Divalproex Extended-Release in Adolescent Migraine Prophylaxis: Results of a Randomized, Double-Blind, Placebo-Controlled Study

Abbott, Abbott Park, IL, USA.
Headache The Journal of Head and Face Pain (Impact Factor: 2.71). 08/2008; 48(7):1012-25. DOI: 10.1111/j.1526-4610.2008.01081.x
Source: PubMed


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.

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    • "However, Apostol et al investigated the efficacy, tolerability, and safety of different doses of divalproex sodium extended-release vs placebo in the prophylaxis of migraine headaches in a 12-week, randomized, placebo-controlled, double-blind, parallel-group study in approximately 300 adolescents.58 They found that, although well tolerated, it did not differ from placebo in the prophylactic treatment of migraine headaches. "
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    ABSTRACT: Migraine is a serious illness that needs correct treatment for acute attacks and, in addition, a treatment prophylaxis, since patients with migraine suffer during acute attacks and also between attacks. A systematic review of the most relevant clinical trials of migraine headache and its epidemiology, pathophysiology, comorbidity, and prophylactic treatment (medical and nonmedical) was carried out using "Medline" and "PsychINFO" from 1973 to 2009. Approximately 110 trials met our inclusion criteria and were included in the current review. The most effective pharmacological treatment for migraine prophylaxis is propranolol and anticonvulsants such as topiramate, valproic acid, and amitriptyline. Nonmedical treatments such as acupuncture, biofeedback, and melatonin have also been proposed. Peripheral neurostimulation has been suggested for the treatment of chronic daily headache that does not respond to prophylaxis and for the treatment of drug-resistant primary headache. The majority of the pharmacological agents available today have limited efficacy and may cause adverse effects incompatible with long-term use. The review was limited by the highly variable and often insufficient reporting of the complex outcome data and by the fact that migraine prophylaxis trials typically use headache diaries to monitor the course of the disease. The results of the different studies were also presented in different ways, making comparison of the results difficult. An adequate prophylaxis is crucial in reducing disability and preventing the evolution of the problem into a chronic progressive illness. The implications of the present findings were discussed.
    Patient Related Outcome Measures 07/2010; 1:107-18. DOI:10.2147/PROM.S9742
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    • "Response (i.e., >50% reduction in migraine frequency) was 46% in the placebo group as compared with 41, 36 and 51% in the DVPX ER 250 mg, 500 or 1,000 mg groups, respectively. DVPX ER was not superior to placebo in the migraine-related quality of life measures either, as assessed by the PedMIDAS [41]. "
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    ABSTRACT: There is a serious lack of controlled studies on the pharmacological treatment of primary migraine in the developmental age; there is, consequently, an urgent need for new, evidence-based approaches to this long-neglected field of research. Moreover, previous studies have stated that the placebo response is greater in pediatric patients than in adults and that a reduction in the attack frequency in the absence of any pharmacological treatment is observed more frequently in pediatric migraine patients than in adults. Besides these preliminary considerations, the shorter duration of migraine attacks and other characteristic semeiological features of the clinical picture in children are such that the design of randomized controlled trial (RCT) is more problematic in the developmental age than in the adult. Bearing in mind all these weak points, the aim of this review was to summarize and update recent guidelines for the treatment of primary migraine in children and adolescents. The most recent guidelines are those published by the Italian Society for the study of Headache, the French Society for the study of Migraine and Headache, and the American Academy of Neurology. We have incorporated into these guidelines the results from the few, recent RCTs, clinical controlled trials, open-label studies, meta-analyses and reviews that have been published since 2004; owing to the lack of strong evidence in this field of research, we have sometimes even mentioned pilot non-controlled studies, case series and expert opinions. Lastly, evidence was classified and the recommendations were categorized according to different levels.
    The Journal of Headache and Pain 03/2010; 11(3):267-76. DOI:10.1007/s10194-010-0205-4 · 2.80 Impact Factor

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