Can Gabapentin Improve Brain Injury Outcomes?

Gabapentin administered on the day of traumatic brain injury (TBI) was tied to a reduced risk of durable cognitive impairment and mortality, a retrospective, longitudinal study of 50,000 patients showed.

Over 2 years, gabapentin was associated with a 22% adjusted lower risk of cognitive impairment in mild TBI (HR 0.78, 95% CI 0.62-0.98, P=0.03) and a 46% adjusted lower risk of mortality in severe TBI (HR 0.54, 95% CI 0.40-0.72, P<0.001), reported Isaac Thorman, ScM, an epidemiology researcher at the Johns Hopkins University School of Medicine in Baltimore and a third-year medical student at New York Medical College (NYMC) in Valhalla, and colleagues.

Adverse outcomes associated with gabapentin over 5 years included psychiatric, sleep, and cardiovascular disorders, Thorman and co-authors said in a poster presentation at the American Academy of Neurology annual meeting.

TBI is a major cause of long-term disability and “one of the most important and intractable challenges, with meaningful improvements in long-term outcomes remaining limited,” observed co-author Fawaz Al-Mufti, MD, also of NYMC.

“Despite decades of work and a very large number of studies, we have made relatively limited progress in reducing the long-term impact of TBI, particularly with respect to post-traumatic epilepsy, cognitive decline, neurobehavioral symptoms, and functional disability,” he told MedPage Today.

“That is what makes this line of inquiry important,” Al-Mufti pointed out. “Even an association, if biologically plausible and reproducible, may help us think differently about therapies that could modify downstream injury rather than treat symptoms after the fact.”

The analysis was prompted by an earlier study of levetiracetam (Keppra), Thorman noted. “We found that levetiracetam was only associated with a decreased risk of early seizures in the week following TBI in severe injuries; there were no associations with late seizures or mild injuries,” he said.

“In light of these findings, we wanted to look further into how anti-seizure medications may modify other risks after TBI, and we hypothesized that anti-seizure medications may have a neuroprotective effect when used in the right role,” Thorman told MedPage Today.

“Gabapentin was originally created as an anti-seizure medication, but in its decades of use, it has become a widely utilized and well-tolerated medication, and it is commonly used in the setting of TBI for pain and agitation,” he added. “As cognitive impairment is a highly prevalent and disabling sequelae of TBI, we questioned whether there may be an association between the drug gabapentin and the outcome of cognitive impairment.”

Thorman and colleagues analyzed health records from 49,925 adult patients who had a first TBI and a same-day Glasgow Coma Scale (GCS) score recorded in the multinational TriNetX Research Network. The GCS measures level of consciousness after a brain injury, with scores ranging from 3 (deep coma) to 15 (fully alert). Individuals with a history of cognitive impairment or prior exposure to gabapentin were excluded from the study.

The primary outcomes were durable cognitive impairment and all-cause mortality within 2 years using adjusted Cox models. Durable cognitive impairment was defined as diagnostic codes for vascular dementia, Alzheimer’s disease, or mild cognitive impairment.

The mean age of the cohort was 47.5 and 32.4% were women. Overall, 34,376 people had mild TBI (GCS 13-15) and 12,845 had severe injury (GCS 3-8).

A total of 1,757 people (3.5%) received gabapentin. Within 2 years, durable cognitive impairment developed in 6.6% of people with mild TBI and in 7.1% of severe TBI.

Causal relationships cannot be inferred from this analysis and residual confounding is likely, Thorman and colleagues emphasized.

“We want to be very clear: this study demonstrates an association, not a causation,” Al-Mufti said. “These findings should be viewed as hypothesis-generating and as a rationale for further prospective study.”