Objective To study the changes in serum β-endorphin (β-EP), dynorphin (DynA1-13), and neuron-specific enolase (NSE) in patients with acute traumatic brain injury (TBI) after treatment with nalmefene hydrochloride and to evaluate the brain-protective effect and adverse reactions of nalmefene hydrochloride in TBI patients.Methods Forty patients with acute TBI were randomly divided into nalmefene hydrochloride treatment group (n=20) and control group (n=20). The patients in control group received conventional treatment, while those in nalmefene hydrochloride treatment group were given nalmefene hydrochloride in addition to the conventional treatment. Serum levels of β-EP, DynA1-13, and NSE were measured before treatment and on days 1, 2, 3, 5, 7, and 10 of treatment in all patients; meanwhile, the heart rate, respiratory rate, and medication-related adverse events were recorded. Glasgow Outcome Scale (GOS) scores were compared between the two groups after three months.Results Serum levels of β-EP, DynA1-13, and NSE were significantly lower in the treatment group than in the control group. The three indices showed an overall decreasing trend in the treatment group; serum β-EP and DynA1-13 showed an overall increasing trend in the control group, while serum NSE showed an overall decreasing trend. The treatment group had significantly lower proportions of individuals with abnormal heart rate and abnormal respiratory rate than the control group(P<0.05). The incidence of medication-related adverse events showed no significant difference between the two groups(P>0.05), while GOS scores showed a significant difference between the two groups.Conclusions For patients with acute TBI, nalmefene hydrochloride can reduce serum β-EP, DynA1-13, and NSE and the secondary pathological damage, exert a certain brain-protective effect, reduce the abnormalities of heart rate and respiratory rate, and improve prognosis, and it causes little adverse reactions.