Expert Consensus on the Use of On‐Demand Treatments for OFF Episodes in Parkinson's Disease: A Modified Delphi Panel

Abstract

BackgroundBackground: On-demand treatments can treat OFF episodes in Parkinson's disease, however, there is limited information regarding when to prescribe them. Objective Objective: Develop expert consensus to determine appropriate clinical factors for considering on-demand treatments. Methods Methods: Using a RAND/UCLA modified Delphi panel method, a panel developed consensus on the use of ondemand treatments for OFF episodes. ResultsResults: The panel agreed on-demand treatments were appropriate when OFF episodes were associated with greater functional impact and interfered with basic daily activities. The panel also agreed on-demand treatment may be appropriate for patients with morning akinesia and/or delayed ON of first levodopa dose and >1 type of OFF episode (eg, early morning OFF or wearing OFF regardless of frequency). Conclusions Conclusions: Experts agreed on-demand treatment is appropriate for many patients with OFF episodes. The greater the functional impact of OFF episodes, the more likely experts agreed that on-demand treatment is appropriate to prescribe.Parkinson's disease (PD) is the most common neurodegenerative disorder affecting mobility with a global prevalence of 6.1 million people in 2016-a figure expected to double over the next generation. 1,2 As PD progresses, fluctuations in symptom control between benefit from levodopa (L-dopa) (ON) and when benefit is no longer present (OFF) are common and often persist despite attempts to optimize dose and timing, and the addition of adjunctive OFF therapies. 3,4 Effective, reliable, and rapid treatment of OFF episodes remain a major unmet need. 1 Three pharmacological approaches are typically considered. [4][5][6] The first is adjusting the current oral L-dopa regimen by increasing the dose, altering dosing frequency, or trying extended

Long-term safety, tolerability and efficacy of apomorphine sublingual film in patients with Parkinson’s disease complicated by OFF episodes: a phase 3, open-label study

“…The authors of this recommendation concluded that on-demand treatments can help to empower patients to recognise and rapidly treat OFF episodes and should therefore be routinely incorporated into shared clinical decision-making [ 8 ]. More recently, a modified Delphi panel was employed by a group of PD experts to develop consensus on the use of on-demand treatments for OFF episodes [ 19 ]. The experts agreed that on-demand treatment is appropriate for many patients with OFF episodes, including those whose OFF episodes have a significant functional impact on their lives, or follow a pattern of delayed ON, dose failure, or morning OFF; those who use higher doses of levodopa in addition to on-extender treatments; and those who experience treatment-related side effects with levodopa and/or on-extender treatments [ 19 ].…”

“…More recently, a modified Delphi panel was employed by a group of PD experts to develop consensus on the use of on-demand treatments for OFF episodes [ 19 ]. The experts agreed that on-demand treatment is appropriate for many patients with OFF episodes, including those whose OFF episodes have a significant functional impact on their lives, or follow a pattern of delayed ON, dose failure, or morning OFF; those who use higher doses of levodopa in addition to on-extender treatments; and those who experience treatment-related side effects with levodopa and/or on-extender treatments [ 19 ]. Overall, the experts highlighted that on-demand treatment could be particularly beneficial for individuals whose OFF episodes significantly affect their quality of life [ 19 ].…”

“…However, the emergence of OFF episodes is also likely to be influenced by factors that impact the optimal delivery of oral levodopa, such as: impaired swallowing and oesophageal dysmotility, including dysphagia for medication [ 10 ] and gastrointestinal mobility disturbances (which are a very common symptom of patients with PD [ 11 ]), associated with resulting gastrointestinal bacterial overgrowth reducing absorption; extensive peripheral breakdown of levodopa by aromatic L -amino acid decarboxylase and catechol- O -methyl transferase; Helicobacter pylori infection [ 12 , 13 ]; a protein-rich diet [ 14 ]; and competition with amino acids for transport into the brain [ 9 , 15 – 18 ]. Several ‘on-demand’ therapies have been developed for the treatment of OFF episodes that specifically address the challenges associated with absorption via the gut, including levodopa inhalation powder (CVT-301) and a subcutaneous injection formulation of the non-ergoline dopamine agonist apomorphine [ 8 , 19 – 22 ]. Apomorphine sublingual film (SL-APO) was developed to address the limitations associated with subcutaneous apomorphine (such as skin irritation and “needle phobia” [ 23 ]).…”

Too little or too much nocturnal movements in Parkinson’s disease: A practical guide to managing the unseen

“…The use of ‘on-demand’ rescue therapies are recommended for early-morning akinesia to ensure subjects are able to rapidly achieve an ON state. These include dispersible levodopa formulations, which takes effect more quickly than tablets or capsules, subcutaneous apomorphine pen injection, or orally inhaled levodopa [56] , [57] , [79] .…”