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.
Introduction
The existence of an intimate relationship between sleep and headache has been recognized for more than a century (1,2). Different clinical evidence supports the existence of mutual relationships between sleep and pain. It is well known that noxious stimuli and painful disorders interfere with sleep; however, sleep disturbances also affect pain perception. In fact, sleep deprivation may enhance the response to pain stimuli; moreover, sleep restriction is one of the most common triggers of migraine attacks (3).
Clinical research correlates specific headache diagnoses and sleep disorders with chronobiologic patterns and sleep processes, suggesting the existence of a correlation and/or comorbidity between sleep disorders and headache, related to common anatomical structures and neurochemical processes that are involved in the regulation of sleep and headaches (4).
What makes sleep disorders and headaches highly relevant is the fact that both conditions highly increase the risk for each other. A previous study by our group showed that the most frequently diagnosed comorbid disorders in children with migraine were sleep disorders followed by anxiety disorders, and that 66% of migraine children with sleep disorders had enduring headache (5).
Moreover, the co-occurrence of sleep and headache disorders, particularly migraine, not only results in overlapping clinical manifestations but also largely determines their natural history and prognosis and often promotes their transformation into a chronic, compound, persistent, and intractable condition (6,7).
Migraine is the most common form of disabling primary headache in pediatrics. Approximately one-third (24%–42%) of migraine patients have attacks almost exclusively related to sleep or awakening (sleep migraine = SM). According to the International Classification of Headache Disorders, second edition (ICHD-II), SM is not a separate migraine subtype, but sleep-related symptoms are among the most frequently cited trigger factors (8).
In young children, for whom language and cognitive abilities may make it difficult to fully verbalize symptoms, either migraine descriptors can be missed or underestimated or sleep symptoms may not be recognized as causative factors for migraine. For these reasons some manifestations related to sleep can be missed or misdiagnosed. Similarly, childhood periodic syndromes that are difficult to diagnose are thought to represent early-life expression of migraine genes that later in life are expressed as migraine headache and include benign paroxysmal torticollis, benign paroxysmal vertigo, abdominal migraine and cyclic vomiting syndrome. Recent research suggests infant colic may also fit into this category (9).
The aim of this review is to highlight the relationship between sleep and migraine in infancy, childhood and adolescence and to elucidate how the interaction between these two conditions could help the clinician in the choice of the best treatment.
The relationship between sleep and migraine in infants and children
There are different ways to approach the relationship between sleep and migraine: a) Migraine could be considered to be a result of sleep disorders; b) migraine may be the cause of the alteration of sleep; c) migraine and sleep could be thought of as an expression of a common pathogenic process.
Several studies reported in migraine children major sleep complaints related to sleep duration, bedtime settling, sleep latency, night awakenings, nocturnal symptoms like nightmares, parasomnias or restless sleep and daytime sleepiness (6–10).
Subjects with migraine reported a higher prevalence of sleep disturbances in parents, sleep disturbances in infancy, and colic, as well as an elevated level of familiarity for migraine, showing that a genetic link might be present between migraine and disturbed sleep and indicating that the common neurobiological substrate might act from the beginning of life and/or that a comorbidity exists between these two disorders (10). Therefore clinicians should be able to detect early symptoms related to sleep that can be predictive of migraine at later ages as demonstrated by the study by Aromaa et al. (11) in which sleep disruption at age 3 years predicted headaches at 6 years.
Early developmental disorders like eating difficulties and sleep disorders have been found in 51% of children with headache (12) and in 78% of children with enduring headache vs. 25% of children showing headache remission (13).
An early precursor of migraine could be represented by infantile colic, which represents one of the earliest manifestations of pain and crying in healthy infants. This association has been corroborated by studies showing an increased prevalence of infantile colic in migraine children (14,15)
Recently a study by Romanello et al. (15) showed that 208 consecutive migraine children aged 6 to 18 years presenting to the emergency department were more likely to have experienced infantile colic than those without migraine (72.6% vs. 26.5%;
Generic sleep disorders
A pioneering study on a large pediatric headache sample showed for the first time that both migraine and tension headache were associated with different sleep disorders but the migraine group tended to have “a more disturbed sleep” with increased prevalence of nocturnal symptoms such as sleep breathing disorders, restless sleep and parasomnias, and of daytime sleepiness (10).
Following this original research, other authors investigated this relation, reporting that children with migraine headaches have a large range of sleep disturbances like bedtime resistance, insufficient and interrupted sleep, sleep-disordered breathing, disorders of arousal, sweating during sleep, difficulty waking up in the morning and daytime sleepiness (18–22). One more recent study reported a significantly higher prevalence of excessive daytime sleepiness, narcolepsy and insomnia but did not find a significantly higher prevalence of symptoms of sleep apnea, restlessness and parasomnias, contradicting previous literature (23).
A deeper analysis of the relation between specific migraine headache characteristics and sleep problems showed that frequency and duration of migraine attacks were related to the occurrence of specific sleep-related behaviors, including shortened sleep duration, parasomnias, sleep anxiety and bedtime resistance (24).
Disorders of arousal
A recent study evaluated the association of sleep terror history in childhood and development of migraines in adolescence, showing that a significantly larger proportion of adolescents with chronic 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 patients with migraine was found whereas frequency of somnambulism in patients with nonmigraine headache was similar to that of the general population. A retrospective study looking for a history of somnambulism in childhood showed that somnambulism and migraine can appear at different ages, the former in the late infancy, the latter in childhood and both could be linked to a different age-related expression of a disorder of serotonin metabolism (26).
The strength of the association between somnambulism and childhood migraine raised the possibility that somnambulism might be considered as a minor diagnostic criterion in the clinical diagnosis of childhood migraine (27). Furthermore, there is some evidence that sleepwalking and headache can be precipitated by sleep-disordered breathing (28).
A hypothesis proposed that the serotonergic system may be a link between sleep-disordered breathing and sleepwalking. Following this hypothesis, hypercapnic acidosis, secondary to sleep-disordered breathing, could stimulate the serotonergic neurons resulting in increased excitability of motoneurons and release of gross movements leading to the appearance of somnambulism. However, the need for concomitantly age-related increased excitability of 5-HT neurons and acidosis explains why abnormal breathing during sleep only rarely induces sleepwalking (29). The association between somnambulism and migraine supports the nature of the serotonin abnormality underlying migraine (30).
Sleep apnea
Few data are available on the relationship between sleep apnea and migraine in children. In this section we refer mainly to adults or to chronic headache and sleep-disordered breathing.
Some migraine patients have been found to have either obstructive or central sleep apnea: In the Paiva et al. (31) study, the authors found three patients with obstructive sleep apnea syndrome among 13 migrainous patients, while the Kudrow et al. study showed evidence of sleep apnea in six out of 10 cluster headache patients: Four of these patients had central apnea, and two obstructive apnea (32).
Several reports showed that migraine attacks in sleep apnea patients occur usually during night time or early morning (33–35). The prevalence of headache in obstructive sleep apnea syndrome (OSAS) patients is very high, varying from 30% to 70% (32,33). Boutros (1989) (34) showed that, although the incidence of headache in general did not differ between sleep apnea patients and controls, those with sleep apnea had a significantly higher incidence of morning headache and a higher severity of pain (34–37), as reported also by Neau et al. (2002) (38), who showed that 33% of OSAS patients had headaches, of whom 58.5% had morning headaches. Recently Mitsikostas et al. identified sleep apnea in 29% of patients with severe refractory headaches diagnosed as medication-overuse (MOH), cluster, and chronic TTHs (CTTHs) (39).
There are a variety of proposed mechanisms to explain the increased incidence of headache in sleep apnea patients: hypercarbia, hypoxemia, altered cerebral blood flow, increased intracranial pressure, alterations in sympathetic nerve activity and increases in blood pressure secondary to multiple arousals (40). However, it seems that early-morning headache is a not specific symptom of sleep apnea (35); in fact, patients with abnormal sleep complained of early-morning headache even more frequently than patients with sleep apnea. These data confirm the hypothesis that migraine attacks could be secondary to sleep disruption rather than to sleep apnea by itself. Because of the multifactorial genesis of migraine in children, the pathogenetic mechanism is difficult to clarify: Future studies may elucidate the character of headache in these patients and address the question if sleep apnea is the primary event leading to headache or if sleep disruption (that could be linked to several other sleep disorders) is the main pathogenetic factor for migraine.
Sleep apnea headache is the only headache secondary to sleep disorder recognized by ICHD-2 and classified as headache attributed to a disorder of homeostasis characterized by recurrent and bilateral headaches of pressing quality present on awakening and lasting less than 30 minutes (41,42).
Although headaches and morning headache were not correlated with sleep architecture and respiratory parameters, nor with excessive daytime sleepiness (EDS), the treatment of OSAS, especially nasal continuous positive airway pressure (CPAP), leads to an improvement in headaches in several cases.
Sleep bruxism (SB)
SB, a sleep-related movement disorder characterized by teeth grinding and clenching, is frequently associated with orofacial pain, headaches, and other more severe sleep disorders, such as sleep-disordered breathing. Although the mechanisms underlying the possible interactions among SB, headaches and sleep-disordered breathing need further research, these conditions are often concomitant. Children with SB may report approximately three times as many headaches than non-SB subjects with an odds ratio of 4.3; on the other hand, children with migraine showed a high prevalence (29%) of SB (43).
Restless legs syndrome (RLS)
Most recently, several evidences reported a possible association between migraine and RLS, which is a common sleep-related movement disorder. Reports in selected patient groups strongly suggest that RLS is more common in migraine without aura patients than in control populations. Sleep disturbances were more frequent in headache patients with RLS (44) Chen et al. (2010) found that 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 occurrence of RLS in migraine adults but also suggested that RLS (the condition itself, or the disruption of sleep patterns often found in patients affected by RLS) might affect migraine clinical presentation, being associated with chronic and highly disabling migraine (46).
The first study suggesting an association between RLS and migraine in the pediatric population was conducted by Seidel et al. (2012) (47) and assessed the frequency of RLS in children and adolescents with migraine compared to headache-free controls. The authors included two control groups: The first group was recruited from an outpatient clinic of pediatrics and adolescent medicine (group 1). These children and adolescents were exclusively screened at follow-up after recovery from a minor illness and did not suffer from a significant medical, neurological or psychiatric condition at the time they were included in this study. The second control group was recruited from primary school (group 2); the aim of the study and the objects of the questionnaires had been explained to the children and to the teachers.
In 111 consecutive patients with a sole diagnosis of migraine with (MWA) or without aura (MWoA) and 73 headache-free controls, the frequency of RLS in migraine patients was significantly higher (22% vs. 5% (
Another recent study investigated daytime dysfunction in 25 children with RLS and the effects of treatment primarily with iron supplements on RLS symptoms. Following treatment, participants’ daytime function had improved to levels similar to those of controls. Sixteen out of 23 cases were successfully treated primarily with iron supplement (49).
Nocturnal enuresis
Several studies also demonstrated a significant relationship between migraine and nocturnal enuresis. Nocturnal enuresis antecedent being consistently higher among adolescents with migraines and a significantly higher age of urinary control achievement suggest a putative role of the hypothalamus in the pathophysiology of migraine. A recent study about the association between nocturnal enuresis and migraine shows that patients with episodic (EM) or CM had significantly more often a history of nocturnal enuresis than the control group (CG = 12%, EM = 41%, CM = 49%).
Recently, according to Park et al. (50), the existence of a shared pathophysiological substrate between migraine and primary nocturnal enuresis may explain the inhibition of vasopressin secretion and increased urinary frequency during a spontaneous attack of migraine.
The hypothalamus plays an important role in the beginning of micturition. Early animal studies, such as those performed by Gjone in 1966 (51), showed that electrical stimulation of forebrain structures, such as the hypothalamus, the anterior cingulate gyrus and septal nuclei, can elicit bladder contractions (52). Recently, Carotenuto et al. proposed that nocturnal enuresis and migraine could be linked to a dysfunction of the arousal system with primary nocturnal enuresis being considered as a migraine equivalent (53).
Trigger factors (TFs) and circadian rhythms in sleep and migraine
There is clinical evidence that sleep disorders may precede the appearance of migraines and could act as TFs. A recent study assessing the prevalence and characterization of migraine TFs in children and adolescents with migraine, shows that stress was the most frequently reported TF (75.5%), followed by the lack of sleep (69.6%), warm climate (68.6%) and video games (64.7%). Lack of sleep was generally put aside with fatigue (54).
These data were confirmed by another study that delineated self-perceived triggers of pain among children and adolescents. The study was conducted on 749 children and adolescents. Headache (60.5%), abdominal pain (43.3%), limb pain (33.6%) and back pain (30.2) were the most prevalent pain types among the respondents. Weather conditions (33%), illness (30.7%), physical exertion (21.9%) and lack of sleep (16.2%) were the most frequent self-perceived triggers for pain noted by the respondents (55). Accordingly, the most frequent causative factors of the headache attack recognized by a group of children and adolescents with headache were represented by “bad sleep” and emotional distress (56).
Moreover, several studies showed that migraine attacks may be precipitated by sleep deprivation or excessive sleep (57). In adults late onset of sleep was reported as an occasional TF by 32% of patients (58) whereas lack of sleep was reported as a TF by 44% to 57% of adult migraineurs.
On the other hand, migraine seems to be able to decrease quality of sleep, emerging during the night and causing sleep disruption (56).
The sleep-wake pattern of migraine analyzed with an objective instrument like actigraphy was characterized by less time spent in quiet, motionless sleep, and waking significantly earlier in the morning (59). A previous study showed that during the interictal period, sleep parameters of children suffering from migraine did not differ from those of controls, but in the night preceding the migraine attack there was a decrease in nocturnal motor activity, indicating a decrease in cortical activation during the sleep period preceding migraine attacks (60).
Treatment for migraine in children
Literature data on the connection between sleep and migraine may have implications for the diagnosis and especially for the treatment of migraine (61).
It is known that sleep deprivation may enhance the response to pain stimuli and is one of the most common triggers of migraine attacks (62,63).However it seems that sleep continuity disturbance, rather than simple sleep restriction, impairs endogenous pain-inhibitory function and increases spontaneous pain (64). Furthermore, the results of subjective (logs) and objective (polysomnography (PSG)) sleep analysis reported by Engstrøm et al. (8) do not seem to be fully consistent with the hypothesis that migraineurs on the average suffer from a relative sleep deprivation and need more sleep than healthy controls (65). Therefore we can assume that some drugs could improve migraine by reducing the sleep deprivation/discontinuity affecting the pain threshold.
The treatment of headaches can be divided into pharmacologic and non-pharmacologic types.
Non-pharmacologic treatment and manipulation of sleep
The use of non-pharmacologic preventive measures in children with migraine include lifestyle adjustments (dietary changes, sleep hygiene), reassurance, stress management, biofeedback and other behavioral therapies. This could represent an alternative approach to the treatment of migraine by correcting an inappropriate sleep behavior without resorting to pharmacological treatment (66,67). Decreased stimulation and relaxation techniques are also useful interventions for the treatment of migraine attacks (68,69).
It is a common notion that sleep is associated with relief of migraine attacks, and especially in children, sleep, spontaneous or induced by hypnotics, is thought to be an important protective factor and constitutes the decisive factor for resolution of a migraine attack (70,71). While headache management requires an individualized approach, there are some general guidelines that can be applied to most of the patients (72). Five component interventions used by Calhoun and Ford may be useful (73):
Schedule consistent bedtime that allows eight hours in bed. Avoid watching television, reading and listening to music in bed. Use visualization techniques to shorten time to sleep onset. Consume supper at least four hours before bedtime and limit fluids within two hours of bedtime. Discontinue daytime naps.
A recent study compared the effectiveness of non-pharmacologic treatment for migraine in preschool children and older school-age children that were instructed to follow specific guidelines: a) sleep hygiene—maintenance of regular sleep hours, with regular bedtimes and waking times, with sufficient sleep time for age to sustain routine daily activities; restriction of beverages, foods and compounds that tend to disrupt sleep before bedtime; and regular exercise; b) proper diet—refraining from food additives, with elimination of smoked lunch meats, smoked cheese, yellow cheese (high tyramine), chocolate and foods containing chocolate, pizza, and foods containing monosodium glutamate; c) no direct sun exposure, with appropriate head coverage, especially in summer (66).
In a pioneering study the sleep hygiene rules have been applied to 70 children and adolescents with migraine. Patients showed a reduction in the mean duration and frequency of migraine attacks, while the severity of the attacks did not change.
In this study, based on the presence of at least two criteria for defining poor sleep hygiene, 70 migraineurs (42.7%) have been selected in a group of 164 migraine patients and randomly assigned to group A or B. The A group had been instructed to follow instructions to improve sleep hygiene; the B group did not have instructions on improvement of sleep hygiene. The 70 migraine children selected showed several differences vs. controls in sleep habits: falling sleep later (falling asleep >11 p.m.: 16% vs. 7%;
After the application of the sleep hygiene guidelines, differences were found between the A and B groups regarding several headache parameters. Mean duration of migraine attacks was significantly reduced at follow-up in the A group while the B group showed an initial reduction but not a significant one. The frequency of migraine attacks showed also an improvement: At the first observation the prevalence of A group subjects with more than one attack per week was 35%; at three months the number decreased to 15% and at six months it was 11%. In the B group the percentage did not change significantly (at first observation 42%; at three months, 37% and at six months, 33%).
No differences have been found regarding the severity of migraine attacks; the prevalence of subjects with mild or high-severity attacks did not change significantly in both groups at follow-up (74).
The application of a multidisciplinary treatment program (MTP) consisting of different approaches (bio-behavioral therapy, covering relaxation techniques, biofeedback treatment, operant pain treatment, pain coping, cognitive-behavioral and multimodal treatment) determined a significant decrease in headache frequency and a significant increase in quality of life (QoL) for children with migraine, TTH, MOH, frequent episodic tension-type headache (FETTH), CTTH and other headaches (75).
Although we acknowledge the efficacy of the behavioral and pharmacological therapy, it should be considered that placebo effects as well as beliefs, concepts, wishes, and concerns of parents have important influence on treatment and outcome (76).
Treatment of sleep-disordered breathing to improve migraine
No data are available on the treatment of sleep apnea and migraine in children but there are some studies referred to chronic headache and sleep-disordered breathing.
Morning headache was reported by 156 (33.6%) of OSAS patients vs. only nine (8.9%) subjects of a control group and apnea-hypopnea index (AHI) was significantly higher in OSAS patients with morning headache compared with patients without. Morning headache was totally resolved in 90% of patients treated with nasal CPAP. Therefore, the history of OSAS should be considered in the differential diagnosis of morning headache (77).
A recent study provides new insights into the effectiveness of the mandibular advancement appliance (MAA) for treating headache associated with SB. Sixteen adolescents reporting SB, headache, or snoring underwent four ambulatory PSGs for baseline (BSL) and while wearing MAA during sleep for one week. SB index decreased up to 60%, and headache intensity showed a decreasing trend with MAA. The results suggest that short-term use of an MAA during sleep in adolescents with SB may help reduce the rhythmic masticatory muscle activity (RMMA) and improve snoring and 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, snoring and reports of headache in adolescents. However, interactions between SB, breathing during sleep, and headache as well as the long-term effectiveness and safety of the MAA in adolescents need further investigation (78).
Pharmacotherapy in migraine and sleep
The common goals of any treatment are to eliminate pain and associated symptoms, return to normal activity, improve the management of headache, minimize side effects, avoid painful recurrence, improve QoL, prevent the abuse of analgesics (rare in childhood compared with adulthood) and reduce the stress related to recurrent headache (79). In contrast to the large number of adult trials, relatively few trials have evaluated prophylactic treatment of pediatric headaches (80). Of the drugs used for prophylaxis of migraine, there are some compounds that act either on pain threshold or by modifying/improving sleep. These drugs, commonly used also in children, are mostly represented by antihistaminics, melatonin and serotoninergic drugs.
Antihistaminics
Alterations in the histaminergic system have been proposed both in neurological and psychiatric diseases, but to date, no specific disorder connected to a specific histaminergic dysfunction has been demonstrated. The role of peripheral acting histamine in migraine has been quite extensively explored, but its role as a potent modulator of meningeal nociceptors’ activity in migraine is not clear. Activation of inhibitory H3 receptors has previously been suggested for migraine prophylaxis; however, the exact role of the central histaminergic system in migraine is virtually unexplored. However, both H3R and H4R ligands may theoretically have migraine prophylactic properties. Despite being promising drug targets for several diseases, the lack of specificity and undesired side effects will probably be a major problem (81).
We can assume, however, that the antihistaminics could act in migraine indirectly through the improvement of sleep, and this effect could decrease the pain in migraine children (82).
Melatonin
There is evidence that melatonin, besides having a role in the biological regulation of circadian rhythms, sleep, mood and aging, is also involved in various headache syndromes, including CM, CH and CTTH. Altered melatonin levels in migraine, CTTH, CM and CH patients during the cluster and an abnormal blunting of melatonin peaks during the active period have been documented (83). Involvement of melatonin in the pathophysiology of headache may be related to its anti-inflammatory effects (i.e. free radical scavenging and reduction of proinflammatory cytokines upregulation), an increase of nitric oxide synthase activity, inhibition of dopamine release, membrane stabilization, potentiation of gamma aminobutyric acid (GABA)- and opiate-induced analgesia, protection from glutamate neurotoxicity, neurovascular regulation and serotoninergic modulation, and the similarity of its chemical structure to that of indomethacin (84,85).
Different studies highlighted the effectiveness of melatonin administration in patients with headache or migraine and circadian rhythm disorders related to the demonstration of a decrease of melatonin levels in these individuals (86–88). The efficacy of melatonin in these cases could be related to regularization of the sleep-wake pattern through its chronobiological and “sleep-hygiene” effect. The impact of sleep-hygiene rules on children with migraine has been previously demonstrated by Bruni et al. (74), showing an improvement of frequency and duration of migraine attacks after the application of sleep-hygiene guidelines. In an open-label study on 22 children with primary headache, melatonin effectively reduced the number, intensity and duration of headache attacks per month: In 14 of the 21 subjects (10 with MWoA and four with CTTH) the attacks had decreased by more than 50% with respect to baseline and four reported having no headache attacks (three with migraine without aura and one with aura). None of the children with CTTH reported a complete remission of headache (88).
Despite several studies showing a decrease of melatonin levels in adults with migraine, a recent study showed no significant difference in urinary 6-sulphatoxymelatonin between the migraine children and control group, indicating that nocturnal production of melatonin is not reduced in children with migraine (89).
Serotoninergic drugs
A congenital alteration of neurotransmitter pathways (serotonergic and dopaminergic) might predispose individuals to sleep disorders and to headache, a result of this neurotransmitter imbalance (90) that might act since the early period of life determining sleep disorders during infancy (i.e. colic, insomnia) followed by the development of migraine later in life (91).
The mechanism by which low 5-HT state predisposes the brain to migraine attack is not clear. 5-HT plays an important role in the endogenous pain control system; the decrease of this transmitter may lower the threshold of pain perception and increase the tendency of having headache, but 5-HT also plays significant roles in modulation of several behaviors such as sleep, therefore, low 5-HT may cause derangement in other behaviors (92).
It has been further demonstrated that a reduction in brain synthesis of serotonin intensifies photophobia and other migrainous symptoms (93).
A recent study (94) investigated the plasma tryptophan, 5-hydroxytryptophan (5-HTP), 5-HT and 5-HIAA levels in migraine adults patients with or without aura and in controls. The plasma 5-HT level was significantly lower in MWA patients than in the controls, whereas no significant difference was observed between the levels in migraine patients without aura (MWoA) and the controls. On the other hand, the plasma 5-HTP levels were not significantly different between the MWA patients, the MWoA patients and the controls. Moreover, the plasma tryptophan levels of the controls and both classes of migraine patients were not significantly different, although the levels in the migraine patients tended to be higher. The plasma 5-HIAA levels were not significantly different among migraine patients and controls. These data suggest that an enzymatic dysfunction in the metabolic pathway from 5-HTP to 5-HT may be present in MWA patients (95,96).
It was also hypothesized that existing agents known to influence serotonin blood level, vascular tone and inflammatory reactions might terminate migraines. The proposed treatment is to use low doses of tryptophan, niacin, calcium, caffeine and acetylsalicylic acid (ASA) soon after migraine symptoms are noticed and to avoid during a migraine high-potassium food and magnesium supplements. Preliminary results in migraine adult patients indicated that 75% had significant benefit from this approach (97).
A report on 48 elementary and junior high school students with primary headache highlighted the association with sleep disorders: Night waking (41.7%) and difficulty falling asleep (20.8%) were the most prevalent disorders; parasomnias were also represented: pavor nocturnus and nightmares (14.6%), enuresis (8.3%), somnambulism (6.3%). Treatment with L-5-hydroxytryptophan in these patients determined the improvement of both conditions, headache and sleep disorders, in particular frequent awakenings and some parasomnias (98).
Conclusions
A thorough understanding of the relationship between sleep and various headache syndromes still needs to be fully elucidated and could be helpful both in diagnoses and management of the headache syndromes. In children with migraine, rest and/or sleep may help or solve the pain. Almost all of the pharmacological studies in children with migraine have not included the evaluation of any sleep parameters, but we believe that screening for sleep disorders with the use of proper tests including PSG and referral to a sleep clinic when appropriate could be very helpful. Patient education and lifestyle modification including sleep hygiene play a significant role in overall success of the treatment. Comorbid sleep conditions should always be screened in children with migraine in order to improve patient management and to choose the most appropriate treatment.
Clinical implications
Comorbid sleep conditions should always be screened in children with migraine in order to improve patient management and to choose the most appropriate treatment. The treatment of sleep disorders like insomnia, sleep apnea, sleep bruxism and restless legs syndrome often leads to an improvement of migraine. Serotoninergic and dopaminergic compounds are commonly used either for sleep disorders or for migraine prophylaxis 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.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest
None declared.