Objective: To assess the efficacy and safety of different apomorphine formulations for managing OFF episodes in Parkinson’s disease (PD) through a systematic review and meta-analysis.

Background: The quality of life of patients with Parkinson’s disease is impacted by OFF episodes, calling for efficient rescue treatments. Although apomorphine comes in several forms, such as sublingual, subcutaneous, inhaled, and intermittent delivery, it is yet unknown how safe and effective each form is compared to the others. Subgrouping meta-analysis could offer valuable information about implementing better treatment plans.

Method: Ten randomized controlled trials (RCTs) with 818 PD patients assessing apomorphine formulations for OFF episodes were found by a search of PubMed, Embase, and Scopus. Inverse variance techniques were used to examine the mean change in the Unified Parkinson’s Disease Rating Scale (UPDRS-III) at 30 and 60 minutes after the dose. Using Mantel-Haenszel odds ratios, safety outcomes (dizziness, nausea, and somnolence) were evaluated. ROB-2 was used to assess the risk of bias. Subgroup analysis was used to evaluate the safety and effectiveness of various formulations.

Results: Sublingual (n=2), inhaled (n=3), intermittent (n=1), and subcutaneous (n=4) apomorphine were all included in the meta-analysis. Apomorphine was favored by the pooled mean difference in UPDRS-III at 30 minutes (-5.83 [95% CI: -10.69, -0.97], P = 0.02) [Figure 1], with sublingual and inhaled formulations demonstrating comparable efficacy. At 60 minutes, statistical significance was not reached (-4.50 [95% CI: -14.79, 5.80], P = 0.39) [Figure 2], with high heterogeneity (I2 = 98%). Subcutaneous apomorphine had the highest rate of adverse events, with reports of nausea (OR: 2.94, P = 0.02), somnolence (OR: 3.40, P = 0.002), and dizziness (OR: 2.58, P = 0.04) occurring across formulations.[Figure 3]

Conclusion: In PD, apomorphine formulations significantly reduce motor symptoms during OFF periods, especially within 30 minutes after a dose. Compared to subcutaneous preparations, sublingual and inhaled formulations show similar efficacy and better tolerability. The use of non-invasive apomorphine substitutes for OFF episodes is supported by these findings. More robust RCTs are required to improve individualized PD treatment plans.

Figure 1)Mean Change in UPDRS-III at (30 min)

Figure 2)Mean Change in UPDRS-III (60 min)

Figure 3)Nausea (AE)

Figure 4)Somnolence (AE)

Figure 5)Dizziness

References: [1] C. W. Olanow et al., “Apomorphine sublingual film for off episodes in Parkinson’s disease: a randomised, double-blind, placebo-controlled phase 3 study,” Lancet Neurol, vol. 19, no. 2, pp. 135–144, Feb. 2020, doi: 10.1016/S1474-4422(19)30396-5.
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