Is perispinal etanercept (Enbrel) effective for stroke recovery?

Perispinal Etanercept for Stroke Recovery

Perispinal etanercept should not be used for stroke recovery, as the highest quality randomized controlled trial (PESTO, 2025) demonstrated no improvement in quality of life or functional outcomes compared to placebo in patients with chronic stroke. 1

Evidence from Definitive Clinical Trial

The PESTO trial provides Class I evidence that definitively answers this question 1:

• 126 patients with chronic stroke (1-15 years post-stroke) were randomized to receive perispinal etanercept 25mg versus placebo 1
• Primary outcome showed no benefit: 53% improved in the etanercept group versus 58% in placebo (adjusted OR 0.82,95% CI 0.40-1.67) 1
• The treatment was safe with similar adverse event rates between groups, but efficacy was equivalent to placebo 1
• Patients had median age 54.5 years, median 3 years post-stroke, and modified Rankin Scale scores of 2-5 1

Why Earlier Observational Data Was Misleading

Prior to PESTO, there were observational studies and case reports suggesting benefit 2, 3:

• A 2011 case series of 3 patients reported rapid improvements within 10 minutes of injection 2
• A 2012 observational study of 629 consecutive patients claimed improvements in multiple domains 3
• However, these were uncontrolled, open-label observations highly susceptible to placebo effect, regression to the mean, and observer bias 2, 3

The PESTO trial's negative results demonstrate that the apparent improvements in observational studies were likely due to placebo response, which was substantial (58% in the placebo arm) 1.

What Guidelines Actually Recommend for Stroke Recovery

The American Heart Association/American Stroke Association guidelines for stroke rehabilitation do not mention perispinal etanercept because there was no evidence supporting its use 4:

For motor recovery after stroke, evidence-based interventions include:

• Intensive, repetitive, task-specific motor training 4
• Lower extremity strengthening and resistance training for community-dwelling individuals ≥6 months post-stroke 4
• Neuromuscular electrical stimulation (NMES) for gait improvement 4
• Ankle-foot orthoses (AFOs) for foot drop 4

For pharmacological enhancement of motor recovery:

• Fluoxetine showed benefit in one double-blind trial, with meta-analyses suggesting SSRIs may reduce overall disability, though evidence quality is insufficient for definitive recommendations 4
• Dextroamphetamine trials were negative 4
• Levodopa showed only short-term benefit in a small trial 4

Critical Pitfalls to Avoid

• Do not use perispinal etanercept based on case reports or observational studies when a high-quality RCT shows no benefit 1
• Recognize that the 58% placebo response rate in PESTO demonstrates how powerful expectation effects are in chronic stroke populations 1
• Avoid medications that may impair neuroplasticity during stroke recovery, including benzodiazepines and some antiepileptic drugs 4
• The theoretical mechanism (TNF inhibition reducing neuroinflammation) did not translate to clinical benefit despite biological plausibility 1, 2

What Actually Works for Chronic Stroke

Focus on evidence-based rehabilitation interventions:

• Task-specific intensive training remains the cornerstone 4
• Exercise programs with balance training reduce falls 4
• Constraint-induced movement therapy for upper extremity recovery 4
• Robotic and electromechanics-assisted training devices 4

For specific post-stroke complications:

• Spasticity: Start with positioning, ROM exercises, stretching; then consider tizanidine, dantrolene, or baclofen; botulinum toxin for focal spasticity 5
• Central post-stroke pain: Amitriptyline 75mg or lamotrigine as first-line 6, 7
• Depression: SSRIs with close monitoring 4