Freezing of gait more likely to occur with long-term levodopa use

Chances of those patients experiencing it rise by about 6.04 times, study finds

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Patients who are on long-term levodopa to treat Parkinson’s disease are more likely to experience self-reported freezing of gait, or FOG, than levodopa-naïve (untreated) patients, a study has found.

These findings suggest that FOG should be taken into account when studying Parkinson’s, with “the ultimate aim to develop improved treatment strategies that carry a lower risk of causing FOG,” researchers wrote.

The study, “Exploring the levodopa-paradox of freezing of gait in dopaminergic medication-naïve Parkinson’s disease populations,” was published in npj Parkinson’s disease.

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A neurodegenerative disease, Parkinson’s is best known for causing a range of motor symptoms, from tremor and slowness of movement to stiffness and difficulty maintaining balance.

Parkinson’s patients also may experience akinesia or freezing, its most common manifestation being FOG, when they feel “glued” to the floor and unable to take a step forward, even if they intend to move.

Levodopa, the mainstay treatment for Parkinson’s, works by being converted into dopamine in the brain. In Parkinson’s, symptoms are caused mainly by a lack of dopamine, a chemical that helps control movement.

By increasing the amount of dopamine in the brain, levodopa helps ease the symptoms of the disease. However, patients who have been taking levodopa for some time may experience on-and-off fluctuations in how well symptoms are controlled.

The ‘so-called levodopa paradox’

So, while levodopa works well to ease FOG, using it over a long time actually may make FOG happen more often. “We have referred to this dual effect as the so-called levodopa paradox,” the researchers wrote.

To find out how common it is for FOG to happen as a side effect of levodopa, the researchers studied 150 levodopa-treated patients (75 from the Netherlands and 75 from Brazil) and 49 levodopa-naïve patients from Brazil.

Levodopa-treated patients had been taking the medication over a mean 5.6 years. Just more than half (51%) also received treatment with other dopamine agonists, or dopamine-increasing medications, in addition to levodopa.

The time since patients first experienced motor symptoms was at least five years, and it was on average 1.2 years longer for levodopa-treated than for levodopa-naïve patients (7.7 vs. 6.5 years).

In addition, levodopa-treated patients scored a mean seven points higher in the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III, where higher scores indicate worse motor symptoms.

Patients used the New Freezing of Gait Questionnaire

Patients were asked to self-report FOG by answering the New Freezing of Gait Questionnaire. Based on their answers, FOG occurred more often in levodopa-treated patients than in levodopa-naïve patients (27% vs. 4%).

After adjusting for disease duration and disease severity, it was found that being on long-term treatment with levodopa increased the chances of experiencing FOG by 6.04 times.

“We found an association between long-term pulsatile levodopa treatment and an increased occurrence of FOG,” the researchers wrote. “The results are in line with the levodopa paradox,” they added.

Rapid Turns and Timed Up-and-Go tests

They also evaluated FOG objectively using the Rapid Turns test — where patients complete four rapid 360-degree turns in alternating directions — and the Timed Up-and-Go test, which times patients as they stand up from a chair, walk a line, turn, return, and sit down again.

“We only observed FOG with alternating trembling of the legs or short shuffling steps, both in treated and untreated individuals,” the researchers wrote. No other manifestation of freezing was observed.

While objective FOG was more common in levodopa-treated patients (14% vs. 2%), this difference was no longer significant when factors such as country of inclusion, assessment location, disease severity, time since onset of motor symptoms and cognitive impairments were included in the analysis. However, objective FOG was associated and more likely with higher disease severity and longer time since onset of motor symptoms.

“We found a lower percentage of objective FOG compared to subjective FOG,” the researchers wrote. However, “this is readily explained by the fact that FOG is notoriously difficult to provoke in a clinical or research setting.”