[Skip to Navigation]
January 19, 2021

Association of Pharmacological Interventions With Symptom Burden Reduction in Patients With Mild Traumatic Brain Injury: A Systematic Review

Author Affiliations
  • 1University of Massachusetts Medical School, Worcester
  • 2Department of Pediatrics, Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
  • 3Department of Emergency Medicine, Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Ontario, Canada
  • 4Department of Psychology, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
  • 5Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
  • 6Sports Medicine and Performance Center, Center for Injury Research and Prevention, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
  • 7Division of Orthopaedics, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 8Sport Injury Prevention Research Centre, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
  • 9Faculty of Kinesiology, Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada
  • 10Department of Pediatrics, Division of Critical Care Medicine, Children’s National Hospital, Washington, District of Columbia
  • 11Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 12Division of Emergency Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA Neurol. 2021;78(5):596-608. doi:10.1001/jamaneurol.2020.5079
Key Points

Question  What are the associations between commonly used pharmacological interventions and symptom burden reduction among patients with mild traumatic brain injury?

Findings  In this systematic review of articles published between 2000 and 2020, 23 studies examining 20 pharmacological interventions used to mitigate the symptoms associated with mild traumatic brain injury were identified. Most studies reported an association between the receipt of pharmacological intervention and symptom burden reduction; however, substantial heterogeneity of assessments and outcomes was observed across studies.

Meaning  This systematic review found that none of the pharmacological interventions examined were consistently associated with symptom burden reduction across the studies included in the review, which is likely owing to the limited number of high-quality studies of mild traumatic brain injury; implementation of standardized measures is needed to provide comparable clinical assessments across studies.


Importance  Mild traumatic brain injury (TBI) is experienced by 55.9 million people globally each year. The symptoms of mild TBI are diverse and sometimes long-lasting, requiring frequent use of pharmacological interventions to mitigate them. A thorough understanding of the data supporting pharmacological interventions is important for decision-making among clinicians treating this common injury.

Objective  To systematically review studies of pharmacological interventions and their associations with symptom burden reduction among patients with mild TBI and to use an evidence-based model to identify potential directions for future research that may aid in clinical decision-making.

Evidence Review  A systematic review was performed in PubMed, Scopus, and Web of Science. Search strings modified for the advanced search interfaces of each search engine were developed in consultation with a librarian and included combinations of search terms, such as brain concussion, post-concussion syndrome, mild traumatic brain injury, and pharmacological treatment. Articles published between January 1, 2000, and July 1, 2020, were analyzed. Studies were included if (1) they were clinical studies with discrete analyses of participants with mild TBI or complicated mild TBI, (2) they were assessments of a pharmacological intervention, (3) they included human participants, and (4) they were published in a peer-reviewed journal in the English language. Studies were excluded if the severity of TBI among participants could not be ascertained (ie, inadequate definition of mild TBI) and the inclusion criteria for the study required intracranial hemorrhage. A total of 23 studies examining 20 pharmacological interventions met the inclusion criteria. Risk of bias was assessed using the Cochrane Risk of Bias for Randomized Trials (for randomized clinical trials) and the Cochrane Risk of Bias in Non-Randomized Studies of Interventions (for all other studies). Data were analyzed from June to September 2020.

Findings  A total of 1495 articles were identified; of those, 131 articles were excluded as duplicates. Titles and abstracts were screened for inclusion and exclusion criteria among the remaining 1364 articles, and 134 of those articles received a full-text review. After exclusions, 23 studies (11 randomized clinical trials, 7 prospective observational studies, 3 retrospective observational studies, and 2 case studies) examining 20 pharmacological interventions were identified for inclusion in the systematic review. Studies included 22 distinct participant populations comprising 8277 participants with mild TBI and 45 participants without TBI. Among 23 total studies, 8 studies specifically addressed the pediatric population, 9 studies had a low risk of bias, and 16 studies reported symptom burden reduction. Of the 20 pharmacological interventions examined in the studies, methylphenidate, sertraline hydrochloride, ondansetron, amitriptyline, and melatonin were the only medications included in multiple studies.

Conclusions and Relevance  This systematic review found a limited number of high-quality, clinically meaningful studies, particularly among children and individuals in the acute stage of injury; therefore, performing an evidence-based analysis that would inform clinical decision-making was not possible. Future studies are needed to focus on standardizing measures and increasing sample sizes (including large multicenter clinical trials) to generate a body of research that may provide additional options for the treatment of patients with mild TBI.

Add or change institution
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words