Curr Pain Headache Rep (2014) 18:422 DOI 10.1007/s11916-014-0422-7
CHILDHOOD AND ADOLESCENT HEADACHE (S EVERS, SECTION EDITOR)
Preventive Drugs in Childhood and Adolescent Migraine Joanne Kacperski & Andrew D. Hershey
Published online: 24 April 2014 # Springer Science+Business Media New York 2014
Abstract While headaches in children are quite common, the study and characterization of headache disorders in the pediatric age group has historically been limited. In the absence of controlled studies on prophylactic treatment of the primary headache disorders in this age group, the diagnosis of childhood migraine rests on criteria similar to those in adults. Data from adult studies are often extrapolated and applied to children as well. Although it appears that many preventive agents are safe in children, none are currently FDA-approved for this age group. As a result, despite experiencing significant disability, the vast majority of children who present to their physician with migraine headache do not receive prophylactic therapy. Furthermore, controlled clinical trials investigating the use of both abortive and preventive medications in children have suffered from high placebo response rates. The shorter duration of headaches and other characteristic features seen in children are such that designing randomized controlled trials in this age group is more problematic and limiting. As such, treatment practices vary widely, even among specialists, due to the absence of evidence-based guidelines from clinical trials. Keywords Migraine . Pediatric migraine . Preventive headache treatment . Prophylactic headache treatment . Nonpharmacologic treatment
This article is part of the Topical Collection on Childhood and Adolescent Headache J. Kacperski (*) : A. D. Hershey (*) Division of Neurology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave – MLC 2015, Cincinnati, OH 45229-3039, USA e-mail: [email protected] e-mail: [email protected] J. Kacperski : A. D. Hershey Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
Introduction Primary headache disorders are one of the most prevalent health problems worldwide. Studies demonstrating the prevalence of childhood headache have been investigated across pediatric age groups, with variable estimates ranging from 3% in school-age children to 20% in adolescents [1–3]. Multiple epidemiological studies have demonstrated the high incidence of headaches in this group, with migraine being the most disabling type [4]. Aydin et al. reported that migraine was the most common type of headache in the pediatric neurology outpatient clinic, comprising 57.1% of all headaches presenting for initial evaluation [5]. In 1962, Bille demonstrated that 25% of children reported a significant headache by the age of 5 years, and up to 75% of children reported a notable headache by the age of 15 years [6] Abu-Arafeh et al. also observed a high global prevalence of migraine, affecting almost 20% of school-age and adolescent children [7]. Prior to puberty, the prevalence of migraine is slightly higher in boys as compared to girls [8]; the mean age of onset is 7 years for boys and 11 years for girls [9]. However, data from the American Migraine Prevalence and Prevention (AMPP) study demonstrated that as children approach adolescence, the incidence and prevalence of migraine appear to increase more rapidly in girls than in boys [10]. Migraine can often become a chronic and disabling disorder, with a substantial effect on the child’s quality of life, contributing to school absenteeism and potentially affecting peer and social interaction. Population studies have demonstrated that over 130,000 school days are missed every two weeks and 3 million bedridden days occur per month as a result of pediatric migraine [11]. Moreover, Powers et al. demonstrated that the negative impact of migraines on a child’s overall quality of life is similar to pediatric cancer, heart disease, and rheumatic disease [12]. Because migraine headaches commonly start in childhood and adolescence,
422, Page 2 of 8
early recognition and establishment of a treatment plan and implementation of lifestyle changes can alter disease progression and ultimately improve the child’s quality of life [13]. The specific diagnostic criteria for migraine in children are complex. In adults, migraine headache is defined by the Classification Committee of the International Headache Society as an idiopathic recurring headache disorder manifesting in attacks lasting 4–72 hours. Typical characteristics of migraine are unilateral location, pulsating quality, moderate to severe intensity, aggravation by routine physical activity, nausea and/or vomiting, photophobia, and phonophobia. However, difficulties may be encountered in diagnosing migraine in the pediatric and adolescent age groups. For example, gastrointestinal complaints such as abdominal pain, nausea, and vomiting are more prevalent. Children also tend to experience headaches that are shorter in duration. Attacks may be as short as one hour, as confirmed by diary entries, and sleep should always be included as part of the headache duration. The location is more likely to be bilateral, and is often described as frontal-temporal as opposed to the more common unilateral headaches seen in adult migraineurs. Because younger children may have difficulty understanding and describing the concepts of photophobia and phonophobia, these signs may need to be inferred by the parents on the basis of the child’s actions [14, 15]. Although the study of migraine has been ongoing for many decades, a full understanding of the pathophysiology remains elusive [16]. Research focusing on the physiologic causes of migraine has revealed a neurovascular etiology, suggesting that migraine attacks are generated in the brain rather than in the vasculature. Neurochemical imbalances, the trigeminal system, and meningeal blood vessels have all been identified as significant components to the production of a migraine headache. The threshold for the initiation of cortical excitation is lower due to neuronal hyperexcitability. Migraine aura is thought to occur when normally non-noxious stimuli trigger spontaneous depolarization. Neuronal function is then subsequently suppressed, and this suppression spreads across the cortex [16–19]. The pathophysiology of migraine in children is presumed to be similar to adults. In children, however, the potential of early intervention with an effective preventive treatment may ultimately impact disease progression before many of the refractory aspects seen in adults become established [7, 16]. Management of migraine headaches requires a tailored regimen of pharmacological and behavioral measures that consider the child’s headache burden and level of disability. However, these agents should be limited to patients whose headaches occur with sufficient frequency or severity to warrant daily treatment. The goal of therapy should be reducing the frequency of headaches, reducing the progression to chronic daily headache, and decreasing associated pain and disability (PedMIDAS 48 hours) should also be considered [24]. Because no standardized guidelines exist for choosing a preventive regimen for children and adolescents, clinicians are often guided by extrapolation from adult studies in addition to the limited number of studies that have been conducted in children. What may be even more concerning is that one-third of adolescents meet the criteria for warranting prophylactic therapy, yet only 10–19% are offered a preventive medication [25]. Children meriting prevention should be provided with appropriate education, thus enabling them to manage their disease and enhance personal control of their migraine. Clinicians should thoroughly discuss the treatment plan so that families understand that the effort will be long-term and the response will not be rapid, as the onset of improvement is often delayed in children [26]. The goals of therapy should include a reduction of reliance on poorly tolerated, ineffective, or unwanted acute pharmacotherapies, and thus avoidance of potential overuse. A typical goal of no more than 1–2 headaches per month is recommended for a sustained period of 4–6 months. The doses also must be titrated up slowly to minimize side effects, and once an effective dose is reached, relief must be sustained for 2–3 months before considering alternative medication. A plan is also necessary to wean the child off the medication once sustained relief is achieved . Both the clinician and family must establish a sense of functional disability before committing the child to a course of daily medication, as a goal of therapy should be the improvement of overall quality of life (often assessed by PedsQL) [23, 26, 27••, 28].
Prophylactic Pharmacological Therapy Several classes of medications may be used for prophylactic therapy, including antidepressants, antiepileptics, antihistamines, and antihypertensives. The majority of these agents have been extensively prescribed for other conditions such as depression, anxiety, epilepsy, and other pain disorders, and thus their side effect profiles are well-described (Table 1). When selecting a prophylactic agent for a patient, the clinician should take into account any comorbid conditions and the side effect profile of each medication [29]. Clear instructions should be given to families regarding the medication’s mechanism of action, possible adverse effects, and the importance of not missing doses. It is also important to provide clear titration instructions in addition to the length of time that it will take for the treatment to become effective, which is often several weeks [28, 30]. Slow titration over a period of 4–12 weeks may be necessary to ensure that the child tolerates the
Curr Pain Headache Rep (2014) 18:422
Page 3 of 8, 422
Table 1 Commonly used preventives for the prevention of pediatric migraine*Not available in the U.S. Preventive Agents for Pediatric Migraine Drug Antidepressants Amitriptyline
Dosing
Available Formulations
Commonly Encountered Adverse Effects
10–150 mg qhs (max 1 mg/kg/day) 10–75 mg qhs
Tablets – 10, 25, 50, 75,100, 125, 150 mg Capsules – 10, 25, 50, 75 mg Liquid susp – 10 mg/5 ml
Sedation, dizziness, constipation, increased appetite, weight gain Drowsiness, dizziness, constipation, increased appetite, orthostatic hypotension, QT prolongation
1–10 mg/kg/day Typical dose 50 mg bid
Tablets – 25, 50, 100, 200 mg Sprinkle caps – 15, 25 mg
Paresthesia, somnolence, dizziness, anorexia, metabolic acidosis, cognitive/memory dysfunction
Valproic Acid
15–30 mg/kg/day
Somnolence, nausea/vomiting, thrombocytopenia, tremor, alopecia, increased appetite, emotional liability
Levetiracetam
500–1500 mg bid
Zonisamide Antihistamines Cyproheptadine
100–600 mg/day
Tablets DR – 125, 250, 500mg Tablets ER – 250, 500mg Sprinkle caps – 125 mg Liquid susp – 250 mg/5 ml Tablets – 250, 500, 750, 1000 mg Liquid susp – 100 mg/ml Tablets – 25, 50, 100 mg
Somnolence, fatigue, irritability, mood/behavioral changes Somnolence, dizziness, anorexia, nausea, irritability
0.25–1.5 mg/kg/day
Tablets – 4 mg Liquid susp – 2 mg/5 ml
Drowsiness, fatigue, increased appetite, weight gain, dizziness
Antihypertensives Propranolol
2–4 mg/kg/day
Tablets – 10, 20, 40, 60, 80 mg Tablets ER – 60, 80, 120, 160 mg Liquid susp – 20, 40 mg/5 ml Tablets – 40, 80, 120mg Tablets ER – 120m 180, 240mg
Fatigue, dizziness, constipation, hypotension, depression
Tablets – 5 mg
Sedation, weight gain
Nortriptyline
Antiepileptics Topiramate
Verapamil
4–10 mg/kg/day tid
Calcium Channel Blockers Flunarizine* 5 mg qhs
medication with minimal side effects. If a trend of improvement is seen, the dose is then adjusted for optimal control. Treatment should not be abandoned until it has been given an adequate trial of at least 6–8 weeks on the full dose unless there are intolerable side effects. Both the patient and the family should understand that improvement in pain is a gradual process and will not be immediate [26]. When improvement is sustained and a satisfying response is achieved over a period of 4–6 months, the child can be slowly weaned off the medication [18, 26, 30].
Antidepressants Antidepressants were first recognized in the 1970s as an effective migraine preventive therapy in adults, with the tricyclic antidepressants being the most widely studied [31]. Amitriptyline Amitriptyline is one of the most widely used prophylactic medications in pediatric migraine. It is the only
Constipation, dizziness, nausea, hypotension
tricyclic antidepressant for which studies have provided consistent evidence in the adult migraine population at doses of 10–150 mg/day. However, most of the studies with amitriptyline in children have been open-label, with no placebo-controlled trials, and thus dosing guidelines in children have yet to be established [32]. Although its efficacy in pediatric migraine has not been assessed in randomized controlled trials, amitriptyline remains one of the most widely used agents in this age group. Starting doses of 5–12.5 mg once daily may be gradually increased to 1 mg/kg/day [33]. Due to its side effects, most notably somnolence, amitriptyline must be titrated slowly over a period of 8–12 weeks, increasing by 0.25 mg/kg/day every two weeks or so [34]. Nortriptyline, with its less sedating effects, is sometimes used to replace amitriptyline, although it does raise the concern for increased risk of arrhythmia, and regular electrocardiograms may need to be performed [34]. Hershey et al. surveyed the perceptions of 192 children with headache who were treated preventively with amitriptyline in slow increments to 1 mg/kg. When the full dose was achieved, migraine attack frequency and severity were
422, Page 4 of 8
reduced by 80–89%, and 84% of patients also reported feeling better [34]. In a retrospective chart review, Eidlitz-Markus et al. assessed the effectiveness of nonpharmacologic measures combined with low-dose amitriptyline or propranolol (n=118). Ninety-three children received propranolol (mean initial dose 0.4±0.17 mg/kg/day), and 25 received amitriptyline (mean initial dose 0.26±0.1 mg/kg/day). In both groups, headache frequency was reduced by more than 50% in approximately 80% of patients. The authors concluded that lowdose propranolol and low-dose amitriptyline, when combined with nonpharmacologic measures, were equally effective in reducing the frequency of migraine. They also reported that significantly more tolerable side effects were experienced by those children receiving amitriptyline [32]. Hershey et al. is currently conducting the Childhood and Adolescent Migraine Prevention Study (CHAMP), which is a double-blind placebo-controlled multicenter trial comparing the effectiveness of amitriptyline and topiramate for the prevention of episodic and chronic migraine. The study will recruit 675 pediatric migraineurs between the ages of 8 and 17 years, who will be randomized to amitriptyline, topiramate, or placebo in a 2:2:1 ratio. The target dose of amitriptyline is 1 mg/kg and 2 mg/kg for the topiramate group. The primary outcome will be a 50% reduction in headache frequency. The fundamental goal of this study is to obtain level 1 evidence for the effectiveness of two of the most widely used preventive agents for the treatment of migraine in the pediatric population, which could subsequently help guide clinicians in treatment decisions and thereby improve disability and outcomes [27••].
Antiepileptics Antiepileptics, which include topiramate, valproic acid, levetiracetam, zonisamide, and gabapentin, have been the most widely studied prophylaxis for migraine in both adults and children. Both topiramate and valproic acid are FDA- approved for prevention of migraine in adult patients. The rationale for their use is based on our current understanding of migraine pathophysiology, which is thought to involve a migrating wave of regional cortical excitation followed by a prolonged period of neuronal depression. Antiepileptics may alter this pathway [35]. Topiramate Topiramate is a first-line option for the treatment of migraines in adults. The effective dose in the pediatric population has not been established, but a dose of 2–4 mg/ kg/day appears to be effective. To achieve this dose, however, it must be titrated slowly, typically increasing the dose by quarter-steps over a period of 8–12 weeks. The most commonly observed side effects include drowsiness, paresthesias,
Curr Pain Headache Rep (2014) 18:422
memory or language dysfunction, decreased appetite and anorexia, metabolic acidosis, hyperthermia, dizziness, and abdominal pain. Over the last decade or so, multiple studies have demonstrated that topiramate is effective in reducing headache burden and disability. Winner et al. performed a placebocontrolled trial in 157 children aged 6–15 years who were randomized to receive placebo or topiramate, with a goal dose of 2 mg/kg. Treatment with topiramate was associated with a mean reduction of 2.6 migraine days per month compared with 2.0 in the placebo group (P=0.061). Response, defined as a 50% reduction in headache frequency, was 55% with topiramate compared to 47% in the placebo group [36]. Lewis et al. confirmed the superiority of topiramate over placebo at a dose of 100 mg/day in a randomized double-blind trial, although topiramate at a dose of 50 mg/day failed to showed superiority [37]. When compared to flunarizine, a calciumchannel blocker and the most rigorously studied preventive in pediatric migraine (not available in the U.S.), Kim et al. reported that among children aged 6–18 years, responder rate in patients treated with topiramate was 80%, compared to 81% in the flunarizine group. There was no significant difference between the two groups in retention and adverse event rates, leading the authors to conclude that the efficacy and tolerability of topiramate was not inferior to flunarizine for prophylaxis in pediatric migraine [38]. When compared to propranolol, topiramate was more effective in reduction of monthly frequency (P=0.001), severity (P=0.0001), duration (P=0.0001), and disability as assessed by PedMIDAS scores (P=0.0001) [39]. Valproic Acid Valproic acid is also considered first-line for migraine prevention in adults, and several open-label and retrospective studies have suggested that it may be effective in children and adolescents. Doses of 15–20 mg/kg/day appear to be effective, and must be titrated over a period of 8–12 weeks to avoid unwanted side effects. Adverse effects include dizziness, drowsiness, alopecia, weight gain, thrombocytopenia, lymphopenia, potential hyperammonemia, and elevated pancreatic enzymes, making laboratory surveillance critical. The risk of teratogenicity and fertility-related side effects must be discussed with female patients of child-bearing age prior to initiation of therapy [23, 26, 40]. A randomized prospective double-blind study comparing valproic acid with propranolol found no significant differences with respect to safety and efficacy. However, when the reduction in baseline headache frequency was evaluated, 83% of propranolol recipients (max dose 3 mg/kg/day) exhibited improvement of >50% headache reduction compared to 63% of those who received valproic acid (max dose 30 mg/kg/day) [41]. In a small retrospective study comparing the effectiveness of valproic acid to topiramate, both antiepileptics demonstrated effectiveness in treating migraines in children. In children
Curr Pain Headache Rep (2014) 18:422
treated with valproic acid, mean monthly headache frequency, headache intensity, headache duration, and PedMIDAS scores decreased from 20.1±10.2 to 6.6±8.6, from 7.1±1 to 3.4±2.1, from 7±12 to 1.4±2.5 hours, and from 20.5±16.1 to 5.5±9.2, respectively (P
CHILDHOOD AND ADOLESCENT HEADACHE (S EVERS, SECTION EDITOR)
Preventive Drugs in Childhood and Adolescent Migraine Joanne Kacperski & Andrew D. Hershey
Published online: 24 April 2014 # Springer Science+Business Media New York 2014
Abstract While headaches in children are quite common, the study and characterization of headache disorders in the pediatric age group has historically been limited. In the absence of controlled studies on prophylactic treatment of the primary headache disorders in this age group, the diagnosis of childhood migraine rests on criteria similar to those in adults. Data from adult studies are often extrapolated and applied to children as well. Although it appears that many preventive agents are safe in children, none are currently FDA-approved for this age group. As a result, despite experiencing significant disability, the vast majority of children who present to their physician with migraine headache do not receive prophylactic therapy. Furthermore, controlled clinical trials investigating the use of both abortive and preventive medications in children have suffered from high placebo response rates. The shorter duration of headaches and other characteristic features seen in children are such that designing randomized controlled trials in this age group is more problematic and limiting. As such, treatment practices vary widely, even among specialists, due to the absence of evidence-based guidelines from clinical trials. Keywords Migraine . Pediatric migraine . Preventive headache treatment . Prophylactic headache treatment . Nonpharmacologic treatment
This article is part of the Topical Collection on Childhood and Adolescent Headache J. Kacperski (*) : A. D. Hershey (*) Division of Neurology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave – MLC 2015, Cincinnati, OH 45229-3039, USA e-mail: [email protected] e-mail: [email protected] J. Kacperski : A. D. Hershey Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
Introduction Primary headache disorders are one of the most prevalent health problems worldwide. Studies demonstrating the prevalence of childhood headache have been investigated across pediatric age groups, with variable estimates ranging from 3% in school-age children to 20% in adolescents [1–3]. Multiple epidemiological studies have demonstrated the high incidence of headaches in this group, with migraine being the most disabling type [4]. Aydin et al. reported that migraine was the most common type of headache in the pediatric neurology outpatient clinic, comprising 57.1% of all headaches presenting for initial evaluation [5]. In 1962, Bille demonstrated that 25% of children reported a significant headache by the age of 5 years, and up to 75% of children reported a notable headache by the age of 15 years [6] Abu-Arafeh et al. also observed a high global prevalence of migraine, affecting almost 20% of school-age and adolescent children [7]. Prior to puberty, the prevalence of migraine is slightly higher in boys as compared to girls [8]; the mean age of onset is 7 years for boys and 11 years for girls [9]. However, data from the American Migraine Prevalence and Prevention (AMPP) study demonstrated that as children approach adolescence, the incidence and prevalence of migraine appear to increase more rapidly in girls than in boys [10]. Migraine can often become a chronic and disabling disorder, with a substantial effect on the child’s quality of life, contributing to school absenteeism and potentially affecting peer and social interaction. Population studies have demonstrated that over 130,000 school days are missed every two weeks and 3 million bedridden days occur per month as a result of pediatric migraine [11]. Moreover, Powers et al. demonstrated that the negative impact of migraines on a child’s overall quality of life is similar to pediatric cancer, heart disease, and rheumatic disease [12]. Because migraine headaches commonly start in childhood and adolescence,
422, Page 2 of 8
early recognition and establishment of a treatment plan and implementation of lifestyle changes can alter disease progression and ultimately improve the child’s quality of life [13]. The specific diagnostic criteria for migraine in children are complex. In adults, migraine headache is defined by the Classification Committee of the International Headache Society as an idiopathic recurring headache disorder manifesting in attacks lasting 4–72 hours. Typical characteristics of migraine are unilateral location, pulsating quality, moderate to severe intensity, aggravation by routine physical activity, nausea and/or vomiting, photophobia, and phonophobia. However, difficulties may be encountered in diagnosing migraine in the pediatric and adolescent age groups. For example, gastrointestinal complaints such as abdominal pain, nausea, and vomiting are more prevalent. Children also tend to experience headaches that are shorter in duration. Attacks may be as short as one hour, as confirmed by diary entries, and sleep should always be included as part of the headache duration. The location is more likely to be bilateral, and is often described as frontal-temporal as opposed to the more common unilateral headaches seen in adult migraineurs. Because younger children may have difficulty understanding and describing the concepts of photophobia and phonophobia, these signs may need to be inferred by the parents on the basis of the child’s actions [14, 15]. Although the study of migraine has been ongoing for many decades, a full understanding of the pathophysiology remains elusive [16]. Research focusing on the physiologic causes of migraine has revealed a neurovascular etiology, suggesting that migraine attacks are generated in the brain rather than in the vasculature. Neurochemical imbalances, the trigeminal system, and meningeal blood vessels have all been identified as significant components to the production of a migraine headache. The threshold for the initiation of cortical excitation is lower due to neuronal hyperexcitability. Migraine aura is thought to occur when normally non-noxious stimuli trigger spontaneous depolarization. Neuronal function is then subsequently suppressed, and this suppression spreads across the cortex [16–19]. The pathophysiology of migraine in children is presumed to be similar to adults. In children, however, the potential of early intervention with an effective preventive treatment may ultimately impact disease progression before many of the refractory aspects seen in adults become established [7, 16]. Management of migraine headaches requires a tailored regimen of pharmacological and behavioral measures that consider the child’s headache burden and level of disability. However, these agents should be limited to patients whose headaches occur with sufficient frequency or severity to warrant daily treatment. The goal of therapy should be reducing the frequency of headaches, reducing the progression to chronic daily headache, and decreasing associated pain and disability (PedMIDAS 48 hours) should also be considered [24]. Because no standardized guidelines exist for choosing a preventive regimen for children and adolescents, clinicians are often guided by extrapolation from adult studies in addition to the limited number of studies that have been conducted in children. What may be even more concerning is that one-third of adolescents meet the criteria for warranting prophylactic therapy, yet only 10–19% are offered a preventive medication [25]. Children meriting prevention should be provided with appropriate education, thus enabling them to manage their disease and enhance personal control of their migraine. Clinicians should thoroughly discuss the treatment plan so that families understand that the effort will be long-term and the response will not be rapid, as the onset of improvement is often delayed in children [26]. The goals of therapy should include a reduction of reliance on poorly tolerated, ineffective, or unwanted acute pharmacotherapies, and thus avoidance of potential overuse. A typical goal of no more than 1–2 headaches per month is recommended for a sustained period of 4–6 months. The doses also must be titrated up slowly to minimize side effects, and once an effective dose is reached, relief must be sustained for 2–3 months before considering alternative medication. A plan is also necessary to wean the child off the medication once sustained relief is achieved . Both the clinician and family must establish a sense of functional disability before committing the child to a course of daily medication, as a goal of therapy should be the improvement of overall quality of life (often assessed by PedsQL) [23, 26, 27••, 28].
Prophylactic Pharmacological Therapy Several classes of medications may be used for prophylactic therapy, including antidepressants, antiepileptics, antihistamines, and antihypertensives. The majority of these agents have been extensively prescribed for other conditions such as depression, anxiety, epilepsy, and other pain disorders, and thus their side effect profiles are well-described (Table 1). When selecting a prophylactic agent for a patient, the clinician should take into account any comorbid conditions and the side effect profile of each medication [29]. Clear instructions should be given to families regarding the medication’s mechanism of action, possible adverse effects, and the importance of not missing doses. It is also important to provide clear titration instructions in addition to the length of time that it will take for the treatment to become effective, which is often several weeks [28, 30]. Slow titration over a period of 4–12 weeks may be necessary to ensure that the child tolerates the
Curr Pain Headache Rep (2014) 18:422
Page 3 of 8, 422
Table 1 Commonly used preventives for the prevention of pediatric migraine*Not available in the U.S. Preventive Agents for Pediatric Migraine Drug Antidepressants Amitriptyline
Dosing
Available Formulations
Commonly Encountered Adverse Effects
10–150 mg qhs (max 1 mg/kg/day) 10–75 mg qhs
Tablets – 10, 25, 50, 75,100, 125, 150 mg Capsules – 10, 25, 50, 75 mg Liquid susp – 10 mg/5 ml
Sedation, dizziness, constipation, increased appetite, weight gain Drowsiness, dizziness, constipation, increased appetite, orthostatic hypotension, QT prolongation
1–10 mg/kg/day Typical dose 50 mg bid
Tablets – 25, 50, 100, 200 mg Sprinkle caps – 15, 25 mg
Paresthesia, somnolence, dizziness, anorexia, metabolic acidosis, cognitive/memory dysfunction
Valproic Acid
15–30 mg/kg/day
Somnolence, nausea/vomiting, thrombocytopenia, tremor, alopecia, increased appetite, emotional liability
Levetiracetam
500–1500 mg bid
Zonisamide Antihistamines Cyproheptadine
100–600 mg/day
Tablets DR – 125, 250, 500mg Tablets ER – 250, 500mg Sprinkle caps – 125 mg Liquid susp – 250 mg/5 ml Tablets – 250, 500, 750, 1000 mg Liquid susp – 100 mg/ml Tablets – 25, 50, 100 mg
Somnolence, fatigue, irritability, mood/behavioral changes Somnolence, dizziness, anorexia, nausea, irritability
0.25–1.5 mg/kg/day
Tablets – 4 mg Liquid susp – 2 mg/5 ml
Drowsiness, fatigue, increased appetite, weight gain, dizziness
Antihypertensives Propranolol
2–4 mg/kg/day
Tablets – 10, 20, 40, 60, 80 mg Tablets ER – 60, 80, 120, 160 mg Liquid susp – 20, 40 mg/5 ml Tablets – 40, 80, 120mg Tablets ER – 120m 180, 240mg
Fatigue, dizziness, constipation, hypotension, depression
Tablets – 5 mg
Sedation, weight gain
Nortriptyline
Antiepileptics Topiramate
Verapamil
4–10 mg/kg/day tid
Calcium Channel Blockers Flunarizine* 5 mg qhs
medication with minimal side effects. If a trend of improvement is seen, the dose is then adjusted for optimal control. Treatment should not be abandoned until it has been given an adequate trial of at least 6–8 weeks on the full dose unless there are intolerable side effects. Both the patient and the family should understand that improvement in pain is a gradual process and will not be immediate [26]. When improvement is sustained and a satisfying response is achieved over a period of 4–6 months, the child can be slowly weaned off the medication [18, 26, 30].
Antidepressants Antidepressants were first recognized in the 1970s as an effective migraine preventive therapy in adults, with the tricyclic antidepressants being the most widely studied [31]. Amitriptyline Amitriptyline is one of the most widely used prophylactic medications in pediatric migraine. It is the only
Constipation, dizziness, nausea, hypotension
tricyclic antidepressant for which studies have provided consistent evidence in the adult migraine population at doses of 10–150 mg/day. However, most of the studies with amitriptyline in children have been open-label, with no placebo-controlled trials, and thus dosing guidelines in children have yet to be established [32]. Although its efficacy in pediatric migraine has not been assessed in randomized controlled trials, amitriptyline remains one of the most widely used agents in this age group. Starting doses of 5–12.5 mg once daily may be gradually increased to 1 mg/kg/day [33]. Due to its side effects, most notably somnolence, amitriptyline must be titrated slowly over a period of 8–12 weeks, increasing by 0.25 mg/kg/day every two weeks or so [34]. Nortriptyline, with its less sedating effects, is sometimes used to replace amitriptyline, although it does raise the concern for increased risk of arrhythmia, and regular electrocardiograms may need to be performed [34]. Hershey et al. surveyed the perceptions of 192 children with headache who were treated preventively with amitriptyline in slow increments to 1 mg/kg. When the full dose was achieved, migraine attack frequency and severity were
422, Page 4 of 8
reduced by 80–89%, and 84% of patients also reported feeling better [34]. In a retrospective chart review, Eidlitz-Markus et al. assessed the effectiveness of nonpharmacologic measures combined with low-dose amitriptyline or propranolol (n=118). Ninety-three children received propranolol (mean initial dose 0.4±0.17 mg/kg/day), and 25 received amitriptyline (mean initial dose 0.26±0.1 mg/kg/day). In both groups, headache frequency was reduced by more than 50% in approximately 80% of patients. The authors concluded that lowdose propranolol and low-dose amitriptyline, when combined with nonpharmacologic measures, were equally effective in reducing the frequency of migraine. They also reported that significantly more tolerable side effects were experienced by those children receiving amitriptyline [32]. Hershey et al. is currently conducting the Childhood and Adolescent Migraine Prevention Study (CHAMP), which is a double-blind placebo-controlled multicenter trial comparing the effectiveness of amitriptyline and topiramate for the prevention of episodic and chronic migraine. The study will recruit 675 pediatric migraineurs between the ages of 8 and 17 years, who will be randomized to amitriptyline, topiramate, or placebo in a 2:2:1 ratio. The target dose of amitriptyline is 1 mg/kg and 2 mg/kg for the topiramate group. The primary outcome will be a 50% reduction in headache frequency. The fundamental goal of this study is to obtain level 1 evidence for the effectiveness of two of the most widely used preventive agents for the treatment of migraine in the pediatric population, which could subsequently help guide clinicians in treatment decisions and thereby improve disability and outcomes [27••].
Antiepileptics Antiepileptics, which include topiramate, valproic acid, levetiracetam, zonisamide, and gabapentin, have been the most widely studied prophylaxis for migraine in both adults and children. Both topiramate and valproic acid are FDA- approved for prevention of migraine in adult patients. The rationale for their use is based on our current understanding of migraine pathophysiology, which is thought to involve a migrating wave of regional cortical excitation followed by a prolonged period of neuronal depression. Antiepileptics may alter this pathway [35]. Topiramate Topiramate is a first-line option for the treatment of migraines in adults. The effective dose in the pediatric population has not been established, but a dose of 2–4 mg/ kg/day appears to be effective. To achieve this dose, however, it must be titrated slowly, typically increasing the dose by quarter-steps over a period of 8–12 weeks. The most commonly observed side effects include drowsiness, paresthesias,
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memory or language dysfunction, decreased appetite and anorexia, metabolic acidosis, hyperthermia, dizziness, and abdominal pain. Over the last decade or so, multiple studies have demonstrated that topiramate is effective in reducing headache burden and disability. Winner et al. performed a placebocontrolled trial in 157 children aged 6–15 years who were randomized to receive placebo or topiramate, with a goal dose of 2 mg/kg. Treatment with topiramate was associated with a mean reduction of 2.6 migraine days per month compared with 2.0 in the placebo group (P=0.061). Response, defined as a 50% reduction in headache frequency, was 55% with topiramate compared to 47% in the placebo group [36]. Lewis et al. confirmed the superiority of topiramate over placebo at a dose of 100 mg/day in a randomized double-blind trial, although topiramate at a dose of 50 mg/day failed to showed superiority [37]. When compared to flunarizine, a calciumchannel blocker and the most rigorously studied preventive in pediatric migraine (not available in the U.S.), Kim et al. reported that among children aged 6–18 years, responder rate in patients treated with topiramate was 80%, compared to 81% in the flunarizine group. There was no significant difference between the two groups in retention and adverse event rates, leading the authors to conclude that the efficacy and tolerability of topiramate was not inferior to flunarizine for prophylaxis in pediatric migraine [38]. When compared to propranolol, topiramate was more effective in reduction of monthly frequency (P=0.001), severity (P=0.0001), duration (P=0.0001), and disability as assessed by PedMIDAS scores (P=0.0001) [39]. Valproic Acid Valproic acid is also considered first-line for migraine prevention in adults, and several open-label and retrospective studies have suggested that it may be effective in children and adolescents. Doses of 15–20 mg/kg/day appear to be effective, and must be titrated over a period of 8–12 weeks to avoid unwanted side effects. Adverse effects include dizziness, drowsiness, alopecia, weight gain, thrombocytopenia, lymphopenia, potential hyperammonemia, and elevated pancreatic enzymes, making laboratory surveillance critical. The risk of teratogenicity and fertility-related side effects must be discussed with female patients of child-bearing age prior to initiation of therapy [23, 26, 40]. A randomized prospective double-blind study comparing valproic acid with propranolol found no significant differences with respect to safety and efficacy. However, when the reduction in baseline headache frequency was evaluated, 83% of propranolol recipients (max dose 3 mg/kg/day) exhibited improvement of >50% headache reduction compared to 63% of those who received valproic acid (max dose 30 mg/kg/day) [41]. In a small retrospective study comparing the effectiveness of valproic acid to topiramate, both antiepileptics demonstrated effectiveness in treating migraines in children. In children
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treated with valproic acid, mean monthly headache frequency, headache intensity, headache duration, and PedMIDAS scores decreased from 20.1±10.2 to 6.6±8.6, from 7.1±1 to 3.4±2.1, from 7±12 to 1.4±2.5 hours, and from 20.5±16.1 to 5.5±9.2, respectively (P
