Review of adjuvant therapies in PD when levodopa is tapering


Levodopa is the standard of care for people with Parkinson’s disease (PD), but many patients develop complications in which motor symptoms worsen as the disease progresses and are no longer controlled by therapy.

A study published in JAMA Neurology reported the results of a randomized clinical trial, conducted primarily in the UK, which examined the quality of life (QOL) of patients when adding different adjuvant therapies to levodopa to help control dyskinesia and a flare-up of symptoms during OFF periods or as disease progresses.

Other classes of drugs are then usually added to the patient’s regimen, namely dopamine agonists and dopamine reuptake inhibitors (DRIs), which include catechol-O-methyltransferase (COMT) inhibitors and monoamine oxidase type B (MAO-B) inhibitors.

It is unclear, however, which class of drugs are preferred by patients, the researchers wrote. To date, indirect comparisons have suggested that dopamine agonists have greater efficacy and that the efficacy of COMTs or MAO-B inhibitors are comparable. Without direct comparisons, the authors warned, this idea is misleading.

The current study stems from Parkinson Disease Medication, a randomized clinical trial (RCT) that compared drug classes used as initial and adjuvant treatment for PD. An open-label, pragmatic semi-factorial (2 × 1) multicenter RCT then examined adjuvant therapy only. Patients with idiopathic PD were included if they developed motor complications uncontrolled by levodopa, alone or in combination with a dopamine agonist or MAO-B inhibitor, and there was uncertainty about the drug class to add next. Patients with dementia were excluded.

The researchers first wanted to determine whether a DRI (either a MAO-B or COMT inhibitor) or a dopamine agonist was more effective as an add-on treatment to levodopa, taking into account the quality of life. Second, they wanted to know if a DRI was more effective, which class of drugs is better for patient-reported quality of life for motor complications – COMTs or MAO-B inhibitors?

The study recruited patients with advanced PD from 64 neurology and geriatrics practices (62 in the UK, 1 in the Czech Republic and 1 in Russia) between February 23, 2001 and December 15, 2009; the data was analyzed between 2017 and 2020.

Five hundred patients with uncontrolled motor complications were randomized on a 1:1:1 basis to receive a dopamine agonist, COMT inhibitor, or MAO-B inhibitor, within the following limits:

  • Patients who were on dopamine agonist for uncontrolled motor complications could be randomized only to COMT or MAO-B inhibitor
  • Patients receiving a MAO-B inhibitor at the onset of motor complications and patients for whom the clinician considered a MAO-B inhibitor to be contraindicated could be randomized only to a COMT inhibitor or a dopamine agonist

Due to the nature of the study, blinding was not possible. During the study, providers could adjust medications within the same drug class and, if symptoms were not controlled, could add or switch to a new treatment from a different drug class.

Almost 63% of participants were male, with a mean (SD) age of 73.0 (8.2) years, and the median follow-up was 4.5 years (range: 0-13.3 years) .

The primary outcomes, which were assessed before study entry, at 6 and 12 months after randomization, and annually thereafter, were the Parkinson’s Disease Questionnaire (PDQ) mobility domain scores -39) to 39 items, which range from 0 to 100 points, with scores indicating greater difficulty.

Secondary outcomes included the EuroQol generic 5-dimensional, 3-level quality of life measure (EQ-5D-3L) (score range, -0.59 to 1.00 points, highest scores indicating a better health-related quality of life).

Statistical analysis included repeated measures and log-rank analyzes in an intention-to-treat approach.

The most notable finding of the study was that participants in the MAO-B group had mean PDQ-39 mobility scores of 4.2 points (95% CI, 0.4-7.9 points; P = .03) higher than those of the COMT group.

Additionally, participants in the MAO-B group had EQ-5D-3L utility scores of 0.05 points (95% CI, 0.003-0.09 points; P = 0.04) better than the COMT group.

These results were consistent with previous indirect comparisons, the authors noted, and there was no benefit to examining dopamine agonists over MAO-B and COMT together.

The dopamine agonist group had a mean PDQ-39 mobility score 2.4 points higher (95% CI, -1.3 to 6.0 points) than the combined MAO-B and COMT groups, but the difference was not statistically significant (P = .20). The researchers speculated that this could be because there were fewer randomized participants in this group.

Comparing MAO-B inhibitors with COMT inhibitors yielded only nonsignificant improvements in the PDQ-39 summary index (mean difference, 2.2 points; 95% CI, -0.2 at 4.5 points; P = 0.07) as well as non-significant reductions in dementia (rate ratio [RR], 0.70; 95% CI, 0.47-1.03; P = 0.07) and mortality (RR, 0.76; 95% CI, 0.56-1.03; P = 0.07).

When dopamine agonists were compared only to MAO-B inhibitors, the results were similar.

Although a cost-effectiveness analysis remains to be done, the authors noted that MAO-B inhibitors are less expensive than COMT inhibitors.

The study had several strengths, such as the fact that it used a National Hospital Registry database with a median follow-up of almost 5 years. Regarding limitations, the study was open-label, but the authors stated that the performance and reporting biases that sometimes occur in these studies would have been more likely to reduce, not increase, treatment differences. in this case.


Gray R, Oatek S, Ives N, et al; PD MED Collaborative Group. Long-term efficacy of adjuvant therapy with catechol-o-methyltransferase or monoamine oxidase b inhibitors compared with dopamine agonists in patients with Parkinson’s disease not controlled by levodopa: the randomized clinical trial PD MED. JAMA Neurol. 2022;79(2):131–140. doi:10.1001/jamaneurol.2021.4736


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