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Highlights of the AAN Updated Guideline on Treating Motor Symptoms in Early Parkinson's Disease

Article In Brief

An updated guideline from the AAN offers guidance to clinicians on how and when to prescribe levodopa to patients with Parkinson's disease, as well as how to monitor and screen for adverse events.

Levodopa is more beneficial for patients with early Parkinson's disease (PD) who are experiencing motor symptoms than dopamine agonists, according to an updated AAN clinical practice guideline published in the November 16 issue of Neurology.

In developing their conclusions, the 23-person author panel searched for peer-reviewed studies of people with early PD that have been published on MEDLINE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov through June 2020. Their final analysis was based on 59 articles that were each reviewed by two panel members.

Lead author Tamara Pringsheim, MD, FRCPC, FAAN, professor of clinical neurosciences at the University of Calgary Cumming School of Medicine in Alberta, Canada, spoke with Neurology Today about how neurologists should apply the updated guideline to their practice.

Why has the committee chosen to update the guideline?

It's been quite some time since the original guidelines were published. The original guideline, the Initiation of Treatment for Parkinson's Disease, came out in 2002. There's new information on the treatment of PD every year so we need to make sure we are continuously updating our guidance to reflect new information that comes out.

How has the guideline changed?

While there has been a lot more information, and we have more evidence to support our conclusions, there are not dramatic changes in the guidance. But I think by incorporating new data, it allows us to feel more confident in the evidence and the recommendations we are making.

Is the standard of care to start patients with early PD on levodopa?

Yes, and that is something we come out saying in this guideline, which I think will be helpful for neurologists. If your patient with early Parkinson's disease requires treatment for motor symptoms, you should recommend levodopa as the initial preferred treatment since it has the greatest treatment effect.

How does the guideline define early PD?

For the purposes of this guideline, we define early disease as people who were in the Hoehn and Yahr stage 1 or 2, or within two years of disease onset.

What are other key takeaways from the guideline?

We have to recognize the potential factors that should influence our decision regarding the use of treatments in Parkinson's disease. When we start treatments there are basically two options for motor symptoms: levodopa and dopamine agonists. For several years, neurologists were preferentially prescribing the dopamine agonists in early disease, but it's become clear over time that dopamine agonists have some important adverse effects that patients need to be screened for and counseled about.

Your choice of dopaminergic therapy has to consider whether patients are at higher risk of developing these potentially impairing adverse effects as well as whether they are at high risk for development of dyskinesias.

Your initial choice of therapy has to be quite nuanced and so it requires thought. I think that a lot of people were hesitant to prescribe levodopa as the initial treatment because of dyskinesias. Levodopa-induced dyskinesias are more frequent in people who we start on levodopa, but the risk of disabling dyskinesias is relatively low and patients have a better motor response with levodopa compared with dopamine agonists.

How do you know dopamine agonists were being prescribed more often than levodopa?

We didn't systematically review the pharmaco-epidemiological data on the topic, but I know this based on the culture of practice. I've been in practice now for 15 years and I know that 15 years ago, most patients were started on dopamine agonists rather than levodopa as initial treatment in early PD.

When dopamine agonists first came out, they were commonly used at high doses. With time, physicians and patients started seeing problems associated with these medications, including impulse control disorders and the devastating effects caused by them. Over time, neurologists have become more conservative with the use of these medications. We try to use the lowest effective dose, and avoid starting them in older patients. We also are very careful about using these medications in people who have important risk factors like a history of impulse control disorders, pre-existing cognitive impartment, hallucinations, or sleepiness. Neurologists are much more mindful of contraindications or potential patients who would not do well on the medication.

What are the challenges in treating early PD?

One of the challenges is some phobia of levodopa among patients. Patients read things on the internet and become afraid of taking levodopa, which is our best treatment. We are trying to convince them that there can be a meaningful improvement in their quality of life with this medication, and that they can do well on this medication for a long time. I'd say one of the challenges is dispelling the myth and getting patients to feel comfortable using the treatment. In early disease, patients experience a great deal of benefit with levodopa for motor symptoms. As a clinician, it is quite satisfying to treat patients with Parkinson's disease because they respond quite well to the medication and you can make a meaningful improvement in their quality of life.

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“One of the challenges is some phobia of levodopa among patients. Patients read things on the internet and become afraid of taking levodopa, which is our best treatment. We are trying to convince them that there can be a meaningful improvement in their quality of life with this medication, and that they can do well on this medication for a long time.—DR. TAMARA PRINGSHEIM

Why might patients be reluctant to take levodopa? How does this guideline help neurologists minimize adverse effects?

Some patients want to delay their treatment with levodopa because they are afraid of developing dyskinesias. I don't think that is what we need to do. I think levodopa makes the biggest impact on motor symptoms. We should be treating patients early with levodopa, but we should be mindful of the dose. We provide specific guidance in terms of dosing of levodopa early in disease. In the rationale for recommendation 2, we discuss evidence that benefit is seen at a dosage of 300 mg per day, and that there is a lower risk of dyskinesia with dosages less than 400 mg per day. That gives clinicians some guidance on prescribing levodopa, but keeping the dosage low. We make the recommendation that you should prescribe the lowest effective dose, that is, the lowest dosage that provides adequate systematic benefit to minimize risk of dyskinesia and other adverse effects.

According to the guideline, studies demonstrate that levodopa provides more improvement in motor scores as compared with dopamine agonists up to five years after initiation of treatment. What should be taken into account after those first five years?

It's very hard to do well-controlled, double-blinded studies that are very long term. What happens over time is more and more patients have levodopa added to their treatment. Because the dopamine agonists don't have as great an effect on motor function, more and more patients who were initially randomized to dopamine agonists are also taking levodopa over time so it becomes harder and harder to tell the difference between the two groups.

What are other important points about treating early motor symptoms that neurologists should know about?

One of the other takeaways is that early in the disease, clinicians should prescribe immediate-release levodopa. There is no evidence to suggest that using a controlled release or an extended release or levodopa in combination with entacapone provides any benefit in early disease. Clinicians should prescribe the lowest effective dosage of the medication to minimize the risk of dyskinesia and other adverse effects.

We provide guidance on routine monitoring that clinicians should perform when patients are started on levodopa and also how the medication should be taken. For dopamine agonists, we provide guidance on screening patients for adverse effects related to dopamine agonists and how to choose between formulations. Because there's no significant difference between the formulations of dopamine agonists in terms of efficacy, the choice should integrate patient preferences concerning formulation, mode of administration, as well as cost.

Disclosures

Dr. Pringsheim had no disclosures.

Link Up for More Information

• Pringsheim T, Day GS, Smiith DB, et al; on behalf of the Guideline Subcommittee of the AAN. Dopaminergic therapy for motor symptoms in early Parkinson disease practice guideline summary: A report of the AAN Guideline Subcommittee. Neurology 2021;97(20):942–957.
• Miyasaki JM, Martin W, Suchowersky O, Weiner WJ, Lang AE. Practice parameter: Initiation of treatment for Parkinson's disease: An evidence-based review https://n.neurology.org/content/58/1/11.long. Neurology 2002;58(1):11–17.