On demand therapy for Parkinson's disease patients: Opportunities and choices

Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), but a major treatment challenge is that over time, many patients experience periods of return of PD symptoms intermittently through the day, known as OFF periods. OFF periods typically manifest as a return of motor symptoms but can also involve non-motor symptoms and these periods can disrupt good control despite optimization of the oral levodopa regimen. OFF periods emerge in large measure due to a shortening of the duration of clinical benefit from oral levodopa, thought to be related to a progressive loss of dopamine neurons and their ability to store and release levodopa-derived dopamine over many hours. The problem is further compounded by impaired absorption of oral levodopa due to gastroparesis and other factors limiting its uptake in the small intestine, including competition for uptake by meals and their protein content. On-demand therapies are now available for the treatment of OFF episodes in PD and are administered intermittently, on an as-needed basis, on top of the patient's maintenance medication regimen. To be useful, an on-demand medication should take effect more rapidly and reliably than oral levodopa. Options for on-demand therapy for OFF periods have recently increased with the approval of levodopa inhalation powder and sublingual apomorphine as alternatives to the older option of subcutaneous apomorphine injection, each of which avoids the gastrointestinal tract and its potential for absorption delay. On-demand therapy is now available for patients experiencing episodic or intermittent need for rapid and reliable onset of benefit. On-demand therapy may also provide an alternative to more invasive treatment such as infusion of levodopa/carbidopa intestinal gel and for patients whose OFF episodes are not controlled despite deep brain stimulation.