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Special Issue Article

Sleep and headache in children: Specificpattern in migraine, implication for thetreatment

Vincenzo Guidetti1, Claudia Dosi2 and Oliviero Bruni2

Abstract

Background: The existence of a correlation and/or comorbidity between sleep disorders and headache, related to

common anatomical structures and neurochemical processes, has important implications for the treatment of both

conditions.

Methods: The high prevalence of certain sleep disorders in children with migraine and the fact that sleep is disrupted in

these patients highlight the importance of a specific therapy targeted to improve both conditions.

Findings: The treatment of sleep disorders like insomnia, sleep apnea, sleep bruxism and restless legs syndrome, either

with behavioral or pharmacological approach, often leads to an improvement of migraine. Drugs like serotoninergic and

dopaminergic compounds are commonly used for sleep disorders and for migraine prophylaxis and treatment: Insomnia,

sleep-wake transition disorders and migraine have been related to the serotonergic system abnormality; on the other

hand prodromal symptoms of migraine (yawning, drowsiness, irritability, mood changes, hyperactivity) support a direct

role for the dopaminergic system that is also involved in sleep-related movement disorders.

Conclusions: Our review of the literature revealed that, beside pharmacological treatment, child education and lifestyle

modification including sleep hygiene could play a significant role in overall success of the treatment. Therefore comorbid

sleep conditions should be always screened in children with migraine in order to improve patient management and to

choose the most appropriate treatment.

Keywords

Migraine, children, sleep disorders, parasomnias, sleep apnea, restless legs syndrome

Date received: 2 April 2014; revised: 27 May 2014; accepted: 8 June 2014

Introduction

The existence of an intimate relationship between sleepand headache has been recognized for more than a cen-tury (1,2). Different clinical evidence supports the exist-ence of mutual relationships between sleep and pain. Itis well known that noxious stimuli and painful dis-orders interfere with sleep; however, sleep disturbancesalso affect pain perception. In fact, sleep deprivationmay enhance the response to pain stimuli; moreover,sleep restriction is one of the most common triggersof migraine attacks (3).

Clinical research correlates specific headache diag-noses and sleep disorders with chronobiologic patternsand sleep processes, suggesting the existence of a cor-relation and/or comorbidity between sleep disordersand headache, related to common anatomical struc-tures and neurochemical processes that are involvedin the regulation of sleep and headaches (4).

What makes sleep disorders and headaches highlyrelevant is the fact that both conditions highly increasethe risk for each other. A previous study by our groupshowed that the most frequently diagnosed comorbiddisorders in children with migraine were sleep disordersfollowed by anxiety disorders, and that 66% ofmigraine children with sleep disorders had enduringheadache (5).

1Department of Pediatrics and Child and Adolescent Neuropsychiatry2Department of Developmental and Social Psychology, Sapienza

University, Italy

Corresponding author:

Vincenzo Guidetti, Department of Pediatrics and Child and Adolescent

Neuropsychiatry, Sapienza University, Via dei Sabelli 108, Rome 00185,

Italy.

Email: vincenzo.guidetti@uniroma1.it

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DOI: 10.1177/0333102414541817

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Moreover, the co-occurrence of sleep and headachedisorders, particularly migraine, not only results inoverlapping clinical manifestations but also largelydetermines their natural history and prognosis andoften promotes their transformation into a chronic,compound, persistent, and intractable condition (6,7).

Migraine is the most common form of disabling pri-mary headache in pediatrics. Approximately one-third(24%–42%) of migraine patients have attacks almostexclusively related to sleep or awakening (sleepmigraine¼ SM). According to the InternationalClassification of Headache Disorders, second edition(ICHD-II), SM is not a separate migraine subtype,but sleep-related symptoms are among the most fre-quently cited trigger factors (8).

In young children, for whom language and cognitiveabilities may make it difficult to fully verbalize symp-toms, either migraine descriptors can be missed orunderestimated or sleep symptoms may not be recog-nized as causative factors for migraine. For these rea-sons some manifestations related to sleep can be missedor misdiagnosed. Similarly, childhood periodic syn-dromes that are difficult to diagnose are thought torepresent early-life expression of migraine genes thatlater in life are expressed as migraine headache andinclude benign paroxysmal torticollis, benign paroxys-mal vertigo, abdominal migraine and cyclic vomitingsyndrome. Recent research suggests infant colic mayalso fit into this category (9).

The aim of this review is to highlight the relationshipbetween sleep and migraine in infancy, childhood andadolescence and to elucidate how the interactionbetween these two conditions could help the clinicianin the choice of the best treatment.

The relationship between sleep and migraine ininfants and children

There are different ways to approach the relationshipbetween sleep and migraine: a) Migraine could be con-sidered to be a result of sleep disorders; b) migrainemay be the cause of the alteration of sleep; c) migraineand sleep could be thought of as an expression of acommon pathogenic process.

Several studies reported in migraine children majorsleep complaints related to sleep duration, bedtime set-tling, sleep latency, night awakenings, nocturnal symp-toms like nightmares, parasomnias or restless sleep anddaytime sleepiness (6–10).

Subjects with migraine reported a higher prevalenceof sleep disturbances in parents, sleep disturbances ininfancy, and colic, as well as an elevated level of famil-iarity for migraine, showing that a genetic link might bepresent between migraine and disturbed sleep and indi-cating that the common neurobiological substrate

might act from the beginning of life and/or that acomorbidity exists between these two disorders (10).Therefore clinicians should be able to detect earlysymptoms related to sleep that can be predictive ofmigraine at later ages as demonstrated by the studyby Aromaa et al. (11) in which sleep disruption at age3 years predicted headaches at 6 years.

Early developmental disorders like eating difficultiesand sleep disorders have been found in 51% of childrenwith headache (12) and in 78% of children with endur-ing headache vs. 25% of children showing headacheremission (13).

An early precursor of migraine could be representedby infantile colic, which represents one of the earliestmanifestations of pain and crying in healthy infants.This association has been corroborated by studiesshowing an increased prevalence of infantile colic inmigraine children (14,15)

Recently a study by Romanello et al. (15) showedthat 208 consecutive migraine children aged 6 to 18years presenting to the emergency department weremore likely to have experienced infantile colic thanthose without migraine (72.6% vs. 26.5%; p< 0.001),either migraine without aura (73.9% vs. 26.5%;p< 0.001), or migraine with aura (69.7% vs. 26.5%;p< 0.001). This association was not found for childrenwith tension-type headache (TTH) (35% vs. 26.5%),confirming the specificity of the association. No specifictherapies have been proven effective in randomizedclinical trials for infants with infantile colic (16). Inone report, an infant with colic experienced improve-ment after starting antimigraine (cyproheptadine) ther-apy, reinforcing the relationships between the twoconditions (17).

Generic sleep disorders. A pioneering study on a largepediatric headache sample showed for the first timethat both migraine and tension headache were asso-ciated with different sleep disorders but the migrainegroup tended to have ‘‘a more disturbed sleep’’ withincreased prevalence of nocturnal symptoms such assleep breathing disorders, restless sleep and parasom-nias, and of daytime sleepiness (10).

Following this original research, other authors inves-tigated this relation, reporting that children withmigraine headaches have a large range of sleep disturb-ances like bedtime resistance, insufficient and inter-rupted sleep, sleep-disordered breathing, disorders ofarousal, sweating during sleep, difficulty waking up inthe morning and daytime sleepiness (18–22). One morerecent study reported a significantly higher prevalenceof excessive daytime sleepiness, narcolepsy and insom-nia but did not find a significantly higher prevalence ofsymptoms of sleep apnea, restlessness and parasomnias,contradicting previous literature (23).

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A deeper analysis of the relation between specificmigraine headache characteristics and sleep problemsshowed that frequency and duration of migraineattacks were related to the occurrence of specificsleep-related behaviors, including shortened sleep dur-ation, parasomnias, sleep anxiety and bedtime resist-ance (24).

Disorders of arousal. A recent study evaluated the associ-ation of sleep terror history in childhood and develop-ment of migraines in adolescence, showing that asignificantly larger proportion of adolescents withchronic migraine (CM) had a history of sleep terrors(40%) vs. adolescents with episodic migraine (26%),and healthy adolescent controls (8%) (25).

A very high frequency of somnambulism in patientswith migraine was found whereas frequency of som-nambulism in patients with nonmigraine headachewas similar to that of the general population. A retro-spective study looking for a history of somnambulismin childhood showed that somnambulism and migrainecan appear at different ages, the former in the lateinfancy, the latter in childhood and both could belinked to a different age-related expression of a disorderof serotonin metabolism (26).

The strength of the association between somnambu-lism and childhood migraine raised the possibility thatsomnambulism might be considered as a minor diag-nostic criterion in the clinical diagnosis of childhoodmigraine (27). Furthermore, there is some evidencethat sleepwalking and headache can be precipitatedby sleep-disordered breathing (28).

A hypothesis proposed that the serotonergic systemmay be a link between sleep-disordered breathing andsleepwalking. Following this hypothesis, hypercapnicacidosis, secondary to sleep-disordered breathing,could stimulate the serotonergic neurons resulting inincreased excitability of motoneurons and release ofgross movements leading to the appearance of som-nambulism. However, the need for concomitantlyage-related increased excitability of 5-HT neuronsand acidosis explains why abnormal breathing duringsleep only rarely induces sleepwalking (29). The associ-ation between somnambulism and migraine supportsthe nature of the serotonin abnormality underlyingmigraine (30).

Sleep apnea. Few data are available on the relationshipbetween sleep apnea and migraine in children. In thissection we refer mainly to adults or to chronic headacheand sleep-disordered breathing.

Some migraine patients have been found to haveeither obstructive or central sleep apnea: In the Paivaet al. (31) study, the authors found three patients withobstructive sleep apnea syndrome among 13

migrainous patients, while the Kudrow et al. studyshowed evidence of sleep apnea in six out of 10 clusterheadache patients: Four of these patients had centralapnea, and two obstructive apnea (32).

Several reports showed that migraine attacks in sleepapnea patients occur usually during night time or earlymorning (33–35). The prevalence of headache inobstructive sleep apnea syndrome (OSAS) patients isvery high, varying from 30% to 70% (32,33). Boutros(1989) (34) showed that, although the incidence ofheadache in general did not differ between sleepapnea patients and controls, those with sleep apneahad a significantly higher incidence of morning head-ache and a higher severity of pain (34–37), as reportedalso by Neau et al. (2002) (38), who showed that 33%of OSAS patients had headaches, of whom 58.5% hadmorning headaches. Recently Mitsikostas et al. identi-fied sleep apnea in 29% of patients with severe refrac-tory headaches diagnosed as medication-overuse(MOH), cluster, and chronic TTHs (CTTHs) (39).

There are a variety of proposed mechanisms toexplain the increased incidence of headache in sleepapnea patients: hypercarbia, hypoxemia, altered cere-bral blood flow, increased intracranial pressure, alter-ations in sympathetic nerve activity and increases inblood pressure secondary to multiple arousals (40).However, it seems that early-morning headache is anot specific symptom of sleep apnea (35); in fact,patients with abnormal sleep complained of early-morning headache even more frequently than patientswith sleep apnea. These data confirm the hypothesisthat migraine attacks could be secondary to sleep dis-ruption rather than to sleep apnea by itself. Because ofthe multifactorial genesis of migraine in children, thepathogenetic mechanism is difficult to clarify: Futurestudies may elucidate the character of headache inthese patients and address the question if sleep apneais the primary event leading to headache or if sleepdisruption (that could be linked to several other sleepdisorders) is the main pathogenetic factor for migraine.

Sleep apnea headache is the only headache second-ary to sleep disorder recognized by ICHD-2 and classi-fied as headache attributed to a disorder of homeostasischaracterized by recurrent and bilateral headaches ofpressing quality present on awakening and lasting lessthan 30 minutes (41,42).

Although headaches and morning headache werenot correlated with sleep architecture and respiratoryparameters, nor with excessive daytime sleepiness(EDS), the treatment of OSAS, especially nasal con-tinuous positive airway pressure (CPAP), leads to animprovement in headaches in several cases.

Sleep bruxism (SB). SB, a sleep-related movement dis-order characterized by teeth grinding and clenching,

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is frequently associated with orofacial pain, headaches,and other more severe sleep disorders, such as sleep-disordered breathing. Although the mechanisms under-lying the possible interactions among SB, headachesand sleep-disordered breathing need further research,these conditions are often concomitant. Children withSB may report approximately three times as manyheadaches than non-SB subjects with an odds ratio of4.3; on the other hand, children with migraine showed ahigh prevalence (29%) of SB (43).

Restless legs syndrome (RLS). Most recently, several evi-dences reported a possible association betweenmigraine and RLS, which is a common sleep-relatedmovement disorder. Reports in selected patientgroups strongly suggest that RLS is more common inmigraine without aura patients than in control popula-tions. Sleep disturbances were more frequent in head-ache patients with RLS (44) Chen et al. (2010) foundthat RLS was more common in migraine patients(11.4%) than in TTH (4.6%) and chronic headache(2.0%) (45). Another study confirmed the higher occur-rence of RLS in migraine adults but also suggestedthat RLS (the condition itself, or the disruption ofsleep patterns often found in patients affected byRLS) might affect migraine clinical presentation,being associated with chronic and highly disablingmigraine (46).

The first study suggesting an association betweenRLS and migraine in the pediatric population was con-ducted by Seidel et al. (2012) (47) and assessed the fre-quency of RLS in children and adolescents withmigraine compared to headache-free controls. Theauthors included two control groups: The first groupwas recruited from an outpatient clinic of pediatricsand adolescent medicine (group 1). These childrenand adolescents were exclusively screened at follow-upafter recovery from a minor illness and did not sufferfrom a significant medical, neurological or psychiatriccondition at the time they were included in this study.The second control group was recruited from primaryschool (group 2); the aim of the study and the objects ofthe questionnaires had been explained to the childrenand to the teachers.

In 111 consecutive patients with a sole diagnosis ofmigraine with (MWA) or without aura (MWoA) and73 headache-free controls, the frequency of RLS inmigraine patients was significantly higher (22% vs.5% (p< 0.001) in group 1 vs. 8% (p< 0.001) in group2) (47,48).

Another recent study investigated daytime dysfunc-tion in 25 children with RLS and the effects of treat-ment primarily with iron supplements on RLSsymptoms. Following treatment, participants’ daytimefunction had improved to levels similar to those of

controls. Sixteen out of 23 cases were successfully trea-ted primarily with iron supplement (49).

Nocturnal enuresis. Several studies also demonstrated asignificant relationship between migraine and nocturnalenuresis. Nocturnal enuresis antecedent being consist-ently higher among adolescents with migraines and asignificantly higher age of urinary control achievementsuggest a putative role of the hypothalamus in the patho-physiology of migraine. A recent study about the asso-ciation between nocturnal enuresis and migraine showsthat patients with episodic (EM) or CMhad significantlymore often a history of nocturnal enuresis than the con-trol group (CG¼ 12%, EM¼ 41%, CM¼ 49%).

Recently, according to Park et al. (50), the existenceof a shared pathophysiological substrate betweenmigraine and primary nocturnal enuresis may explainthe inhibition of vasopressin secretion and increasedurinary frequency during a spontaneous attack ofmigraine.

The hypothalamus plays an important role in thebeginning of micturition. Early animal studies, suchas those performed by Gjone in 1966 (51), showedthat electrical stimulation of forebrain structures, suchas the hypothalamus, the anterior cingulate gyrus andseptal nuclei, can elicit bladder contractions (52).Recently, Carotenuto et al. proposed that nocturnalenuresis and migraine could be linked to a dysfunctionof the arousal system with primary nocturnal enuresisbeing considered as a migraine equivalent (53).

Trigger factors (TFs) and circadian rhythms in sleep and

migraine. There is clinical evidence that sleep disordersmay precede the appearance of migraines and could actas TFs. A recent study assessing the prevalence andcharacterization of migraine TFs in children and ado-lescents with migraine, shows that stress was the mostfrequently reported TF (75.5%), followed by the lack ofsleep (69.6%), warm climate (68.6%) and video games(64.7%). Lack of sleep was generally put aside withfatigue (54).

These data were confirmed by another study thatdelineated self-perceived triggers of pain among chil-dren and adolescents. The study was conducted on749 children and adolescents. Headache (60.5%),abdominal pain (43.3%), limb pain (33.6%) and backpain (30.2) were the most prevalent pain types amongthe respondents. Weather conditions (33%), illness(30.7%), physical exertion (21.9%) and lack of sleep(16.2%) were the most frequent self-perceived triggersfor pain noted by the respondents (55). Accordingly,the most frequent causative factors of the headacheattack recognized by a group of children and adoles-cents with headache were represented by ‘‘bad sleep’’and emotional distress (56).

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Moreover, several studies showed that migraineattacks may be precipitated by sleep deprivation orexcessive sleep (57). In adults late onset of sleep wasreported as an occasional TF by 32% of patients (58)whereas lack of sleep was reported as a TF by 44% to57% of adult migraineurs.

On the other hand, migraine seems to be able todecrease quality of sleep, emerging during the nightand causing sleep disruption (56).

The sleep-wake pattern of migraine analyzed with anobjective instrument like actigraphy was characterizedby less time spent in quiet, motionless sleep, and wakingsignificantly earlier in the morning (59). A previousstudy showed that during the interictal period, sleepparameters of children suffering from migraine didnot differ from those of controls, but in the night pre-ceding the migraine attack there was a decrease in noc-turnal motor activity, indicating a decrease in corticalactivation during the sleep period preceding migraineattacks (60).

Treatment for migraine in children

Literature data on the connection between sleep andmigraine may have implications for the diagnosis andespecially for the treatment of migraine (61).

It is known that sleep deprivation may enhance theresponse to pain stimuli and is one of the most commontriggers of migraine attacks (62,63).However it seemsthat sleep continuity disturbance, rather than simplesleep restriction, impairs endogenous pain-inhibitoryfunction and increases spontaneous pain (64).Furthermore, the results of subjective (logs) and object-ive (polysomnography (PSG)) sleep analysis reportedby Engstrøm et al. (8) do not seem to be fully consistentwith the hypothesis that migraineurs on the averagesuffer from a relative sleep deprivation and need moresleep than healthy controls (65). Therefore we canassume that some drugs could improve migraine byreducing the sleep deprivation/discontinuity affectingthe pain threshold.

The treatment of headaches can be divided intopharmacologic and non-pharmacologic types.

Non-pharmacologic treatment and manipulationof sleep

The use of non-pharmacologic preventive measures inchildren with migraine include lifestyle adjustments(dietary changes, sleep hygiene), reassurance, stressmanagement, biofeedback and other behavioral thera-pies. This could represent an alternative approach to thetreatment of migraine by correcting an inappropriatesleep behavior without resorting to pharmacologicaltreatment (66,67). Decreased stimulation and relaxation

techniques are also useful interventions for the treat-ment of migraine attacks (68,69).

It is a common notion that sleep is associated withrelief of migraine attacks, and especially in children,sleep, spontaneous or induced by hypnotics, is thoughtto be an important protective factor and constitutes thedecisive factor for resolution of a migraine attack(70,71). While headache management requires an indi-vidualized approach, there are some general guidelinesthat can be applied to most of the patients (72). Fivecomponent interventions used by Calhoun and Fordmay be useful (73):

. Schedule consistent bedtime that allows eight hoursin bed.

. Avoid watching television, reading and listening tomusic in bed.

. Use visualization techniques to shorten time to sleeponset.

. Consume supper at least four hours before bedtimeand limit fluids within two hours of bedtime.

. Discontinue daytime naps.

A recent study compared the effectiveness of non-pharmacologic treatment for migraine in preschoolchildren and older school-age children that wereinstructed to follow specific guidelines: a) sleephygiene—maintenance of regular sleep hours, withregular bedtimes and waking times, with sufficientsleep time for age to sustain routine daily activities;restriction of beverages, foods and compounds thattend to disrupt sleep before bedtime; and regular exer-cise; b) proper diet—refraining from food additives,with elimination of smoked lunch meats, smokedcheese, yellow cheese (high tyramine), chocolate andfoods containing chocolate, pizza, and foods containingmonosodium glutamate; c) no direct sun exposure, withappropriate head coverage, especially in summer (66).

In a pioneering study the sleep hygiene rules havebeen applied to 70 children and adolescents withmigraine. Patients showed a reduction in the mean dur-ation and frequency of migraine attacks, while theseverity of the attacks did not change.

In this study, based on the presence of at least twocriteria for defining poor sleep hygiene, 70 migraineurs(42.7%) have been selected in a group of 164 migrainepatients and randomly assigned to group A or B. The Agroup had been instructed to follow instructions toimprove sleep hygiene; the B group did not haveinstructions on improvement of sleep hygiene. The 70migraine children selected showed several differencesvs. controls in sleep habits: falling sleep later (fallingasleep >11 p.m.: 16% vs. 7%; p< 0.001), waking uplater (wake time >8:00 a.m.: 3.5% vs. 0.2%;p< 0.0001), napping during daytime (7.4% vs. 3.3%;

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p< 0.005); having a reduced night’s sleep duration (558minutes vs. 565 minutes; p< 0.05), having an irregularschedule: Bedtime (10.6% vs. 5.8% p< 0.05) andwaking up time (9.2% vs. 1.7%; p< 0.0001) varies bymore than an hour on school days.

After the application of the sleep hygiene guidelines,differences were found between the A and B groupsregarding several headache parameters. Mean durationof migraine attacks was significantly reduced at follow-up in the A group while the B group showed an initialreduction but not a significant one. The frequency ofmigraine attacks showed also an improvement: At thefirst observation the prevalence of A group subjectswith more than one attack per week was 35%; atthree months the number decreased to 15% and at sixmonths it was 11%. In the B group the percentage didnot change significantly (at first observation 42%; atthree months, 37% and at six months, 33%).

No differences have been found regarding the sever-ity of migraine attacks; the prevalence of subjects withmild or high-severity attacks did not change signifi-cantly in both groups at follow-up (74).

The application of a multidisciplinary treatment pro-gram (MTP) consisting of different approaches (bio-behavioral therapy, covering relaxation techniques,biofeedback treatment, operant pain treatment, paincoping, cognitive-behavioral and multimodal treat-ment) determined a significant decrease in headachefrequency and a significant increase in quality of life(QoL) for children with migraine, TTH, MOH, fre-quent episodic tension-type headache (FETTH),CTTH and other headaches (75).

Although we acknowledge the efficacy of the behav-ioral and pharmacological therapy, it should be con-sidered that placebo effects as well as beliefs,concepts, wishes, and concerns of parents have import-ant influence on treatment and outcome (76).

Treatment of sleep-disordered breathing to improve

migraine. No data are available on the treatment ofsleep apnea and migraine in children but there aresome studies referred to chronic headache and sleep-disordered breathing.

Morning headache was reported by 156 (33.6%) ofOSAS patients vs. only nine (8.9%) subjects of a con-trol group and apnea-hypopnea index (AHI) was sig-nificantly higher in OSAS patients with morningheadache compared with patients without. Morningheadache was totally resolved in 90% of patients trea-ted with nasal CPAP. Therefore, the history of OSASshould be considered in the differential diagnosis ofmorning headache (77).

A recent study provides new insights into the effect-iveness of the mandibular advancement appliance(MAA) for treating headache associated with SB.

Sixteen adolescents reporting SB, headache, or snoringunderwent four ambulatory PSGs for baseline (BSL)and while wearing MAA during sleep for one week.SB index decreased up to 60%, and headache intensityshowed a decreasing trend with MAA. The results sug-gest that short-term use of an MAA during sleep inadolescents with SB may help reduce the rhythmic mas-ticatory muscle activity (RMMA) and improve snoringand headache. Compared with other treatments,the MAA appears to be the most effective for SB.Short-term use of an MAA appears to reduce SB, snor-ing and reports of headache in adolescents. However,interactions between SB, breathing during sleep, andheadache as well as the long-term effectiveness andsafety of the MAA in adolescents need further investi-gation (78).

Pharmacotherapy in migraine and sleep

The common goals of any treatment are to eliminatepain and associated symptoms, return to normal activ-ity, improve the management of headache, minimizeside effects, avoid painful recurrence, improve QoL,prevent the abuse of analgesics (rare in childhood com-pared with adulthood) and reduce the stress related torecurrent headache (79). In contrast to the largenumber of adult trials, relatively few trials have evalu-ated prophylactic treatment of pediatric headaches(80). Of the drugs used for prophylaxis of migraine,there are some compounds that act either on painthreshold or by modifying/improving sleep. Thesedrugs, commonly used also in children, are mostly rep-resented by antihistaminics, melatonin and serotoniner-gic drugs.

Antihistaminics. Alterations in the histaminergic systemhave been proposed both in neurological and psychi-atric diseases, but to date, no specific disorder con-nected to a specific histaminergic dysfunction hasbeen demonstrated. The role of peripheral acting hista-mine in migraine has been quite extensively explored,but its role as a potent modulator of meningeal noci-ceptors’ activity in migraine is not clear. Activation ofinhibitory H3 receptors has previously been suggestedfor migraine prophylaxis; however, the exact role of thecentral histaminergic system in migraine is virtuallyunexplored. However, both H3R and H4R ligandsmay theoretically have migraine prophylactic proper-ties. Despite being promising drug targets for severaldiseases, the lack of specificity and undesired sideeffects will probably be a major problem (81).

We can assume, however, that the antihistaminicscould act in migraine indirectly through the improve-ment of sleep, and this effect could decrease the pain inmigraine children (82).

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Melatonin. There is evidence that melatonin, besideshaving a role in the biological regulation of circadianrhythms, sleep, mood and aging, is also involved invarious headache syndromes, including CM, CH andCTTH. Altered melatonin levels in migraine, CTTH,CM and CH patients during the cluster and an abnor-mal blunting of melatonin peaks during the activeperiod have been documented (83). Involvement ofmelatonin in the pathophysiology of headache maybe related to its anti-inflammatory effects (i.e. free rad-ical scavenging and reduction of proinflammatorycytokines upregulation), an increase of nitric oxidesynthase activity, inhibition of dopamine release,membrane stabilization, potentiation of gamma ami-nobutyric acid (GABA)- and opiate-induced analgesia,protection from glutamate neurotoxicity, neurovascu-lar regulation and serotoninergic modulation, and thesimilarity of its chemical structure to that of indo-methacin (84,85).

Different studies highlighted the effectiveness ofmelatonin administration in patients with headache ormigraine and circadian rhythm disorders related to thedemonstration of a decrease of melatonin levels in theseindividuals (86–88). The efficacy of melatonin in thesecases could be related to regularization of the sleep-wake pattern through its chronobiological and ‘‘sleep-hygiene’’ effect. The impact of sleep-hygiene rules onchildren with migraine has been previously demon-strated by Bruni et al. (74), showing an improvementof frequency and duration of migraine attacks after theapplication of sleep-hygiene guidelines. In an open-label study on 22 children with primary headache,melatonin effectively reduced the number, intensityand duration of headache attacks per month: In 14 ofthe 21 subjects (10 with MWoA and four with CTTH)the attacks had decreased by more than 50% withrespect to baseline and four reported having no head-ache attacks (three with migraine without aura and onewith aura). None of the children with CTTH reported acomplete remission of headache (88).

Despite several studies showing a decrease ofmelatonin levels in adults with migraine, a recentstudy showed no significant difference in urinary 6-sul-phatoxymelatonin between the migraine children andcontrol group, indicating that nocturnal production ofmelatonin is not reduced in children with migraine (89).

Serotoninergic drugs. A congenital alteration of neuro-transmitter pathways (serotonergic and dopaminergic)might predispose individuals to sleep disorders and toheadache, a result of this neurotransmitter imbalance(90) that might act since the early period of life deter-mining sleep disorders during infancy (i.e. colic, insom-nia) followed by the development of migraine later inlife (91).

The mechanism by which low 5-HT state predisposesthe brain to migraine attack is not clear. 5-HT plays animportant role in the endogenous pain control system;the decrease of this transmitter may lower the thresholdof pain perception and increase the tendency of havingheadache, but 5-HT also plays significant roles in modu-lation of several behaviors such as sleep, therefore, low5-HT may cause derangement in other behaviors (92).

It has been further demonstrated that a reduction inbrain synthesis of serotonin intensifies photophobiaand other migrainous symptoms (93).

A recent study (94) investigated the plasma trypto-phan, 5-hydroxytryptophan (5-HTP), 5-HT and5-HIAA levels in migraine adults patients with or with-out aura and in controls. The plasma 5-HT level wassignificantly lower inMWApatients than in the controls,whereas no significant difference was observed betweenthe levels in migraine patients without aura (MWoA)and the controls. On the other hand, the plasma5-HTP levels were not significantly different betweenthe MWA patients, the MWoA patients and the con-trols. Moreover, the plasma tryptophan levels of thecontrols and both classes of migraine patients were notsignificantly different, although the levels in the migrainepatients tended to be higher. The plasma 5-HIAA levelswere not significantly different among migraine patientsand controls. These data suggest that an enzymaticdysfunction in the metabolic pathway from 5-HTP to5-HT may be present in MWA patients (95,96).

It was also hypothesized that existing agents knownto influence serotonin blood level, vascular tone andinflammatory reactions might terminate migraines.The proposed treatment is to use low doses of trypto-phan, niacin, calcium, caffeine and acetylsalicylic acid(ASA) soon after migraine symptoms are noticed andto avoid during a migraine high-potassium food andmagnesium supplements. Preliminary results inmigraine adult patients indicated that 75% had signifi-cant benefit from this approach (97).

A report on 48 elementary and junior high schoolstudents with primary headache highlighted the associ-ation with sleep disorders: Night waking (41.7%) anddifficulty falling asleep (20.8%) were the most prevalentdisorders; parasomnias were also represented: pavornocturnus and nightmares (14.6%), enuresis (8.3%),somnambulism (6.3%). Treatment with L-5-hydroxy-tryptophan in these patients determined the improve-ment of both conditions, headache and sleep disorders,in particular frequent awakenings and some parasom-nias (98).

Conclusions

A thorough understanding of the relationship betweensleep and various headache syndromes still needs to be

Guidetti et al. 7

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fully elucidated and could be helpful both in diagnosesand management of the headache syndromes. In chil-dren with migraine, rest and/or sleep may help or solvethe pain. Almost all of the pharmacological studies inchildren with migraine have not included the evaluationof any sleep parameters, but we believe that screeningfor sleep disorders with the use of proper tests including

PSG and referral to a sleep clinic when appropriatecould be very helpful. Patient education and lifestylemodification including sleep hygiene play a significantrole in overall success of the treatment. Comorbid sleepconditions should always be screened in children withmigraine in order to improve patient management andto choose the most appropriate treatment.

Clinical implications

. Comorbid sleep conditions should always be screened in children with migraine in order to improve patientmanagement and to choose the most appropriate treatment.

. The treatment of sleep disorders like insomnia, sleep apnea, sleep bruxism and restless legs syndrome oftenleads to an improvement of migraine.

. Serotoninergic and dopaminergic compounds are commonly used either for sleep disorders or for migraineprophylaxis and treatment.

. Child education and lifestyle modification (dietary changes, sleep hygiene, reassurance, stress management,biofeedback, etc.) play a significant role in success of the treatment.

Funding

This research received no specific grant from any fundingagency in the public, commercial, or not-for-profit sectors.

Conflict of interest

None declared.

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