Efficacy and Outcomes of Pharmacological Treatments for Headaches after Traumatic Brain Injury: A Systematic Review

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Structured Background/Objective: Headache following traumatic brain injury (TBI) is a common, yet disabling, disorder with diverse mechanisms and treatment needs that remain poorly defined. Pharmacological regimens are the primary source of remedies for individuals with post-traumatic headaches (PTH). The main objective of this review is to describe the efficacy of pharmacological medications for the treatment of PTH with a specific focus on the effect of these medications on headache characteristics and patients’ quality of life (QoL). Methods: This systematic review (CRD42024537710) followed PRISMA and SWiM guidelines. PubMed, CINAHL, Scopus, PsycINFO, and the Cochrane Library were searched in April 2024 for peer-reviewed articles published in English between 2009 and 2024. Eligible studies included randomized controlled trials, controlled cohort studies, and systematic reviews or meta-analyses evaluating pharmacological treatments for PTH in adults. Studies were excluded if they did not assess outcomes related to PTH pain, included pediatric populations, used animal models, investigated only non-pharmacological interventions, were case reports, narrative reviews, editorials, or conference abstracts, or did not involve human participants with TBI- or whiplash-related headache. Risk of bias was assessed using RoB-2 for RCTs and the Newcastle-Ottawa Scale (NOS) for controlled cohort studies. Result: Sixteen studies were included in the final review. Most studies reported some improvements in headache frequency and intensity, with some also noting benefits in headache burden and QoL. Study designs included retrospective observational (n=7), non-randomized prospective (n=4), and randomized controlled trials (n=6). Of the RCTs, only three had a low risk of bias, and just one focused specifically on PTH. Conclusion: Erenumab showed potential benefits for persistent headache symptoms and improved quality of life in civilian populations, while Prazosin demonstrated similar benefits in military populations, both with minimal side effects. Metoclopramide, co-administered with diphenhydramine to minimize side effects, demonstrated short-term efficacy as an abortive treatment for headache in emergency settings. However, due to the limited high-quality evidence, current pharmacological treatments for PTH should be used with caution. Future research should prioritize rigorous, controlled studies—particularly comparative effectiveness trials—and explore holistic, personalized approaches that incorporate treatment of psychiatric comorbidities and consider patient context.

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