Opportunities for and Challenges of Pulmonary Drug Delivery in the Management of Acute Exacerbations of CNS Disorders.

Advances in pulmonary (PM) drug delivery through inhalation devices have enabled effective treatments for acute exacerbations of central nervous system (CNS) episodes, addressing previously unmet medical needs. While PM formulations of loxapine and levodopa are approved for agitation and off periods in Parkinson's disease (PD), respectively, there remains an unmet need for rapid-acting therapies for other acute exacerbations of neurologic disorders. In this review, the potential of PM delivery to address this gap in the management of acute CNS disorders is critically assessed, focusing on Staccato® loxapine for agitation, Inbrija® (levodopa) for PD, the investigational drug inhaler device Staccato® alprazolam for epilepsy, and other investigational drug inhaler devices. PM delivery benefits from bypassing first-pass metabolism, utilizing inhalation devices to enable rapid drug delivery to the densely perfused alveolar space, arterial bloodstream, and brain. However, challenges include lung tissue sensitivity, low dose volume (compared with oral and intravenous administration), and difficulties with administration during certain acute episodes. Pharmacokinetic, efficacy, and safety data from approved or investigational PM therapies for agitation, PD, epilepsy, migraine, and insomnia present inhalation as a promising option for patients requiring acute episode management by facilitating fast absorption and onset of action and generally good tolerability. In particular, for epilepsy, on-demand medication that may be administered by patients or caregivers early at seizure onset may translate to improved patient outcomes. To enhance PM management of acute exacerbations of CNS disorders, further research and user training for optimal PM administration are required.