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Chronic daily headache in children and adolescents: science and conjecture
Practice Points
Mark Connelly*1,2 & Jennifer Bickel1,2 Chronic daily headache (CDH) is defined as a group of disorders that involve headaches occurring on 15
or more days/month for at least 3 months and lasting for at least 4 h each episode. CDH is one of the most common pain disorders of childhood, disproportionately affecting females and
often associated with a family history of frequent headache; however, there is no extant evidence of a reliable genetic risk of developing CDH. In most cases, CDH develops from a history of episodic headaches, potentially via central sensitization,
with those most at risk for headache chronification being children who experience physical trauma or illness, are obese, are overwhelmed by stressors and/or are chronically taking abortive medication for headache at least a few times per week. Evaluation of CDH rarely requires further testing, given that classification and treatment can usually be
adequately performed from the patient history and physical examination. The evaluation of children with CDH should proceed from a biopsychosocial framework to determine
differential diagnoses and identify psychological and social factors that may be relevant to the presentation and prognosis. Limited data exist to guide the pharmacological treatment of pediatric CDH and there are no US FDA-
approved treatments. Headache prevention is critical, with choice of specific preventative medicine based primarily on the potential benefit or harm from side effects. Relaxation training and cognitive–behavioral therapy are the leading evidence-based
nonpharmacological treatments for reducing headache pain in children, but their efficacy in reducing disability and improving emotional functioning is less clear. The majority of children with CDH improve with time and treatment, but some will have enduring
headaches and disability into adulthood.
Children’s Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA University of Missouri-Kansas City School of Medicine, 2411 Holmes Street, Kansas City, MO 64110, USA *Author for correspondence: Fax: +1 816 460 1080; [email protected] 1 2
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REVIEW Connelly & Bickel SUMMARY Chronic daily headache comprises a group of headache disorders in which headaches occur almost daily or continuously over several months. Although chronic daily headache is one of the most common chronic pain disorders in pediatrics, data on pathophysiological mechanisms and relative efficacy of treatments remain sparse. In this review, we aim to provide contemporary information on classification, epidemiology, etiology and treatment of pediatric chronic daily headache based on extant empirical data when available, or general consensus in the field when not. Headaches that occur almost daily or continuously affect an increasing number of children and adolescents [1–3] , with chronic daily headache (CDH) now being regarded as one of the most common chronic pain disorders occurring in the pediatric population. Recent population-based studies have shown a significant proportion of children with CDH scoring in the severe range of headache disability measures, such as the PedsMIDAS [4] , with frequent headaches adversely affecting the child’s school attendance (and therefore parent’s work attendance), social participation, emotional functioning and family relationships. Despite the prevalence and impact of CDH in childhood, however, training in evaluating and managing the condition remains negligible [5,6] and limited data exist on evidence-based treatments. Healthcare practitioners are therefore likely to encounter a growing number of children with CDH while equipped with a limited armamentarium. In this article, we review the current understanding of the characteristics, classification, epidemiology, evaluation and treatment of pediatric CDH based on extant data when available, and theoretical or clinical inference when not. Classification & characteristics The first publication describing CDH in the pediatric literature appeared in 1994 [7] . However, definitions and classification have been actively debated since then, rendering it difficult to compare study conclusions over time. In general, CDH is defined as a headache disorder of at least a 3-month duration in which the headache episode lasts at least 4 h and occurs on 15 or more days per month [8,9] . Thus, the term is limited to conveying information on symptom frequency and duration, and primarily requires self- or parent-report for its determination. Typically, CDH comprises headaches for which other etiologies have been ruled out (e.g., head/neck trauma, vascular disorder, intracranial mass or increased intracranial pressure), however, the term debatably may still be applied if the
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underlying headache type is secondary to another condition [10] . Falling within the definition of CDH are several distinct, but putatively related, headache subtypes that are classified primarily based on the temporal pattern of symptoms. Characteristics of the CDH subtypes are generally comparable between pediatric and adult presentations [10] . However, children often have a more limited vocabulary for describing their headaches and may express their pain differently from adults, depending on their cognitive development. Children may also have greater difficulty articulating when headaches start and stop. As such, nuances in diagnosing and differentiating subtypes of CDH in pediatrics are more pronounced than in adults. Figure 1 shows prototypical symptom patterns plotted over time for the three most common CDH subtypes in children. For most children with CDH, headaches begin as episodic tension-type or migraine headaches, but increase in frequency over time. In what is currently classified as ‘chronic migraine,’ intermittent ‘throbbing’ or ‘stabbing’ headaches that are usually bilateral, severe in intensity and associated with migraine features (e.g., nausea and/or vomiting and sensitivity to light, sound, and/or smell) begin to occur, together with less intense, continuous, daily or near daily ‘pressure’ or ‘band-like’ headaches [11,12] . The frequency of headache episodes with migraine features may range from once per month to a few times per week. In addition, a small percentage of children with chronic migraine report brief and intermittent severe stabbing (‘ice-pick’) pain sensations at multiple locations around the head occurring many times per day [13] . The diagnostic classification for chronic migraine continues to be actively debated, owing, in part, to whether the condition should be considered a frequent occurrence of migraine without aura or a complication/transformation of migraine [14] . Currently, however, the revised criteria of the second edition of the International Classification of Headache Disorders [12] are generally preferred [15] and are shown in Table 1.
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A second common subtype of pediatric CDH is ‘chronic tension-type headache,’ which is classified based on a history of episodic tensiontype headache that begins occurring daily or near daily in the absence of accompanying migraine characteristics [16] . Diagnostic classification for chronic tension-type headache is currently based on the second edition of the International Classification of Headache Disorders and is shown in Table 1 [11] . Differences from chronic migraine may include more mildto-moderate intensity headaches (vs severe), more pressure/pushing quality to the headache (vs throbbing), absence of aggravation with routine activity and absence of gastrointestinal symptoms (nausea/vomiting). However, it is difficult to distinguish between chronic tension-type headache and chronic migraine due to overlapping features and the distinction is further complicated in pediatrics due to limits in a child’s ability to describe headache qualities and features. A third subtype of CDH, ‘new daily persistent headache,’ is unique in that there is a relative absence of a prior history of headache: a child with no or minimal history of headaches suddenly develops a daily headache within 3 days of initial onset that lasts for at least 4 h per day and that is usually moderate in intensity, ‘pressing’ in quality and poorly localized [17–19] . For the majority of patients, the headache is perceived as continuous from onset [18] . Frequently, the child or parent can recall the exact date of onset. Diagnostic classification for new daily persistent headache is currently based on the second edition of the International Classification of Headache Disorders and is shown in Table 1 [11] . Although the diagnostic criteria for this CDH subtype excluded patients with prominent migraine features (i.e., nausea, sensitivity to lights and/or sounds and aggravation with movement), more recent data suggest no clinical or prognostic value for doing so and that migraine symptoms occur in more than half of patients who otherwise meet the criteria for new daily persistent headache [20] . While there are additional headache presentations falling within the broad umbrella of CDH (e.g., hemicrania continua and chronic cluster headache), these are rare in pediatrics and are not further discussed in this review. Epidemiology & genetics The epidemiology of CDH has been challenged by heterogeneity in symptom classification and
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Pain severity
Chronic daily headache in children & adolescents: science & conjecture
Chronic migraine Chronic tension type Newly daily persistent Migraine features Time
Figure 1. Chronic daily headache subtype symptom patterns.
diagnostic terminology. Extant studies suggest that CDH affects approximately 1–2% of the pediatric population in developed countries [4,21–23] . Girls are affected as much as three times as frequently as boys across the pediatric age range [19,21,22] . Incidence increases after early childhood but CDH can occur in children below 6 years of age [24] . In headache clinic samples, approximately one in every three children evaluated meet criteria for CDH [25] . However, only a small minority of children with CDH in the community present to a healthcare provider for treatment [4] . Based on tertiary care samples, a diagnosis of new daily persistent headache or chronic tension-type headache is more frequent in adolescents than adults, whereas a diagnosis of chronic migraine is represented in a larger proportion in adults with CDH, relative to adolescents [26] . A family history of headache is common for children with CDH and, in particular, headache frequency has been found to aggregate in families [27,28] . Although familial aggregation cannot discount the role of shared environment, it supports the plausibility of a genetic risk for CDH. However, the extent of genetic contribution to CDH is not presently known. No evidence exists for the relevance of variations in genes responsible for such processes and structures as serotonin transport, catecholamine metabolism, folate metabolism, and potassium,
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REVIEW Connelly & Bickel sodium and calcium channels [29] . While, at present, there are no identified genetic risk factors for CDH in children, one hypothesis is that the ‘strength’ of genetic predisposition to developing CDH varies between children [30] ; those with a strong genetic predisposition may develop CDH early in the absence of specific risk factors, whereas those with a ‘weaker’ predisposition require the occurrence of specific risk factors for CDH to develop.
Etiology & pathophysiology Etiological mechanisms for CDH remain almost entirely based on clinical inference and speculation, owing, in part, to wide phenotypic heterogeneity in the absence of clear genetic, biochemical or historical markers of the disorder [31] . Given this heterogeneity and the range of potential risk factors for developing CDH, it seems unlikely that a single theory will fully explain etiology and that unique
Table 1. International Classification of Headache Disorders 2/International Classification of Headache Disorders 2R criteria for chronic daily headache subtypes. Subtype
Diagnostic criteria
Chronic migraine
1. Headache (tension-type and/or migraine) on ≥15 days per month for ≥3 months 2. At least five attacks fulfilling the following criteria for migraine without aura (see 3.1 and 3.2) 3. On at least 8 days per month for at least 3 months the headache has fulfilled the following criteria for migraine without aura: 3.1. At least two of the following are true: a) The location is bilateral b) The quality is pulsating c) The intensity is moderate to severe d) The intensity is worsened with routine physical activity And at least one of the following are true: a) Nausea and/or vomiting b) Both sensitivity to sound (phonophobia) and sensitivity to light (photophobia) 3.2. Or, headache episodes are treated and relieved by triptan(s) or ergot before the expected development of 3.1 above 4. The headache is not attributed to medication overuse or another causative disorder Chronic tension-type headache 1. Headache episodes occur for at least 15 days per month on average 2. Headaches have persisted for at least 3 months 3. Headache episodes last for 30 min to 7 days† 4. At least two of the following are true: a) The location is bilateral b) The quality is pressing/tightening (nonpulsating) c) The intensity is mild to moderate d) The intensity is not worsened with routine physical activity 5. At least one of the following are true: a) Absence of nausea and vomiting b) Sensitivity to light (photophobia) or sound (phonophobia) 6. The headache is not secondary to another disorder New daily persistent headache 1. Daily and unremitting headache starting within 3 days of initial onset 2. Persistence of the headache for at least 3 months 3. At least two of the following are true: a) The location is bilateral b) The quality is not described as pulsating c) The intensity is mild to moderate d) The intensity is worsened with routine physical activity 4. The headache has no more than one of the following characteristics: a) Sensitivity to sound (phonophobia) b) Sensitivity to light (photophobia) c) Mild nausea 5. The headache is not associated with moderate-to-severe nausea or vomiting 6. The headache is not secondary to another disorder Headache duration of at least 4 h is typically required to meet the criteria for chronic daily headache. Data taken from [11,12]. †
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Chronic daily headache in children & adolescents: science & conjecture (but inter-related) models may need to be considered for each CDH subtype. Viable proposed pathophysiological models must, at minimum, explain why: (a) a history of episodic headache is not sufficient for developing CDH (i.e., only in a moderate proportion of cases does episodic headache lead to a headache disorder that meets definitional criteria for CDH); and (b) a history of episodic headache is not necessary for developing CDH (i.e., CDH can start abruptly in the absence of a prior history of headache). Pathophysiological processes that are thought to be implicated in episodic migraine (e.g., neuronal hyperexcitability, cortical spreading depression, serotonin dysregulation and vascular reactivity) and episodic tensiontype headache (e.g, referred pain from craniocervical muscle trigger points and pressure-pain hypersensitivity) are presumably still necessary for the development of chronic migraine and chronic tension-type headache, respectively [30,32–34] . These explanations, however, are insufficient for understanding CDH development per se. Increasingly, perspectives on the etiology of CDH have turned towards segmental sensitization of the parts of the peripheral and central nervous systems involved in the initial episodic headache disorder [35,36] . In essence, sensitization models suggest that headaches beget more headaches via molecular and chemical changes occurring peripherally and, ultimately, centrally that reduce the threshold for trigeminovascular neuronal activation, enhance ascending pain facilitation and decrease descending pain inhibition [33,35,37] . Comparable models have been suggested as explanations for a wide variety of pain syndromes [38] . It is implied in sensitization models that recurring pain is necessary prior to the development of more sustained or broader pain problems (‘usedependent plasticity’) and, as such, sensitization does not fit as well as an explanation for new daily persistent headache. However, central sensitization as a model for CDH has clinical appeal because early intervention for episodic migraine and/or tension-type headaches may preempt later CDH development. Assuming that central sensitization is at least one critical component of the development of CDH, a plausible hypothesis is that some children have a greater propensity for sensitization and are therefore at greater risk of developing CDH. However, research has not yet uncovered reliable
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risk factors in the development of pediatric CDH. Accumulated or sudden stressors to the nervous system through physical trauma (e.g., injury or surgery), illness or infection (e.g., flu or upper respiratory infection), and stressful or traumatic life events (e.g., child maltreatment) have been shown, in some studies, to be associated with the development of CDH [20,39,40] . Furthermore, evidence from prospective and cross-sectional studies has suggested that children with CDH may be more reactive to typical daily stressors and that perceived stress is one of the most reliable ‘triggers’ of headache episodes in this population [39,41] . Recent studies have also suggested obesity to be a potential risk factor in CDH. In particular, adult research has shown obesity to be a risk factor for chronification of migraine, especially in females [42] . A retrospective review of pediatric headache clinic patients suggested that obesity rates are higher overall in children with headache and chronic tension-type headache but not in children with chronic migraine [43] . Conversely, some data support a relationship between obesity and migraine frequency, with the hypothesized mechanism being the overlap of neurotransmitter (e.g., serotonin), peptide (e.g., orexin) and adiopocytokine (e.g., leptin) regulation of feeding and migraine [44] . Prospective data linking obesity to subsequent development of CDH are not presently available. In addition, using certain abortive medicines, such as nonsteroidal anti-inf lammatories, opioids or triptans more than a few times per week for at least a few months seems to reliably increase the likelihood of developing and maintaining frequent headache in children [45] . Thus, medication overuse may be a contributor to central sensitization. At present, however, medication-overuse headache is classified and treated as a headache disorder in its own right based on adult criteria, rather than medication overuse being principally viewed as a risk factor for CDH development [46] . Overuse of medications for headache may occur at a lower incidence in children relative to adults [8] but, nonetheless, may still occur at a high rate [47] and is important to evaluate, given its potential role in headache transformation and persistence. Comorbid conditions Further complicating the understanding and treatment of CDH in children are conditions that
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REVIEW Connelly & Bickel tend to co-occur at a rate beyond what is expected in the general population. CDH in children, therefore, may be part of a spectrum of disorders that have similar multifaceted etiologies. Other pain syndromes
Children with headache often report co-occurrence of persistent pain at other body sites, such as abdominal pain, back pain and/or widespread musculoskeletal pain [21,48,49] . Similarly, children with other pain syndromes may develop frequent headache concurrently or in the future [50] . The co-occurrence of headaches with other pain syndromes suggests a possible common pathophysiology and supports the plausibility of central sensitization as a unifying feature. However, data are not yet available on the specific association of pediatric CDH per se with other pain syndromes. Sleep disorder
Children with frequent headaches often report increased sleep onset latency and poor sleep maintenance [51] , but there are limited published data available specifically in pediatric CDH samples. Results of polysomnographic studies have suggested that children with tension-type headache tend to have bruxism and that those with chronic migraine are likely to have disrupted sleep architecture (reduced rapid eye movement and slow-wave sleep) [52] . However, in the absence of prospective data, it remains unclear if CDH precedes or follows on from the development of sleep disturbance. Thus, the association between sleep disorders per se and CDH in children remains speculative and requires further elucidation through prospective research. Psychiatric comorbidity
The assumption that pediatric CDH is essentially a psychiatric condition is unfortunately prevalent and not well-supported by extant data. Prospective data needed to detangle directional relationships are lacking and data on clinical samples can produce a biased perspective, given that only a minority of pediatric patients with CDH seek treatment. With these caveats in mind, extant data suggest that up to approximately one-third of treatment-seeking children with CDH have a diagnosable anxiety or depressive disorder [43] ; this exceeds rates of anxiety and depression in the general pediatric population. It remains unclear, however, whether disordered mood in children with CDH predates headache development or
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whether it develops as a consequence of living with frequent headaches. The neurobiological structures and mechanisms activated in CDH are at least partly relevant to the pathophysiology of anxiety and mood disorders (e.g., neuroplastic changes in the corticolimbic system and serotonergic dysregulation), supporting the likelihood of a bidirectional link [53] . Recent studies have also found a concerning link between CDH in adolescents and increased risk of suicidal thoughts (not necessarily behavior), but the relationship is not fully explained by the common association with depression [54,55] . Evidence is mixed with regards to elevated rates of other psychiatric conditions in children with CDH, with some studies showing increased rates relative to normative data or matched controls, and others showing no reliable differences [54,56] . The most recent data suggest that approximately 35% of pediatric patients with CDH have at least one lifetime psychiatric diagnosis and that these patients had greater functional disability and a poorer quality of life than those without a psychiatric diagnosis [57] ; in this study, no significant relationship between psychiatric status and headache frequency, duration or severity was found. Taken together, extant evidence suggests that a minority of children with CDH have clinically significant psychiatric comorbidity and that the most likely associated psychiatric conditions are depressive and anxiety disorders. Given the evidence that psychiatric comorbidity adversely affects functioning and quality of outcomes of CDH [57] , treatment of comorbid conditions with medical management and/or nonpharmacological interventions, such as psychotherapy, should be considered. Evaluation of pediatric CDH The goal in evaluating CDH in children is to facilitate classification of headache, determine what factors may contribute to occurrence and maintenance, set the stage for the treatment plan, and determine potential barriers to a positive treatment prognosis. As such, adequate attention to both medical factors and psychosocial context in the evaluation of CDH is recommended. An identifiable secondary cause exists in fewer than 10% of cases of pediatric CDH [8,58] . Thus, the majority of children with CDH will not require further specific investigation and adequate assessment can be completed from history and physical examination alone. Moreover, liberal use
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Chronic daily headache in children & adolescents: science & conjecture of imaging (e.g., MRI) or testing (e.g., lumbar puncture) may create iatrogenic problems; incidental findings are detected in nearly 20% of MRIs performed for evaluation of pediatric headache [59] and children with migraine are at an elevated risk of postlumbar puncture headache [60] . The history portion of the evaluation should include a detailed headache history (length of time with headaches, frequency, severity, time of onset, duration, quality, location, precipitating/ alleviating factors and associated symptoms), treatment history, family history of pain syndromes and mental health conditions, inquiry into academic, social and family functioning (e.g., school attendance, intensity of extracurricular activities, experiences of bullying/social exclusion or rejection and maltreatment), lifestyle factors (diet, sleep and activity level), perceived stressors, and evaluation of mood and self-harm thoughts or behaviors [61] . Specific signs to be aware of for potential secondary headache that would require additional imaging and/or laboratory work include absence of family history of migraine, abnormal focal neurological findings on examination, gait abnormalities, occurrence of seizures, headache worsening with posture change or coughing, personality change and headache awakening the child from sleep [10,59] . Indicators that additional services beyond only medication management should be considered (e.g., counseling referral) include significant school absence, reinforcement for avoiding regular activities (e.g., parent attention or avoidance of stressors), exclusive focus on a potential underlying medical condition and untreated psychiatric disorders. In addition, if a patient fails to respond to typical management of CDH, idiopathic intracranial hypertension without papilledema should then be considered. While most patients with increased intracranial pressure will have papilledema on examination, there have been reports of increased pressure without papilledema in children [62] . While the quality of headache may not differ from typical CDH, the presence of pulsatile tinnitus and obesity may increase suspicion of idiopathic intracranial hypertension. Opening pressure should be obtained via lumbar puncture in the lateral decubitus position. While controversial, evidence suggests that opening pressures of up to 28 cm of water, which is the metric on which opening pressure is measured, may be normal [63] .
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Management of pediatric CDH Management options for CDH include both pharmacological treatments (e.g., medications and supplements) and nonpharmacological treatments (e.g., relaxation training, manual therapies, massage therapy, chiropractic or osteopathic manipulation, and acupuncture). In general, the empirical evidence for any particular treatment modality for CDH in children is lacking and based primarily on inference from observational studies, treatment of episodic headaches and clinical anecdote. Accumulated experience at different treatment centers suggests that a combination of medication, headache education and adjuvant therapies is often needed to optimize outcomes, particularly for children with high levels of functional disability [64] . Pharmacological treatment
Despite the high prevalence of CDH in children and adolescents, there is a significant lack of well-designed trials to guide management of the condition with medication and/or supplements/herbal therapies. The lack of data relates partly to individuals with CDH being excluded from headache prevention trials for many years. Currently, there are no FDA-approved treatments for CDH in the pediatric population and thus, determination of medications for pediatric CDH is primarily based on clinical acumen. Abortive headache medications have a limited role in treating CDH. The general consensus is that the use of abortive medications for CDH should be restricted to no more than 8 days per month in order to decrease the risk of medication overuse headaches [65] . Thus, children should choose two or fewer headaches per week that necessitate abortive treatment; typically, these will be the headaches that, without treatment, would lead to significant disability or an emergency room visit. Opioid analgesics and barbiturates should be avoided in the management of CDH due to their role in migraine chronification and their potential for misuse [65] . If abortive therapy is used, it should typically begin with over-the-counter preparations of ibuprofen, acetaminophen, naproxen, or a combination product, such as oral aspirin/acetaminophen/caffeine [12] . It is frequently necessary to provide the child with a 20 min break in a quiet area to improve treatment response. To increase the effectiveness of an NSAID, caffeine, diphenhydramine and/or an
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REVIEW Connelly & Bickel antiemetic may be used as well. Migraines may respond better to a combination of medications rather than just one abortive alone. With regards to headache prevention, there is no consensus on first-line pharmaceutical treatment for CDH. Instead, medications are chosen based on headache classification, sideeffect profile and patient preference. The goal of headache prevention when treating CDH is not headache freedom, but rather to gradually decrease headache severity and frequency to the point that headaches are no longer significantly affecting daily functioning and quality of life. Typically, at least a 6 week medication trial is necessary before determining efficacy. Table 2 provides a listing of medicines used in the preventative management of pediatric CDH, along with dosing information and comments based on existing studies and opinion [66,67] . The medicines recommended for use in pediatric CDH have primarily been adapted from use in episodic headaches; there are clearly limitations to this approach given the differences in pathophysiology and perhaps medication tolerance in CDH. The most well-studied preventative medications for pediatric headache are topiramate and amitriptyline. In a randomized placebocontrolled trial, topiramate (100 mg given twice daily) decreased mean monthly migraine frequency from a baseline of 16.14 to 4.27 over the course of 12 weeks [68] . Given that topiramate may lead to weight loss, it may be an ideal first choice preventative headache medicine for the overweight child with chronic migraine. In an open-label trial of 279 children with either migraine or tension-type headaches (average frequency of 17.1 days per month), amitriptyline, on average, reduced headache frequency by nearly half and significantly reduced headache severity and duration [69] . Cyproheptadine, propranolol and valproic acid are thought to be potentially efficacious based on their efficacy in treating episodic migraine [8,70,71] and clinical experience. However, these medications have not been studied through randomized trials in pediatric CDH samples. In addition, despite almost no empirical data in pediatric CDH, onabotulinumtoxin A (the first treatment to receive US FDA approval for the treatment of adult CDH), occipital nerve blocks and trigger point injections might be considered in rare cases in which children have failed to respond to at least two adequate trials of other headache preventatives [72,73] .
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For intractable continuous headache, most tertiary headache centers will offer inpatient and/ or outpatient repetitive infusions in an attempt to stop the headache. However, there are no published data on this approach. Given that intravenous dihydroergotamine is an established treatment for status migrainosis [74,75] , it is sometimes adopted for use in a hospital-based treatment of pediatric CDH when traditional headache prophylaxis has failed. In these cases, patients often receive infusions of dihydroergotamine combined with metaclopromide, valproic acid and magnesium sulfate. Often, inpatient treatment can be paired with nonpharmacological treatments and there are some data suggesting that inpatient treatment of pediatric headache may be superior to outpatient treatment in certain refractory cases [76] . Nonpharmacological treatment
All studies that have been conducted on nonpharmacological treatments for pediatric headache have included mixed diagnoses (i.e., not explicitly CDH), such that there is no definitive evidence of the efficacy of any particular nonpharmacological treatment for CDH per se. Furthermore, there is a lack of comparative efficacy trials, meaning that there is no evidence to guide which treatment(s) may work better for which children with CDH. The most well-studied among the nonpharmacological treatment options for headache in children are relaxation training, with or without biofeedback assistance (e.g., diaphragmatic breathing, progressive muscle relaxation, visualization/imagery and selfhypnosis), and cognitive–behavioral therapy (training in identifying, challenging, and modifying beliefs and behaviors that may be contributing to headaches, disability and/or emotional distress) [77] . A recent meta-ana lysis that included 16 trials of self-guided or therapist-led relaxation training and/or cognitive–behavioral therapy for primary headaches in children found that these therapies led to clinically significant improvements in pain but, interestingly, did not reliably reduce disability or improve emotional functioning [78] . Nevertheless, psychological interventions for pediatric CDH may be beneficial as primary or adjuvant therapy for children with high levels of headache-related disability and/or comorbid psychiatric symptoms. The efficacy of other nonpharmacological treatment options for children with CDH
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Table 2. Preventative medications used to treat chronic daily headache in children. Medicine
Target dose
Potential side effects
Comments
2–3 mg/kg once daily
Exercise intolerance, exacerbation of asthma and nightmares
5 mg (above 5 years of age) once daily
NA
Not available in the USA. Data are unclear as to whether other calcium channel blockers are equally effective
1 mg/kg once daily
Sedation, weight gain, dry mouth and suicidal thoughts
Consider EKG monitoring and consider switch to nortriptyline if too sedating
Fluoxetine
20 mg once daily
Suicidal thoughts
Studies indicate effectiveness in adults but have not been studied in children
Venlafaxine XR
150 mg once daily
Elevation of blood pressure
b-blockers Propranolol Calcium channel blockers Flunarizine
Tricyclic antidepressants Amitriptyline SSRIs/SNRIs
Anticonvulsants Topiramate
Divalproex sodium Gabapentin
2–3 mg/kg once daily
Paresthesias, weight loss/decreased appetite, nephrolithiasis, acute angle glaucoma, metabolic acidosis, difficulty in thinking and suicidal thoughts 15–45 mg/kg once daily Birth defects (female), weight gain, Blood monitoring is recommended. Use with tremor and hair loss caution in females of child-bearing age 300–400 mg t.i.d. Drowsiness and dizziness
Antihistamines Cyproheptadine
2–4 mg every 8–12 h
Weight gain and sedation
Supplements/vitamins/herbal therapies Magnesium oxide or gluconate Riboflavin Petasites
9 mg/kg once daily
Diarrhea
200–400 mg once daily Unknown 50–75 mg b.i.d. Eructation
Purified extract from butterbur plant; avoid nonpurified formulations, which have been linked to liver toxicity
Medicines are best tolerated if started at approximately 20% of the target dose, with gradual titration as tolerated. If tolerability is an issue, consider dosing only after 12 pm. If no response is seen after 12 weeks at the target dose, the medication is unlikely to be helpful at higher doses. However, if partial response is demonstrated, the practitioner should use clinical judgment to consider a higher dose in order to obtain better relief. b.i.d.: Twice daily; EKG: Electrocardiography; NA: Not applicable; t.i.d.: Three-times daily; SNRI: Serotonin/norepinephrine-reuptake inhibitors; SSRI: Selective serotonin-reuptake inhibitors; XR: Extended release.
beyond psychological interventions essentially remains unknown. Although manual therapies, such as massage and chiropractic manipulation, are used to treat chronic headache in children and, by case report, can be effective, there have been no trials published on their safety or efficacy in this population [79,80] . In the only double-blind, randomized, placebo-controlled trial of a nonpharmacological treatment for pediatric headache, ‘active’ laser acupuncture led to a greater reduction in the number of headache days than placebo laser acupuncture in a sample of 43 children with migraine or tension-type
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headache [81] . Overall, much more research is needed to make sound recommendations for nonpharmacological treatment options to families of children with CDH. Prognosis Outcome data are sparse for children treated for CDH and length of follow-up for published studies varies greatly (
Chronic daily headache in children and adolescents: science and conjecture
Practice Points
Mark Connelly*1,2 & Jennifer Bickel1,2 Chronic daily headache (CDH) is defined as a group of disorders that involve headaches occurring on 15
or more days/month for at least 3 months and lasting for at least 4 h each episode. CDH is one of the most common pain disorders of childhood, disproportionately affecting females and
often associated with a family history of frequent headache; however, there is no extant evidence of a reliable genetic risk of developing CDH. In most cases, CDH develops from a history of episodic headaches, potentially via central sensitization,
with those most at risk for headache chronification being children who experience physical trauma or illness, are obese, are overwhelmed by stressors and/or are chronically taking abortive medication for headache at least a few times per week. Evaluation of CDH rarely requires further testing, given that classification and treatment can usually be
adequately performed from the patient history and physical examination. The evaluation of children with CDH should proceed from a biopsychosocial framework to determine
differential diagnoses and identify psychological and social factors that may be relevant to the presentation and prognosis. Limited data exist to guide the pharmacological treatment of pediatric CDH and there are no US FDA-
approved treatments. Headache prevention is critical, with choice of specific preventative medicine based primarily on the potential benefit or harm from side effects. Relaxation training and cognitive–behavioral therapy are the leading evidence-based
nonpharmacological treatments for reducing headache pain in children, but their efficacy in reducing disability and improving emotional functioning is less clear. The majority of children with CDH improve with time and treatment, but some will have enduring
headaches and disability into adulthood.
Children’s Mercy Hospitals and Clinics, 2401 Gillham Road, Kansas City, MO 64108, USA University of Missouri-Kansas City School of Medicine, 2411 Holmes Street, Kansas City, MO 64110, USA *Author for correspondence: Fax: +1 816 460 1080; [email protected] 1 2
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REVIEW Connelly & Bickel SUMMARY Chronic daily headache comprises a group of headache disorders in which headaches occur almost daily or continuously over several months. Although chronic daily headache is one of the most common chronic pain disorders in pediatrics, data on pathophysiological mechanisms and relative efficacy of treatments remain sparse. In this review, we aim to provide contemporary information on classification, epidemiology, etiology and treatment of pediatric chronic daily headache based on extant empirical data when available, or general consensus in the field when not. Headaches that occur almost daily or continuously affect an increasing number of children and adolescents [1–3] , with chronic daily headache (CDH) now being regarded as one of the most common chronic pain disorders occurring in the pediatric population. Recent population-based studies have shown a significant proportion of children with CDH scoring in the severe range of headache disability measures, such as the PedsMIDAS [4] , with frequent headaches adversely affecting the child’s school attendance (and therefore parent’s work attendance), social participation, emotional functioning and family relationships. Despite the prevalence and impact of CDH in childhood, however, training in evaluating and managing the condition remains negligible [5,6] and limited data exist on evidence-based treatments. Healthcare practitioners are therefore likely to encounter a growing number of children with CDH while equipped with a limited armamentarium. In this article, we review the current understanding of the characteristics, classification, epidemiology, evaluation and treatment of pediatric CDH based on extant data when available, and theoretical or clinical inference when not. Classification & characteristics The first publication describing CDH in the pediatric literature appeared in 1994 [7] . However, definitions and classification have been actively debated since then, rendering it difficult to compare study conclusions over time. In general, CDH is defined as a headache disorder of at least a 3-month duration in which the headache episode lasts at least 4 h and occurs on 15 or more days per month [8,9] . Thus, the term is limited to conveying information on symptom frequency and duration, and primarily requires self- or parent-report for its determination. Typically, CDH comprises headaches for which other etiologies have been ruled out (e.g., head/neck trauma, vascular disorder, intracranial mass or increased intracranial pressure), however, the term debatably may still be applied if the
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underlying headache type is secondary to another condition [10] . Falling within the definition of CDH are several distinct, but putatively related, headache subtypes that are classified primarily based on the temporal pattern of symptoms. Characteristics of the CDH subtypes are generally comparable between pediatric and adult presentations [10] . However, children often have a more limited vocabulary for describing their headaches and may express their pain differently from adults, depending on their cognitive development. Children may also have greater difficulty articulating when headaches start and stop. As such, nuances in diagnosing and differentiating subtypes of CDH in pediatrics are more pronounced than in adults. Figure 1 shows prototypical symptom patterns plotted over time for the three most common CDH subtypes in children. For most children with CDH, headaches begin as episodic tension-type or migraine headaches, but increase in frequency over time. In what is currently classified as ‘chronic migraine,’ intermittent ‘throbbing’ or ‘stabbing’ headaches that are usually bilateral, severe in intensity and associated with migraine features (e.g., nausea and/or vomiting and sensitivity to light, sound, and/or smell) begin to occur, together with less intense, continuous, daily or near daily ‘pressure’ or ‘band-like’ headaches [11,12] . The frequency of headache episodes with migraine features may range from once per month to a few times per week. In addition, a small percentage of children with chronic migraine report brief and intermittent severe stabbing (‘ice-pick’) pain sensations at multiple locations around the head occurring many times per day [13] . The diagnostic classification for chronic migraine continues to be actively debated, owing, in part, to whether the condition should be considered a frequent occurrence of migraine without aura or a complication/transformation of migraine [14] . Currently, however, the revised criteria of the second edition of the International Classification of Headache Disorders [12] are generally preferred [15] and are shown in Table 1.
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A second common subtype of pediatric CDH is ‘chronic tension-type headache,’ which is classified based on a history of episodic tensiontype headache that begins occurring daily or near daily in the absence of accompanying migraine characteristics [16] . Diagnostic classification for chronic tension-type headache is currently based on the second edition of the International Classification of Headache Disorders and is shown in Table 1 [11] . Differences from chronic migraine may include more mildto-moderate intensity headaches (vs severe), more pressure/pushing quality to the headache (vs throbbing), absence of aggravation with routine activity and absence of gastrointestinal symptoms (nausea/vomiting). However, it is difficult to distinguish between chronic tension-type headache and chronic migraine due to overlapping features and the distinction is further complicated in pediatrics due to limits in a child’s ability to describe headache qualities and features. A third subtype of CDH, ‘new daily persistent headache,’ is unique in that there is a relative absence of a prior history of headache: a child with no or minimal history of headaches suddenly develops a daily headache within 3 days of initial onset that lasts for at least 4 h per day and that is usually moderate in intensity, ‘pressing’ in quality and poorly localized [17–19] . For the majority of patients, the headache is perceived as continuous from onset [18] . Frequently, the child or parent can recall the exact date of onset. Diagnostic classification for new daily persistent headache is currently based on the second edition of the International Classification of Headache Disorders and is shown in Table 1 [11] . Although the diagnostic criteria for this CDH subtype excluded patients with prominent migraine features (i.e., nausea, sensitivity to lights and/or sounds and aggravation with movement), more recent data suggest no clinical or prognostic value for doing so and that migraine symptoms occur in more than half of patients who otherwise meet the criteria for new daily persistent headache [20] . While there are additional headache presentations falling within the broad umbrella of CDH (e.g., hemicrania continua and chronic cluster headache), these are rare in pediatrics and are not further discussed in this review. Epidemiology & genetics The epidemiology of CDH has been challenged by heterogeneity in symptom classification and
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Pain severity
Chronic daily headache in children & adolescents: science & conjecture
Chronic migraine Chronic tension type Newly daily persistent Migraine features Time
Figure 1. Chronic daily headache subtype symptom patterns.
diagnostic terminology. Extant studies suggest that CDH affects approximately 1–2% of the pediatric population in developed countries [4,21–23] . Girls are affected as much as three times as frequently as boys across the pediatric age range [19,21,22] . Incidence increases after early childhood but CDH can occur in children below 6 years of age [24] . In headache clinic samples, approximately one in every three children evaluated meet criteria for CDH [25] . However, only a small minority of children with CDH in the community present to a healthcare provider for treatment [4] . Based on tertiary care samples, a diagnosis of new daily persistent headache or chronic tension-type headache is more frequent in adolescents than adults, whereas a diagnosis of chronic migraine is represented in a larger proportion in adults with CDH, relative to adolescents [26] . A family history of headache is common for children with CDH and, in particular, headache frequency has been found to aggregate in families [27,28] . Although familial aggregation cannot discount the role of shared environment, it supports the plausibility of a genetic risk for CDH. However, the extent of genetic contribution to CDH is not presently known. No evidence exists for the relevance of variations in genes responsible for such processes and structures as serotonin transport, catecholamine metabolism, folate metabolism, and potassium,
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REVIEW Connelly & Bickel sodium and calcium channels [29] . While, at present, there are no identified genetic risk factors for CDH in children, one hypothesis is that the ‘strength’ of genetic predisposition to developing CDH varies between children [30] ; those with a strong genetic predisposition may develop CDH early in the absence of specific risk factors, whereas those with a ‘weaker’ predisposition require the occurrence of specific risk factors for CDH to develop.
Etiology & pathophysiology Etiological mechanisms for CDH remain almost entirely based on clinical inference and speculation, owing, in part, to wide phenotypic heterogeneity in the absence of clear genetic, biochemical or historical markers of the disorder [31] . Given this heterogeneity and the range of potential risk factors for developing CDH, it seems unlikely that a single theory will fully explain etiology and that unique
Table 1. International Classification of Headache Disorders 2/International Classification of Headache Disorders 2R criteria for chronic daily headache subtypes. Subtype
Diagnostic criteria
Chronic migraine
1. Headache (tension-type and/or migraine) on ≥15 days per month for ≥3 months 2. At least five attacks fulfilling the following criteria for migraine without aura (see 3.1 and 3.2) 3. On at least 8 days per month for at least 3 months the headache has fulfilled the following criteria for migraine without aura: 3.1. At least two of the following are true: a) The location is bilateral b) The quality is pulsating c) The intensity is moderate to severe d) The intensity is worsened with routine physical activity And at least one of the following are true: a) Nausea and/or vomiting b) Both sensitivity to sound (phonophobia) and sensitivity to light (photophobia) 3.2. Or, headache episodes are treated and relieved by triptan(s) or ergot before the expected development of 3.1 above 4. The headache is not attributed to medication overuse or another causative disorder Chronic tension-type headache 1. Headache episodes occur for at least 15 days per month on average 2. Headaches have persisted for at least 3 months 3. Headache episodes last for 30 min to 7 days† 4. At least two of the following are true: a) The location is bilateral b) The quality is pressing/tightening (nonpulsating) c) The intensity is mild to moderate d) The intensity is not worsened with routine physical activity 5. At least one of the following are true: a) Absence of nausea and vomiting b) Sensitivity to light (photophobia) or sound (phonophobia) 6. The headache is not secondary to another disorder New daily persistent headache 1. Daily and unremitting headache starting within 3 days of initial onset 2. Persistence of the headache for at least 3 months 3. At least two of the following are true: a) The location is bilateral b) The quality is not described as pulsating c) The intensity is mild to moderate d) The intensity is worsened with routine physical activity 4. The headache has no more than one of the following characteristics: a) Sensitivity to sound (phonophobia) b) Sensitivity to light (photophobia) c) Mild nausea 5. The headache is not associated with moderate-to-severe nausea or vomiting 6. The headache is not secondary to another disorder Headache duration of at least 4 h is typically required to meet the criteria for chronic daily headache. Data taken from [11,12]. †
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Chronic daily headache in children & adolescents: science & conjecture (but inter-related) models may need to be considered for each CDH subtype. Viable proposed pathophysiological models must, at minimum, explain why: (a) a history of episodic headache is not sufficient for developing CDH (i.e., only in a moderate proportion of cases does episodic headache lead to a headache disorder that meets definitional criteria for CDH); and (b) a history of episodic headache is not necessary for developing CDH (i.e., CDH can start abruptly in the absence of a prior history of headache). Pathophysiological processes that are thought to be implicated in episodic migraine (e.g., neuronal hyperexcitability, cortical spreading depression, serotonin dysregulation and vascular reactivity) and episodic tensiontype headache (e.g, referred pain from craniocervical muscle trigger points and pressure-pain hypersensitivity) are presumably still necessary for the development of chronic migraine and chronic tension-type headache, respectively [30,32–34] . These explanations, however, are insufficient for understanding CDH development per se. Increasingly, perspectives on the etiology of CDH have turned towards segmental sensitization of the parts of the peripheral and central nervous systems involved in the initial episodic headache disorder [35,36] . In essence, sensitization models suggest that headaches beget more headaches via molecular and chemical changes occurring peripherally and, ultimately, centrally that reduce the threshold for trigeminovascular neuronal activation, enhance ascending pain facilitation and decrease descending pain inhibition [33,35,37] . Comparable models have been suggested as explanations for a wide variety of pain syndromes [38] . It is implied in sensitization models that recurring pain is necessary prior to the development of more sustained or broader pain problems (‘usedependent plasticity’) and, as such, sensitization does not fit as well as an explanation for new daily persistent headache. However, central sensitization as a model for CDH has clinical appeal because early intervention for episodic migraine and/or tension-type headaches may preempt later CDH development. Assuming that central sensitization is at least one critical component of the development of CDH, a plausible hypothesis is that some children have a greater propensity for sensitization and are therefore at greater risk of developing CDH. However, research has not yet uncovered reliable
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risk factors in the development of pediatric CDH. Accumulated or sudden stressors to the nervous system through physical trauma (e.g., injury or surgery), illness or infection (e.g., flu or upper respiratory infection), and stressful or traumatic life events (e.g., child maltreatment) have been shown, in some studies, to be associated with the development of CDH [20,39,40] . Furthermore, evidence from prospective and cross-sectional studies has suggested that children with CDH may be more reactive to typical daily stressors and that perceived stress is one of the most reliable ‘triggers’ of headache episodes in this population [39,41] . Recent studies have also suggested obesity to be a potential risk factor in CDH. In particular, adult research has shown obesity to be a risk factor for chronification of migraine, especially in females [42] . A retrospective review of pediatric headache clinic patients suggested that obesity rates are higher overall in children with headache and chronic tension-type headache but not in children with chronic migraine [43] . Conversely, some data support a relationship between obesity and migraine frequency, with the hypothesized mechanism being the overlap of neurotransmitter (e.g., serotonin), peptide (e.g., orexin) and adiopocytokine (e.g., leptin) regulation of feeding and migraine [44] . Prospective data linking obesity to subsequent development of CDH are not presently available. In addition, using certain abortive medicines, such as nonsteroidal anti-inf lammatories, opioids or triptans more than a few times per week for at least a few months seems to reliably increase the likelihood of developing and maintaining frequent headache in children [45] . Thus, medication overuse may be a contributor to central sensitization. At present, however, medication-overuse headache is classified and treated as a headache disorder in its own right based on adult criteria, rather than medication overuse being principally viewed as a risk factor for CDH development [46] . Overuse of medications for headache may occur at a lower incidence in children relative to adults [8] but, nonetheless, may still occur at a high rate [47] and is important to evaluate, given its potential role in headache transformation and persistence. Comorbid conditions Further complicating the understanding and treatment of CDH in children are conditions that
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REVIEW Connelly & Bickel tend to co-occur at a rate beyond what is expected in the general population. CDH in children, therefore, may be part of a spectrum of disorders that have similar multifaceted etiologies. Other pain syndromes
Children with headache often report co-occurrence of persistent pain at other body sites, such as abdominal pain, back pain and/or widespread musculoskeletal pain [21,48,49] . Similarly, children with other pain syndromes may develop frequent headache concurrently or in the future [50] . The co-occurrence of headaches with other pain syndromes suggests a possible common pathophysiology and supports the plausibility of central sensitization as a unifying feature. However, data are not yet available on the specific association of pediatric CDH per se with other pain syndromes. Sleep disorder
Children with frequent headaches often report increased sleep onset latency and poor sleep maintenance [51] , but there are limited published data available specifically in pediatric CDH samples. Results of polysomnographic studies have suggested that children with tension-type headache tend to have bruxism and that those with chronic migraine are likely to have disrupted sleep architecture (reduced rapid eye movement and slow-wave sleep) [52] . However, in the absence of prospective data, it remains unclear if CDH precedes or follows on from the development of sleep disturbance. Thus, the association between sleep disorders per se and CDH in children remains speculative and requires further elucidation through prospective research. Psychiatric comorbidity
The assumption that pediatric CDH is essentially a psychiatric condition is unfortunately prevalent and not well-supported by extant data. Prospective data needed to detangle directional relationships are lacking and data on clinical samples can produce a biased perspective, given that only a minority of pediatric patients with CDH seek treatment. With these caveats in mind, extant data suggest that up to approximately one-third of treatment-seeking children with CDH have a diagnosable anxiety or depressive disorder [43] ; this exceeds rates of anxiety and depression in the general pediatric population. It remains unclear, however, whether disordered mood in children with CDH predates headache development or
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whether it develops as a consequence of living with frequent headaches. The neurobiological structures and mechanisms activated in CDH are at least partly relevant to the pathophysiology of anxiety and mood disorders (e.g., neuroplastic changes in the corticolimbic system and serotonergic dysregulation), supporting the likelihood of a bidirectional link [53] . Recent studies have also found a concerning link between CDH in adolescents and increased risk of suicidal thoughts (not necessarily behavior), but the relationship is not fully explained by the common association with depression [54,55] . Evidence is mixed with regards to elevated rates of other psychiatric conditions in children with CDH, with some studies showing increased rates relative to normative data or matched controls, and others showing no reliable differences [54,56] . The most recent data suggest that approximately 35% of pediatric patients with CDH have at least one lifetime psychiatric diagnosis and that these patients had greater functional disability and a poorer quality of life than those without a psychiatric diagnosis [57] ; in this study, no significant relationship between psychiatric status and headache frequency, duration or severity was found. Taken together, extant evidence suggests that a minority of children with CDH have clinically significant psychiatric comorbidity and that the most likely associated psychiatric conditions are depressive and anxiety disorders. Given the evidence that psychiatric comorbidity adversely affects functioning and quality of outcomes of CDH [57] , treatment of comorbid conditions with medical management and/or nonpharmacological interventions, such as psychotherapy, should be considered. Evaluation of pediatric CDH The goal in evaluating CDH in children is to facilitate classification of headache, determine what factors may contribute to occurrence and maintenance, set the stage for the treatment plan, and determine potential barriers to a positive treatment prognosis. As such, adequate attention to both medical factors and psychosocial context in the evaluation of CDH is recommended. An identifiable secondary cause exists in fewer than 10% of cases of pediatric CDH [8,58] . Thus, the majority of children with CDH will not require further specific investigation and adequate assessment can be completed from history and physical examination alone. Moreover, liberal use
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Chronic daily headache in children & adolescents: science & conjecture of imaging (e.g., MRI) or testing (e.g., lumbar puncture) may create iatrogenic problems; incidental findings are detected in nearly 20% of MRIs performed for evaluation of pediatric headache [59] and children with migraine are at an elevated risk of postlumbar puncture headache [60] . The history portion of the evaluation should include a detailed headache history (length of time with headaches, frequency, severity, time of onset, duration, quality, location, precipitating/ alleviating factors and associated symptoms), treatment history, family history of pain syndromes and mental health conditions, inquiry into academic, social and family functioning (e.g., school attendance, intensity of extracurricular activities, experiences of bullying/social exclusion or rejection and maltreatment), lifestyle factors (diet, sleep and activity level), perceived stressors, and evaluation of mood and self-harm thoughts or behaviors [61] . Specific signs to be aware of for potential secondary headache that would require additional imaging and/or laboratory work include absence of family history of migraine, abnormal focal neurological findings on examination, gait abnormalities, occurrence of seizures, headache worsening with posture change or coughing, personality change and headache awakening the child from sleep [10,59] . Indicators that additional services beyond only medication management should be considered (e.g., counseling referral) include significant school absence, reinforcement for avoiding regular activities (e.g., parent attention or avoidance of stressors), exclusive focus on a potential underlying medical condition and untreated psychiatric disorders. In addition, if a patient fails to respond to typical management of CDH, idiopathic intracranial hypertension without papilledema should then be considered. While most patients with increased intracranial pressure will have papilledema on examination, there have been reports of increased pressure without papilledema in children [62] . While the quality of headache may not differ from typical CDH, the presence of pulsatile tinnitus and obesity may increase suspicion of idiopathic intracranial hypertension. Opening pressure should be obtained via lumbar puncture in the lateral decubitus position. While controversial, evidence suggests that opening pressures of up to 28 cm of water, which is the metric on which opening pressure is measured, may be normal [63] .
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Management of pediatric CDH Management options for CDH include both pharmacological treatments (e.g., medications and supplements) and nonpharmacological treatments (e.g., relaxation training, manual therapies, massage therapy, chiropractic or osteopathic manipulation, and acupuncture). In general, the empirical evidence for any particular treatment modality for CDH in children is lacking and based primarily on inference from observational studies, treatment of episodic headaches and clinical anecdote. Accumulated experience at different treatment centers suggests that a combination of medication, headache education and adjuvant therapies is often needed to optimize outcomes, particularly for children with high levels of functional disability [64] . Pharmacological treatment
Despite the high prevalence of CDH in children and adolescents, there is a significant lack of well-designed trials to guide management of the condition with medication and/or supplements/herbal therapies. The lack of data relates partly to individuals with CDH being excluded from headache prevention trials for many years. Currently, there are no FDA-approved treatments for CDH in the pediatric population and thus, determination of medications for pediatric CDH is primarily based on clinical acumen. Abortive headache medications have a limited role in treating CDH. The general consensus is that the use of abortive medications for CDH should be restricted to no more than 8 days per month in order to decrease the risk of medication overuse headaches [65] . Thus, children should choose two or fewer headaches per week that necessitate abortive treatment; typically, these will be the headaches that, without treatment, would lead to significant disability or an emergency room visit. Opioid analgesics and barbiturates should be avoided in the management of CDH due to their role in migraine chronification and their potential for misuse [65] . If abortive therapy is used, it should typically begin with over-the-counter preparations of ibuprofen, acetaminophen, naproxen, or a combination product, such as oral aspirin/acetaminophen/caffeine [12] . It is frequently necessary to provide the child with a 20 min break in a quiet area to improve treatment response. To increase the effectiveness of an NSAID, caffeine, diphenhydramine and/or an
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REVIEW Connelly & Bickel antiemetic may be used as well. Migraines may respond better to a combination of medications rather than just one abortive alone. With regards to headache prevention, there is no consensus on first-line pharmaceutical treatment for CDH. Instead, medications are chosen based on headache classification, sideeffect profile and patient preference. The goal of headache prevention when treating CDH is not headache freedom, but rather to gradually decrease headache severity and frequency to the point that headaches are no longer significantly affecting daily functioning and quality of life. Typically, at least a 6 week medication trial is necessary before determining efficacy. Table 2 provides a listing of medicines used in the preventative management of pediatric CDH, along with dosing information and comments based on existing studies and opinion [66,67] . The medicines recommended for use in pediatric CDH have primarily been adapted from use in episodic headaches; there are clearly limitations to this approach given the differences in pathophysiology and perhaps medication tolerance in CDH. The most well-studied preventative medications for pediatric headache are topiramate and amitriptyline. In a randomized placebocontrolled trial, topiramate (100 mg given twice daily) decreased mean monthly migraine frequency from a baseline of 16.14 to 4.27 over the course of 12 weeks [68] . Given that topiramate may lead to weight loss, it may be an ideal first choice preventative headache medicine for the overweight child with chronic migraine. In an open-label trial of 279 children with either migraine or tension-type headaches (average frequency of 17.1 days per month), amitriptyline, on average, reduced headache frequency by nearly half and significantly reduced headache severity and duration [69] . Cyproheptadine, propranolol and valproic acid are thought to be potentially efficacious based on their efficacy in treating episodic migraine [8,70,71] and clinical experience. However, these medications have not been studied through randomized trials in pediatric CDH samples. In addition, despite almost no empirical data in pediatric CDH, onabotulinumtoxin A (the first treatment to receive US FDA approval for the treatment of adult CDH), occipital nerve blocks and trigger point injections might be considered in rare cases in which children have failed to respond to at least two adequate trials of other headache preventatives [72,73] .
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For intractable continuous headache, most tertiary headache centers will offer inpatient and/ or outpatient repetitive infusions in an attempt to stop the headache. However, there are no published data on this approach. Given that intravenous dihydroergotamine is an established treatment for status migrainosis [74,75] , it is sometimes adopted for use in a hospital-based treatment of pediatric CDH when traditional headache prophylaxis has failed. In these cases, patients often receive infusions of dihydroergotamine combined with metaclopromide, valproic acid and magnesium sulfate. Often, inpatient treatment can be paired with nonpharmacological treatments and there are some data suggesting that inpatient treatment of pediatric headache may be superior to outpatient treatment in certain refractory cases [76] . Nonpharmacological treatment
All studies that have been conducted on nonpharmacological treatments for pediatric headache have included mixed diagnoses (i.e., not explicitly CDH), such that there is no definitive evidence of the efficacy of any particular nonpharmacological treatment for CDH per se. Furthermore, there is a lack of comparative efficacy trials, meaning that there is no evidence to guide which treatment(s) may work better for which children with CDH. The most well-studied among the nonpharmacological treatment options for headache in children are relaxation training, with or without biofeedback assistance (e.g., diaphragmatic breathing, progressive muscle relaxation, visualization/imagery and selfhypnosis), and cognitive–behavioral therapy (training in identifying, challenging, and modifying beliefs and behaviors that may be contributing to headaches, disability and/or emotional distress) [77] . A recent meta-ana lysis that included 16 trials of self-guided or therapist-led relaxation training and/or cognitive–behavioral therapy for primary headaches in children found that these therapies led to clinically significant improvements in pain but, interestingly, did not reliably reduce disability or improve emotional functioning [78] . Nevertheless, psychological interventions for pediatric CDH may be beneficial as primary or adjuvant therapy for children with high levels of headache-related disability and/or comorbid psychiatric symptoms. The efficacy of other nonpharmacological treatment options for children with CDH
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Table 2. Preventative medications used to treat chronic daily headache in children. Medicine
Target dose
Potential side effects
Comments
2–3 mg/kg once daily
Exercise intolerance, exacerbation of asthma and nightmares
5 mg (above 5 years of age) once daily
NA
Not available in the USA. Data are unclear as to whether other calcium channel blockers are equally effective
1 mg/kg once daily
Sedation, weight gain, dry mouth and suicidal thoughts
Consider EKG monitoring and consider switch to nortriptyline if too sedating
Fluoxetine
20 mg once daily
Suicidal thoughts
Studies indicate effectiveness in adults but have not been studied in children
Venlafaxine XR
150 mg once daily
Elevation of blood pressure
b-blockers Propranolol Calcium channel blockers Flunarizine
Tricyclic antidepressants Amitriptyline SSRIs/SNRIs
Anticonvulsants Topiramate
Divalproex sodium Gabapentin
2–3 mg/kg once daily
Paresthesias, weight loss/decreased appetite, nephrolithiasis, acute angle glaucoma, metabolic acidosis, difficulty in thinking and suicidal thoughts 15–45 mg/kg once daily Birth defects (female), weight gain, Blood monitoring is recommended. Use with tremor and hair loss caution in females of child-bearing age 300–400 mg t.i.d. Drowsiness and dizziness
Antihistamines Cyproheptadine
2–4 mg every 8–12 h
Weight gain and sedation
Supplements/vitamins/herbal therapies Magnesium oxide or gluconate Riboflavin Petasites
9 mg/kg once daily
Diarrhea
200–400 mg once daily Unknown 50–75 mg b.i.d. Eructation
Purified extract from butterbur plant; avoid nonpurified formulations, which have been linked to liver toxicity
Medicines are best tolerated if started at approximately 20% of the target dose, with gradual titration as tolerated. If tolerability is an issue, consider dosing only after 12 pm. If no response is seen after 12 weeks at the target dose, the medication is unlikely to be helpful at higher doses. However, if partial response is demonstrated, the practitioner should use clinical judgment to consider a higher dose in order to obtain better relief. b.i.d.: Twice daily; EKG: Electrocardiography; NA: Not applicable; t.i.d.: Three-times daily; SNRI: Serotonin/norepinephrine-reuptake inhibitors; SSRI: Selective serotonin-reuptake inhibitors; XR: Extended release.
beyond psychological interventions essentially remains unknown. Although manual therapies, such as massage and chiropractic manipulation, are used to treat chronic headache in children and, by case report, can be effective, there have been no trials published on their safety or efficacy in this population [79,80] . In the only double-blind, randomized, placebo-controlled trial of a nonpharmacological treatment for pediatric headache, ‘active’ laser acupuncture led to a greater reduction in the number of headache days than placebo laser acupuncture in a sample of 43 children with migraine or tension-type
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headache [81] . Overall, much more research is needed to make sound recommendations for nonpharmacological treatment options to families of children with CDH. Prognosis Outcome data are sparse for children treated for CDH and length of follow-up for published studies varies greatly (
