Levodopa Response in Patients With Early Parkinson Disease

Abstract

Background and objectives:The Levodopa in EArly Parkinson´s disease (LEAP) study enabled us to conduct post-hoc analyses concerning the effects of levodopa in patients with early Parkinson’s disease.Methods:The LEAP-study was a double-blind, placebo-controlled, randomized, delayed-start trial in which patients with early Parkinson’s disease were randomized to receive levodopa/carbidopa 300/75 mg daily for 80 weeks (early-start group) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed-start group). We analyzed the effect of levodopa with the Unified Parkinson’s Disease Rating Scale on bradykinesia, rigidity, and tremor. At week 80, participants answered three questions regarding motor response fluctuations.Results:A total of 222 patients were randomized to the early-start group (mean±SD age at baseline 64.8±8.7 years; 71% male) and 223 to the delayed-start group (mean±SD age at baseline 65.5±8.8 years; 69% male). The difference between the early and delayed-start group in mean change from baseline to week four, expressed as Hedges’geffect size, was -0.33 for bradykinesia, -0.29 for rigidity, and -0.25 for tremor (for all symptoms indicating a small effect in favor of the early-start group); from baseline to week 22 respectively -0.49, -0.36, and -0.44 (small to medium effect); and from baseline to week 40 respectively -0.32, -0.19, and -0.27 (small effect). At 80 weeks, fewer patients in the early-start group (46 of 205 patients, 23%) experienced motor response fluctuations than patients in the delayed-start group (81 of 211, 38%; p<0.01).Discussion:In patients with early Parkinson’s disease levodopa improves bradykinesia, rigidity, and tremor to the same order of magnitude. For all three symptoms, effects were larger at 22 weeks compared to four weeks. At 80 weeks there were fewer patients with motor response fluctuations in the group that had started levodopa earlier.Classification of evidence:This study provides Class II evidence that the effect of levodopa on bradykinesia, rigidity and tremor is larger after 22 weeks compared to four weeks of treatment.Trial registration LEAP-study:ISRCTN30518857, EudraCT number 2011-000678-72

Pharmacological Treatment of Tremor in Parkinson’s Disease Revisited

“…The first double-blind, placebo-controlled trial of levodopa reported a similar long-term effect of levodopa on bradykinesia, rigidity, and tremor [ 74 ]. A recently published post-hoc analysis of the randomized-controlled LEAP-study [ 75 ] also reported similar effect sizes of levodopa for the three cardinal motor domains bradykinesia, tremor, and rigidity in early PD (see Supplementary Material for further details and studies).…”

Levodopa Impairs the Energy Metabolism of the Basal Ganglia In Vivo

“…Besides in-vitro evidence pointing toward a direct neurotoxic effect of L-DOPA or its metabolites, clinical studies have shown no long-term detrimental effects after initiating L-DOPA treatment in PwPD. [24][25][26] In addition, the results of L-DOPA on cerebral bioenergetics within the individual disease course of PwPD (eg, de-novo compared to early-and late-stage PwPD) can only be addressed by longitudinal studies. Longitudinal neuroimaging studies, however, demonstrated that neuronal loss in the SN is more pronounced in the initial compared to later disease stages following a negative exponential function.…”

“…The temporal dynamics of these effects have yet to be discovered. Besides in‐vitro evidence pointing toward a direct neurotoxic effect of L‐DOPA or its metabolites, clinical studies have shown no long‐term detrimental effects after initiating L‐DOPA treatment in PwPD 24–26 . In addition, the results of L‐DOPA on cerebral bioenergetics within the individual disease course of PwPD (eg, de‐novo compared to early‐ and late‐stage PwPD) can only be addressed by longitudinal studies.…”

Beyond the Dopaminergic System: Lessons Learned from levodopa Resistant Symptoms in Parkinson's Disease

“…Bradykinesia and rigidity usually present a satisfying and sustained response to l ‐dopa while rest‐tremor may be more difficult to treat in some patient. 6 …”