Clinical Use of On-Demand Therapies for Patients with Parkinson's Disease and OFF Periods

Abstract

On-demand therapies for Parkinson's disease (PD) provide rapid, reliable relief for patients experiencing OFF periods; however, practical guidelines on the use of these therapies are not generally available. This paper reviews the use of on-demand treatments. Motor fluctuations occur in nearly all patients with PD after long-term use of levodopa. As the goal of PD treatment is to provide good ON time, on-demand treatments that have a more rapid reliable onset than the slower-acting oral medications provide rapid relief for OFF periods. All current on-demand treatments bypass the gastrointestinal tract, providing dopaminergic therapy directly into the blood stream by subcutaneous injection, through the buccal mucosa, or by inhalation into the pulmonary circulation. On-demand treatments are fast acting (10- to 20-min onset), with maximum, reliable, and significant responses reached within 30 min after administration. Oral medications pass through the gastrointestinal tract and thus have slower absorption owing to gastroparesis and competition with food. On-demand therapies, by providing fast-acting relief, can have a positive impact on a patient's quality of life when patients are experiencing OFF periods.

Keywords: Apomorphine; Levodopa; On-demand therapy; Parkinson’s disease; Rescue therapy.

Fig. 1

Different types of OFF: Early-morning OFF, or morning akinesia, is when the first oral dose of the day takes a long time to work. End-of-dose wearing OFF is the process when the oral dose no longer relives symptoms leading to the patients being OFF. Delayed ON (similar to morning akinesia) is when the oral dose takes very much longer to relieve symptoms than usual (often because of GI dysfunction). Dose failure or no ON is when oral CD/LD does not produce an ON state [15, 16, 82, 83]. CD/LD carbidopa/levodopa, GI gastrointestinal

Fig. 2

Examples of questions that can be used to ask patients about their OFF periods

Fig. 3

Individual plasma LD profiles after a single inhaled dose of LD inhalation powder and after a single ingested dose of CD/LD in patients with PD and in a fed state. In this study, levodopa was more rapidly absorbed when inhaled as LD inhalation powder (84 mg) than when ingested via an oral CD/LD tablet (100 mg), with C_10min and C_30min values of 522.9 and 531.5 ng/mL for LD inhalation powder, respectively, and 247.3 and 300.9 ng/mL for oral LD/CD. The patients’ plasma LD profiles also had much less variability after LD inhalation powder than after oral CD/LD ingestion (range of t_max values was 5–90 min for LD inhalation powder vs. 57–240 min for oral CD/LD. LD inhalation powder n = 20, CD/LD n = 17. C_10min, C_30min, observed concentrations at 10 and 30 min; CD carbidopa, LD levodopa, t_max time to maximum plasma concentration. Adapted from Safirstein et al. [87]

Fig. 4

Treatment options for motor fluctuations from early to advanced PD incorporating on-demand treatment [–86]. CD carbidopa, CLES CD/LD enteral suspension, COMT catechol-O-methyltransferase, CR controlled release, DBS deep brain stimulation, ER extended release, IR immediate release, LD levodopa, MAO-B monoamine oxidase-B, NMDA N-methyl-d-aspartate, SC subcutaneous