Divalproex extended-release in adolescent migraine prophylaxis: Results of a randomized, double-blind, placebo-controlled study
ABSTRACT To evaluate the efficacy, tolerability, and safety of 3 different doses of divalproex sodium extended-release vs placebo in the prophylaxis of migraine headaches in adolescents.
Divalproex sodium has been approved for migraine prophylaxis in adults, and previous uncontrolled data suggest divalproex sodium may be effective in preventing migraine in children and adolescents with acceptable tolerability.
This was a 12-week, phase 3, randomized, placebo-controlled, double-blind, parallel-group, multicenter study in approximately 300 adolescents aged 12 to 17 years with migraine headaches. At the end of the baseline phase, subjects still meeting study criteria were randomized in a 1:1:1:1 ratio to receive divalproex sodium extended-release 250 mg, 500 mg, or 1000 mg once daily, or placebo. The primary efficacy variable was reduction from baseline in 4-week migraine headache rate for each active treatment group vs placebo. Standard safety assessments were conducted and testosterone and sex hormone-binding globulin levels were collected for postmenarchal females.
There was no statistically significant treatment difference between any divalproex sodium extended-release dose group and placebo for the primary efficacy variable, reduction from baseline in 4-week migraine headache rate. There were no statistically significant differences in adverse events between any active treatment group and placebo. A notable dose-related decrease in platelets was observed, and individuals in all 4 treatment groups had increases in ammonia levels; treatment differences in other laboratory variables were generally small. Among postmenarchal female subjects who were not taking hormonal contraceptives or other steroids, there was no statistically significant change in testosterone levels, but a statistically significant dose-related increase in sex hormone-binding globulin was observed.
In the current study, divalproex sodium extended-release did not differentiate from placebo in the prophylactic treatment of migraine headaches but was generally well-tolerated in adolescents aged 12 to 17 years.
Article: Chapter 9 The Aldan terrain
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ABSTRACT: Nach den Richtlinien der „evidence-based medicine“ wurden die spezifischen kontrollierten Studien für die Behandlung von idiopathischen Kopfschmerzen im Kindes- und Jugendalter analysiert und in Therapieempfehlungen zusammengefasst. Mit der höchsten Evidenz wird für die Behandlung akuter Migräneattacken oder von Kopfschmerzen vom Spannungstyp Ibuprofen (10mg pro kg Körpergewicht) empfohlen. Als Mittel der zweiten Wahl für alle Altersstufen gilt Paracetamol (15mg/kg KG). Ab dem 12. Lebensjahr ist für Migräneattacken auch Sumatriptan Nasenspray (10–20mg) Mittel der zweiten Wahl (im Einzelfall kann es auch bei jüngeren Kindern eingesetzt werden). Bei Versagen der Akutmedikamente der ersten und zweiten Wahl kann auf Substanzen der dritten Wahl wie Zolmitriptan 2,5mg als Schmelztablette, Zolmitriptan 5mg als Nasenspray, Rizatriptan 5–10mg, Almotriptan 12,5 und Dihydroergotamin 20–40µg/kg KG ausgewichen werden. Für die medikamentöse Prophylaxe der Migräne werden Magnesium, Betablocker (Propranolol oder Metoprolol) und Flunarizin empfohlen. Flunarizin ist auch prophylaktisches Mittel der ersten Wahl bei migräneähnlichen Syndromen. Für andere Kopfschmerzarten liegen keine kontrollierten Studien für das Kindesalter vor. In der nichtmedikamentösen Prophylaxe von Kopfschmerzen im Kindesalter werden mit höchster Evidenz Entspannungsverfahren (progressive Muskelrelaxation), Biofeedbackverfahren und kindgerechte kognitiv-verhaltensorientierte Therapieprogramme empfohlen. According to the principles of evidence-based medicine, controlled studies on the treatment of idiopathic headache in childhood and adolescence were analysed and compiled into treatment recommendations. For acute treatment of migraine attacks or tension-type headache, ibuprofen (10mg/kg body weight) is most highly recommended. Drugs of second choice are acetaminophen (15mg/kg body weight) for all ages and for migraine attacks only, intranasal sumatriptan (10–20mg) for the age of 12 years and older, in isolated cases also below 12years of age. If the first or second choice acute drugs are not effective alternative drugs of third choice are zolmitriptan 2.5mg as melting tablet, intranasal zolmitriptan 5mg, rizatriptan 5–10mg, almotriptan 12.5 and dihydroergotamine 20–40µg/kg body weight. For the prophylaxis of migraine, magnesium, betablockers (propranolol and metoprolol) and flunarizine are recommended. Flunarizine is also the drug of first choice for the prophylactic treatment of migraine-related disorders. No controlled studies are available on the treatment of further headache types in childhood. First line methods recommended for the non-drug prophylactic treatment of headache in childhood are progressive relaxation therapy, biofeedback procedures and specific cognitive-behavioral therapeutic schedules.Monatsschrift Kinderheilkunde 01/2008; 157(6):599-610. DOI:10.1007/s00112-009-2002-1 · 0.28 Impact Factor
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ABSTRACT: To evaluate the long-term safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches in adolescents. Divalproex sodium has been approved for migraine prophylaxis in adults. A previous double-blind, placebo-controlled study of the efficacy and safety of divalproex sodium extended-release for prevention of migraine in adolescents was followed by the present long-term extension trial, which was designed to collect additional safety and tolerability data. This was a 12-month, Phase 3, open-label extension of a 3-month, double-blind, placebo-controlled, multicenter study of adolescents aged 12 to 17 years with migraine headaches who had either completed the previous study or had discontinued because of lack of efficacy. Subjects from the previous trial who had experienced serious adverse events possibly or probably related to study drug were excluded. Divalproex sodium extended-release 500 mg daily was administered for 15 days then increased to 1000 mg. Study visits were conducted at days 1 and 15 and months 1, 2, 3, 6, 9, and 12. Safety assessments included adverse event collection, laboratory testing, physical and neurological examinations, vital signs, and electrocardiograms, as well as reproductive endocrine analyses for postmenarchal female subjects. Efficacy was evaluated by sequential 4-week migraine headache rates calculated from subjects' headache diaries. A total of 112 subjects enrolled in the trial. The most common adverse events were weight gain (15%), nausea (14%), somnolence (12%), upper respiratory tract infection (11%), increased ammonia (8%), and sinusitis (8%). Five (4%) subjects experienced serious adverse events, and 15 (13%) subjects prematurely discontinued because of an adverse event. Increased ammonia levels were noted in some individuals, and the mean ammonia level for all subjects increased 19.2 microm from baseline. No other clinically significant changes were observed in laboratory values, vital signs, or electrocardiograms. Improvement in mean and median 4-week migraine headache rates occurred by the fourth month and lasted for the duration of the trial. In this long-term open-label extension study, the safety profile of divalproex sodium extended-release in adolescents with migraine was consistent with that observed in the preceding 3-month, double-blind trial and in previous adult studies. Overall, divalproex sodium extended-release was well-tolerated in adolescents aged 12 to 17 years.Headache The Journal of Head and Face Pain 12/2008; 49(1):36-44. DOI:10.1111/j.1526-4610.2008.01299.x · 3.19 Impact Factor