Highlight
– The ESTREL randomized clinical trial examined levodopa’s efficacy as an adjunct to standardized rehabilitation in acute stroke patients with hemiparesis.
– Levodopa, enhancing dopaminergic signaling, did not significantly improve motor function compared to placebo at 3 months, measured by the Fugl-Meyer Assessment.
– Safety profiles were comparable between levodopa and placebo groups, with infections being the most common serious adverse events.
– These findings question the routine use of levodopa in stroke rehabilitation protocols aimed at boosting motor recovery.
Study Background and Disease Burden
Stroke remains a leading cause of long-term disability worldwide, with hemiparesis severely impacting patients’ quality of life and independence. Neuroplasticity—the brain’s ability to reorganize and forge new neural connections after injury—is a key target for enhancing motor recovery during rehabilitation. Levodopa, a precursor of dopamine, is widely used in Parkinson’s disease to replenish dopaminergic deficits and has shown potential neuroplasticity-stimulating properties. Its off-label use in stroke rehabilitation has been explored to augment motor recovery, given dopamine’s role in motor learning and cortical plasticity. However, evidence has been mixed, with prior smaller studies and meta-analyses providing inconclusive results about levodopa’s efficacy in this context. Resolving this uncertainty is critical to optimizing post-stroke rehabilitation strategies and resource allocation.
Study Design
The ESTREL trial was a double-blind, placebo-controlled, multicenter randomized clinical study conducted between June 2019 and August 2024 across 13 stroke units and 11 rehabilitation centers in Switzerland. It enrolled 610 adults with acute ischemic or hemorrhagic stroke and clinically meaningful hemiparesis (NIHSS motor arm, leg, or limb ataxia score ≥3 points). Participants were randomized 1:1 to receive levodopa/carbidopa (100 mg/25 mg) or placebo three times daily for 39 days, in addition to standardized rehabilitation therapy emphasizing active task-oriented training. The primary outcome was the adjusted mean difference in motor function assessed by the Fugl-Meyer Assessment (FMA) total score—a validated, widely used scale ranging from 0 (severe impairment) to 100 (normal motor function)—at 3 months post-intervention. A 6-point difference was predefined as clinically relevant. Secondary outcomes included safety and incidence of serious adverse events.
Key Findings
Of the randomized 610 participants (median age 73 years; 41.3% female), 28 died by 3 months, yielding 582 eligible for primary analysis. Baseline median FMA total score was 34 (interquartile range: 14 to 54). At 3 months, median FMA scores were 68 (42-85) in the levodopa group and 64 (44-83) in the placebo group. The adjusted mean difference between groups was -0.90 points (95% confidence interval: -3.78 to 1.98), indicating no statistically or clinically significant improvement with levodopa (P = .54).
Serious adverse events occurred at nearly equal frequency: 126 events in the levodopa cohort versus 129 in placebo. The predominant serious adverse event was infection (levodopa: 55; placebo: 44). No unexpected safety signals emerged with levodopa use, confirming its tolerability in the acute stroke rehabilitation setting.
The lack of meaningful improvement in FMA scores suggests that levodopa’s dopaminergic enhancement does not translate into augmented motor recovery beyond what is achievable with optimized, standardized rehabilitation. This challenges prior smaller-scale studies that suggested potential benefits and highlights the importance of large, rigorously controlled trials in validating pharmacologic adjuncts in neurorehabilitation.
Expert Commentary
Stroke rehabilitation specialists have long sought adjunct therapies to potentiate neuroplasticity and functional recovery. Dopamine’s role in motor learning and synaptic plasticity provides a strong biological rationale for levodopa use. Yet, ESTREL’s robust findings underscore that pharmacologic modulation alone is insufficient; the complex interplay of lesion characteristics, timing, rehabilitation intensity, and individual patient factors likely shapes outcomes.
Limitations acknowledged by the investigators include a median baseline FMA indicating moderate impairment, which might limit generalizability to patients with milder or more severe deficits. Additionally, while the 39-day levodopa administration captures early rehabilitation phases, longer treatment or combination with other neuromodulatory techniques might warrant investigation.
Current stroke rehabilitation guidelines do not recommend routine dopaminergic agents for motor recovery outside clinical trials. ESTREL provides compelling evidence to support this stance and cautions against indiscriminate off-label levodopa use.
Conclusion
The ESTREL randomized clinical trial conclusively demonstrates that adding levodopa to standardized task-oriented rehabilitation in acute stroke patients with hemiparesis does not significantly enhance motor recovery at 3 months. Safety profiles between levodopa and placebo were comparable. These results do not support the adjunctive use of levodopa in stroke rehabilitation to improve motor outcomes, emphasizing the need for continued research into effective neurorestorative therapies. Clinicians should prioritize evidence-based rehabilitation approaches and await future advances that combine pharmacological agents with neurorehabilitation to optimize post-stroke recovery.
References
Engelter ST, Kaufmann JE, Zietz A, Luft AR, Polymeris A, Altersberger VL, Wiesner K, Wiegert M, Held JPO, Rottenberger Y, Schwarz A, Medlin F, Accolla EA, Foucras S, Kägi G, De Marchis GM, Politz S, Greulich M, Tarnutzer AA, Sturzenegger R, Katan M, Fischer U, Nedeltchev K, Schär J, Van Den Keybus Deglon K, Rapin PA, Salerno A, Seiffge DJ, Auer E, Lippert J, Bonati LH, Schuster-Amft C, Gäumann S, Chabwine JN, Humm A, Möller JC, Schweinfurther R, Bujan B, Jedrysiak P, Sandor PS, Gonzenbach R, Mylius V, Lutz D, Lienert C, Peters N, Michel P, Müri RM, Schädelin S, Hemkens LG, Ford GA, Lyrer PA, Gensicke H, Traenka C; ESTREL Investigators. Levodopa Added to Stroke Rehabilitation: The ESTREL Randomized Clinical Trial. JAMA. 2025 Sep 22:e2515185. doi: 10.1001/jama.2025.15185. Epub ahead of print. PMID: 40982270; PMCID: PMC12455486.
Additional references for context:
– Cramer SC et al. (2011). Emerging Treatments for Stroke Recovery. Stroke, 42(2), 527-533.
– Boyd LA, Hayward KS. (2022). Stroke Neurorehabilitation. Continuum (Minneap Minn), 28(1), 41-67.
