Dopaminergic Therapy for Motor Symptoms in Early Parkinson Disease Practice Guideline Summary: A Report of the AAN Guideline Subcommittee

Abstract

Background and objectives: To review the current evidence on the options available for initiating dopaminergic treatment of motor symptoms in early-stage Parkinson disease and provide recommendations to clinicians.

Methods: A multidisciplinary panel developed practice recommendations, integrating findings from a systematic review and following an Institute of Medicine-compliant process to ensure transparency and patient engagement. Recommendations were supported by structured rationales, integrating evidence from the systematic review, related evidence, principles of care, and inferences from evidence.

Results: Initial treatment with levodopa provides superior motor benefit compared to treatment with dopamine agonists, whereas levodopa is more likely than dopamine agonists to cause dyskinesia. The comparison of different formulations of dopamine agonists yielded little evidence that any one formulation or method of administration is superior. Long-acting forms of levodopa and levodopa with entacapone do not appear to differ in efficacy from immediate-release levodopa for motor symptoms in early disease. There is a higher risk of impulse control disorders associated with the use of dopamine agonists than levodopa. Recommendations on initial therapy for motor symptoms are provided to assist the clinician and patient in choosing between treatment options and to guide counseling, prescribing, and monitoring of efficacy and safety.

Figure 1. Levodopa vs Dopamine Agonist: Change in Unified Parkinson's Disease Rating Scale Motor Score

Chart shows random effects meta-analysis for each time (red text = number of articles, class). eTable 1 (links.lww.com/WNL/B569) shows raw mean difference (levodopa – dopamine agonist) for each study and time. For change in motor function, levodopa as compared to dopamine agonists is possibly no more effective at 6 months (raw mean difference 0.2 [95% confidence interval (CI) −2.3 to 2.7], low confidence); possibly more effective at 1 year (−2.1 [−3.6 to −0.7], low confidence); likely more effective at 2 years (−5.0 [−7.2 to −2.5], moderate confidence); possibly more effective at 4 years (−4.9 [−7.8 to −1.9], low confidence); and likely more effective at 5 years (−3.4 [−5.2 to −1.6], moderate confidence). There is insufficient evidence to determine whether levodopa is better or worse than dopamine agonists at 3 years (−5.6 [−7.6 to −3.6]), 6 years (−2.7 [−5.9 to 0.6]), and 10 years (−3.2 [−12.1 to 5.6]). The confidence in the evidence is algorithmically determined, as outlined in the Clinical Practice Guideline Process Manual.

Figure 2. Levodopa vs Dopamine Agonist: Risk Difference for Dyskinesia

Chart shows random effects meta-analysis for each time (red text = number of articles, class). eTable 2 (links.lww.com/WNL/B569) shows risk difference (levodopa – dopamine agonist) for each study and time. The induction of dyskinesia, with levodopa as compared to dopamine agonists, is probably more likely at 2 years (risk difference 18.7% [95% confidence interval (CI) 13.7%–23.8%], moderate confidence); possibly more likely at 3 years (12.5% [2.8%–22.1%], low confidence); probably more likely at 4 years (29.2% [19.6%–38.8%], moderate confidence); and possibly more likely at 5 years (17.5% [4.5%–30.5%], low confidence). There is insufficient evidence to determine whether levodopa is more or less likely than dopamine agonists to induce dyskinesia at 6 years (16.5% [4.6%–27.7%]), 7 years (7.1% [2.4%–11.8%]), 10 years (14.3% [−0.4% to 29.1%]), and 14 years (1.6% [−17.3% to 20%]), all with very low confidence. The confidence in the evidence is algorithmically determined, as outlined in the Clinical Practice Guideline Process Manual.

Figure 3. Levodopa vs Dopamine Agonist: Risk Differences for Development of Hallucinations

Chart shows random effects meta-analysis for each time (red text = number of articles, class). eTable 3 (links.lww.com/WNL/B569) shows risk difference (levodopa – dopamine agonist) for each study and time. Hallucinations with dopamine agonists as compared to levodopa are possibly more likely at 2 years (risk difference −5.7% [95% confidence interval (CI) −10.3% to −1.2%], low confidence); possibly no more likely at 4 years (6.6% [−13.9% to 0.7%], low confidence); and possibly no more likely at 5 years (−5.6% [−16.6% to 5.5%], low confidence). There is insufficient evidence to determine whether dopamine agonists are more or less likely than levodopa to induce hallucinations at 3 years (−3.4% [−7.7% to −0.2%], very low confidence). The confidence in the evidence is algorithmically determined, as outlined in the Clinical Practice Guideline Process Manual.

Figure 4. Levodopa vs Dopamine Agonist: Risk Difference for Discontinuation Due to Adverse Events

Chart shows random effects meta-analysis for each time (red text = number of articles, class). eTable 4 (links.lww.com/WNL/B569) shows risk difference (levodopa – dopamine agonist) for each study and time. The discontinuation of medication due to adverse effects, with dopamine agonists as compared to levodopa, is possibly more likely at 2 years (risk difference −6.1% [95% confidence interval (CI) −10.7% to −1.4%], low confidence); possibly no more likely at 3 years (−4.3% [−9.6% to 0.9%], low confidence); and probably no more likely at 5 years (−1% [−12.3% to 10.4%], moderate confidence). There is insufficient evidence to determine whether dopamine agonists are more or less likely than levodopa to cause medication discontinuation due to adverse effects at 1 year (−18.8% [−43% to 5%]), 4 years (−9.1% [−14% to −4.4%]), and 10 years (−26.2% [−30% to −22.5%]), all with very low confidence. The confidence in the evidence is algorithmically determined, as outlined in the Clinical Practice Guideline Process Manual.