Dopaminergic Therapy for Motor Symptoms in Early Parkinson’s Disease
In the November 16, 2021 issue of Neurology, the AAN Guideline Subcommittee published a practice guideline on dopaminergic therapy for motor symptoms in early Parkinson’s disease. Practice recommendations were generated by an international multidisciplinary panel, based on findings from a systematic review and following an Institute of Medicine complaint process to ensure transparency and patient engagement. Focusing on people with PD in the early stages, studies comparing the efficacy of dopamine agonists, levodopa, monoamine oxidase type B inhibitors and catechol-O-methyltransferase inhibitors to treat motor symptoms were included. The guideline sought to answer eight specific clinical questions, and synthesized data from 59 clinical studies. Twenty treatment recommendations were made.
Using the Unified Parkinson’s Disease Rating Scale part III as the preferred outcome measure, and a minimal clinically important difference of 3 points, data from comparative trials supported significantly greater motor improvement with levodopa than dopamine agonists at one, two, four and five years.
The risk of dyskinesia was higher with levodopa than dopamine agonists at two, three, four and five years. Minimal differences in efficacy and adverse effects were found in comparative trials of different formulations of dopamine agonists and in trials comparing long-acting versus immediate release levodopa. Dopamine agonists were more likely to cause impulse control disorders than levodopa, used either alone or in combination with levodopa.
Based on analysis of the evidence, the panel stated that clinicians should recommend levodopa as the initial preferential dopaminergic therapy in patients with early PD who seek treatment for motor symptoms, and that clinicians should avoid prescribing dopamine agonists to patients at higher risk of medication related adverse effects, including individuals greater than 70 years of age, and patients with a history of ICDs, pre-existing cognitive impairment, excessive daytime sleepiness, or hallucinations. Although there was no evidence to support superiority of one formulation of levodopa over another, the panel recommended that immediate release levodopa should be initially prescribed in early disease rather than controlled release levodopa or levodopa/carbidopa/entacapone.
Clinicians are encouraged to prescribe the lowest effective dose that provides symptomatic benefit to minimize the risk of dyskinesia. Guidance is provided on prescribing dopamine agonists and how to appropriately monitor drug safety. Physicians are encouraged to integrate patient preferences concerning formulation, mode of administration and cost when prescribing dopamine agonists, and to monitor for dopamine agonist withdrawal syndrome when discontinuing treatment. Regarding the use of MAO-B inhibitors, clinicians should counsel patients that levodopa provides greater monitor benefit, but may consider prescribing MAO-B inhibitors as initial therapy for mild motor symptoms in early PD.
These guidelines did not address the use of nonpharmacological treatments or disease modification in early PD, or the treatment of non-motor symptoms. Future research should prioritize improving our understanding of how genetics influence treatment response in early PD, and if new methods which provide stable levodopa plasma levels can delay dyskinesia onset.