New Insight Into Best Add-on Meds for Parkinson's Motor Fluctuations

Erik Greb

December 28, 2021

Dopamine agonists and dopamine reuptake inhibitors (DRIs) appear to have equal efficacy for Parkinson's disease (PD) and motor fluctuations uncontrolled by levodopa. However, some DRIs are more effective than others.

In a "pragmatic, real-life clinical trial," mean mobility score on the 39-item Parkinson's Disease Questionnaire (PDQ-39) was 2.4 points higher for patients who received an adjuvant dopamine agonist vs those who received a DRI. However, the difference was not statistically significant.

Mobility scores were better for participants receiving monoamine oxidase type B (MAO-B) inhibitors than for those receiving catechol-O-methyltransferase (COMT) inhibitors.

"To many people's surprise, adding a MAO-B inhibitor was at least as effective as adding one of the more expensive dopamine agonists," lead investigator Richard Gray, DPhil, emeritus professor of medical statistics at the University of Oxford, United Kingdom, told Medscape Medical News.

"Although the differences are small, they favor the least expensive drugs; so it makes sense to use these," Gray said.

The findings were published online December 28 in JAMA Neurology.

Head-to-Head Comparison

Even with levodopa, dyskinesias and motor fluctuations often develop over time in patients with PD. At this point in the disease course, adjuvant therapy with dopamine agonists or DRIs, which include MAO-B inhibitors and COMT inhibitors, can help address these symptoms.

However, until now there was no research directly comparing these two drug classes or the efficacy of MAO-B and COMT inhibitors.

The study, known as PD MED, included 500 patients with idiopathic PD who had developed motor complications uncontrolled with levodopa therapy, requiring the addition of another class of drug.

"Before PD MED, there had been no trials directly comparing the main drug classes used, one versus another," said Gray.

Patients were randomly assigned, in groups of equal size, to receive a dopamine agonist, a COMT inhibitor, or an MAO-B inhibitor. Clinicians could choose whichever drug from the assigned class they deemed appropriate.

The study groups were not blinded because of the long duration of the trial and the need for dose adjustments.

The study's primary outcome was functional status, as measured by the mobility domain of the PDQ-39. Secondary outcomes included other PDQ-39 domains, total PDQ-39 score, and adherence to treatment. Patients and caregivers submitted reports before randomization and at 6 months, 1 year, and annually thereafter.

The population's mean age was 73 years, and 62.8% were men. Patient characteristics at baseline were similar between the treatment groups.

The most common agents chosen for patients assigned to a dopamine agonist were ropinirole (43.2%) and pramipexole (35.0%). Common MAO-B inhibitors included oral selegiline (51.6%), rasagiline (29.5%), and sublingual selegiline (13.8%). Most patients (90.8%) assigned to a COMT inhibitor received entacapone.

Mobility Differences

Discontinuation rates were similar at 1 year for dopamine agonists (30%), MAO-B inhibitors (38%), and COMT inhibitors (36%). Discontinuation rates at 5 years also were similar.

Older age was the only baseline factor associated with treatment adherence, and adverse events were the main reason for discontinuation in all drug classes.

At a median follow-up of 4.5 years, PDQ-39 mobility scores were 2.4 points higher in the dopamine agonist group vs the MAO-B and COMT inhibitor groups combined, but this was not statistically significantly different. The researchers also did not find significant differences between the two groups on other measures.

However, PDQ-39 mobility score was a significant 4.2 points higher in the MAO-B inhibitor group than in the COMT inhibitor group (P = .03). The MAO-B inhibitor group also had higher scores for activities of daily living (4 points, P = .03), emotional well-being (4.4 points, P = .009), and social support (3.7 points, P = .01).

Rate of dementia onset was lower in the MAO-B inhibitor group (32%) than in the COMT inhibitor group (37%), as was mortality (55% vs 63%, respectively). However, neither difference was statistically significant.

Mobility and overall quality of life were better when a dopamine agonist or an MAO-B inhibitor was added vs adding a COMT inhibitor, as revealed by patient reports.

Gray noted the PD MED study included typical patients who received treatment as they would in a real-world clinical practice. In addition, the patient population was large enough to ensure the statistical reliability of the findings.

"The results can be trusted and are generalizable into routine practice," Gray said.

Strengths, Limitations

Commenting on the study for Medscape Medical News, Peter Hedera, MD, PhD, Raymond Lee Lebby Endowed Chair of Parkinson’s Disease Research and director of the Movement Disorders Program at the University of Louisville, Kentucky, said there are few head-to-head drug trials.

However, the limitations placed on the study clinicians' practice, which were necessary to compare the various drug classes, introduced a certain artificiality to the study, said Hedera, who was not involved in the research.

"Very commonly, you'd use a combination of COMT and MAO-B inhibition together," he noted.

The advantage of MAO-B inhibitors is their greater effect on nonmotor symptoms compared with COMT inhibitors, he said. "It's almost unfair to compare them, because the pharmacology is much more complex for MAO-B inhibition," said Hedera.

This difference could partially explain the apparent superiority of MAO-B inhibitors over COMT inhibitors.

"It's still a good study, a very useful study in showing the relative value of these classes of medication as adjuvant therapies," said Hedera.

Levodopa remains the keystone of PD treatment, but there are limitations on its maximum dose, he added.

"We shouldn't hesitate to use adjuvant therapy if indicated, if the motor control is not achieved," Hedera concluded.

The study was funded by the Health Technology Assessment Program of the UK National Institute for Health Research (NIHR), the UK Department of Health and Social Care, the UK Medical Research Council, and Parkinson's UK. Gray received grants from the Health Technology Assessment Program of the UK NIHR during the study. Hedera has reported no relevant financial relationships.

JAMA Neurology. Published online December 28, 2021. Abstract.

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