A Randomized Trial of Propranolol versus Sodium Valproate for the Prophylaxis of Migraine in Pediatric Patients

Guilan University of Medical Sciences, No. 15-135 Ave., Golsar, Rasht, Iran.
Paediatric Drugs (Impact Factor: 1.98). 08/2010; 12(4):269-75. DOI: 10.2165/11316270-000000000-00000
Source: PubMed


Migraine is the most common of the paroxysmal disorders to affect the brain in the pediatric population. Both propranolol and sodium valproate (valproic acid) have been advocated as prophylactic agents for childhood migraine.
To compare the efficacy and tolerability of propranolol and sodium valproate in the prevention of migraine in the pediatric population.
Sixty-three children (aged 5-15 years) with migraine without aura, as defined by the 2004 International Headache Society (IHS) criteria, were included in this prospective, double-blind clinical trial and were randomly assigned to two groups. Group A (n = 32 patients) received propranolol 3 mg/kg/day and group B (n = 31 patients) received sodium valproate 30 mg/kg/day, with at least 6 months of follow up. The propranolol dosage was adjusted to 2 mg/kg/day and the sodium valproate dosage to 15 mg/kg/day, after the first follow-up visit. Participants were evaluated by using a detailed questionnaire that asked about the features of headaches and general health characteristics. The study endpoints were successful treatment for a 4- to 6-month period; 3 months of a persistent unsuccessful or incomplete response to treatment; intolerable side effects; and/or patient non-adherence. All data were analyzed longitudinally by comparing baseline data with data from each follow-up.
A total of 60 patients completed the full headache prophylaxis period. The baseline headache frequency was reduced by more than 50% in 83% of propranolol recipients and in 63% of sodium valproate recipients (statistically not significant); the overall reduction of baseline headache frequency per month was better in group A (p = 0.044). The mean headache frequency per month was reduced from 13.86 +/- 2.11 to 4.23 +/- 3.24 in group A, and from 13.23 +/- 2.43 to 5.83 +/- 4.04 in group B; the difference between the two groups was statistically significant (p < 0.01). The mean headache duration per week was decreased from 9.9 +/- 7.4 hours to 3.2 +/- 5.9 hours in group A, and from 9.1 +/- 6.9 hours to 3.7 +/- 5.0 hours in group B; although there was no statistically significant difference between propranolol and sodium valproate, headache duration was markedly improved with each drug (p < 0.002). Reduction of headache severity by at least one grade was seen in 64% of patients in group A and in 56% in group B, and complete cessation of headache attacks occurred in 14% of patients in group A and 10% in group B (not significant). Minor side effects appeared to be fairly well tolerated by patients in both groups, with no significant difference in side effects between the two groups.
This prospective study supports the efficacy of propranolol and sodium valproate as prophylaxis for pediatric migraine without aura, based on IHS criteria. There were no significant differences between these two drugs in all evaluated parameters except for the mean headache frequency per month, which was lower with propranolol than with sodium valproate.

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    • "Frequent disruption of the 24h sleep/wake cycle as a consequence of ALAN exposure, often with shortened sleep duration, melatonin suppression, and CTS desynchronization, is quite common in evening chronotype children, adolescents, and young adults (Adan et al., 2012;Wittmann et al., 2006), but also in neither evening nor morning chronotypes when staying up late to study, complete school/ college assignments, and partake in late-night, typically weekend, social events (Collado Mateo et al., 2012;Touitou, 2013). Additionally, short-term, and presumably long-term, late day or evening treatment of infants and children with b 1 -adrenoreceptor antagonist medications, e.g., to manage hemangioma (Ng et al., 2015) and migraine (Bidabadi &amp; Mashouf, 2010), and of adults with b 1 -adrenoreceptor (e.g., atenolol, bisoprolol, metoprol , and propranolol) and a 1 -adrenoreceptor (e.g., alfuzosin, doxazosin, and terazosin) antagonists, e.g., to manage benign prostatic hyperplasia, cardiac arrhythmias , glaucoma, hypertension, ischemic heart disease, and situational anxiety (Akbar &amp; Alorainy, 2014;Chon et al., 1999;DiNicolantonio et al., 2015;Zhang et al., 2015), mimics the melatonin suppression of ALAN exposure (for review, seeHaus &amp; Smolensky, 2013;Smolensky et al., 2012), with possible risk of CTS disruption. Melatonin is considered to be a valuable treatment for dyssomnias of youngsters, especially those diagnosed with delayed sleep phase syndrome, attention-deficit hyperactivity disorder, autism spectrum disorders , mood and anxiety syndromes, and certain neurologic conditions (Appleton et al., 2012;Bruni et al., 2015;Sánchez-Barceló et al., 2011). "
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    ABSTRACT: Routine exposure to artificial light at night (ALAN) in work, home, and community settings is linked with increased risk of breast and prostate cancer (BC, PC) in normally sighted women and men, the hypothesized biological rhythm mechanisms being frequent nocturnal melatonin synthesis suppression, circadian time structure (CTS) desynchronization, and sleep/wake cycle disruption with sleep deprivation. ALAN-induced perturbation of the CTS melatonin synchronizer signal is communicated maternally at the very onset of life and after birth via breast or artificial formula feedings. Nighttime use of personal computers, mobile phones, electronic tablets, televisions, and the like - now epidemic in adolescents and adults and highly prevalent in pre-school and school-aged children - is a new source of ALAN. However, ALAN exposure occurs concomitantly with almost complete absence of daytime sunlight, whose blue-violet (446-484 nm ) spectrum synchronizes the CTS and whose UV-B (290-315 nm ) spectrum stimulates vitamin D synthesis. Under natural conditions and clear skies, day/night and annual cycles of UV-B irradiation drive corresponding periodicities in vitamin D synthesis and numerous bioprocesses regulated by active metabolites augment and strengthen the biological time structure. Vitamin D insufficiency and deficiency are widespread in children and adults in developed and developing countries as a consequence of inadequate sunlight exposure. Past epidemiologic studies have focused either on exposure to too little daytime UV-B or too much ALAN, respectively, on vitamin D deficiency/insufficiency or melatonin suppression in relation to risk of cancer and other, e.g., psychiatric, hypertensive, cardiac, and vascular, so-called, diseases of civilization. The observed elevated incidence of medical conditions the two are alleged to influence through many complementary bioprocesses of cells, tissues, and organs led us to examine effects of the totality of the artificial light environment in which humans reside today. Never have chronobiologic or epidemiologic investigations comprehensively researched the potentially deleterious consequences of the combination of suppressed vitamin D plus melatonin synthesis due to life in todays man-made artificial light environment, which in our opinion is long overdue.
    Preview · Article · Sep 2015 · Chronobiology International
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    • "Valproate—a highly potent anticonvulsant, successfully used for prophylactics (Bidabadi and Mashouf, 2010; Corbo, 2003; D&apos;Amico, 2010; Freitag, 2003; Lovell and Marmura, 2010; Mathew, 2001) and abortive migraine treatments (Edwards et al., 2001; Leniger et al., 2005; Mathew et al., 2000; Shahien et al., 2011; Stillman et al., 2004)—also exhibits similar properties. Experiments on rats demonstrated that microiontophoretically applied valproate inhibited the VPM neuronal responses to both superior sagittal sinus electrical stimulation and intrathalamic ejection of L-glutamate (Andreou et al., 2010). "
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    ABSTRACT: Valproate is widely used for migraine treatments, although precise mechanisms of its anticephalgic action are poorly understood. Migraine attacks are thought to occur due to trigemino-vascular system activation, which in turn, stimulates nociceptive transmission in trigemino-thalamo-cortical pathway. The ventroposteromedial (VPM) nucleus of the thalamus is considered to play a prominent role in neurobiology of headaches by serving as the highest subcortical relay for conveying nociceptive information from intra- and extracranial structures to the cortex. While it has been demonstrated that valproate can modulate trigemino-vascular nociceptive neurotransmission in the VPM, its effects have been investigated using only intrathalamic ejection of the compound in pentobarbitone sodium anesthetized rats. The objective of our study was to evaluate the effects of intravenously administered valproate on both ongoing firing of the VPM neurons and their activity induced by electrical stimulation of the dura mater. The experiments were performed on rats under nonbarbiturate anesthesia. To define the dose-dependent properties and longevity of the studied effects of valproate, two distinguished dosing regiments were used: bolus (single infusion at a dose of 300mg/kg) and cumulative (thrice-repeated administration of 100mg/kg performed 30min apart). Intravenous administration of valproate produced the dose-dependent suppression of both the ongoing activity of the thalamic VPM neurons and their responses to electrical stimulation of the dura mater. This effect was fast-developing (within 5min) and short-lasting (no longer than 30min). These data suggest that intravenous administration of valproate could produce a reduction of the thalamo-cortical nociceptive transmission associated with trigemino-vascular activation.
    Full-text · Article · May 2013 · European journal of pharmacology
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    ABSTRACT: For the last thirty years ocean bottom seismometers (OBSs) have been used to survey the oceans. However, the quality of the data they produce is often degraded due to poor coupling or high levels of ambient noise. In contrast, sensors placed beneath the seafloor avoid many of these problems. For the last two decades burials have relied on Ocean Drilling Program (ODP) boreholes. This approach is expensive and demands numerous human resources. In addition, the locations of these boreholes, determined by the ODP, are rarely desirable for monitoring seismic activity. In this paper a sub-bottom seismic acquisition system is presented that uses free-fall devices, or deep ocean seismic penetrators (DOSP), to place sensors several tens of metres beneath the seafloor. The DOSPs weigh approximately 1800 kg, achieve terminal velocities between 30-50 m/s and penetrate to depths of 20-30 metres in soft sea sediments. Once buried, they record seismic activity and transmit data back to the surface using a frequency shift keyed (FSK) modulation technique. The results of an experiment conducted in the Mediterranean using this system are presented. These confirm the predicted dynamic and kinematic behaviour of the DOSP and allow an assessment of the ambient seismic noise level at a depth of &ap;30 metres beneath the seafloor. In conclusion this paper discusses the potential use of free-fall devices to increase our understanding of processes in the deep oceans, with particular emphasis on their applicability to future deep ocean seismology
    No preview · Conference Paper · Nov 1997
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