Neonatal and Pediatric Medicine
Open Access

Migraine is the most important cause of pediatric consultations due to headaches [1-3] because of significant distress and disability for child and their family [4]. For this reason, a correct and timely treatment is very important.

More than half of migraineurs have their attack before they’re 15 years of age [5]. The mean age of onset of migraine is 7 years in boys and 11 years in girls [6]. The overall mean prevalence of migraine in the pediatric population is 9.1% (95% CI 7.1-11.1) [1]. According an extensive review of 64 cross-sectional studies, published in 32 different countries, including a total of 227,249 subjects, the prevalence of migraine steadily increases through childhood. The male:female ratio shifts during adolescence according to the age (increases with age) and the gender [7] (Table 1).

Table 1: Prevalence of migraine headache through childhood [1].

Formal diagnostic criteria for primary and secondary headaches have been revised and published in the International Classification of Headache Disorders, 3rd edition. Headache Classification Committee of the International Headache Society (IHS) classified migraine into different subtypes: a) migraine without aura, b) migraine with aura, c) chronic migraine, d) complications of migraine, e) probable migraine, and f) multiple episodic syndromes that may be associated with migraine [8].

Diagnostic evaluation

The diagnosis is based on clinical criteria established by the International Classification of Headache Disorders, 3rd edition (ICHD-3) [7]. Detailed clinical history and general neurologic examination [9,10] are very important to distinguish between primary and secondary headache and to make the correct diagnosis and to choose the appropriate therapies (Tables 2 and 3).

Table 2: Potential causes of secondary headache [4].

Table 3: Essential elements of the headache history [11].

It is not supported by laboratory or other specific examinations. Neuroimaging should be considered when various “red flags”, warning symptoms and signs suggestive of a secondary headache, are present (Table 4) [12]. Electroencephalography (EEG) is recommended only in case of an underlying seizure disorder [13]. Lumbar puncture, in the same way, should be performed only in a suspicion of subarachnoid hemorrhage or neurological infections.

Table 4: Red flags for secondary headache [4,5].

This article reviews the current knowledge about treatment of migraine in children and adolescents. With the term “migraine” we refers to all the above indicates subtypes.

Literature search was carried out in PubMed for all studies and reviews published until August 31st, 2018. The keywords searched for were “treatment migraine and children”, “pharmacological and nonpharmacological treatment migraine and children”, “prophylactic/ preventive treatment migraine and children” and “drugs for the acute treatment of migraine in children”. Studies were included if they focused on the pediatric population, if they were published in peer reviewed journals and written in English.

The treatment of pediatric migraine is multidisciplinary and includes pharmacological and non-pharmacological interventions [14].

Approximately 60% of children and adolescents with migraine will improve with a three-pronged treatment approach that includes general measures, acute and preventive pharmacological and nonpharmacological treatments [15]. Therapeutic strategies should be based not only on the characteristics of the migraine episodes, the daily migraine disability and the impact on quality of life [8], measured by PedMIDAS and PedsQL 4.0 Course Scale [16,17], but especially on the biological (patient’s age), socio-family (family structure, culture, beliefs) and psychological aspects of patients [17,18].

For the remaining 40% of children and adolescents having continuous headache or medication-overuse headache, the clinician’s judgment remains the best guide to preventive therapy selection.

The first step in avoiding migraine attack is to recognize and to eliminate triggering factors such as: poor sleep habits, dietary (irregular meals, alcoholic beverages, caffeine excess, nitrates and nitrites, foods with tyramine), environmental (media abuse, odors), medication (estrogen, histamine, nifedipine, ranitidine, reserpine…), psychological (stress, anxiety, worry, depression) and physical triggers (fever, fatigue, hypoglycemia, dehydration) [10]. Any trigger factors should be addressed and modified when possible, to promote general health (SMART, Sleep, Meals, Activity, Relaxation Trigger avoidance) (Table 5) [19].

Acute treatment includes abortive (or rescue) medications that are taken during acute migraine attack to provide quick relief from headache.

Drug used in symptomatic treatment are chosen according to the headache type and frequency, type of symptoms associated, their adverse-effect profile and comorbidities.

The common goals of acute treatment are: reduction or removal of pain and associated symptoms, recover of the global functioning, reduction or removal of side effects, improvement of the quality of life and reduction or removal headache recurrences. Their use should be limited to no more than two to three times per week to avoid Medication Overuse Headache (MOH).

The main indications are: migraine attacks with limited frequency (≤4 episodes/month), contraindications to prophylaxis therapies and poor compliance to prophylaxis therapy.

Lastly we remind you that in pediatric age the share of placebo-responders to symptomatic migraine therapy is even higher (40-70%) than the adult (30-45%), so that the results in the controlled trials are less comprehensible and more difficult [8].

 Paracetamol (or acetaminophen) and ibuprofen are the most commonly used over-the counter (OTC) drugs. Few and limited controlled studies have been performed on the use of analgesics in the pediatric migraine.

Regarding acetaminophen, there isn’t sufficient evidence for the acute treatment of migraine in children and adolescents. In a double-blind, randomized, placebo-controlled, crossover study acetaminophen (15 mg/kg) was not superior to placebo or ibuprofen (7.5-10 mg/kg), while ibuprofen was significantly more effective than placebo and in reducing pain intensity [9,13,20,21].

The rare adverse effects of acetaminophen are skin rash, erythema, urticaria, while gastralgia, nausea and vomiting for ibuprofen. At the moment, acetaminophen is not contraindicated as an analgesic since the first years of life. Contraindications are drug hypersensitivity, liver failure and haemolytic anemia [22].

Ibuprofen is another NSAID (Non-Steroidal anti-Inflammatory Drug) used in the acute treatment of migraine in children [23]. Treatment should be initiated at the onset of pain or aura, if present, even before the head pain begins. The initial dose could be repeated once in 4-6 h for the same headache, if needed.

Ketorolac is used mostly in the emergency department. It is used an intravenous formula, starting from 0.5 mg/kg. It is effective in 55.2% of the patients in one hour. When combined with prochlorperazine, the response rate improves to 93% [24]. According a randomized, doubleblind trial of prochlorperazine versus ketorolac, recurrence rate within 24 h with ketorolac alone is 30% [25].

Indomethacin is another NSAID used in a heterogeneous group of headache such as Valsalva-induced headaches (cough, exercise or sex headache), primary stabbing headache, hypnic headache and the trigeminal autonomic cephalalgias (TACs) [a group of primary headache disorders that includes cluster headache (CH), paroxysmal hemicrania (PH), hemicrania continua (HC) and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/cranial autonomic features (SUNCT/SUNA)] [26].

Its mechanisms are not clear. It is a reversible inhibitor of prostaglandins, blocking both COX-1 and COX-2 synthesis.

Treatment usually starts with a dose of 25 mg three times daily with meals, and a response is usually fast. Otherwise after 48 hours the dosage can be increased to 50 mg three times daily. The most important side effects are vomiting, upset stomach, heartburn, diarrhea, a feeling of bowel fullness, constipation, bloating, gas, rectal irritation, dizziness, drowsiness, nervousness, headache, skin rash, itching or blurred vision.

Alternative over-the-counter anti-inflammatory medications, including naproxen sodium and aspirin. Naproxen is a different NSAID that, when given in combination with sumatriptan, is FDA approved for use in pediatric migraineurs. Aspirin should be avoided in children under the age of 16 years to avoid the risk of Reye syndrome [13].

In the current body of literature, there is no evidence for use of diclofenac in children with migraine.

Table 6 summarizes the most common analgesics and NSAIDs, their doses, adverse effects and contraindications.

Table 6: Analgesics and NSAIDs [12].

Antidopaminergic agents

Antidopaminergic agents, such as prochlorperazine and metoclopramide, are indicated in the treatment of significant nausea and vomiting associated with migraine attack, in the emergency department (ED). A multi-center retrospective study of common practices in the ED for management of migraine compared numerous treatments (non-opioid analgesics, dopamine agonists and diphenhydramine): prochlorperazine was used with equal frequency to metoclopramide and appeared more effective than metoclopramide in preventing the return of patients in the ED [27]. In a 2011 study has been showed that prochlorperazine, when given intravenously with a load of intravenous fluids, determined a 75% improvement with 50% headache freedom at 1 h, and 95% improvement with 60% headache freedom at 3 h [13,28]. However, given the risk of dystonic reaction, it is usually recommended the combination with diphenhydramine. Its sedating effect could be beneficial for patients who need to sleep after their migraine attack [4]. One randomized double-blinded study comparing prochlorperazine and intravenous ketorolac found that prochlorperazine was more effective than ketorolac in reducing recurrence rate within 24 h [29].

Other neuroleptics, administered via the parental route, for the management of status migrainosus include haloperidol and chlorpromazine. Only one pediatric retrospective study of the IV use of chlorpromazine versus prochlorperazine found higher rate of relapse and side effects in the chlorpromazine group.

At the moment, there have not been carried out prospective study about the efficacy of intravenous neuroleptics in migraineurs children (Table 7) [30,31].

Table 7: Antidopaminergic agents [12].

Ergot-based therapies

The use of ergot alkaloids should be limited for their vasoconstrictive properties. The effect of dihydroergotamine is due to its 5HT-1A-1B-1D-1F receptor agonist affinity leading to central vasoconstriction. Common side effects include nausea, vomiting, abdominal discomfort, flushed face, muscle cramps, vasospasm, transient elevations in blood pressure and bradycardia [32].

Oral dihydroergotamine is not effective in the acute treatment of migraine in children and adolescents. In a small cross-over study dihydroergotamine was not more effective to placebo [33].

Triptans

Triptans are 5-HT1B/1D serotonergic receptors agonists and have an anti-migraine and antiemetic action. Triptans cause the cephalic vessels vasoconstriction, inhibiting the trigeminal perivascular nerve terminals and the release of vasoactive neuropeptides [34,35]. There are different formulations of triptans as injections (sumatriptan), nasal spray (sumatriptan and zolmitriptan), tablets (sumatriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, naratriptan and frovatriptan) and dissolving tablets (zolmitriptan and rizatriptan). The intranasal, sublingual or subcutaneous route may be preferable in patients who have migraine associated with significant nausea and vomiting. Furthermore, the intranasal route may be preferable in patients who are unable to swallow pills [36]. Commonly adverse events include fatigue, dizziness, dry mouth, and nausea or vomiting with oral preparations, and taste disturbance, nasal symptoms, and nausea with intranasal preparations. If this happens, it is worth trying a different triptan or formulation.

According the most recent practice parameter guidelines for treatment of pediatric headaches analgesics and triptans are recommended as the first-line treatment for acute migraine [37]. Triptans are used to treat moderate or severe migraine attacks, while analgesics are reserved for mild or moderate ones. The triptan should be taken at the onset of migraine and may be repeated after two hours if required. It is necessary to give the patient and parent clear instructions on the maximum dose, “two doses in 24 hours and on no more than two days a week” to prevent transformation into an analgesic overuse headache (AOH). Contraindications are hypersensitivity to triptans, cerebrovascular or peripheral vascular syndromes, severe hepatic impairment, uncontrolled hypertension, hemiplegic migraine, pregnancy, and combinations with monoamineoxidase inhibitors, ergot alkaloids or other 5-HT1B/1D agonists (increasing the risk of serotonin syndrome).

Triptans should be considered as an acute treatment option for children and adolescents with migraines, although their use is mostly ‘off-label’ (Table 8). Few triptans have been approved by the US Food and Drug Administration (FDA) for children migraine abortive therapy. In Italy only intranasal sumatriptan 10 mg is authorized from 12 years [38].

Table 8: Triptans [12].

According to a recent review on acute pharmacological treatment of migraine in children and adolescents, including 27 clinical studies, triptans appear to be effective in treating of pediatric migraine [21] (Tables 9 and 10). Generally triptans are safe, however show an increased risk of minor adverse events. No statistically significant differences regarding efficacy were found between the different subgroups of triptans: rizatriptan, sumatriptan and zolmitriptan were statistically more effective than placebo. It must be remembered that interpretation of results among studies of triptan efficacy in adolescents is difficult for the presence of high placebo response rates [39]. No statistically significant difference regarding efficacy was found between oral and intranasal triptans. Patients may prefer oral preparations in case of chronic rhinitis or intranasal preparations if they vomit. The association with non-steroidal anti-inflammatory drugs (NSAIDs) increases triptan’s effectiveness.

Table 9: Comparison between triptans versus placebo in children, outcome Pain free [40].

Table 10: Comparison between triptans versus placebo in adolescents, outcome pain free [40].

Sumatriptan remains the most widely studied of the triptans. This, in combination with naproxen sodium, is more effective than placebo in treating adolescent migraine attack (in producing pain freedom), while there aren’t studies in children [22].

Intranasal sumatriptan is safe and effective in children moderate or severe migraine attack: in a randomized, double blind, placebocontrolled study a statistical difference, in producing pain freedom, was found at 2 hours in those who took the 20 mg nasal spray dose than placebo group [36,41]. The main side effect is taste disturbance.

An open-label study on the subcutaneous sumatriptan in treating of children and adolescents with migraine in the emergency department showed an overall efficacy of 72% at 30 min and 78% at 2 h, with a recurrence rate of 6% [42].

There are conflicting evidences regarding other triptans. Different American studies showed that oral and nasal spray Zolmitriptan is well tolerated and effective in improving headache symptoms [43,44].

Rizatriptan has been approved by FDA for the treatment of acute migraine after 6 years, using 5 mg for children less than 39 kg and 10 mg for those 40 kg or more. A randomized, placebo-controlled trial showed that rizatriptan has been well tolerated with minimal adverse effects including dizziness, somnolence, dry mouth [45,46].

FDA approved Almotriptan for the treatment of acute migraine after 12 years. It is more effective in the treatment of migraine attack than placebo, at the 12.5 mg dose [47].

No significant statistically difference has been showed between Eletriptan and placebo in improving pain at 2 hours post-dose [48].

Magnesium sulfate

Intravenous magnesium sulfate is increasingly being used in ED acutely for the treatment of pediatric headache; however there is a paucity of evidence for its use in children with headache.

A pediatric case series reported that patients with migraine ages 5 to 18 years old treated with a standard dose of intravenous magnesium sulfate (30 mg/kg of IV magnesium sulfate with maximum dose of 2000 mg) showed a favorable response in 35% of children and experienced minimal side-effects [49].

The main indications of preventive treatment are high frequency of migraine attacks (1 to 2 per week or >3 to 4 per month), impairment of both the quality of life (e.g., lower score on PedsQL) and the daily activities (e.g., PedMIDAS score greater than 30 or Grade III or Grade IV), severe and prolonged attacks (>4 h), irregularity of school attendance and the ineffective, not tolerated, contraindicated or overused acute treatment of migraine attacks. In addition, we remember the presence of complex and severe accompanying symptoms or long uncomfortable aura symptoms [50-52]. The choice of the preventive drug should take into account any comorbidity, such as anxiety and depression. Although 1/3 of adolescent migraine patients have the criteria to undertake pharmacological prophylaxis, this is proposed in less than 20% of these patients [53].

Pain improvement is a gradual process and will not be instantaneous. For this reason, any drug used for prophylactic treatment should be evaluated for about 6-12 weeks before it can be considered ineffective. If effective, the medication should be continued for 6 months [54,55].

Prophylaxis treatment can be interrupted when severe migraine attacks are reduced to one or two per month (for 3-6 months). This period may be altered based on the school year. Children typically have improved headaches over the summer when they are out of school, so early summer provides an opportunity to reduce medication. Headaches often worsen with the start of school, in late spring and fall; thus, these are less desirable times to discontinue preventive medication [56].

The most commonly used medications for migraine prophylaxis are: beta blockers (propanolol), calcium channel blockers (flunarizine), the antihistaminics drugs (cyproheptadine), the antidepressants (amitriptyline) and the anticonvulsivants (valproate, topiramate and gabapentin) (Table 11).

Complementary and alternative medicine may play an important role in the migraine preventive treatment.

The main advantages of non-pharmacological therapy are: the absence of side effects and the best patient and family compliance. Patients prefer this approach to pharmacological therapies for one or more of the following aspects: insufficient or no response to pharmacologic therapy; limited tolerability to drugs, medical contraindications, pregnancy/breastfeeding and the frequent or excessive use of analgesic or acute medications.

These treatments include psychological and behavioral therapies on the one hand and nutraceuticals/supplements on the other.

Psychological and behavioral therapies

Psychological and behavioral treatments include Mindfulness, Cognitive-Behavioral Therapy (CBT), Operant-Behavioural Therapy (OBT), Relaxation and Biofeedback Training or combination of these treatments [106].

Mindfulness has the purpose to teach individuals how to maintain focus on a stimulus while simultaneously allowing intruding thoughts/ feelings to be acknowledged, but not judged. Recent studies used mindfulness in a limited group of patients with migraine with encouraging results [107]. In a recent pilot study on mindfulness intervention in adolescents with chronic or episodic high frequency migraine, has been showed a reduction of headache frequency and medication intake and a good feasibility and acceptability of the treatments (although not specifically evaluated) [108].

CBT should be considered the first-line psychological treatment for individuals with chronic pain disorder. Main CBT’ indications are the parents' refusal to use drugs, psychiatric comorbidities (such as anxiety, depression, social phobia, performance anxiety), family problems, ineffectiveness or inadequate response to drug therapy [106,109,110]. There aren’t rigorous and reliable scientific evidence about CBT and other psychological treatments. A randomized clinical trial looking at children and adolescents with chronic migraine indicated that those patients treated with amytriptyline and CBT showed a reduction of headache frequency compared to those treated with headache education and amitriptlyne [109]. Many other studies, instead, showed a positive effect of CBT on migraine and its psychological comorbidities [106,107,111].

OBT focuses on pain behaviors as a major component of the pain problem, and postulates that they are subject to environmental contingencies. Three therapeutic techniques were shown to be effective: graded activity, activity pacing, and time-contingent medication management [112].

Biofeedback (BFB) Training is a method through which a subject receives information on its autonomic physiological functions (for example heart rate, skin conductance, muscle tone, respiratory rate) through instruments. The BFB training allows to decrease anxiety or improve achievements in short term missions such as sports. According to two recent meta-analyses, biofeedback techniques were highly efficient in management of migraine or tension-type headache in child and adolescent population [113-115].

Nutraceuticals/supplements

Vitamins and supplements could be an attractive option for families who wish to avoid prescription medications and their side effects. Alone or/and in combination, magnesium, riboflavin, coenzyme Q10 and the herbal extracts of butterbur, feverfew and ginkolide B have all been suggested as preventives for migraine [116]. Although there are only a small number of controlled trials, the results from the CHAMP study may increase the use of these supplements [117].

Magnesium oxide: It is an ion involved in brain excitation. Low levels of magnesium have been found in migraineurs. Few pediatric migraine prevention studies established equivocal results. It is recommended a dose of 400 mg daily. The most common side effect includes diarrhea [118,119].

Riboflavin (vitamin B2): It is a cofactor necessary for mitochondrial oxidation. Low levels of vitamin B2 have been found in migraineurs. There are few and controversial pediatric migraine studies. One randomized, double-blind, placebo-controlled study found that high doses of riboflavin were shown to be initially effective, although this difference was not maintained at 6 months. Other studies showed a high placebo response rate, which complicates interpretation of the results [120-122]. It is recommended a dose of 25-400 mg/day. The most common side effect includes bright yellow urine and diarrhea.

Coenzyme Q10: It is an antioxidant and a cofactor necessary for mitochondrial oxidation. Low levels of Coenzyme Q10 have been found in migraineurs. In a large open-label trial on pediatric migraine supplementation of Coenzime Q10 showed an improvement of headache frequency and disability scores [123]. It is recommended a dose of 50-100 mg/day. The most common side effect includes nausea, anorexia, dyspepsia, diarrhea.

Vitamin D: Low levels of vitamin B2 have been found in migraineurs. Some studies showed the effectiveness of vitamin D supplementation in reducing headache frequency [124].

Tanacetum parthenium: Feverfew is a derived from a weed plant Tanacetum parthenium. It has anti-inflammatory properties. There are not also studies on the efficacy and safety of feverfew in pediatric age [125,126].

Butterbur extract (Petasites hybridus): It contains pyrolizidine alkaloids. It has antispasmodic and anti-inflammatory properties. Two studies showed an improvement in headache frequency. Side effects are minimal and include burping. It has also a known carcinogenic effect [127,128].

Non-invasive neurostimulation is an innovative strategy for the symptomatic and preventive treatment of migraine and cluster headache, even in episodic form. We remember two procedures.

The first, called non-invasive Vagal Nerve Stimulation (nVNS), consists in the application of a stimulator, called GammaCore, which electrically stimulates the vagus nerve on the lateral cutaneous surface of the neck.

The procedure, when it is used to interrupt the painful attack, consists in applying the stimulator for 2 minutes on both sides of the neck. In preventive use, however, the nVNS is performed 3 times a day, daily, for at least 3 months, each time providing an electrical stimulus lasting 2 minutes on each side of the neck.

The technique is safe and generally well tolerated. The nVNS has been shown to significantly influence the activity of glutamate in the trigeminal nucleus, a key center for the propagation of headaches.

In a recent Italian study non-invasive the nVNS used for the acute treatment of migraine without aura in adolescents, showed a favorable safety and tolerability. This option is able to reduce the number of medication for aborting attacks in this particular and sensitive category of patients where options without side effect are suitable [129].

Additional studies with larger population of patients and sham condition are warranted.

Other non-invasive neurostimulation technique is the Transcranial Magnetic Stimulation (TMS). In a recent review about nonpharmacological approaches for headaches in young age it was investigated the efficacy of single-pulse TMS in adolescents with chronic migraine. During the 12 week treatment period, patients were instructed to use the device twice daily: a significant reduction in headache frequency (33.8%) was found [130].

Migraine in pediatric population, as well as in adults, is often unrecognized or misattributed to secondary causes such as sinus disease or emotional disorders. A detailed anamnesis is a very important component of diagnosis. It takes a lot of time and practical experience. History-taking consists in having the right suspicions, asking the right questions in the right sequence to arrive at the right diagnosis and initiate the right treatment [131].

In the literature, data on the current clinical practice on treatment of pediatric migraine are very limited.

We evaluated the use of acute and preventive drugs, nutraceuticals and non-pharmacological treatments.

Acute or symptomatic treatment is always more effective when given early during the attack. NSAIDs, especially ibuprofen, should be preferred to acetaminophen for treating acute attacks of migraine, because they were usually more effective and well tolerated. If NSAID are not effective, triptans could be used more frequently as first for treating migraine attack in adolescents.

Migraine prophylaxis includes a large number of drugs but relatively few rigorous, randomized controlled studies have been carried out in children and adolescents. According to the main guidelines or systematic reviews for preventive treatment of paediatric migraine flunarizine is recognized as the first choice drug for prophylaxis, followed by propanolol, amitryptiline, pizotifen, cyproheptadine and antiepileptic drugs (topiramate and valproate).

As concerns preventive treatments, further studies on nutraceuticals are necessary in particular to establish mechanisms of action of the molecules contained in these multiple compounds and their efficacy.

Therefore, the use of non-pharmacological preventive treatments (i.e. relaxation techniques, biofeedback, cognitive-behavioral therapy) should be implemented in clinical practice, especially in cases with contraindications or poor tolerability or efficacy to preventive drugs. The combination of behavioral approaches with pharmacological therapies has been shown to be superior to each individually and appear to maximize long-term efficacy [132].

Finally, according to the National Headache Foundation a correct management of headache includes writing and keeping a headache diary. It is very important in keeping detailed records of headache episodes, identifying trigger factors (avoiding them) and defining patterns migraine to begin the most effective treatments [133].

The treatment of pediatric migraine is multidisciplinary. It includes lifestyle changes (nutrition, stress, sleep, physical activity,…), symptomatic and preventive pharmacological therapies, nonpharmacological preventive therapies (psychological and behavioral therapies, nutraceuticals) and compilation of the headache diary.

Pediatric RCTs, based on larger samples sizes and innovative study protocols, involving multicenter studies and primary care services (to reduce selection bias), are needed to better understand the most effective and safe treatment strategies for pediatric migraine patients and define “responders” profile.