RARE DISEASE
Moderate and severe traumatic brain injury
Moderate and severe traumatic brain injury
Moderate and severe traumatic brain injury
Drug discovery
15
drugs
With orphan designations
Overview
Moderate to severe traumatic brain injury (TBI) involves structural brain damage with Glasgow Coma Scale (GCS) scores of 3-12, prolonged unconsciousness (>30 minutes), and post-traumatic amnesia [1][5][16]. These injuries often require acute neurosurgical intervention, multimodal monitoring, and long-term rehabilitation to address cognitive, motor, and behavioral deficits [3][5][13]. Mortality risks increase with severity, while survivors frequently face lifelong disability [6][10][16].
Therapies
Acute care: ICP monitoring, osmotic therapy (mannitol), decompressive craniectomy [5][13][18]
Pharmacologic: Anti-seizure prophylaxis, beta-blockers, amantadine for cognitive recovery [3][8][18]
Rehabilitation: Multidisciplinary programs with cognitive therapy, physiotherapy, and vocational retraining [6][10][15]
Categories: rare neurological diseases
Research Papers
1,715 drug discovery papers about Moderate and severe traumatic brain injury, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,715 drug discovery papers about Moderate and severe traumatic brain injury, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-13 | Gabapentin and cognitive impairment after traumatic brain injury: A multinational cohort of 49,925 patients.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality, and cognitive impairment can be devastating among survivors. The objective was to assess an association between gabapentin and cognitive impairment after TBI. This retrospective cohort study used the multinational TriNetX Research Network (>150 million patients). Adults (≥18 years) with a first TBI and Glasgow Coma Scale (GCS) score recorded on the day of injury were included. Patients with known cognitive impairment or gabapentin exposure were excluded. The cohort (n = 49,925) was stratified into mild (GCS 13-15; n = 34,376), moderate (9-12; n = 4035), and severe (3-8; n = 12,845) TBI. The risk of cognitive impairment and mortality were assessed using Cox proportional hazard models adjusted for known predictors. Secondary analyses examined levetiracetam use (as seizure prophylaxis) and long-term medical and functional outcomes. Among 49,925 included patients w, 3.5% received gabapentin on the day of TBI. After adjustment, gabapentin was associated with a 22% lower risk of cognitive impairment in mild TBI (HR = 0.78; 95% CI, 0.62-0.98; P = .03) and a 46% lower risk of mortality in severe TBI (HR = 0.54; 95% CI, 0.40-0.72; P < .001). Levetiracetam showed no protective association with cognition. Long-term follow-up associated gabapentin use with lower mortality but higher rates of psychiatric/sleep diagnoses, reduced mobility, atrial fibrillation, and pulmonary embolism. Although causality cannot be inferred, these findings suggest gabapentin warrant prospective investigation as a candidate neuroprotective therapy.
2026-08-12 | Scoping review of pharmacological and non-pharmacological management of agitation in post traumatic brain injury patients.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Agitation is a common complication after moderate to severe TBI and managing it in the acute hospital setting can be challenging. Currently, there are no standardised interventions to manage agitation in TBI. This review aims to evaluate contemporary research over the past 10 years which addresses pharmacological and non-pharmacological strategies for managing agitation post-TBI. A scoping review literature search was conducted using PRISMA guidelines. The protocol was pre-registered on PROSPERO (ID 1295903). The literature search used Mesh and Boolean keywords 'traumatic brain injury and 'agitation management' in PubMed, and a free-text search of 'traumatic brain injury and agitation management' with 'map term to subject heading' in Embase (Ovid) and Cochrane, covering studies from 01 January 2015 to 09 March 2026. Findings were analysed and discussed between two reviewers. A total of 65 studies were identified, and after careful review, 13 papers were selected from PubMed and Embase for our Scoping Review. Non-pharmacological strategies highlighted the importance of orienting the patient and the supportive role of family during the acute recovery period. Pharmacological strategies included found that the antipsychotic olanzapine was helpful in managing agitation in moderate to severe TBI. Valproic acid in a small male sample [1] and a separate study using dextromethorphan and quinidine [2] found that these medications were also helpful in managing agitation in TBI. DISCUSSION AND CONCLUSION: Clinicians and health professionals reported that treating the patient holistically, with the medical, social, and psychiatric history was of benefit. Antipsychotic Olanzapine and Valproic acid may have their uses in the short-term, interim acute setting under supervision. Future research with larger sample sizes further investigating these medications would be useful, along with personalisation of medications to the patient's medical history. Most of the studies included in the review are observational and reviews, rather than randomised controlled trials, with a lack of primary evidence which may be a limitation. PROSPERO CRD 1295903.
2026-08-06 | Propranolol attenuates systemic inflammatory response in aged traumatic brain injury patients.
Aged traumatic brain injury (TBI) patients typically have a worse prognosis than younger individuals, though the underlying mechanisms remain incompletely understood. Secondary neuroinflammation is a key determinant of outcomes following TBI, but how aging reshapes the neuroinflammatory response post-TBI remains poorly understood. Propranolol, a clinically available non-selective beta-adrenergic receptor blocker, has garnered increasing interest for its potential therapeutic value in TBI management. Published clinical studies have shown that early administration of propranolol reduces mortality, shortens hospital stays, and improves outcomes in patients with moderate-to-severe TBI. However, its effects and underlying mechanisms in aged patients remain unclear. Here, we investigated the regulatory mechanisms by which propranolol modulates systemic inflammatory responses in aged TBI mice and conducted a retrospective exposure-based clinical cohort study enrolling aged TBI patients. We found that propranolol significantly reduced the production of peripheral blood-derived neutrophils and classical monocytes, and inhibited their infiltration into the brain. In contrast, both peripheral and brain-infiltrating non-classical monocyte populations were expanded. Mechanistically, propranolol substantially reversed the inflammatory transcriptomic profiles in both the bone marrow and brain of aged TBI mice, as evidenced by the downregulation of myeloid cell differentiation and inflammation-related signaling pathways. Behavioral outcomes of aged TBI mice were also significantly improved. It is worth noting that transcriptomic analysis of patient-derived peripheral blood mononuclear cells (PBMCs) and proteomic analysis of cerebrospinal fluid (CSF) also indicated that systemic inflammatory responses are attenuated in aged TBI patients treated with propranolol. In summary, our study suggests that propranolol holds significant clinical potential for alleviating systemic inflammation and improving outcomes in aged TBI patients.
2026-08-06 | Lacosamide Use After Traumatic Brain Injury: A Scoping Review.
Lacosamide (LCM) is a newer antiepileptic drug that enhances slow inactivation of voltage-gated sodium channels and modulates collapsin response mediator protein-2, suggesting potential roles in seizure control and axonal protection after traumatic brain injury (TBI). However, its role in TBI remains unclear. This scoping review aimed to characterize preclinical and clinical research on LCM use in TBI, focusing on seizure prophylaxis, seizure treatment, and potential neuroprotective effects. A comprehensive search of MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index of Nursing and Allied Health (CINAHL), Web of Science, and ClinicalTrials.gov was conducted. Studies involving human patients or animal TBI models evaluating acute LCM use were included, and data were charted descriptively. Ten studies were included, comprising five preclinical and five clinical investigations. Preclinical studies evaluated seizure-related, electrophysiological, histological, inflammatory, and behavioral outcomes in experimental TBI models. Clinical studies included two randomized trials, two observational cohorts, and one case report involving patients with moderate to severe TBI. LCM was administered for seizure prophylaxis or treatment. Seizure-related and safety outcomes were reported across clinical studies, whereas neurological and functional outcomes were less consistently assessed. Overall, evidence supporting LCM use in acute TBI remains limited, with differences between preclinical and clinical outcome domains.
2026-08-04 | Early versus Late Pharmacologic Thromboprophylaxis in Traumatic Brain Injury: A Propensity-Score Matched Cohort Study.
The optimal timing of pharmacological thromboprophylaxis in traumatic brain injury (TBI) remains uncertain due to competing risks of thrombosis and bleeding. This study evaluated whether early heparin initiation (≤72 hours) reduces vascular occlusive events (VOEs), mortality, and hospital stay without increasing bleeding. We compared early versus late (>72 hours) heparin use via propensity score matching (PSM), subgroup analyses, and multivariable logistic regression. Outcomes included VOEs (deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischemic stroke), bleeding, 30- and 180-day mortality, and length of stay. After PSM, late heparin was associated with higher VOEs (25.16 vs. 12.24%, p < 0.001), 30-day mortality (20 vs. 11.89%, p = 0.03), 180-day mortality (32.26 vs. 19.58%, p = 0.004), and prolonged hospitalization (median: 15.7 vs. 9.7 days, p < 0.001), without increased bleeding risk (16.77 vs. 22.03%, p = 0.24). Subgroup analyses revealed late heparin as an independent risk factor for VOEs in mild TBI (odds ratio: 2.62, 95% confidence interval: 1.54-4.45; p < 0.001) regardless of fracture status, coagulation profile, or hemorrhagic classification, with nonsignificant associations in nonhemorrhagic and moderate-to-severe TBI subgroups. Multivariable analysis identified late heparin, higher comorbidity index, elevated platelet count, and cranial surgery as independent predictors of VOEs, with late heparin also independently associated with increased mortality. These findings suggest early heparin initiation reduces thromboembolic complications, mortality, and hospital stay without markedly increasing bleeding risk, supporting early anticoagulation in selected patients following individualized risk-benefit assessment.
2026-08-13 | Gabapentin and cognitive impairment after traumatic brain injury: A multinational cohort of 49,925 patients.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality, and cognitive impairment can be devastating among survivors. The objective was to assess an association between gabapentin and cognitive impairment after TBI. This retrospective cohort study used the multinational TriNetX Research Network (>150 million patients). Adults (≥18 years) with a first TBI and Glasgow Coma Scale (GCS) score recorded on the day of injury were included. Patients with known cognitive impairment or gabapentin exposure were excluded. The cohort (n = 49,925) was stratified into mild (GCS 13-15; n = 34,376), moderate (9-12; n = 4035), and severe (3-8; n = 12,845) TBI. The risk of cognitive impairment and mortality were assessed using Cox proportional hazard models adjusted for known predictors. Secondary analyses examined levetiracetam use (as seizure prophylaxis) and long-term medical and functional outcomes. Among 49,925 included patients w, 3.5% received gabapentin on the day of TBI. After adjustment, gabapentin was associated with a 22% lower risk of cognitive impairment in mild TBI (HR = 0.78; 95% CI, 0.62-0.98; P = .03) and a 46% lower risk of mortality in severe TBI (HR = 0.54; 95% CI, 0.40-0.72; P < .001). Levetiracetam showed no protective association with cognition. Long-term follow-up associated gabapentin use with lower mortality but higher rates of psychiatric/sleep diagnoses, reduced mobility, atrial fibrillation, and pulmonary embolism. Although causality cannot be inferred, these findings suggest gabapentin warrant prospective investigation as a candidate neuroprotective therapy.
2026-08-12 | Scoping review of pharmacological and non-pharmacological management of agitation in post traumatic brain injury patients.
Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Agitation is a common complication after moderate to severe TBI and managing it in the acute hospital setting can be challenging. Currently, there are no standardised interventions to manage agitation in TBI. This review aims to evaluate contemporary research over the past 10 years which addresses pharmacological and non-pharmacological strategies for managing agitation post-TBI. A scoping review literature search was conducted using PRISMA guidelines. The protocol was pre-registered on PROSPERO (ID 1295903). The literature search used Mesh and Boolean keywords 'traumatic brain injury and 'agitation management' in PubMed, and a free-text search of 'traumatic brain injury and agitation management' with 'map term to subject heading' in Embase (Ovid) and Cochrane, covering studies from 01 January 2015 to 09 March 2026. Findings were analysed and discussed between two reviewers. A total of 65 studies were identified, and after careful review, 13 papers were selected from PubMed and Embase for our Scoping Review. Non-pharmacological strategies highlighted the importance of orienting the patient and the supportive role of family during the acute recovery period. Pharmacological strategies included found that the antipsychotic olanzapine was helpful in managing agitation in moderate to severe TBI. Valproic acid in a small male sample [1] and a separate study using dextromethorphan and quinidine [2] found that these medications were also helpful in managing agitation in TBI. DISCUSSION AND CONCLUSION: Clinicians and health professionals reported that treating the patient holistically, with the medical, social, and psychiatric history was of benefit. Antipsychotic Olanzapine and Valproic acid may have their uses in the short-term, interim acute setting under supervision. Future research with larger sample sizes further investigating these medications would be useful, along with personalisation of medications to the patient's medical history. Most of the studies included in the review are observational and reviews, rather than randomised controlled trials, with a lack of primary evidence which may be a limitation. PROSPERO CRD 1295903.
2026-08-06 | Propranolol attenuates systemic inflammatory response in aged traumatic brain injury patients.
Aged traumatic brain injury (TBI) patients typically have a worse prognosis than younger individuals, though the underlying mechanisms remain incompletely understood. Secondary neuroinflammation is a key determinant of outcomes following TBI, but how aging reshapes the neuroinflammatory response post-TBI remains poorly understood. Propranolol, a clinically available non-selective beta-adrenergic receptor blocker, has garnered increasing interest for its potential therapeutic value in TBI management. Published clinical studies have shown that early administration of propranolol reduces mortality, shortens hospital stays, and improves outcomes in patients with moderate-to-severe TBI. However, its effects and underlying mechanisms in aged patients remain unclear. Here, we investigated the regulatory mechanisms by which propranolol modulates systemic inflammatory responses in aged TBI mice and conducted a retrospective exposure-based clinical cohort study enrolling aged TBI patients. We found that propranolol significantly reduced the production of peripheral blood-derived neutrophils and classical monocytes, and inhibited their infiltration into the brain. In contrast, both peripheral and brain-infiltrating non-classical monocyte populations were expanded. Mechanistically, propranolol substantially reversed the inflammatory transcriptomic profiles in both the bone marrow and brain of aged TBI mice, as evidenced by the downregulation of myeloid cell differentiation and inflammation-related signaling pathways. Behavioral outcomes of aged TBI mice were also significantly improved. It is worth noting that transcriptomic analysis of patient-derived peripheral blood mononuclear cells (PBMCs) and proteomic analysis of cerebrospinal fluid (CSF) also indicated that systemic inflammatory responses are attenuated in aged TBI patients treated with propranolol. In summary, our study suggests that propranolol holds significant clinical potential for alleviating systemic inflammation and improving outcomes in aged TBI patients.
2026-08-06 | Lacosamide Use After Traumatic Brain Injury: A Scoping Review.
Lacosamide (LCM) is a newer antiepileptic drug that enhances slow inactivation of voltage-gated sodium channels and modulates collapsin response mediator protein-2, suggesting potential roles in seizure control and axonal protection after traumatic brain injury (TBI). However, its role in TBI remains unclear. This scoping review aimed to characterize preclinical and clinical research on LCM use in TBI, focusing on seizure prophylaxis, seizure treatment, and potential neuroprotective effects. A comprehensive search of MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index of Nursing and Allied Health (CINAHL), Web of Science, and ClinicalTrials.gov was conducted. Studies involving human patients or animal TBI models evaluating acute LCM use were included, and data were charted descriptively. Ten studies were included, comprising five preclinical and five clinical investigations. Preclinical studies evaluated seizure-related, electrophysiological, histological, inflammatory, and behavioral outcomes in experimental TBI models. Clinical studies included two randomized trials, two observational cohorts, and one case report involving patients with moderate to severe TBI. LCM was administered for seizure prophylaxis or treatment. Seizure-related and safety outcomes were reported across clinical studies, whereas neurological and functional outcomes were less consistently assessed. Overall, evidence supporting LCM use in acute TBI remains limited, with differences between preclinical and clinical outcome domains.
2026-08-04 | Early versus Late Pharmacologic Thromboprophylaxis in Traumatic Brain Injury: A Propensity-Score Matched Cohort Study.
The optimal timing of pharmacological thromboprophylaxis in traumatic brain injury (TBI) remains uncertain due to competing risks of thrombosis and bleeding. This study evaluated whether early heparin initiation (≤72 hours) reduces vascular occlusive events (VOEs), mortality, and hospital stay without increasing bleeding. We compared early versus late (>72 hours) heparin use via propensity score matching (PSM), subgroup analyses, and multivariable logistic regression. Outcomes included VOEs (deep vein thrombosis, pulmonary embolism, myocardial infarction, and ischemic stroke), bleeding, 30- and 180-day mortality, and length of stay. After PSM, late heparin was associated with higher VOEs (25.16 vs. 12.24%, p < 0.001), 30-day mortality (20 vs. 11.89%, p = 0.03), 180-day mortality (32.26 vs. 19.58%, p = 0.004), and prolonged hospitalization (median: 15.7 vs. 9.7 days, p < 0.001), without increased bleeding risk (16.77 vs. 22.03%, p = 0.24). Subgroup analyses revealed late heparin as an independent risk factor for VOEs in mild TBI (odds ratio: 2.62, 95% confidence interval: 1.54-4.45; p < 0.001) regardless of fracture status, coagulation profile, or hemorrhagic classification, with nonsignificant associations in nonhemorrhagic and moderate-to-severe TBI subgroups. Multivariable analysis identified late heparin, higher comorbidity index, elevated platelet count, and cranial surgery as independent predictors of VOEs, with late heparin also independently associated with increased mortality. These findings suggest early heparin initiation reduces thromboembolic complications, mortality, and hospital stay without markedly increasing bleeding risk, supporting early anticoagulation in selected patients following individualized risk-benefit assessment.
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Drug Discovery Landscape
15 orphan drug designations for Moderate and severe traumatic brain injury.
15 orphan drug designations for Moderate and severe traumatic brain injury.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Exenatide | peptides | EMA | 2023-06-20 | — | Boyd Consultants Limited |
Progesterone [BHR-100] | small molecules | EMA | 2013-02-08 | — | [INACTIVE] Bhr Pharma Belgium |
Apomorphine hydrochloride | small molecules | EMA | 2011-05-13 | — | Dr Elkan Raphael Gamzu |
cyclosporine; ciclosporin | small molecules | FDA | 2010-11-23 | — | Owl Therapeutics |
Ciclosporin | small molecules | EMA | 2010-10-01 | — | ICON Clinical Research Limited |
progesterone | small molecules | FDA | 2009-09-03 | — | BHR Pharma, LLC |
(-)-(2R)-3-(2-hydroxymethylindanyl-4-oxy)-phenyl-4,4,4-trifluorobutane-1-sulfonate | small molecules | EMA | 2008-09-05 | — | KeyNeurotek Pharmaceuticals AG |
4-amino-(6R,S)-5,6,7,8-tetrahydro-L-biopterin dihydrochloride | small molecules | EMA | 2006-08-28 | — | veriNOS operations GmbH |
Apomorphine hydrochloride | small molecules | FDA | 2006-05-23 | — | NeuroHealing Pharmaceuticals, Inc. |
dimethyl sulfoxide | small molecules | EMA | 2005-03-03 | — | Aop Orphan Pharmaceuticals GmbH |
dexanabinol | small molecules | FDA | 2004-08-11 | — | Pharmos Corporation |
N-3[[4(aminoiminomethyl)benzoyl]amino]propyl]-1-[[2,4-dichloro-3-[[2,4-dimethyl-8-quinolinyl) oxy]methyl] phenyl]sulphonyl]-(2S)-2-pyrrolidinecarboxamide, di(methanesulfonate) | small molecules | EMA | 2004-02-23 | — | Xytis Pharmaceuticals Limited |
Sodium dichloroacetate | small molecules | FDA | 1999-06-14 | — | Questcor Pharmaceuticals, Inc. |
Enadoline hydrochloride | small molecules | FDA | 1997-01-28 | — | Warner-Lambert Company |
Dimethyl sulfoxide | small molecules | FDA | 1994-11-22 | — | Abela Pharmaceuticals, Inc. |
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