Divalproex in the long-term treatment of chronic daily headache

OBJECTIVE: The purpose of this study was to assess the safety and efficacy of divalproex sodium in the long-term treatment of chronic daily headache. Correlations between treatment variables were assessed. BACKGROUND: Controlled and open-label trials of divalproex sodium have previously demonstrated its efficacy and safety in the treatment of migraine and chronic daily headaches. These data were primarily short-term and did not examine interaction between treatment variables. METHODS: Retrospective chart review with data extraction was conducted from headache diaries of 642 current patients under treatment with divalproex sodium for chronic daily headaches. One hundred thirty-eight of the patients were treated with only divalproex sodium. Demographic variables including age, sex, initial and final body weights, adverse events, dose of divalproex sodium, duration of treatment, and the ability to differentiate their chronic daily headache into its migraine and tension-type headache components were analyzed. Baseline and end of study headache frequency indices were obtained. RESULTS: The mean improvement was 47%, with an improvement in migraine of about 65%. At least a 50% reduction in headache frequency was reported by 93 of the 138 patients receiving treatment with only divalproex sodium. No correlation between response and age, sex, duration of treatment, and the prescribed dose of divalproex sodium was demonstrated. Adverse events occurred in approximately 35% of the patients. None were severe. Women were more likely to experience adverse effects than men. Weight gain, however, occurred less commonly in women (mean, 1.9 lbs) than in men (mean, 7 lbs). Initial body weight and age did not correlate with the weight change. CONCLUSIONS: Divalproex sodium can be used for a prolonged period as a sole agent for the successful treatment of chronic daily headache. Nearly 75% of the patients had at least a 50% reduction in headache frequency, and adverse effects occurred in approximately one third. Weight gain was negligible and hepatotoxicity did not occur during treatment periods of up to 6 years.     

The efficacy of divalproex sodium in the prophylactic treatment of children with migraine

OBJECTIVE: To determine the beneficial use of divalproex sodium as a prophylactic treatment for migraine in children. BACKGROUND: Previous studies for treatment of migraine in adults have shown a greater than 50% reduction in migraine attack frequencies. Few data exist, however, regarding the efficacy and safety of divalproex sodium use in children with migraine. METHODS: We studied the incidence of headache relief in our patients with migraine aged 16 years and younger treated with divalproex sodium prophylactically at our institution from July 1996 to December 1998 to determine medication dosage used, concomitant headache medications, and possible adverse effects. RESULTS: A total of 42 patients, ranging in age from 7 to 16 years (mean age, 11.3 years), were treated with divalproex sodium for headache. All had a history of migraine with or without aura. Baseline headache frequency during a minimum 6-month period was one to four headaches per month. Divalproex sodium dosage ranged from 15 mg/kg/day to 45 mg/kg/day. Of the 42 patients, 34 (80.9%) successfully discontinued their abortive medications. After 4 months' treatment, 50% headache reduction was seen in 78.5% of patients, 75% reduction in 14.2% of patients, and 9. 5% of patients became headache-free. CONCLUSION: These results indicate divalproex sodium to be an effective and well-tolerated treatment for the prophylaxis of migraine in children.     

Chronic Daily Headache in the Posttrauma Syndrome: Relation to Extent of Head Injury

OBJECTIVE: To evaluate the occurrence of continued intermittent headache and chronic daily headache in patients with head injury and the relationship between severity of the headache problem and intensity of the head injury. BACKGROUND: In the majority of patients with posttraumatic headache, the condition is self-limited, but a minority of patients may develop persistent headaches. The features of posttraumatic headache may vary, but the most distressing type is the chronic daily headache. This study evaluates occurrence of chronic daily headache in relation to the intensity of head injury. METHODS: All patients with head injury who were seen by the senior author (J.R.C.) in the Southern Illinois University Medical School (SIUMS) Neurology Clinic between 1980 and 1991 were identified from the SIUMS headache registry. Data on headache status before and after head injury was obtained, and patients with more than one headache per week before head injury were excluded. Each patient's headache status at the time of the clinic visit was classified as chronic daily headache (headache occurring at least 5 of 7 days for 6 months), intermittent migraine, or no headache. Head injury severity was graded by duration of loss of consciousness or amnesia as minimal (less than 5 minutes), mild (5 to 60 minutes), moderate (1 to 24 hours), or severe (more than 24 hours). RESULTS: There was an inverse relation between extent of head injury and occurrence of chronic daily headache. For minimal head injury (n = 54), 80% had chronic daily headache, and 11% had no headache, while for moderate/severe head injury (n = 23), only 27% had chronic daily headache, and 68% had no headache (P<.001, chi2). CONCLUSION: This study suggests that the risk of developing posttraumatic chronic daily headache is greater for less severe head injury compared with moderate/severe head injury. The reason for this relation is unclear.     

Management of chronic daily headache utilizing a uniform treatment pathway

OBJECTIVE: To determine if the use of a uniform treatment pathway might be effective in treating patients with primary chronic daily headache. METHODS: Thirty-three consecutive patients with primary chronic daily headache were managed according to a treatment pathway which involved sequential administration of divalproex sodium, amitriptyline, amitriptyline plus phenelzine, or methadone. RESULTS: Twenty-two patients (67%) reported a 50% or greater reduction in headache days per month following initiation of treatment. Most positive treatment responses (17 [77%] of 22) were attributed to divalproex sodium. CONCLUSION: Implementation of a uniform treatment pathway may result in significant clinical improvement in a sizable proportion of patients with chronic daily headache.     

Roller coaster migraine: an underreported injury?

A 28-year-old woman presented with severe headache, sleep problems, memory problems, and irritability 2 months after a violent roller coaster ride. She was diagnosed with posttraumatic migraine, and intravenous dihydroergotamine resolved her symptoms. Imaging studies, electroencephalogram, and visual and auditory evoked responses were normal. Imipramine, divalproex sodium, and propranolol were prescribed to prevent the headaches from recurring and dihydroergotamine nasal spray was prescribed for breakthrough headaches. We consider the many short but significant brain insults delivered during the roller coaster ride a critical factor in triggering this instance of posttraumatic migraine, which while unmanaged was a source of significant disability for the patient.     

Headaches After Concussion in US Soldiers Returning From Iraq or Afghanistan

(Headache 2010;50:1262‐1272) Objectives.— To determine the prevalence, characteristics, impact, and treatment patterns of headaches after concussion in US Army soldiers returning from a deployment to Iraq or Afghanistan. Methods.— A cross‐sectional study was conducted with a cohort of soldiers undergoing postdeployment evaluation during a 5‐month period at the Madigan Traumatic Brain Injury Program at Ft. Lewis, WA. All soldiers screening positive for a deployment‐related concussion were given a 13‐item headache questionnaire. Results.— A total of 1033 (19.6%) of 5270 returning soldiers met criteria for a deployment‐related concussion. Among those with a concussion, 957 (97.8%) reported having headaches during the final 3 months of deployment. Posttraumatic headaches, defined as headaches beginning within 1 week after a concussion, were present in 361 (37%) soldiers. In total, 58% of posttraumatic headaches were classified as migraine. Posttraumatic headaches had a higher attack frequency than nontraumatic headaches, averaging 10 days per month. Chronic daily headache was present in 27% of soldiers with posttraumatic headache compared with 14% of soldiers with nontraumatic headache. Posttraumatic headaches interfered with duty performance in 37% of cases and caused more sick call visits compared with nontraumatic headache. In total, 78% of soldiers with posttraumatic headache used abortive medications, predominantly over‐the‐counter analgesics, and most perceived medication as effective. Conclusions.— More than 1 in 3 returning military troops who have sustained a deployment‐related concussion have headaches that meet criteria for posttraumatic headache. Migraine is the predominant headache phenotype precipitated by a concussion during military deployment. Compared with headaches not directly attributable to head trauma, posttraumatic headaches are associated with a higher frequency of headache attacks and an increased prevalence of chronic daily headache.     

Intravenous valproate sodium in the treatment of daily headache

BACKGROUND: Treatment of chronic daily headache/transformed migraine is challenging, especially when it is complicated by overuse of analgesics, triptans, or both. One common approach involves the use of repetitive intravenous dihydroergotamine. We investigated the use of intravenous valproate sodium in the treatment of chronic daily headache/transformed migraine in patients who had contraindications to the use of or had failed treatment with dihydroergotamine. METHODS: We administered intravenous valproate sodium (Depacon) to patients with chronic daily headache/transformed migraine (loading dose 15 mg/kg, followed by 5 mg/kg every 8 hours). All analgesics and triptans were discontinued prior to treatment with divalproex sodium, and preventative medications for migraine were begun or continued. All patients received instruction in behavioral modification and the proper use of analgesics and triptans. RESULTS: Improvement in headache was reported by 80% of the patients treated, and valproate sodium was tolerated well by most. CONCLUSION: Intravenous valproate sodium may be of assistance in the initial management of patients with chronic daily headache/transformed migraine and analgesic/triptan overuse, especially when dihydroergotamine is ineffective or contraindicated.     

Posttraumatic Headache: Permanency and Relationship to Legal Settlement

In our increasingly litigious society there is persistence of an attitude that posttraumatic headache (or other injuries) will either improve or disappear following resolution of a claim. In some states (Florida) in order for a person to initiate a claim, an injury must be considered permanent. This is often a difficult task with a subjective symptom. This retrospective study was performed to evaluate the reliability of criteria used to diagnose a "permanent" posttraumatic headache and whether these headaches stay "permanent" after legal settlement. Data was obtained by a structured telephone interview of fifty adult outpatients diagnosed as having permanent posttraumatic headache and their litigation settled at least one year previously. Patients with previous headaches, other accidents or head injuries were excluded. The average length of time from settlement to interview was 23 months. Forty-six had been in automobile accidents and four either had falls or blunt trauma to the head. (Eight cases involved Workman's Compensation). Criteria used at this clinic for determining permanency were either posttraumatic headache persisting for longer than one year with no evidence of further improvement (43 patients) or patients with headaches persisting longer than 6 months with a plateau (no change) in their pattern for three months or more with an adequate trial of treatment (in our judgement). These criteria did seem reliable. All fifty patients interviewed continued to report persistent headache symptoms one year or more following legal settlement. Improvement in headache pattern after legal settlement was only reported by four patients.     

Safety of divalproex sodium in migraine prophylaxis: an open-label, long-term study. Long-term Safety of Depakote in Headache Prophylaxis Study Group

CONTEXT: The adverse event profile of long-term divalproex therapy for epilepsy is well established, but little is known about the tolerability or safety of divalproex in long-term migraine prophylaxis. OBJECTIVE: Evaluate the long-term safety and efficacy of divalproex sodium in migraine prophylaxis. DESIGN: Open-label, long-term study, of up to 3 years, of patients who completed one of two multicenter, double-blind, randomized, placebo-controlled studies. SETTING: Eighteen headache/neurology centers throughout the United States. PATIENTS: One hundred sixty-three patients: 46 treated with placebo, 117 treated with divalproex for migraine in previous studies. INTERVENTION: Divalproex therapy initiated at 500 mg/day (250 mg twice daily), with adjustment in dose and dosing frequency possible after 1 to 3 days. MAIN OUTCOME MEASURES: Number and proportion of patients reporting treatment-emergent adverse events, prevalence and incidence for each treatment-emergent adverse event, vital signs, body weight, 4-week migraine rates and proportion of patients with 50% or greater reduction in rate over time. RESULTS: Treatment lasted more than 180 days for 71% of patients and more than 360 days for 48% of patients. Improvements in the 4-week, change-from-baseline migraine rates were seen during each of the 3- and 6-month time intervals. CONCLUSIONS: Divalproex is effective for migraine prophylaxis, and initial benefits are maintained for periods in excess of 1080 days.     

Chronic daily headache: a time perspective

OBJECTIVE: To determine the development and outcome of chronic daily headache in 258 headache practice patients, consisting of 50 men and 208 women. Chronic daily headache was defined as headaches occurring on at least 5 days per week for at least 1 year. METHODS: Two hundred fifty-eight patients with headache were interviewed and evaluated. Ninety-one patients were contacted by telephone for follow-up. RESULTS: Twenty-two percent of the patients had daily headaches from the onset, and 78% initially experienced intermittent headaches. Of the patients with initially intermittent headaches, 19% experienced an abrupt transition into daily headaches and 81%, a gradual one. In the patients with gradual transition, the transition of the initial, intermittent headaches into daily headaches took an average of 10.7 years. The initial headaches were mild in 33% of the patients and severe in 67%. The severe headaches were associated with nausea and vomiting significantly more often than the mild ones. However, the daily headaches that these patients ultimately developed were the same, regardless of whether the initial headaches were mild or severe. The patients who gradually developed daily headaches from initially intermittent headaches were contacted to determine the outcome of their headaches. Of these patients, 33% continued to have daily headaches and 67% again experienced intermittent headaches. Of the latter group, 88% of the patients who now had migraine also had migraine initially.     

Divalproex extended-release in adolescent migraine prophylaxis: results of a randomized, double-blind, placebo-controlled study

Objective.— 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. Background.— 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. Methods.— 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. Results.— 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. Conclusions.— 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.     

Intravenous lignocaine (lidocaine) infusion for the treatment of chronic daily headache with substantial medication overuse

Patients with chronic daily headache with medication overuse are difficult to treat, especially when the doses of analgesia are substantial. We have previously shown that intravenous lignocaine (lidocaine) infusion is useful in maintaining pain control while the offending analgesic agent is withdrawn in these patients. The published data on long-term efficacy of this treatment is limited. We undertook a retrospective survey of 71 consecutive patients admitted for lignocaine infusion (mean 8.7 days) for treatment of chronic daily headache, with substantial analgesic abuse. Ninety percent of patients had a history of migraine headaches. In 80% of patients codeine was the predominant agent implicated in the analgesic rebound headaches (mean 1053 mg/week) and 24% used ergotamine-containing medications (mean 16 mg/week). Thirty-one percent frequently used injected narcotics. At completion 90% reported that their daily headache was absent or improved, and the analgesic agent was withdrawn successfully in 97%. At six month follow-up, 70% of patients reported that their daily headache was absent or improved and 72% of patients remained free of the offending analgesic agent. Intravenous lignocaine is a useful treatment in the management of chronic daily headache with substantial medication overuse. The benefits of the program last for at least six months.     

Chronic daily headache in U.S. soldiers after concussion

(Headache 2012;52:732‐738) Objective.— To determine the prevalence and characteristics of, and factors associated with, chronic daily headache (CDH) in U.S. soldiers after a deployment‐related concussion. Methods.— A cross‐sectional, questionnaire‐based study was conducted with a cohort of 978 U.S. soldiers who screened positive for a deployment‐related concussion upon returning from Iraq or Afghanistan. All soldiers underwent a clinical evaluation at the Madigan Traumatic Brain Injury Program that included a history, physical examination, 13‐item self‐administered headache questionnaire, and a battery of cognitive and psychological assessments. Soldiers with CDH, defined as headaches occurring on 15 or more days per month for the previous 3 months, were compared to soldiers with episodic headaches occurring less than 15 days per month. Results.— One hundred ninety‐six of 978 soldiers (20%) with a history of deployment‐related concussion met criteria for CDH and 761 (78%) had episodic headache. Soldiers with CDH had a median of 27 headache days per month, and 46/196 (23%) reported headaches occurring every day. One hundred seven out of 196 (55%) soldiers with CDH had onset of headaches within 1 week of head trauma and thereby met the time criterion for posttraumatic headache (PTHA) compared to 253/761 (33%) soldiers with episodic headache. Ninety‐seven out of 196 (49%) soldiers with CDH used abortive medications to treat headache on 15 or more days per month for the previous 3 months. One hundred thirty out of 196 (66%) soldiers with CDH had headaches meeting criteria for migraine compared to 49% of soldiers with episodic headache. The number of concussions, blast exposures, and concussions with loss of consciousness was not significantly different between soldiers with and without CDH. Cognitive performance was also similar for soldiers with and without CDH. Soldiers with CDH had significantly higher average scores on the posttraumatic stress disorder (PTSD) checklist compared to soldiers with episodic headaches. Forty‐one percent of soldiers with CDH screened positive for PTSD compared to only 18% of soldiers with episodic headache. Conclusions.— The prevalence of CDH in returning U.S. soldiers after a deployment‐related concussion is 20%, or 4‐ to 5‐fold higher than that seen in the general U.S. population. CDH following a concussion usually resembles chronic migraine and is associated with onset of headaches within the first week after concussion. The mechanism and number of concussions are not specifically associated with CDH as compared to episodic headache. In contrast, PTSD symptoms are strongly associated with CDH, suggesting that traumatic stress may be an important mediator of headache chronification. These findings justify future studies examining strategies to prevent and treat CDH in military service members following a concussive injury.     

Development of chronic daily headache: a clinical study

We studied the development of chronic daily headache in 258 headache practice patients, 50 men and 208 women. Chronic daily headache was defined as headaches occurring at least 5 days per week for at least 1 year. Twenty-two percent of the patients had daily headaches from the onset, and 78% initially experienced intermittent headaches. Of the patients with initially intermittent headaches, 19% experienced an abrupt transition into daily headaches and 81% a gradual one. The distribution of the age of daily headache onset was the same in the patients with daily headaches from the onset and in those with initially intermittent headaches but with abrupt transition into daily headaches. The distribution of the circumstances of daily headache onset was also the same in the groups. The most common circumstance of abrupt onset of daily headaches was head, neck, or back injury, in 61% caused by a motor vehicle accident. In the patients with initially intermittent headaches but with gradual transition into daily headaches, the transition took an average of 10.7 years.     

Presentation of Chronic Daily Headache: A Clinical Study

We studied the presentation of chronic daily headache in 258 patients from a private headache practice, 50 men and 208 women. Chronic daily headache was defined as headaches, occurring at least 5 days per week for at least 1 year.
Seventy-seven percent of the patients experienced the onset of headache before the age of 30. The daily headaches were present on awakening in the morning or came about in the course of the morning in 79% of the patients. In 53%, they were worst in the afternoon or evening. The headaches awoke the patients at night at least once per week in 36%. At least twice per week, they were associated with nausea in 35% of the patients and with vomiting in 9%. Common aggravating factors included light, physical activity, bending over, noise, stress or tension, and menstruation. Ninety-four percent of the patients experienced severe headaches in addition to the daily headaches. In 63%, the severe headaches occurred 10 days per month or less. The daily caffeine intake of the patients averaged 170 mg, and the daily analgesic intake, 1860 mg of aspirin equivalents.     

Valproate in the Treatment of Persistent Chronic Daily Headache. An Open Label Study

Thirty patients with persistent chronic daily headache, unresponsive to various combinations of pharmacological and nonpharmacological treatment were selected for an open label study using divalproex sodium. All patients had normal liver function tests. After a baseline observation period of 1 month, patients were given divalproex sodium 1000 to 2000 mg per day, for a period of 3 months. Blood valproic acid levels were kept between 75 and 100 mcg/ml. Liver function studies and blood ammonia levels were obtained periodically. Based on weekly headache index, headache-free days, dysfunctional days and patients' general well-being rating and physicians' global assessment, two thirds of the patients improved significantly. The common side effects included weight gain, tremor, hair loss and nausea. Liver functions were unaffected by treatment. The possible mechanism of action of valproate in headache is discussed. Valproate appears to be a worthwhile addition to the prophylactic treatment of chronic recurrent headache.     

Posttraumatic Headache: Determining Chronicity

SYNOPSIS
In the headache literature, there exists a great deal of discrepancy regarding when posttraumatic headache (PTH) may be classified as chronic. Although chronic pain is usually described as pain persisting for longer than six months, many view chronic posttraumatic headache as persisting for more than two months, including the International Headache Society criteria. Observations made by Brenner and Friedman in 1944 have been repeatedly cited for this determination. Surprisingly, a review of this original source revealed that the term "chronic" was never used when discussing posttraumatic headache over two months duration. The authors, in fact, suggested two months as an "arbitrary" dividing line. Recent studies suggest that many patients with PTH continue to improve or change over the first six months but start to plateau after that time. We feel six months serves as a better time indicator for defining chronicity in cases of posttraumatic headache. This would be more consistent with the current literature concerning chronic pain and the International Headache Society criteria for chronic tension headache.     

Chronic tension-type headache in children and adolescents

In this study, the causes, predisposing factors and clinical features of chronic daily headache in children and adolescents were studied within the population of patients attending a specialist headache. The International Headache Society's (IHS) criteria for the diagnosis of chronic tension type headache (CTTH) were assessed for their applicability in the paediatric age group. Over a period of three years, demographic and clinical data were collected prospectively on all children who attended the clinic and suffered from daily attacks of headache. One hundred and fifteen children and adolescents (32% of all clinic population) had chronic daily headache, of whom 93 patients (81%) fulfilled the IHS criteria for the diagnosis of CTTH. They were between 3-15 years of age (mean: 11.1, SD: 2.3) and their female to male ratio was 1.2 : 1. Around one third of the patients also suffered from migraine (mainly migraine without aura). The headache was described as mild in 60.9%, moderate 36.5% and severe 2.6%. Headache was located at the forehead in 53% or over the whole of the head in 29.6%. Pain was described as 'just sore' or dull by 73.9%. During attacks of headache, at least half the patients reported light intolerance, noise intolerance, anorexia or nausea. Thirty-two percent of patients had at least one underlying chronic disease that may have contributed to the pathogenesis of the CTTH. Eleven percent had serious stressful events related to family illnesses and in four patients headaches were triggered by family bereavement. Fourteen percent were investigated with neuroimaging and 22% were referred for clinical psychology assessment and management. In conclusion, CTTH is a common cause of headache in children attending a specialist headache clinic. The clinical features closely match those of adult population and the IHS criteria for the diagnosis of CTTH can be adapted for use in children. Predisposing stressful risk factors, physical or emotional, are present in a large proportion.     

Safety and Tolerability of Divalproex Sodium Extended-Release in the Prophylaxis of Migraine Headaches: Results of an Open-Label Extension Trial in Adolescents

Objective.— To evaluate the long‐term safety and tolerability of divalproex sodium extended‐release in the prophylaxis of migraine headaches in adolescents. Background.— 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. Methods.— 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. Results.— 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 µm 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. Conclusions.— 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.     

An Open-Label Pilot Study of Divalproex Sodium for Posttraumatic Stress Disorder Related to Childhood Abuse

Background: Few effective pharmacotherapeutic strategies have been established for the treatment of symptoms associated with posttraumatic stress disorder (PTSD). Preliminary evidence supports the efficacy of serotonergic agents and anticonvulsants, such as divalproex sodium, for the treatment of PTSD symptoms, particularly in military populations.Objective: The aim of this study was to obtain pilot data on the use of divalproex sodium for the treatment of PTSD among adult civilian outpatients with a history of childhood physical and/or sexual abuse.Methods: Outpatients with a primary psychiatric diagnosis of PTSD received open-label, flexibly dosed divalproex sodium as adjuvant therapy or monotherapy for 8 weeks. Overall and subcluster PTSD features, as well as affective symptoms and clinical global improvement, were monitored using standardized assessment scales.Results: A total of 7 patients (5 women, 2 men; mean age, 44.1 years [range, 29-57 years]) were enrolled. At a mean (SD) peak dosage of 1500 (661) mg/d, significant improvement occurred in overall PTSD symptom severity (P<0.02) and in the diagnostic subclusters of hyperarousal and avoidance (P<0.02 for both). Depressive symptoms also were significantly improved from baseline (P<0.02). Divalproex sodium was well tolerated, except in 1 patient who prematurely discontinued treatment due to cognitive adverse events.Conclusions: These provisional findings support the possible utility of divalproex sodium therapy for adult outpatients with PTSD related to physical and/or sexual abuse during childhood. Controlled trials with larger sample sizes powered to show safety and efficacy are needed to substantiate these initial findings.