Is Levodopa Neurotoxic?

Is early levodopa treatment hazardous?

Most patients on levodopa (Sinemet®) develop motor fluctuations (dyskinesias, on-off, freezing, etc.) starting about 5 years after beginning levodopa treatment. Such motor fluctuations are not typically seen in patients treated solely with dopamine agonists (Pramipexole (Permax®), Ropinerole (Requip®), Pergolide (Permax®), Bromocriptine (Parlodel®)) until levodopa is added. This observation has led to the speculation that levodopa is somehow responsible for a neurotoxic effect that induces these fluctuations. Because of concern about earlier induction of motor fluctuations, most movement disorder specialists recommend avoiding levodopa (Sinemet®) treatment early in the course of the disease, and using agonist drugs instead in young (<70-75 year old) patients. Older patients do not tolerate agonists as well as younger patients and early treatment with levodopa may be the best approach in these patients.

Whether the apparent earlier motor fluctuations in levodopa-treated patients is truly a toxicity or just a reflection of a later stage of the disease is unknown. In patients without Parkinson's treated with high dose levodopa there is no evidence of neurotoxic effects. There is some evidence that patients initially treated with agonists will develop motor fluctuations after levodopa is added to the same extent as patients who have been treated with levodopa from onset, if the time from onset of the condition is the same. One study reported 4/2002 at the American Academy of Neurology meeting compared patients begun on fixed dose levodopa with those on fixed dose pramipaxole. Patients could have additional open label levodopa added. At the conclusion of the study, the patients in the levodopa-only arm had more non-disabling dyskinesias but were better functionally (i.e. had better mobility) than patients in the pramipaxole arm.

The Quality Standards Subcommittee of the American Academy of Neurology concluded that in Parkinson's Disease patients who require the initiation of dopaminergic treatment either levodopa or a dopamine agonist may be used. The choice depends on the relative impact of improving motor disability (better with levodopa) compared with the lessening of motor complications (better with agonists) for each individual patient.

There is no advantage to starting with controlled-release (Sinemet CR®) versus immediate release levodopa (sometimes called "regular Sinemet") in the rate of motor complications at 5 years.

In any case, if the neurologist makes the decision to begin treatment with levodopa rather than an agonist, it is suggested to "go low and go slow" with dosing and dose titration, to reduce side effects and improve tolerability and compliance.