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

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.

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.

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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by the U.S. Department of Defense through the U.S. Army Medical Research and Materiel Command, Congressionally Directed Medical Research Programs, Psychological Health and Traumatic Brain Injury Research Program award [E01 HT9425-23-1-1046] (PI: Donald D. McGeary, PhD) Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Conflict of Interest: The authors have no relevant financial or non-financial interests to disclose. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the U.S. Department of Defense through the U.S. Army Medical Research and Materiel Command, Congressionally Directed Medical Research, Programs, Psychological Health and Traumatic Brain Injury Research Program award [E01 HT9425-23-1-1046] (PI: Donald D. McGeary, PhD) Supplemental material: Supplemental material for this article is available online. Prospero Link: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024537719 Data Availability All data used in this study are from previously published sources, which are cited in the manuscript. Abbreviations - TBI - Traumatic Brain Injury - mTBI - Mild Traumatic Brain Injury - PTH - Post-Traumatic Headache - PPTH - Persistent Post-Traumatic Headache - PTSD - Posttraumatic Stress Disorder - QoL - Quality of Life - RCT - Randomized Controlled Trial