Add-on therapies to levodopa improve pain modulation in Parkinson's disease with motor fluctuations: A prospective cohort study

Background: Pain is a common and often underestimated non-motor symptom in Parkinson's disease (PD), affecting quality of life (QOL) and frequently associated with motor fluctuations. Although the pathophysiological mechanisms underlying pain in PD remain unclear, most hypothesize the involvement of dopaminergic and non-dopaminergic pathways. Objective: To evaluate the effect of MAO-B and COMT inhibitors, used as add-on therapies to levodopa, on pain thresholds in people with PD (pwPD) with motor fluctuations, either with or without pain. Methods: This prospective cohort study enrolled 40 pwPD with motor fluctuations who were started on selegiline, rasagiline, safinamide, or opicapone. Pain thresholds (tactile, pain, and tolerance) were assessed using electrical stimulation at baseline and after 3 and 6 months. Normative data were collected from 11 healthy subjects. Outcome measures in pwPD targeted motor impairment (UPDRS), pain perception (King's PD Pain Scale), mood, fatigue, sleep, and QOL. Results: PwPD showed higher tactile thresholds and lower pain and pain tolerance thresholds than controls. At 6 months, both rasagiline and safinamide significantly improved pain thresholds and tolerance compared to opicapone. Experiencing pain was more frequent in women and was associated with anxiety, poor sleep, and motor complications. Regression analyses revealed that cognitive status, sex, disease duration, age, anxiety levels and treatment with MAO-B inhibitors were key modulators of pain processing. Conclusion: Pain processing is altered in pwPD, independently of subjective pain complaints. MAO-B inhibitors, particularly safinamide and rasagiline, appear to restore pain thresholds and improve QOL, supporting their role in managing pain in PD.