521128
research-article2014
AOPXXX10.1177/1060028014521128Annals of PharmacotherapyDeaton and Mauro
Review Article-Drug Information Rounds
Topiramate for Migraine Prophylaxis in Pediatric Patients
Annals of Pharmacotherapy 2014, Vol. 48(5) 638–643 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014521128 aop.sagepub.com
Tamara L. Deaton, PharmD1, and Laurie S. Mauro, PharmD1
Abstract Objective: To evaluate the currently published data pertaining to the efficacy and safety of topiramate for prophylaxis of classic and common migraine in pediatric patients. Data Sources: The literature was identified via PubMed (through April 2013) and Iowa Drug Information System (through April 2013). References from identified articles were also reviewed. Study Selection and Data Extraction: Data were included from studies of efficacy and safety in pediatric patients experiencing migraine (with or without aura), as defined by the International Headache Society. Studies including patients with more specific types of migraine, such as basilar migraine, were excluded. Data Synthesis: Eight publicatons were identified, including 3 randomized controlled trials (RCTs), a subgroup analysis, and 4 observational studies. These studies reported a decrease in headache frequency ranging from 63% to 100% for doses of 100 mg/d and 65% for 200 mg/d. Response to therapy, defined as ≥50% reduction in migraine rate, was also reported in 83% to 95% of patients receiving topiramate. Topiramate is generally well tolerated. Adverse effects were dose related and included paresthesias, weight loss, and cognitive adverse effects. Conclusion: Topiramate is an effective and well-tolerated prophylactic therapy for use in pediatric migraine patients. Doses of 100 and 200 mg/d (1.47-2.0 mg/kg/d) effectively decrease the frequency of migraine headaches, with 100 mg/d providing optimal benefit-to-risk ratio. Additional randomized, double-blind, placebo-controlled studies are needed to determine the impact of the drug on quality-of-life outcomes, such as school function, and migraine severity and duration. Keywords topiramate, pediatric, adolescent, migraine, prophylaxis
Request Question: What is the evidence regarding the use of topiramate for migraine prophylaxis in pediatric patients?
Response Background Migraine headache occurs in 3% to 11% of children and has the potential to be significantly debilitating.1 Migraines can have a negative impact on every aspect of a child’s quality of life, affecting school performance, daily activities, interactions with peers, and family dynamics.2,3 The prevalence of migraine headaches increases throughout childhood into adolescence and may be as high as 28% in older children.2 Understanding of the pathophysiology of migraine headache has evolved in recent years. Migraine is now believed to be caused by a neuronal dysfunction characterized by cortical spreading depression, a progression that is supported by the pharmacological mechanisms of current therapies used to treat migraine.4-6 Neuronal activity associated with these headaches originates in the brainstem and travels
to the peripheral intracranial blood vessels, dura mater, and venous sinuses, where it is perceived as pain.7 Continual stimulation of these areas of the brain can lead to sensitization of neurons and a consequent hyperalgesic state accompanied by the increased nociceptive response to previously nonpainful stimuli, characteristic of migraine.5 Antiepileptic medications such as topiramate are thought to help prevent migraine through the blockade of ion channels and reduction in conductive properties of the neural membranes involved in this signaling. Preventive migraine medications are recommended for use in children who experience more than 3 migraines per month and for those who experience a significant level of impairment because of their headaches.8 The goals of preventive therapy include reduction in the frequency and 1
University of Toledo, Toledo, OH, USA
Corresponding Author: Laurie S. Mauro, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 3000 Arlington Ave, MS 1013, Toledo, OH 43614, USA. Email: [email protected]
Downloaded from aop.sagepub.com at FRESNO PACIFIC UNIV on January 19, 2015
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Deaton and Mauro intensity of migrainous attacks, improvement in the patient’s overall quality of life, and reduction in the frequency of need for acute therapies.9 Several medications, including topiramate, currently have FDA approval for the prophylaxis of migraine in adults. Efficacy of preventative therapies can be seen in adults as early as the first month of treatment for topiramate doses of 100 and 200 mg/d10,11; however, it may take 2 to 3 months to realize the full benefits of prophylactic treatment.12 Currently, there are no therapies approved for migraine prophylaxis in the pediatric population. Although topiramate has been used off-label for migraine prophylaxis in children, relatively little data are available to validate its use for migraine prophylaxis in this population. The purpose of this review is to evaluate the efficacy and safety of topiramate for prophylaxis of migraine with and without aura (previously termed classic and common migraine, respectively) in pediatric patients.
Literature Search A search of PubMed and the Iowa Drug Information System databases resulted in 8 publications, including 3 randomized controlled trials (RCTs), a subgroup analysis, and 4 observational studies evaluating the efficacy and safety of topiramate in the prophylaxis of pediatric migraine (Table 1).13-20 Two studies identified were not included—one because of the inclusion of an unspecified number of patients with chronic migraine and an especially high mean monthly migraine frequency and the second because of the focus on basilar migraine.21,22
Observational Trials Three observational trials (Table 1) of topiramate for migraine in pediatrics provided a foundation for later controlled studies. All patients in these trials fulfilled International Headache Society (IHS) criteria (1998 or 2004) for migraine.9 Topiramate was initiated or added to the patients’ concurrent regimen and was titrated for efficacy and tolerability. Average topiramate dosages used in these trials ranged from 1.4 to 1.8 mg/kg/d (absolute range = 0.5-5.5 mg/kg/d).13-15 Significant decreases in migraine frequency, severity, and duration were observed 3 to 12 months later. Adverse effects noted in these trials included cognitive effects (12.5%-13.5%), paresthesias (2.7%8.3%), and weight and appetite loss (5.6%-16.6%).13-15 Overall, these trials provided strong suggestive evidence for topiramate’s efficacy in pediatric migraine along with useful data regarding safety and dosing. Limitations of these studies include their retrospective nature and lack of placebo control. The potential for notable placebo effect is a particular concern in both pediatrics and migraine therapy. Other concurrent prophylactic therapies and biobehavioral
therapy in the study by Hershey et al13 confounded determination of the sole impact of topiramate on migraine. In the study of Campistol et al,14 the relatively low migraine frequency at baseline may not have allowed detection of a significant decrease in migraine frequency. In the study by Cruz et al,15 43% of the patients received topiramate as a second agent. The inclusion of patients experiencing chronic migraine (>15 episodes per month) in studies by Hershey et al13 and Cruz et al15 confound the determination of efficacy because overuse of analgesics and abortive migraine treatments may have led to the these patients appearing to be more resistant to the effects of topiramate. With these limitations in mind, the authors of these studies recommended double-blind, placebo-controlled trials to better define long-term safety and efficacy of topiramate in pediatric migraine.
Randomized Controlled Trials In 2005, Winner et al16 evaluated the efficacy of topiramate for the prophylaxis of migraine in patients (6-15 years old) who experienced an average of 3 to 10 (but 5%) were anorexia, weight loss, abdominal pain, paresthesias, somnolence, and fatigue. Based on these results, the authors concluded that topiramate may be an effective and well-tolerated option for migraine prevention in children. The disproportionate treatment randomization, whereby twice as many patients were assigned to receive topiramate as placebo was postulated to confound the response rate because of high variability in placebo response rates commonly noted in pediatrics. The authors suggest that the lack of significance shown for the primary outcome may be attributable to averaging of the number of monthly migraine days over the entire treatment period, which included the titration period because preventative efficacy may take time to fully manifest. This is supported by the significant decrease in monthly migraine days seen during the last 28 days of the 4-month treatment period. Finally, outcomes were not reported in correlation with specific doses of topiramate, preventing determination of an optimal dose of topiramate that maximizes efficacy and safety (Table 1). Winner et al17 also published a study in 2006 providing a pooled subgroup analysis of adolescents (12-17 years old)
Downloaded from aop.sagepub.com at FRESNO PACIFIC UNIV on January 19, 2015
640
Downloaded from aop.sagepub.com at FRESNO PACIFIC UNIV on January 19, 2015
Design/Duration
OL, MC, 4 months
R, DB, PC, 4 months
R, DB, PC, MC, 4 months
Lakshmi et al (2007)19
Lewis et al (2009)20 P (33), T 50 (35), T 100 (35)
P (22), T 100 (22)
14.4, 14.2, 14.2
10.14, 10.95
57.5, 55.7, 57.8
29, 30
59.5, 67.4, 68.3, 62.7
15, 14, 14, 14
P (12), T 50 (12), T 100 (13), T 200 (14)
49.2
11.1
P (50), T 2.0a (112)
40.9
14
10.4
T 3.5a (24)
65
Weight (kg), Mean
T 50-200 (37)
14.9
Age (years), Mean
T 84 (75)
Daily Dose (mg/d), Mean/(n)
↓ Monthly migraine attack ratec,e; ↓monthly migraine attack rateb,c; responder rate (≥50% ↓in migraine frequency)c,e
Migraine frequency (days/months), PedMIDAS
↓ Number monthly migraine days, intention to treat; ↓ number monthly migraine days, per protocol; ↓ number monthly migraine days,b intention to treat % ↓ median monthly migraine frequencyc; % ↓ median monthly migraine frequencyd
Number of headaches per month
↓ Monthly migraine frequency; % patients experiencing severe migraine; % with shorter migraine duration than at baseline
Headache frequency (per month); headache duration (hours); PedMIDAS score; school absenteeism (days/semester)
Outcomes
P 2.0 (3.1), T 2.6(2.6), P = .061; P 2.2(2.1), T 2.8 (2.4), P = .033; P 2.4 (2.8), T 3.1 (3.0), P = .023 P 16%, T 50 46% (NS), T 100 63% (P ≤ .04), T 200 65%, P ≤ .04; P 13%, T 50: 59%, NS;, T 100 63%, P ≤ .04; T 200 65%, P ≤ .04 P Initial 13.38 (7.48), 4 months 7.48 (5.94); T Initial 16.14 (9.35), 4 months 4.27(1.95), P = .025; P Initial 42.66 ± 27.5, 4 months 23.7 ± 19.1, T initial 50.66 (32.1), 4 months 10.42 (6.39), P = .003 P 42.3% (NS), T 50 34.1% (NS); T 100 70.1%, P < .016; P 49.7% (NS), T 50 52.5% (NS); T 100 75.9%, P < .015); P 45%, T 50 46%, T100 83%, P < .002
Initial: 16.5 (10.0), 3 months: 11.6 (10.2), P < .001; initial: 8.0 (9.0), 3 months: 5.7(9.8), P < .01; initial: 36.0 (42.3), 3 months: 21.0 (34), P < .05; initial: 2.7 (7.4), 3 months: 1.3 (2.8), P < .05 Initial: 3.6 (2.7), 4 months: 2.7 (4.2); initial: 45.8%; 4 months: 4.5%, P = .001; 4 months: 95.4% Initial: 15 (7); 12 months: 3 (3.4), P < .001
Results, Mean (SD)
Abbreviations: OL, open label; T, topiramate; PedMIDAS, Pediatric Migraine Disability Assessment; MC, multicenter; Ret, retrospective; R, randomized; DB, double-blind; PC, placebo controlled; P, placebo; SA, subset analysis; NS, not significant. a In mg/kg/d. b Last month of double-blind versus prospective baseline. c 48-Hour rule. d 24-Hour rule. e Last 12 weeks of double-blind phase versus baseline.
SA of 3 R, DB, PC studies, 4 months
Winner et al (2006)17
Cruz et al Ret, 12 months (2009)15 Randomized controlled trials Winner et al R, DB, PC, MC, (2005)16 5 months
Campistol et al (2005)14
Observational trials Hershey et al OL/3 months (2002)13
Study
Table 1. Studies of Topiramate for Pediatric Migraine.
641
Deaton and Mauro who experienced 3 to 12 (but
research-article2014
AOPXXX10.1177/1060028014521128Annals of PharmacotherapyDeaton and Mauro
Review Article-Drug Information Rounds
Topiramate for Migraine Prophylaxis in Pediatric Patients
Annals of Pharmacotherapy 2014, Vol. 48(5) 638–643 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014521128 aop.sagepub.com
Tamara L. Deaton, PharmD1, and Laurie S. Mauro, PharmD1
Abstract Objective: To evaluate the currently published data pertaining to the efficacy and safety of topiramate for prophylaxis of classic and common migraine in pediatric patients. Data Sources: The literature was identified via PubMed (through April 2013) and Iowa Drug Information System (through April 2013). References from identified articles were also reviewed. Study Selection and Data Extraction: Data were included from studies of efficacy and safety in pediatric patients experiencing migraine (with or without aura), as defined by the International Headache Society. Studies including patients with more specific types of migraine, such as basilar migraine, were excluded. Data Synthesis: Eight publicatons were identified, including 3 randomized controlled trials (RCTs), a subgroup analysis, and 4 observational studies. These studies reported a decrease in headache frequency ranging from 63% to 100% for doses of 100 mg/d and 65% for 200 mg/d. Response to therapy, defined as ≥50% reduction in migraine rate, was also reported in 83% to 95% of patients receiving topiramate. Topiramate is generally well tolerated. Adverse effects were dose related and included paresthesias, weight loss, and cognitive adverse effects. Conclusion: Topiramate is an effective and well-tolerated prophylactic therapy for use in pediatric migraine patients. Doses of 100 and 200 mg/d (1.47-2.0 mg/kg/d) effectively decrease the frequency of migraine headaches, with 100 mg/d providing optimal benefit-to-risk ratio. Additional randomized, double-blind, placebo-controlled studies are needed to determine the impact of the drug on quality-of-life outcomes, such as school function, and migraine severity and duration. Keywords topiramate, pediatric, adolescent, migraine, prophylaxis
Request Question: What is the evidence regarding the use of topiramate for migraine prophylaxis in pediatric patients?
Response Background Migraine headache occurs in 3% to 11% of children and has the potential to be significantly debilitating.1 Migraines can have a negative impact on every aspect of a child’s quality of life, affecting school performance, daily activities, interactions with peers, and family dynamics.2,3 The prevalence of migraine headaches increases throughout childhood into adolescence and may be as high as 28% in older children.2 Understanding of the pathophysiology of migraine headache has evolved in recent years. Migraine is now believed to be caused by a neuronal dysfunction characterized by cortical spreading depression, a progression that is supported by the pharmacological mechanisms of current therapies used to treat migraine.4-6 Neuronal activity associated with these headaches originates in the brainstem and travels
to the peripheral intracranial blood vessels, dura mater, and venous sinuses, where it is perceived as pain.7 Continual stimulation of these areas of the brain can lead to sensitization of neurons and a consequent hyperalgesic state accompanied by the increased nociceptive response to previously nonpainful stimuli, characteristic of migraine.5 Antiepileptic medications such as topiramate are thought to help prevent migraine through the blockade of ion channels and reduction in conductive properties of the neural membranes involved in this signaling. Preventive migraine medications are recommended for use in children who experience more than 3 migraines per month and for those who experience a significant level of impairment because of their headaches.8 The goals of preventive therapy include reduction in the frequency and 1
University of Toledo, Toledo, OH, USA
Corresponding Author: Laurie S. Mauro, College of Pharmacy and Pharmaceutical Sciences, University of Toledo, 3000 Arlington Ave, MS 1013, Toledo, OH 43614, USA. Email: [email protected]
Downloaded from aop.sagepub.com at FRESNO PACIFIC UNIV on January 19, 2015
639
Deaton and Mauro intensity of migrainous attacks, improvement in the patient’s overall quality of life, and reduction in the frequency of need for acute therapies.9 Several medications, including topiramate, currently have FDA approval for the prophylaxis of migraine in adults. Efficacy of preventative therapies can be seen in adults as early as the first month of treatment for topiramate doses of 100 and 200 mg/d10,11; however, it may take 2 to 3 months to realize the full benefits of prophylactic treatment.12 Currently, there are no therapies approved for migraine prophylaxis in the pediatric population. Although topiramate has been used off-label for migraine prophylaxis in children, relatively little data are available to validate its use for migraine prophylaxis in this population. The purpose of this review is to evaluate the efficacy and safety of topiramate for prophylaxis of migraine with and without aura (previously termed classic and common migraine, respectively) in pediatric patients.
Literature Search A search of PubMed and the Iowa Drug Information System databases resulted in 8 publications, including 3 randomized controlled trials (RCTs), a subgroup analysis, and 4 observational studies evaluating the efficacy and safety of topiramate in the prophylaxis of pediatric migraine (Table 1).13-20 Two studies identified were not included—one because of the inclusion of an unspecified number of patients with chronic migraine and an especially high mean monthly migraine frequency and the second because of the focus on basilar migraine.21,22
Observational Trials Three observational trials (Table 1) of topiramate for migraine in pediatrics provided a foundation for later controlled studies. All patients in these trials fulfilled International Headache Society (IHS) criteria (1998 or 2004) for migraine.9 Topiramate was initiated or added to the patients’ concurrent regimen and was titrated for efficacy and tolerability. Average topiramate dosages used in these trials ranged from 1.4 to 1.8 mg/kg/d (absolute range = 0.5-5.5 mg/kg/d).13-15 Significant decreases in migraine frequency, severity, and duration were observed 3 to 12 months later. Adverse effects noted in these trials included cognitive effects (12.5%-13.5%), paresthesias (2.7%8.3%), and weight and appetite loss (5.6%-16.6%).13-15 Overall, these trials provided strong suggestive evidence for topiramate’s efficacy in pediatric migraine along with useful data regarding safety and dosing. Limitations of these studies include their retrospective nature and lack of placebo control. The potential for notable placebo effect is a particular concern in both pediatrics and migraine therapy. Other concurrent prophylactic therapies and biobehavioral
therapy in the study by Hershey et al13 confounded determination of the sole impact of topiramate on migraine. In the study of Campistol et al,14 the relatively low migraine frequency at baseline may not have allowed detection of a significant decrease in migraine frequency. In the study by Cruz et al,15 43% of the patients received topiramate as a second agent. The inclusion of patients experiencing chronic migraine (>15 episodes per month) in studies by Hershey et al13 and Cruz et al15 confound the determination of efficacy because overuse of analgesics and abortive migraine treatments may have led to the these patients appearing to be more resistant to the effects of topiramate. With these limitations in mind, the authors of these studies recommended double-blind, placebo-controlled trials to better define long-term safety and efficacy of topiramate in pediatric migraine.
Randomized Controlled Trials In 2005, Winner et al16 evaluated the efficacy of topiramate for the prophylaxis of migraine in patients (6-15 years old) who experienced an average of 3 to 10 (but 5%) were anorexia, weight loss, abdominal pain, paresthesias, somnolence, and fatigue. Based on these results, the authors concluded that topiramate may be an effective and well-tolerated option for migraine prevention in children. The disproportionate treatment randomization, whereby twice as many patients were assigned to receive topiramate as placebo was postulated to confound the response rate because of high variability in placebo response rates commonly noted in pediatrics. The authors suggest that the lack of significance shown for the primary outcome may be attributable to averaging of the number of monthly migraine days over the entire treatment period, which included the titration period because preventative efficacy may take time to fully manifest. This is supported by the significant decrease in monthly migraine days seen during the last 28 days of the 4-month treatment period. Finally, outcomes were not reported in correlation with specific doses of topiramate, preventing determination of an optimal dose of topiramate that maximizes efficacy and safety (Table 1). Winner et al17 also published a study in 2006 providing a pooled subgroup analysis of adolescents (12-17 years old)
Downloaded from aop.sagepub.com at FRESNO PACIFIC UNIV on January 19, 2015
640
Downloaded from aop.sagepub.com at FRESNO PACIFIC UNIV on January 19, 2015
Design/Duration
OL, MC, 4 months
R, DB, PC, 4 months
R, DB, PC, MC, 4 months
Lakshmi et al (2007)19
Lewis et al (2009)20 P (33), T 50 (35), T 100 (35)
P (22), T 100 (22)
14.4, 14.2, 14.2
10.14, 10.95
57.5, 55.7, 57.8
29, 30
59.5, 67.4, 68.3, 62.7
15, 14, 14, 14
P (12), T 50 (12), T 100 (13), T 200 (14)
49.2
11.1
P (50), T 2.0a (112)
40.9
14
10.4
T 3.5a (24)
65
Weight (kg), Mean
T 50-200 (37)
14.9
Age (years), Mean
T 84 (75)
Daily Dose (mg/d), Mean/(n)
↓ Monthly migraine attack ratec,e; ↓monthly migraine attack rateb,c; responder rate (≥50% ↓in migraine frequency)c,e
Migraine frequency (days/months), PedMIDAS
↓ Number monthly migraine days, intention to treat; ↓ number monthly migraine days, per protocol; ↓ number monthly migraine days,b intention to treat % ↓ median monthly migraine frequencyc; % ↓ median monthly migraine frequencyd
Number of headaches per month
↓ Monthly migraine frequency; % patients experiencing severe migraine; % with shorter migraine duration than at baseline
Headache frequency (per month); headache duration (hours); PedMIDAS score; school absenteeism (days/semester)
Outcomes
P 2.0 (3.1), T 2.6(2.6), P = .061; P 2.2(2.1), T 2.8 (2.4), P = .033; P 2.4 (2.8), T 3.1 (3.0), P = .023 P 16%, T 50 46% (NS), T 100 63% (P ≤ .04), T 200 65%, P ≤ .04; P 13%, T 50: 59%, NS;, T 100 63%, P ≤ .04; T 200 65%, P ≤ .04 P Initial 13.38 (7.48), 4 months 7.48 (5.94); T Initial 16.14 (9.35), 4 months 4.27(1.95), P = .025; P Initial 42.66 ± 27.5, 4 months 23.7 ± 19.1, T initial 50.66 (32.1), 4 months 10.42 (6.39), P = .003 P 42.3% (NS), T 50 34.1% (NS); T 100 70.1%, P < .016; P 49.7% (NS), T 50 52.5% (NS); T 100 75.9%, P < .015); P 45%, T 50 46%, T100 83%, P < .002
Initial: 16.5 (10.0), 3 months: 11.6 (10.2), P < .001; initial: 8.0 (9.0), 3 months: 5.7(9.8), P < .01; initial: 36.0 (42.3), 3 months: 21.0 (34), P < .05; initial: 2.7 (7.4), 3 months: 1.3 (2.8), P < .05 Initial: 3.6 (2.7), 4 months: 2.7 (4.2); initial: 45.8%; 4 months: 4.5%, P = .001; 4 months: 95.4% Initial: 15 (7); 12 months: 3 (3.4), P < .001
Results, Mean (SD)
Abbreviations: OL, open label; T, topiramate; PedMIDAS, Pediatric Migraine Disability Assessment; MC, multicenter; Ret, retrospective; R, randomized; DB, double-blind; PC, placebo controlled; P, placebo; SA, subset analysis; NS, not significant. a In mg/kg/d. b Last month of double-blind versus prospective baseline. c 48-Hour rule. d 24-Hour rule. e Last 12 weeks of double-blind phase versus baseline.
SA of 3 R, DB, PC studies, 4 months
Winner et al (2006)17
Cruz et al Ret, 12 months (2009)15 Randomized controlled trials Winner et al R, DB, PC, MC, (2005)16 5 months
Campistol et al (2005)14
Observational trials Hershey et al OL/3 months (2002)13
Study
Table 1. Studies of Topiramate for Pediatric Migraine.
641
Deaton and Mauro who experienced 3 to 12 (but
