Levodopa for Stroke Rehabilitation: Why a Negative Trial Doesn’t Tell the Whole Story

Berlin, Germany – A large-scale clinical trial has cast doubt on the common practice of adding levodopa to rehabilitation programs for stroke patients. The study, known as ESTREL – Enhancement of Stroke Rehabilitation With Levodopa – found no significant benefit in motor recovery when the medication was administered alongside standard rehabilitation therapy. The findings, published in JAMA, challenge existing beliefs about the drug’s potential to enhance neuroplasticity and improve outcomes after stroke.

Stroke remains a leading cause of long-term disability worldwide. According to the World Health Organization, approximately 10 million people experience a stroke each year, and nearly 6 million die as a result. For those who survive, regaining motor function is a primary goal of rehabilitation. Levodopa, a medication commonly used to treat Parkinson’s disease, has been explored as a potential adjunct to stroke rehabilitation due to its ability to increase dopamine levels in the brain, which are often disrupted after a stroke. However, the evidence supporting its effectiveness has been mixed.

The ESTREL trial, conducted across 13 Swiss stroke centers and 11 rehabilitation clinics, aimed to definitively answer this question. Researchers randomly assigned 610 patients with acute ischemic or hemorrhagic stroke – those experiencing weakness on one side of the body – to receive either levodopa/carbidopa (100 mg/25 mg three times daily) or a placebo for 39 days, in addition to standardized rehabilitation based on active task-oriented training. The primary outcome measure was the Fugl-Meyer Assessment (FMA) total score at three months, a widely used tool to assess motor function in stroke patients. A 6-point difference on the FMA is considered clinically relevant.

Levodopa and Stroke Rehabilitation: The ESTREL Trial Findings

The results of the ESTREL trial, conducted between June 14, 2019, and August 27, 2024, revealed a surprisingly small difference between the two groups. The adjusted mean difference in FMA total score at three months was -0.90 points (95% Confidence Interval: -3.78 to 1.98). This indicates that adding levodopa did not significantly improve motor recovery compared to placebo.

Researchers noted that 28 participants died by the three-month mark, leaving 582 participants eligible for the primary analysis. The median age of participants was 73 years, and 41.3% were female. The median baseline FMA total score was 34, indicating moderate impairment. Despite these detailed demographics, the study failed to demonstrate a benefit from levodopa supplementation.

The study’s findings, led by Prof. Stefan Engelter, Dr. Josefin Kaufmann, Prof. Henrik Gensicke and PD Dr. Christopher Tränka from University Geriatric Medicine FELIX PLATTER & University Hospital Basel, challenge long-held assumptions in stroke rehabilitation. The research team suggests that the widespread use of levodopa in stroke rehabilitation may require to be re-evaluated.

Understanding the Fugl-Meyer Assessment

The Fugl-Meyer Assessment (FMA) is a performance-based impairment index used to assess the motor function of patients following a stroke. It evaluates movement across three domains: upper extremity, lower extremity, and trunk. Each domain is scored separately, with higher scores indicating better function. The total FMA score ranges from 0 to 100, with 0 representing complete paralysis and 100 representing normal function. Clinicians use the FMA to track a patient’s progress during rehabilitation and to identify areas where further intervention is needed. A 6-point difference on the FMA is generally considered to be a clinically meaningful improvement, representing a noticeable change in a patient’s ability to perform daily activities.

Why the Lack of Benefit? Exploring Potential Factors

While the ESTREL trial provides strong evidence against the routine use of levodopa in stroke rehabilitation, researchers acknowledge that the results may not tell the whole story. The original editorial accompanying the publication of the trial results suggested that the null result might mask clinically relevant heterogeneity, meaning that the drug may be beneficial for certain subgroups of patients but not others. Several potential effect modifiers were not examined in the study.

One possibility is that the timing of levodopa administration is crucial. The ESTREL trial began levodopa treatment relatively late after the stroke, potentially missing a critical window for neuroplasticity. Another factor could be the severity of the stroke. Levodopa might be more effective in patients with specific types of stroke or with less severe impairments. Individual differences in dopamine pathways and receptor sensitivity could influence the response to levodopa. Future research should investigate these potential effect modifiers to identify which patients, if any, might benefit from levodopa supplementation.

The study’s design, a double-blind, placebo-controlled randomized clinical trial, is considered the gold standard for evaluating the effectiveness of medical interventions. This rigorous methodology strengthens the reliability of the findings. However, it’s important to note that the study focused on patients with clinically meaningful hemiparesis, defined as a score of at least 3 points on specific items of the National Institutes of Health Stroke Scale (NIHSS). This inclusion criterion means that the results may not be generalizable to all stroke patients.

The Role of Dopamine in Stroke Recovery

Dopamine is a neurotransmitter that plays a critical role in motor control, motivation, and reward. After a stroke, damage to brain regions involved in dopamine production and transmission can lead to motor impairments and reduced motivation to engage in rehabilitation. Levodopa is a precursor to dopamine, meaning that it can be converted into dopamine in the brain. The rationale for using levodopa in stroke rehabilitation is that increasing dopamine levels might stimulate neuroplasticity – the brain’s ability to reorganize itself by forming novel neural connections – and thereby enhance motor recovery.

However, the relationship between dopamine and stroke recovery is complex. While dopamine is essential for motor function, excessive dopamine levels can also have adverse effects. The brain’s response to dopamine can change after a stroke, making it difficult to predict how patients will respond to levodopa. The ESTREL trial suggests that simply increasing dopamine levels is not enough to improve motor recovery in most stroke patients.

Implications for Clinical Practice and Future Research

The findings of the ESTREL trial have significant implications for clinical practice. The study suggests that routinely adding levodopa to stroke rehabilitation programs is not justified, given the lack of demonstrated benefit and the potential for side effects. Clinicians should carefully consider the risks and benefits of levodopa before prescribing it to stroke patients.

Future research should focus on identifying subgroups of stroke patients who might benefit from levodopa. This could involve investigating the effects of levodopa in patients with specific stroke subtypes, different levels of impairment, or variations in dopamine-related genes. Studies should also explore the optimal timing and dosage of levodopa administration. Research is needed to identify other potential pharmacological interventions that could enhance neuroplasticity and improve stroke recovery. The Swiss National Science Foundation (SNSF) funded the ESTREL study through its “Investigator Initiated Clinical Trials (IICT)” program, highlighting the importance of investigator-driven research in advancing medical knowledge.

The next steps in understanding the role of medication in stroke recovery will likely involve more targeted trials, focusing on specific patient populations and exploring alternative pharmacological approaches. The ESTREL trial serves as a crucial reminder that even well-established medications require rigorous evaluation before being widely adopted for new indications.

What are your thoughts on the ESTREL trial findings? Share your comments below, and let’s continue the conversation about stroke rehabilitation and the pursuit of better outcomes for patients.