Objective: To assess the safety profiles of inhaled, sublingual, and subcutaneous apomorphine in patients with Parkinson’s disease (PD).

Background: Apomorphine is a direct-acting D1/D2 agonist primarily used as a rescue therapy for acute motor complications in PD, particularly during levodopa ‘off’ periods [1]. It can be administered subcutaneously, sublingually, or intranasally, providing rapid relief from unpredictable and debilitating motor fluctuations [2]. However, its use can be limited by adverse effects, which vary by route of administration [3].

Method: We systematically searched four databases, PubMed, Embase, Cochrane Library, and Web of Science, from inception until February 21, 2025, for relevant studies. We included randomized controlled trials (RCTs) only. The primary endpoints were (1) total adverse events (AEs), (2) severe AEs, (3) AEs resulting in treatment discontinuation, and (4) specific AEs. Two independent reviewers conducted data collection and quality assessment of the included studies. The Cochrane Risk of Bias 2.0 (ROB 2.0) tool was used to assess RCTs. A random-effect meta-analysis model was performed to report pooled Risk Ratios (RRs) with 95% confidence intervals for AEs using R 4.3.2. Heterogeneity was assessed using the I² statistic and further analyzed using meta-regression in cases of significant heterogeneity.

Results: Six studies were included in this meta-analysis (N = 393 patients, N = 222 in apomorphine groups). The pooled risk ratios of dyskinesia and other neurological AEs were more significant in patients administered apomorphine compared to placebo recipients [figure1, figure2]. High heterogeneity in neurological AEs (I² = 82%) is explained by the route of administration (ROA), as both subcutaneous and sublingual routes demonstrated more neurological AEs than inhalation. Rhino-oropharyngeal and nausea/vomiting (N/V) AE risk ratios were significantly higher in intervention groups compared to controls [figure3 – figure5]. There was no significant difference in the incidence of total AEs between groups treated with apomorphine versus control groups [figure6].

Conclusion: Apomorphine administration in PD is associated with higher risks of neurological, N/V, and rhino-oropharyngeal AEs in subcutaneous and sublingual ROAs. Inhalation had lower AE rates, highlighting important future directions for subsequent well-designed RCTs.

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References: [1] Hauser RA, LeWitt PA, Comella CL. On-demand therapy for Parkinson’s disease patients: opportunities and choices. Postgrad Med 2021;133:721-727.

[2] Jenner P, et al. Apomorphine – Pharmacological properties and clinical trials in Parkinson’s disease. Parkinsonism Relat Disord 2017;33:S13-S21.

[3] Carbone F, Djamshidian A, Seppi K, Poewe W. Apomorphine for Parkinson’s disease: efficacy and safety of current and new formulations. CNS Drugs 2019;33:905-918.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/comparative-safety-of-different-routes-of-apomorphine-administration-in-parkinsons-disease-a-systematic-review-and-meta-analysis/