.Monitor for efficacy over 3-4wk. Maximum 60 mg/day inadolescents.

Not approved yet for pediatric use. Somestudies have shown efficacy inadolescent pain, including migraine.Monitor for suicidal ideation.

ntithistamine Cyproheptadine Periactin 4 mg tablets, 2 mg/5 mLsolution. Start low, 2-4 mgorally every night for thefirst week and then twice aday. May need 3 times aday, but prefer twice a day ifeffective. Goal 0.25-0.5 mg/kg/d, maximum 12 mg/d (2-6 y), 16 mg/d (7-14 y).

Do not use in patients with reactiveairways disease. Very helpful in thelittlest migraineurs because low sideeffects. Useful in abdominal migraineand other variants.

eta-blockers Propranolol Inderal Start at 20-40 mg orally perday if patient over 35 kg.Increase weekly up to 40-80mg 3 times a day. If helpful,but too sleepy, change tothe once a day, sustained-release pill. Maximum 120mg (under age 12), 240 mg(13-17-year olds).

Do not use if patient has reactive airwaysdisease, or if competitive athlete. Mayworsen depression.

alcium channelblockers

Verapamil Calan Start at 40 mg orally per day ifpatient over 35 kg. Increaseweekly up to 40-80 mg 3time a day. If helpful, but toosleepy, change to the oncea day, sustained-release pill.Maximum 120 mg (underage 12), 240 mg (13-17 yearolds).

Increase slowly, but get up to a gooddose before declaring it unhelpful.Watch for dizziness.

nticonvulsants Topiramate Topamax Start at 15 mg orally everynight. Increase weekly by 15mg, up to 1-2 mg/kg/d.

Start low and go slow to avoid cognitivedulling. Teenagers often appreciate theconcomitant appetite suppression butwatch for missed meals in migraineurs.

Valproic acid Depakote Use extended release once aday at night. Use lowerdoses than in epilepsy. Startwith 250 mg orally for 2 wk,increase if needed to 500mg. Maximum inadolescents 750-1,000 mg.

If on >500 mg/d for more than 3 mo,check liver enzymes and completeblood count. Can cause easy bruising,tremor, and hair loss (disturbing inteenage girls) as well as weight gain.

ose recommendations are based upon the author’s opinion and practice, and are felt to be accurate; however, physicians should alwaysconsult full, current prescribing information on any medication to confirm accurate dosing for age and weight in their patients. Sites, suchas http://www.pdr.net or http://www.rxlist.com are recommended.

O, oral.

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Pediatric headache 229

raine prevention is fairly robust in adults, but pediatric data areore limited. There have been some prospective double-blind

rials comparing propranolol with other preventative medica-ions.13 Although patient recruitment may be easier with such atudy design, the data may be less convincing than comparisonsith placebo. Propranolol is relatively contraindicated in

sthma and can cause exercise intolerance as well as a loweredood, so the correct population needs to be determined beforese. The caveat of starting low and going slow also pertains here,nd the recommendation is to use the immediate-acting formnitially given 3 times a day. If efficacy is shown, then switchingo a once-a-day, long-acting formulation of propranolol can im-rove compliance and enhance the clinical effect.

nticonvulsantshe medications in this class include topiramate and valproiccid. Both of these are approved by the FDA for migraine pre-ention in adults. Even though there is no FDA approval inediatric migraine, the safety data are well established in pedi-tric patients because both medications are FDA approved inhildren (down to age 2 years for topiramate and 10 years foralproic acid) for their other indication (ie, seizure prophylaxis),o child neurologists are usually very comfortable using theseedications for pediatric migraine prevention. There have been

ome randomized, double-blind, placebo-controlled trials14,15

s well as retrospective efficacy studies,16 comparisons betweenhe 2,17 and reviews of multiple antiepileptic drugs in pediatricigraine.18,19 Gabapentin and pregabalin have also been used inigraine prevention in adults although there is a dearth of pe-iatric data.

alcium Channel Blockershe most common calcium channel blocker used in migrainerophylaxis is verapamil although pediatric data are again quite

imited. Verapamil is reasonably well tolerated despite occa-ional rash and constipation. It seems to have efficacy in hemi-legic migraines both in adults and teenagers, mostly on a case-tudy basis. Flunarizine is a nonselective calcium channellocker used fairly extensively in Europe and Canada for mi-raine prevention, but it is not available in the United States.

onclusionsediatric migraine is a common disorder, and the effects can beuite devastating in terms of missed school days, social isolation,nd reduced productivity. Treatment options are often based onecommendations arising from adult practice and studies. Thisractice often ignores the unique aspects of this disorder in veryoung children and adolescents (eg, the teenager’s unwilling-ess to use nasal sprays). Because studies are often underpow-red and at times show such a powerful placebo effect as toegate their value, it is difficult to glean from the literature theest choices for the prevention and rescue of pediatric mi-raines. If practice parameters are followed,20 then only a fewnalgesics (acetaminophen and ibuprofen) plus sumatriptan na-al spray are well supported for migraine rescue, and only flu-arizine (a medication not available in the United States) can be

onsidered “probably effective” for migraine prevention in pe-

iatrics. It is important to critically review these parameters ando continue rigorous medication studies for pediatric migraine.t this time, however, medication choices both for rescue and

or the prevention of migraines in the pediatric population areargely based on trial and error, personal experience of the phy-ician, and individual considerations for each patient. A formu-aic approach is not feasible in the management of pediatric

igraine, and clinicians must carefully consider all the aspects ofach case.

eferences1. Silberstein SD: Migraine pathophysiology and its clinical implications.

Cephalalgia 24:1045-1048, 20042. Cutrer FM: Pathophysiology of migraine. Semin Neurol 30:120-130, 20103. Villalon CM, Olesen J: The role of CGRP in the pathophysiology of

migraine and efficacy of CGRP receptor antagonists as acute antimi-graine drugs. Pharmacol Ther 124:309-323, 2009

4. Hohoff C, Marziniak M, Lesch KP, et al: An adenosine A2A receptorgene haplotype is associated with migraine with aura. Cephalalgia 27:177-181, 2007

5. Linder SL: Treatment of childhood headache with dihydroergotaminemesylate. Headache 34:578-580, 1994

6. Callenbach PM, Pels LP, Mulder PG, et al: Sumatriptan nasal spray inthe acute treatment of migraine in adolescents and children. Eur JPaediatr Neurol 11:325-330, 2007

7. Linder SL, Mathew NT, Cady RK, et al: Efficacy and tolerability ofalmotriptan in adolescents: A randomized, double-blind, placebo-con-trolled trial. Headache 48:1326-1336, 2008

8. Ho TW, Ferrari MD, Dodick DW, et al: Efficacy and tolerability ofMK-0974 (telcagepant), a new oral antagonist of calcitonin gene-re-lated peptide receptor, compared with zolmitriptan for acute migraine:A randomised, placebo-controlled, parallel-treatment trial. Lancet 372:2115-2123, 2008

9. De Felice M, Ossipov MH, Wang R, et al: Triptan-induced latent sen-sitization: A possible basis for medication overuse headache. Ann Neu-rol 67:325-337, 2010

0. Edvinsson L, Linde M: New drugs in migraine treatment and prophy-laxis: Telgagepant and topiramate. Lancet 376:645-655, 2010

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2. Eiland LS, Jenkins LS, Durham SH: Pediatric migraine: Pharmacologicagents for prophylaxis. Ann Pharmacother 41:1181-1190, 2007

3. Bidabadi E, Mashouf M: A randomized trial of propranolol versus so-dium valproate for the prophylaxis of migraine in pediatric patients.Paediatr Drugs 12:269-275, 2010

4. Winner P, Pearlman EM, Linder SL, et al: Topiramate for migraineprevention in children: A randomized, double-blind, placebo-con-trolled trial. Headache 45:1304-1312, 2005

5. Lakshmi CV, Singhi P, Malhi P, et al: Topiramate in the prophylaxis ofpediatric migraine: A double-blind placebo-controlled trial. J ChildNeurol 22:829-835, 2007

6. Cruz MJ, Valencia I, Legido A, et al: Efficacy and tolerability of topira-mate in pediatric migraine. Pediatr Neurol 41:167-170, 2009

7. Unalp A, Uran N, Ozturk A: Comparison of the effectiveness of topira-mate and sodium valproate in pediatric migraine. J Child Neurol 23:1377-1381, 2008

8. Cuvellier JC, Riquet A, Vallee L: Antiepileptic drugs in pediatric mi-graine. Arch Pediatr 15:1693-1699, 2008

9. Cuvellier JC: Antiepileptic drugs for the prevention of pediatric mi-graine. Rev Neurol 165:1002-1009, 2009

0. Lewis D, Ashwal S, Hershey A, et al: Practice parameter: Pharmacolog-ical treatment of migraine headache in children and adolescents: Reportof the American Academy of Neurology Quality Standards Subcommit-tee and the Practice Committee of the Child Neurology Society. Neu-

rology 63:2215-2224, 2004