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Objective: Evaluate the efficacy and tolerability of prazosin for prophylaxis of headaches following mild traumatic brain injury in active‐duty service members and military veterans. Background: Prazosin is an alpha‐1 adrenoreceptor antagonist that reduces noradrenergic signaling. An open‐label trial in which prazosin reduced headache frequency in veterans following mild traumatic brain injury provided the rationale for this pilot study. Methods: A 22‐week parallel‐group randomized controlled trial which included 48 military veterans and active‐duty service members with mild traumatic brain injury–related headaches was performed. The study design was based on International Headache Society consensus guidelines for randomized controlled trials for chronic migraine. Following a pre‐treatment baseline phase, participants with at least eight qualifying headache days per 4 weeks were randomized 2:1 to prazosin or placebo. After a 5‐week titration to a maximum possible dose of 5 mg (morning) and 20 mg (evening), participants were maintained on the achieved dose for 12 weeks. Outcome measures were evaluated in 4‐week blocks during the maintenance dose phase. The primary outcome measure was change in 4‐week frequency of qualifying headache days. Secondary outcome measures were percent participants achieving at least 50% reduction in qualifying headache days and change in Headache Impact Test‐6 scores. Results: Intent‐to‐treat analysis of randomized study participants (prazosin N = 32; placebo N = 16) demonstrated greater benefit over time in the prazosin group for all three outcome measures. In prazosin versus placebo participants, reductions from baseline to the final rating period for 4‐week headache frequency were −11.9 ± 1.0 (mean ± standard error) versus −6.7 ± 1.5, a prazosin minus placebo difference of −5.2 (−8.8, −1.6 [95% confidence interval]), p = 0.005 and for Headache Impact Test‐6 scores were −6.0 ± 1.3 versus +0.6 ± 1.8, a difference of −6.6 (−11.0, −2.2), p = 0.004. The mean predicted percent of participants at 12 weeks with ≥50% reduction in headache days/4 weeks, baseline to final rating, was 70 ± 8% for prazosin (21/30) versus 29 ± 12% for placebo (4/14), odds ratio 5.8 (1.44, 23.6), p = 0.013. The trial completion rate of 94% in the prazosin group (30/32) and 88% in the placebo group (14/16) indicated that prazosin was generally well tolerated at the administered dose regimen. Morning drowsiness/lethargy was the only adverse effect that differed significantly between groups, affecting 69% of the prazosin group (22/32) versus 19% of the placebo group (3/16), p = 0.002. Conclusions: This pilot study provides a clinically meaningful efficacy signal for prazosin prophylaxis of posttraumatic headaches. A larger randomized controlled trial is needed to confirm and extend these promising results. [ABSTRACT FROM AUTHOR]

This was an observational study of a cohort of 63 Operation Iraqi Freedom/Operation Enduring Freedom veterans with mild traumatic brain injury (mTBI) associated with an explosion. They had headaches, residual neurological deficits (NDs) on neurological examination, and posttraumatic stress disorder (PTSD) and were seen on average 2.5 years after their last mTBI. We treated them with sleep hygiene counseling and oral prazosin. We monitored headache severity, daytime sleepiness using the Epworth Sleepiness Scale, cognitive performance using the Montreal Cognitive Assessment test, and the presence of NDs. We quantitatively measured olfaction and assessed PTSD severity using the PTSD Checklist-Military Version. Nine weeks after starting sleep counseling and bedtime prazosin, the veterans' headache severity decreased, cognitive function as assayed with a brief screening tool improved, and daytime sleepiness diminished. Six months after completing treatment, the veterans demonstrated additional improvement in headache severity and daytime sleepiness and their improvements in cognitive function persisted. There were no changes in the prevalence of NDs or olfaction scores. Clinical improvements correlated with reduced PTSD severity and daytime sleepiness. The data suggested that reduced clinical manifestations following mTBI correlated with PTSD severity and improvement in sleep, but not the presence of NDs or olfaction impairment.

Traumatic brain injury (TBI) has garnered increased public attention in the past several years because of high-profile athletes with possible long-term effects of their injuries as well as large numbers of returning combat veterans injured by blast explosions. Most of these injuries are mild in nature and require no specific surgical treatment but may benefit from brief rehabilitation interventions. To appropriately rehabilitate patients with mild traumatic brain injury (mTBI), one must fully understand its clinical course and the factors that accelerate or delay recovery. Education is the centerpiece of mTBI treatment and should be included in the rehabilitation plan. When devising the rehabilitation plan, the neurologist should take into account the goals of the patient and establish a reasonable time frame for treatment paralleling the expected recovery course. Cognitive and vestibular functions are commonly affected after mTBI and are particularly responsive to rehabilitation interventions. Vocational rehabilitation and community reentry planning are aspects of the global rehabilitation plan that should not be neglected. Combat-injured veterans with mTBI present unique challenges to the rehabilitation team, and assessment of these patients often needs to include assessment of psychological function.