Levodopa trial for poststroke recovery misses mark

Incorporating levodopa into standardized rehabilitation therapy does not confer meaningful benefits in terms of motor function in patients recovering from stroke, as shown in the ESTREL trial.

At 3 months, the primary outcome of the Fugl-Meyer Assessment (FMA) total score increased from a median of 34 points at baseline to 68 points in the levodopa arm and to 64 points in the placebo arm. The difference of –0.9 points (95 percent confidence interval [CI], −3.78 to 1.98) between the two arms was not significant (p=0.54). [JAMA 2025;doi:10.1001/jama.2025.15185]

A total of 255 serious adverse events (AEs) occurred, 126 in the levodopa arm and 129 in the placebo arm. The most frequent serious AE was infection. As for prespecified AEs of interest (ie, possibly related to levodopa therapy), 79 and 67 events were documented in the levodopa and placebo arms, respectively. The most common was confusion in the levodopa arm and hallucinations in the placebo arm.

“In ESTREL, levodopa/carbidopa treatment—administered in addition to rehabilitation therapy based on active task-oriented training—showed neither benefit regarding motor recovery nor harm after acute stroke,” according to the investigators.

“Furthermore, none of the secondary outcomes showed a difference between the treatment arms,” they added.

The 3-month results for the levodopa arm were comparable to that for the placebo arm across the following measures: overall quality of life (mean difference in PROMIS-29 scores, –0.37 points, 95 percent CI, –3.34 to 2.61), motor function in the upper extremity (mean difference in FMA score, −0.73 points, 95 percent CI, −2.97 to 1.50) and the lower extremity (mean difference in FMA score, −0.13 points, 95 percent CI, −1.02 to 0.77), overall neurological status (mean difference in NIHSS score, −0.14 points, 95 percent CI, −0.61 to 0.33), and mobility (mean difference in mean Rivermead Mobility Index score, −0.33, 95 percent CI, −1.04 to 0.37).

These findings strengthen the case against using levodopa to improve motor recovery after a stroke, the investigators said. They confirm similar findings from the Dopamine Augmented Rehabilitation in Stroke trial, which showed that walking ability after stroke did not improve in patients treated with levodopa compared with placebo, and stand in contrast with the results of a recent meta-analysis and existing clinical practices suggesting the drug is helpful. [Efficacy Mech Eval 2019;doi:10.3310/eme06050; Eur Stroke J 2024;9:1093-1102; Eur Neurol 2012;68:28-33]

Genetic differences at play

“Levodopa is a dopamine precursor that enhances dopaminergic signalling and may stimulate neuroplasticity, which could potentially enhance motor recovery after stroke. This drug is used in stroke rehabilitation despite mixed evidence for its effectiveness,” the investigators noted.

They emphasized that interindividual patient differences could potentially modify the effect of levodopa in enhancing motor recovery. “It is possible that some patients might benefit from levodopa-enhanced rehabilitation while others experience harm,” owing to genetic polymorphisms of the dopaminergic system. [PLoS One 2013;8:e61197]

To get a clearer picture of the role of levodopa in poststroke recovery, future studies with detailed subgroup analyses using data from multiple trials should be conducted, according to the investigators. These analyses should include biomarkers, genetic information, and brain imaging to see if specific patient characteristics influence response to the drug, they added.

ESTREL included 610 participants (median age 73 years, 41.3 percent female, median baseline FMA total score 34 points) with acute ischaemic or haemorrhagic stroke that led to clinically meaningful hemiparesis (ie, a total score of ≥3 points on the following NIHSS items: motor arm, motor leg, or limb ataxia) who were required to undergo in-hospital rehabilitation based on active task-oriented training.

The participants were randomly assigned to receive levodopa/carbidopa at 100 mg/25 mg (n=307) or placebo (n=303) three times daily for 39 days, alongside standardized rehabilitation therapy. A total of 28 participants died by 3 months, leaving 582 (95.4 percent) eligible for the primary analysis.