The trial’s findings will dampen enthusiasm for the drug in stroke recovery, though research questions remain, one expert says.
The addition of levodopa doesn’t improve motor function among patients receiving inpatient rehabilitation therapy after an acute stroke, according to the results of the placebo-controlled ESTREL trial.
Overall, motor function increased at 3 months for all patients enrolled, with no difference seen between study and control groups, lead author Stefan Engelter, MD (University of Basel, Switzerland), and colleagues report in a paper published online this week in JAMA.
Secondary outcomes were unaffected by adjunct levodopa as well, leading researchers to conclude that the “results do not support routine use of levodopa for motor recovery in unselected patients with stroke undergoing rehabilitation.”
Steven Cramer, MD (University of California, Los Angeles), who wasn’t involved in the study, called the results disappointing.
We were hoping this would be positive. Steven Cramer
The ESTREL Trial
Levodopa is a dopaminergic drug that stimulates neuroplasticity, thought to potentially help the brain heal after an acute stroke. A small 53-patient trial published in 2001 demonstrated a benefit for motor recovery when combined with physiotherapy but subsequent trials didn’t replicate those results. Still, levodopa is used in some stroke rehabilitation centers despite the lack of robust efficacy evidence.
ESTREL was conducted at 13 stroke units and centers, along with 11 collaborating rehab centers in Switzerland between June 2019 and August 2024. The researchers enrolled 610 patients (median age 73 years; 41.3% female) who had had an acute ischemic or hemorrhagic stroke within the last 7 days and had clinically meaningful hemiparesis, defined by a score of 3 or more on three NIHSS items: motor arm, motor leg, and limb ataxia.
Patients were randomized to levodopa 100 mg/carbidopa 25 mg or placebo administered orally three times daily for 39 days, in addition to standardized rehab therapy designed to improve motor function. After excluding patients who died before 3 months, there were 582 patients available for the primary analysis.
The primary outcome was the between-group difference in the Fugl-Meyer Assessment (FMA) total score—which ranges from 0-100, with lower scores indicating poorer motor function—at 3 months. At baseline, median FMA total score was 34 points and at follow-up, it was 68 points in the levodopa group and 64 in the placebo group. The mean difference between groups of -0.90 points was not significant (P = 0.54).
A similar number of serious adverse events were seen in the two groups (126 with levodopa and 129 with placebo). The most common was infection.
Final Word?
The authors leave room for additional research on the impact of levodopa in stroke rehab, noting that it’s possible some patients derive a benefit and others harm, resulting in the neutral overall effect seen in this trial.
“To better understand the trial results in the context of the current evidence, subgroup analyses using individual participant data, including previous trials and analyses on recovery trajectories, would be valuable,” they write.
Cramer, too, indicated an opportunity for further studies of levodopa as an adjunct in stroke rehab and its effect on increasing dopamine. “There’s a lot of reasons to think if you turn that up to 11, that somebody will like the rehab more, somebody will learn more, somebody will have more brain rewiring, and to some extent that works well in animals.”
With the ESTREL trial failing to replicate the benefits seen in the earlier small trial, “a lot of us in the field let out a sad sigh,” Cramer said, adding that “we have one less therapeutic candidate for which we had high hopes.”
Over the short term, these results are likely to dampen enthusiasm for levodopa used in stroke recovery, but it’s not the end of the line overall, he indicated. Though it’s possible the drug simply doesn’t work in this setting, it’s also possible that other issues—like treatment timing and the type of rehab used—could have influenced the results, he said.
“We don’t know quite enough about the training regimen here,” Cramer said. “No doubt it was good, but was it intense enough? That’s at least a thought when asking the question: is it possible that this might work in a different population or in a different protocol?”
There will be additional studies looking at use of levodopa in different populations and in conjunction with various types of training.
“The authors are to be congratulated for designing and completing and analyzing a very large study,” Cramer said. “This was a major effort that was meticulously done, and the team deserves our congratulations and gratitude.”