Efficacy and safety of adjunctive oral therapy in Parkinson’s disease with motor complications: a systematic review and network meta-analysis: a systematic review and network meta-analysis

Background The aim of this manuscript is to review the evidence and compare the efficacy and safety of catecholO-methyltransferase inhibitors (COMT-Is), dopamine receptor agonists (DRAs) and monoamine-oxidase B inhibitors (MAOB-Is) as adjunctive treatment to levodopa in patients with Parkinson’s disease (PD) experiencing motor complications. Methods In this systematic review and network meta-analysis, literature searches were performed in MEDLINE and Embase to identify eligible randomised controlled trials (RCTs) with a minimal follow-up of at least 4 weeks published in English between 1980 and 2021. RCTs were included if either a COMT-I, DRA or MAOB-I was evaluated as an adjunctive therapy to levodopa in patients with PD experiencing motor complications and dyskinesia. The main outcomes included daily off-medication time, motor and non-motor examination scales, and adverse events including dyskinesia. Results 74 RCTs reporting on 18 693 patients were included. All three studied drug classes decreased daily off-medication time compared with placebo (COMT-Is mean −0.8 hours (95% CI −1.0 to −0.6), DRAs −1.1 hours (95% CI −1.4 to −0.8), MAOB-Is −0.9 hours (95% CI −1.2 to −0.6)). Safety analysis showed an increased risk of dyskinesia for all three drug classes (COMT-Is OR 3.3 (95% CI 2.7 to 4.0), DRAs 3.0 (95% CI 2.5 to 3.5), MAOB-Is 1.6 (95% CI 1.2 to 2.2)). According to surface under the cumulative ranking curve scores, pramipexole IR was associated with the most favourable benefit–risk profile. Conclusions COMT-Is, DRAs and MAOB-Is effectively reduce motor complications and increase incidence of dyskinesia. In the network meta-analysis, adjunctive use of DRAs appeared most effective.