Randomized controlled pilot trial of prazosin for prophylaxis of posttraumatic headaches in active-duty service members and veterans.
mild traumatic brain injury
noradrenergic signaling
posttraumatic headache
prazosin
Journal
Headache
ISSN: 1526-4610
Titre abrégé: Headache
Pays: United States
ID NLM: 2985091R
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
revised:
19
04
2023
received:
14
09
2022
accepted:
21
04
2023
medline:
21
6
2023
pubmed:
14
6
2023
entrez:
14
6
2023
Statut:
ppublish
Résumé
Evaluate the efficacy and tolerability of prazosin for prophylaxis of headaches following mild traumatic brain injury in active-duty service members and military veterans. 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. 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. 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. 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.
Sections du résumé
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.
Substances chimiques
Prazosin
XM03YJ541D
Types de publication
Journal Article
Randomized Controlled Trial
Langues
eng
Sous-ensembles de citation
IM
Pagination
751-762Subventions
Organisme : Department of Defense
ID : NCT02965027
Organisme : Veterans Administration Medical Center
ID : NCT02266329
Informations de copyright
Published 2023. This article is a U.S. Government work and is in the public domain in the USA.
Références
Couch JR, Stewart KE. Persistence of headache and its relation to other major sequelae following traumatic brain injury at 2-8 years after deployment-related traumatic brain injury in veterans of Afghanistan and Iraq wars. Headache. 2022;62:700-717.
Lew HL, Lin PH, Fuh JL, Wang SJ, Clark DJ, Walker WC. Characteristics and treatment of headache after traumatic brain injury: a focused review. Am J Phys Med Rehabil. 2006;85:619-627.
Watanabe TK, Bell KR, Walker WC, Schomer K. Systematic review of interventions for post-traumatic headache. PM R. 2012;4:129-140.
Schwedt TJ. Post-traumatic headache due to mild traumatic brain injury: current knowledge and future directions. Cephalalgia. 2021;41:464-471.
Menkes DB, Baraban JM, Aghajanian GK. Prazosin selectively antagonizes neuronal responses mediated by alpha1-adrenoceptors in brain. Naunyn Schmiedebergs Arch Pharmacol. 1981;317:273-275.
Tsujii T. Comparison of prazosin, terazosin and tamsulosin in the treatment of symptomatic benign prostatic hyperplasia: a short-term open, randomized multicenter study. BPH Medical Therapy Study Group. Benign prostatic hyperplasia. Int J Urol. 2000;7:199-205.
Raskind MA, Peterson K, Williams T, et al. A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry. 2013;170:1003-1010.
Ruff RL, Ruff SS, Wang XF. Improving sleep: initial headache treatment in OIF/OEF veterans with blast-induced mild traumatic brain injury. J Rehabil Res Dev. 2009;46:1071-1084.
Silberstein S, Tfelt-Hansen P, Dodick DW, et al. Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults. Cephalalgia. 2008;28:484-495.
Erickson JC. Treatment outcomes of chronic post-traumatic headaches after mild head trauma in US soldiers: an observational study. Headache. 2011;51:932-944.
Theeler BJ, Flynn FG, Erickson JC. Chronic daily headache in U.S. soldiers after concussion. Headache. 2012;52:732-738.
Finkel AG, Ivins BJ, Yerry JA, Klaric JS, Scher A, Sammy CY. Which matters more? A retrospective cohort study of headache characteristics and diagnosis type in soldiers with mTBI/concussion. Headache. 2017;57:719-728.
Diener HC, Bussone G, Van Oene JC, et al. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia. 2007;27:814-823.
Silberstein SD, Lipton RB, Dodick DW, et al. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache. 2007;47:170-180.
Management of Concussion/Mild Traumatic Brain Injury Working Group. VA/DoD clinical practice guideline for management of concussion/mild traumatic brain injury. J Rehabil Res Dev. 2009;46:CP1-68:1059-1068.
R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing; 2020.
Headache Classification Committee of the International Headache Society. The International Classification Of Headache Disorders, 3rd edition. Cephalalgia. 2018;38:1-211.
Ashina H, Porreca F, Anderson T, et al. Post-traumatic headache: epidemiology and pathophysiological insights. Nat Rev Neurol. 2019;15:607-617.
Blumenfeld A, McVige J, Knievel K. Post-traumatic headache: pathophysiology and management-a review. J Concussion. 2022;6:1-10.
Wei X, Yan J, Tillu D, et al. Meningeal norepinephrine produces headache behaviors in rats via actions both on dural afferents and fibroblasts. Cephalalgia. 2015;35:1054-1064.
Llorca-Torralba M, Borges G, Neto F, Mico JA, Berrocoso E. Noradrenergic locus coeruleus pathways in pain modulation. Neuroscience. 2016;338:93-113.
Taylor BK, Westlund KN. The noradrenergic locus coeruleus as a chronic pain generator. J Neurosci Res. 2017;95:1336-1346.
Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4:147ra111.
Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342:373-377.
Vatz KA. Alpha 1-adrenergic blockers: do they have a place in the prophylaxis of migraine? Headache. 1997;37:107-108.
Bonuso S, Di Stasio E, Marano E, et al. The antimigraine effect of ergotamine: a role for alpha-adrenergic blockade? Acta Neurol (Napoli). 1994;16:1-10.