From OFF to ON—Treating OFF Episodes in Parkinson’s Disease

Abstract

In Parkinson’s disease (PD), OFF episodes continue to present a serious burden for patients, and their effective management remains a substantial unmet clinical need. Understanding of the pathophysiology of OFF episodes has advanced in recent years, providing valuable insights for improved treatments. OFF episodes generally appear 3–5 years after starting levodopa treatment, but can begin much earlier. They are characterized by motor symptoms (including tremor, rigidity, slowness, incoordination, and weakness) and are almost always associated with some non-motor symptoms (including psychological symptoms, pain, urinary problems, swallowing difficulties, and shortness of breath). In PD, higher doses of levodopa are associated with increased risk of motor and non-motor complications, which are notable limitations for longterm therapy. Their occurrence is associated with intermittent levodopa delivery and consequent fluctuating plasma levels. These issues can be offset using lower levodopa doses where possible, incremental dose increases, and combinations of levodopa with other pharmacological agents. OFF episodes in PD can be caused by gastroparesis and/or by Helicobacter pylori infection, which delays delivery of levodopa. These issues can be addressed using new formulations for continuous intrajejunal administration. In addition, pen injector, intranasal, and inhaled dosing systems have been studied and may provide relief via non-intestinal routes. Other approaches include deep-brain stimulation, which is effective but is restricted by costs and potential adverse events. This report presents the highlights of a satellite symposium held at the 14th International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD™ 2019), Lisbon, Portugal, which discussed the nature of OFF episodes in PD, associated risk factors and the potential of current and future treatments to effectively manage them and increase ON time.