A 2016 American Academy of Neurology (AAN) practice advisory evaluated the effectiveness, safety, and tolerability of etanercept for poststroke disability and identified two nonmasked, uncontrolled retrospective case series involving 3 and 617 patients with stroke; both were classified as Class IV evidence because of a high risk of bias. In the larger study, patients received posterior cervical perispinal injections of etanercept 25 mg followed by Trendelenburg positioning, with reported improvements across multiple functional domains immediately after treatment and maintenance of improvement in most patients assessed at 3 weeks. Neither study described adverse events following treatment; however, the advisory noted potentially serious adverse events reported with etanercept for other conditions and uncertainty regarding their applicability to time-limited perispinal administration. The authors concluded that evidence was insufficient to support or refute the efficacy of perispinal etanercept for poststroke disability and recommended counseling patients regarding uncertain effectiveness, potential adverse outcomes, and high cost. [1]
A 2025 systematic review evaluated the safety and effectiveness of perispinal etanercept for persistent post-stroke deficits, including five studies: two randomized controlled trials, one observational cohort, one case series, and one case report. Six databases were searched through September 2025, with two reviewers independently screening studies, extracting data, and assessing risk of bias; findings were synthesized qualitatively because differences in outcome measures and assessment times precluded quantitative pooling. A multicenter, double-blind randomized trial involving 126 participants found no significant improvement in the proportion achieving a ≥5-point increase in Short Form-36 scores with etanercept versus placebo (53% vs 58%; odds ratio [OR] 0.82; 95% confidence interval [CI] 0.40 to 1.67; p= 0.58). A smaller, double-blind randomized trial involving 22 participants reported reductions in pain scores and improved shoulder flexion following two 25-mg injections administered 14 days apart, with effects sustained through day 30. Uncontrolled studies reported improvements in motor function, cognition, speech, pain, and hemispatial neglect, but were assessed as having a high risk of bias; the larger randomized trial was rated as having low risk of bias, whereas the smaller trial had some concerns. Serious adverse events occurred at similar frequencies in the larger trial (2% with etanercept vs 3% with placebo), while one participant in the smaller trial developed shingles and was withdrawn. Safety assessment was limited by short follow-up and predominantly one- or two-dose exposure. The authors concluded that the overall evidence remains inconclusive and does not support routine clinical use, emphasizing the need for larger randomized trials with standardized outcomes and longer follow-up. [2]
A 2022 network meta-analysis evaluated pharmacotherapies for central post-stroke pain using 13 randomized controlled trials identified through searches of four databases from inception to March 30, 2022. Evidence for perispinal etanercept was derived from one parallel-group randomized trial involving 26 participants that compared etanercept 25 mg with 0.9% saline over a 2-week treatment period. Etanercept significantly reduced pain intensity compared with placebo (standardized mean difference [MD] −0.92; 95% CI −1.80 to −0.03). The review reported shingles in 1 of 13 etanercept recipients and no serious adverse events across the included pharmacotherapies; adverse events were not quantitatively pooled because reporting varied among trials. Functional status and quality of life were not assessed in the meta-analysis, and evidence of benefit beyond 3 months was lacking. The authors recommended further randomized trials of etanercept and additional evaluation of long-term effectiveness and safety. [3]