To evaluate whether gabapentin use on the day of traumatic brain injury (TBI) is associated with risk of durable cognitive impairment and mortality.

TBI is a leading cause of long-term disability, and no pharmacologic therapy has reliably reduced the risk of chronic cognitive decline or death. Gabapentin, commonly prescribed for pain and agitation after TBI, may have broader neuroprotective effects.

This retrospective cohort study used the multinational TriNetX Research Network, encompassing >150 million patients. Adults (≥18 years) with a first TBI and Glasgow Coma Scale (GCS) score recorded on the day of injury were included; those with prior cognitive impairment or gabapentin exposure were excluded. Primary outcomes were durable cognitive impairment and all-cause mortality within two years. Cox proportional hazards models adjusted for demographics and acute factors predictive of poor neurotrauma outcomes. 

Among 49,925 patients with TBI (mean [SD] age 47.5 [20.1] years; 32.4% women), 34,376 were mild (GCS 13-15) and 12,845 were severe (GCS 3-8); 3.5% received gabapentin. Durable cognitive impairment developed within two years of 6.6% of mild TBIs and 7.1% of severe TBIs, and two-year mortality rose from 4.8% to 39.3% across these groups. 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 (as seizure prophylaxis) showed no protective associations. Long-term follow-up revealed reduced 5-year mortality but higher rates of psychiatric, sleep, and cardiovascular disorders among gabapentin users.

Gabapentin use at the time of TBI was associated with reduced cognitive impairment after mild injury and reduced mortality after severe injury. While causality cannot be inferred, these findings support further prospective evaluation of gabapentin as a potential neuroprotective therapy in TBI.