Objective: This sub-analysis of the REONPARK study aims to identify predictive factors for the greater effectiveness of COMT inhibitors (COMTi) in alleviating motor complications in Parkinson’s disease (PD) patients with early motor fluctuations.

Background: Levodopa (L-dopa) remains the gold standard for PD treatment, but chronic use at high doses (>4 – 5.6 mg/kg/day) increases the risk of motor complications, such as wearing-off episodes and dyskinesia [1-2]. Since COMTi extend L-dopa’s half-life and reduce peak-trough fluctuations, optimizing levodopa dosing [3], this study examines whether introducing COMTi at lower L-dopa doses impacts the progression of motor complications in clinical practice.

Method: A cohort from the REONPARK study was categorized into three L-dopa dosing groups: group 1 (<4.5 mg/kg/day, n=24), group 2 (4.5-7.5 mg/kg/day, n=33), and group 3 (>7.5 mg/kg/day, n=14). The likelihood of improvement in the MDS-UPDRS part IV score after 12 months was assessed using logistic regression, focusing on predictors of motor complication progression.

Results: Baseline MDS-UPDRS IV scores and L-dopa doses at COMTi initiation were significant predictors of motor complication progression. Patients receiving less than 4.5 mg/kg/day had a 3.70-fold higher likelihood of improving their MDS-UPDRS IV scores after 12 months of COMTi initiation compared to those receiving 4.5–7.5 mg/kg/day (p=0.043). Similarly, they had a 5.26-fold higher likelihood of improvement compared to those receiving more than 7.5 mg/kg/day (p=0.037) [Table 1] [Figure 1]. The logistic regression model demonstrated good predictive performance, with an area under the ROC curve (AUC) of 0.74.

Conclusion: Initiation of COMTi at lower L-dopa doses are associated with a higher probability of improving motor complications after 12 months. These findings suggest that optimizing L-dopa dosing by introducing COMTi at lower L-dopa doses may be key to long-term improving dyskinesias and motor fluctuations in PD patients.

Table 1

Figure 1

References: 1. Sharma, J.C. et al. (2006) ‘Cascade of levodopa dose and weight-related dyskinesia in parkin-son’s disease (LD–WD-PD Cascade)’, Parkinsonism & Related Disorders, 12(8), pp. 499–505. doi:10.1016/j.parkreldis.2006.07.002.
2. Olanow, C. et al. (2013) ‘Factors predictive of the development of levodopa‐induced dyskinesia and wearing‐off in parkinson’s disease’, Movement Disorders, 28(8), pp. 1064–1071. doi:10.1002/mds.25364.
3. Jenner, P. et al. (2021) ‘Redefining the strategy for the use of COMT inhibitors in parkinson’s disease: The role of opicapone’, Expert Review of Neurotherapeutics, 21(9), pp. 1019–1033. doi:10.1080/14737175.2021.1968298.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/early-introduction-of-comt-inhibitors-at-low-levodopa-doses-improves-long-term-motor-complications-in-parkinsons-disease-a-sub-analysis-of-the-reonpark-study/