Effective Management of “OFF” Episodes in Parkinson’s Disease: Emerging Treatment Strategies and Unmet Clinical Needs

Figures & data

Table 1 Types of off Episodes

Type	Definition
Early morning OFF	Symptoms are experienced upon awakening, prior to the first dose of medication (“morning bradykinesia / akinesia”)
Delayed On	Increased latency for the therapeutic dose of levodopa to alleviate symptoms; usually occurs with the first dose of the day or after eating
Wearing OFF / End-of-dose deterioration	Gradual recurrence of symptoms as patient gets closer to the end of a dosing interval, prior to the next dose
Sudden OFF	Random and unpredictable switch from “On” state to “Off”
Dose failure	Failure of therapeutic dose of levodopa to achieve any motor control

Note: Data from these studies.^6,125,128

Figure 1 Pathogenesis of motor fluctuations in Parkinson’s disease. Both central and peripheral mechanisms contribute to the eventual development of ON/OFF fluctuations by leading to pulsatile non-physiologic dopamine receptor stimulation in the basal ganglia. Successful pharmacologic management of OFF episodes attempts to achieve more continuous drug delivery in order to mitigate the combined effects of these mechanisms.

Box 1 Strategies for Management of off Episodes

Non-pharmacologic modifications  → Dietary changes  → Assess for underlying HP Dose fractionation Adjunctive use of longer acting dopamine receptor agonists Continuous Dopamine Stimulation (CDS)  →Prolong levodopa plasma half-life (inhibition of enzymatic degradation)  →Continuous drug delivery (infusions) Adjunctive use of non-dopaminergic medications Rescue therapies Device Aided therapies

Abbreviations: HP, Helicobacter pylori; SIBO, small intestine bacterial overgrowth.

Table 2 Effect of Dopamine Agonists When Used as Adjuncts to Levodopa

Drug Name (Generic)	Brand Name (Manufact-urer)	Route of Administration / Dosing Frequency	Effect on Off Time	Effect on Levodopa Dose	Side Effects
Ropinirole Ropinirole ER	Requip ® Requip XL ® (GSK)	Both oral. TID for standard formulation, once daily for ER	Reduce (−1.5 hr/day for standard, −2.1 hr/day for ER)	Reduction possible (19.4% mean reduction with standard, 34% reduction with ER)	Nausea Dizziness Somnolence Fatigue Hallucinations Impulse control disorders
Pramipexole Pramipexole ER	Mirapex ® Mirapex ER ® (Boehringer Ingelheim)	Both oral. TID for standard formulation, once daily for ER	Reduce (−1.1hr change from baseline standard, −1hr for ER).	Reduction possible (27% reduction in levodopa dose for standard; Pramipexole ER increases levodopa Cmax by 40%)	Nausea Dizziness Somnolence Hallucinations Constipation
Rotigotine	Neupro ® (UCB)	Transdermal patch, applied to skin every 24 hours	Reduce (PREFER study: −2.7hr 8mg, −2.1hr 12 mg; CLEOPATRA: study −2.5hr for up to 16mg)	Reduction is possible, amount not specified	Nausea Vomiting Somnolence Dizziness Application site reactions

Notes: All information adapted from FDA drug labels and trials mentioned within.

Abbreviations: TID, three times daily; Cmax, maximum plasma concentration.

Table 3 Effect of Enzyme Inhibitors When Used as Adjuncts to Levodopa

COMT INHIBITORS
Drug Name	Brand Name (Manufacturer)	Route of Administration/ Dosing Frequency	Effect on OFF Time	Effect on Levodopa Dose	Side Effects
Entacapone	Comtan ® (Orion Pharma)	Oral, with each levodopa dose up to 8 times/day	Reduce (−1.2 to -1.3hr reduction)	Reduce (average reduction about 25% in trials)	Dyskinesias Nausea Diarrhea Urine discoloration
Levodopa-Carbidopa-Entacapone	Stalevo ® (Orion Pharma)	Oral, up to 8 times daily with 200mg pill	Reduce (−1.2 to −1.3hr reduction)	Reduce	Dyskinesias Nausea Diarrhea Urine Discoloration
Tolcapone	Tasmar ® (Bausch, Valeant)	Oral, TID	Reduce (−1.4 to −2hr for 100mg; −1.6 to −3hr for 200mg)	Reduce (−32 to −166mg for 100mg dose; −21 to −207mg for 200mg dose)	BLACK BOX WARNING – severe hepatic injury Dyskinesias, nausea, sleep disorder, dystonia
Opicapone	Ongentys ® (Neurocrine Biosciences)	Oral, once daily	Reduce (−1.95 to −1.98hr)	Reduce (peak Cmax for levodopa increased 43–44% and AUC 62–94%)	Dyskinesia Constipation Hypotension Weight loss
MAO-B INHIBITORS
Drug Name	Brand Name (Manufacturer)	Route of Administration/Dosing Frequency	Effect on OFF Time	Effect on Levodopa Dose	Side Effects
Rasagiline	Azilect ® (Teva Neuroscience)	Oral, once daily	Reduce (PRESTO study: −0.49hr for 0.5mg and −0.91hr for 1mg) (LARGO study: −1.18hr for 1mg)	Minimal (LARGO trial: −24mg/day decrease in levodopa dose)	Orthostatic hypotension Dyskinesias Nausea Constipation
Selegiline Selegiline ODT	Eldepryl ® (Apotex) Zelapar ® (Valeant)	Oral, BID Oral disintegrating, once daily	Reduce (ODT reduced by −2.2hr)	Reduce (10–30% for oral; 24% for ODT)	Nausea Dizziness Syncope Confusion
Safinamide	Xadago ® (US WorldMeds)	Oral, once daily	Reduce (−1.3hr to −1.56hr)	No change	Dyskinesia Fall Nausea Insomnia

Notes: All information adapted from^129–131.

Abbreviations: COMT, catechol-O-methyltransferase; MAOB, monoamine oxidase B; ODT, orally disintegrating tablets; hr, hour.

Table 4 Comparison of DBS Target Sites

Authors (Year)	Study Design (Study Length)	Outcome Measures	Results
Follet et al (2010)^Citation132	Randomized, blinded (24 months)	Primary: change in motor function on UPDRS III with “stimulation on” and “no medication” Secondary: Self reported function, QoL, level of depression, serious adverse events	Both targets reached the primary outcome, however there was no statistically significant difference between the two No significant difference in self-reported function or QoL. Level of depression worsened after STN and improved after GPi. No significant intra-group differences between STN and GPi in regards to adverse events at 24 months. Effect on motor complications: change in ON time WITH troublesome dyskinesias from baseline to 6 months GPi −3.23hr, STN −2.1hr change in ON time WITHOUT troublesome dyskinesias from baseline to 6 months GPi +4.9hr, STN +4hr LEDD reduction from baseline → 24 months (mg) GPi: 1631 ± 545 → 1118 ± 562 (−513) STN: 1295 ± 585 → 887 ± 545 (−408)
Odekerken et al (2013)^Citation133	Randomized (12 months)	Primary endpoint: functional health as measured by ADLs as well as a composite score for cognitive, mood, and behavioral effects for up to 12 months after surgery Secondary endpoint: symptom scales, QoL, Adverse events, drug use	Both reached significance for the primary outcomes. There was no statistically significant difference between the two targets.Larger improvements in the “off drug” phase were seen in the STN group in regards to mean change in UPDRS III score, ALDS score, and medication reduction. All other secondary endpoints had no statistically significant difference between the two sites. Effect on motor complications: change in ON time WITH troublesome dyskinesias from baseline to 12 months GPi −2hr, STN −2.1hr change in ON time WITHOUT troublesome dyskinesias from baseline to 12 months GPi +3hr, STN +3.1hr change in OFF time per day from baseline to 12 months GPi −1.2hr, STN −1.7hr LEDD reduction from baseline → 12 months: GPi: 1331 → 1112 (−208) STN: 1254 → 708 (−546)

Notes: Trials are referenced with each author name.

Abbreviations: STN, subthalamic nucleus; GPi, globus pallidus interna; UPDRS III, Unified Parkinson Disease Rating Scale motor subscore; ADL, activities of daily living; QoL, quality of life; hr, hour.

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