Efficacy and Safety of Inhaled and Sublingual Apomorphine for On‑Demand Treatment of OFF Episodes in Parkinson Disease: A Systematic Review and Meta-Analysis With Exploratory Network Comparison.

OBJECTIVES

OFF episodes are a major source of disability in Parkinson disease (PD). Noninjectable apomorphine formulations, including inhaled (INH) and sublingual (SL) delivery systems, provide rapid dopaminergic stimulation for on-demand symptom relief. However, their efficacy and safety remain incompletely characterized.

METHODS

We conducted a systematic review and meta-analysis of randomized parallel-group and crossover trials evaluating inhaled or sublingual apomorphine for OFF episodes in PD. The primary outcome was change from baseline in MDS-UPDRS III scores at 30 and 60 minutes post-dose, pooled as mean differences (MD). Safety outcomes were summarized as risk ratios (RR). Random-effects models were applied when substantial heterogeneity was present. PROSPERO (CRD420261440116).

RESULTS

Four randomized controlled trials (n=406) were included. At 30 minutes, noninjectable apomorphine significantly improved motor function compared with control interventions (MD: -11.66 points, 95% CI: -17.56 to -5.76; I2= 92%). A similar effect was observed at 60 minutes (MD: -13.03 points, 95% CI: -20.75 to -5.31; I2=87%). Formulation type was not a significant moderator of treatment effect, although subgroup analyses suggested greater persistence of benefit with SL formulations at 60 minutes. Somnolence/fatigue (RR: 2.19, 95% CI: 1.11-4.31) and yawning (RR: 3.90, 95% CI: 1.06-14.00) were more frequent with apomorphine. Certainty of evidence for motor outcomes was moderate according to GRADE.

CONCLUSIONS

INH and SL apomorphine provide clinically meaningful short-term motor improvement during OFF episodes in PD. Despite substantial heterogeneity, these findings support their use as effective on-demand therapies and highlight the need for individualized treatment strategies and further comparative-effectiveness research.