Systematic review and meta-analysis of 13 randomized trials (557 patients) finding apomorphine—especially intermittent subcutaneous injection—significantly improves motor symptoms and reduces OFF time in Parkinson’s disease versus placebo, at the cost of increased mild-to-moderate adverse events.

Delivers actionable clinical evidence on optimal apomorphine delivery routes for on-demand symptom control and trial design, improving translational decision-making for symptomatic therapies though it provides little new mechanistic or disease-modifying insight.

BACKGROUND: Motor fluctuations and OFF episodes are common complications of long-term levodopa therapy in Parkinson's disease (PD) and significantly impair quality of life. Apomorphine, a short-acting dopamine agonist, is available in multiple formulations for on-demand symptom relief; however, comparative evidence across administration routes remains limited. OBJECTIVES: To evaluate the efficacy and safety of apomorphine across various routes of administration in patients with PD. DESIGN: Systematic review and meta-analysis of randomized controlled trials and randomized crossover trials. DATA SOURCES AND METHODS: A comprehensive search of PubMed, Scopus, Web of Science, CENTRAL, and Embase was conducted from inception to December 28, 2025. Eligible studies included randomized controlled or crossover trials assessing apomorphine versus placebo in PD. Primary outcomes were motor improvement measured by Unified Parkinson's Disease Rating Scale III (UPDRS-III) or Movement Disorder Society-UPDRS-III (MDS-UPDRS-III) and OFF time. Safety outcomes included treatment-related adverse events. Risk of bias was assessed using the Cochrane RoB 2 tool. Pooled analyses were conducted using standardized mean differences (SMD), mean differences (MD), and risk ratios (RR) with 95% confidence intervals (CIs). RESULTS: Thirteen studies involving 557 patients were included. Apomorphine significantly improved motor symptoms across multiple administration routes. Intermittent subcutaneous (SC) injection showed the greatest efficacy (SMD: -2.19, 95% CI: (-3.32, -1.05), p < 0.0001). The inhalation and sublingual routes also showed significant improvement (SMD: -1.11, 95% CI: (-1.52, -0.7), p < 0.0001, I 2 = 0%), (SMD: -1.69, 95% CI: (-1.99, -1.38), p < 0.0001, I 2 = 0%) respectively. Intermittent SC injections also significantly reduced OFF time (MD = -1.62 h; 95% CI = (-2.59, -0.65); p < 0.00001). Adverse events were more frequent with apomorphine (RR 1.50, 95% CI = 1.09-2.06), particularly nausea, vomiting, dyskinesia, somnolence, yawning, and rhinorrhea. CONCLUSION: Apomorphine is an effective on-demand therapy for reducing motor symptoms and OFF time in PD, particularly when administered as intermittent SC injection. Although associated with increased mild-to-moderate adverse events, treatment choice should be individualized. TRIAL REGISTRATION: PROSPERO (CRD42024548330).