Article 3 (see Poster 14): Amantadine Hydrochloride for Treatment of Symptoms of the Posttraumatic Confusional State: A Randomized, Double-Blind, Placebo-Controlled Trial

Objective: To test the hypothesis that amantadine hydrochloride (AH), an NMDA antagonist and indirect dopamine receptor agonist, hastens resolution of symptoms of the posttraumatic confusional state (PTCS) observed during early recovery from severe nonpenetrating traumatic brain injury (TBI). Design: Randomized, double-blind, placebo-controlled, parallel group trial. Setting: Inpatient brain injury unit of free-standing rehabilitation hospital affiliated with the National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems of Care. Participants: Consented neurorehabilitation admissions with posttraumatic confusion after initial nonpenetrating TBI ≤ 90 days earlier (N=79), randomly assigned to the AH (n=39) or placebo (n=40) groups. Group assignment was adjusted for baseline confusion severity at time of randomization. Intervention: AH 100mg twice daily or identical placebo for 14 days, or until confusion symptom resolution (if ≤ 14 days) as measured by the Confusion Assessment Protocol (CAP). Main Outcome Measures: The primary outcome measure was confusion severity score as measured by the CAP after 14 days. The secondary outcome measures were (1) time to reach “nonconfused” CAP score; and (2) number of patients withdrawn from study due to predetermined, safety-related “escape” criteria. Results: There was no difference in the number of symptoms of PTCS, as measured by the CAP, between the AH and placebo-treated patients at day 14 of treatment (AH=2.56, placebo=2.7; Wilcoxon Mann-Whitney rank-sum test P=0.57). However, the mean difference in time to first “nonconfused” CAP score between groups approached significance (AH=7.7d, placebo=9.3d; Cox survival P=.053). No patients were withdrawn due to fulfillment of safety-related escape criteria. Conclusions: Although the natural course of symptom recovery from PTCS is favorable, these results provide tentative support to reports suggesting that AH safely hastens recovery from nonpenetrating TBI.