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Review Examines Newer Therapies to Manage Off Periods and Motor Complications in PD


A review published earlier this year examined new advances in drug therapies for Parkinson disease (PD) aimed at easing the off periods and dyskinesia common to the condition.

Motor fluctuations are changes from the “on” state, when dopaminergic therapy is working, to “off,” when symptoms return, typically towards the end of a dosage period, but these changes can also happen at any time.

While levodopa is the gold standard of PD treatment, it has a short half life and it does not last long; this worsens over time, as a progressive loss of dopaminergic neurons leads to motor complications and shorter spans spent in an off state.

“The underlying etiology of motor complications is complex and not completely delineated,” noted the authors.

Drug interventions aimed at reducing these motor fluctuations aim to relieve symptoms with rescue medications, or reduce the time a patient spends in an off state with adjunctive therapy, longer-acting levodopa formulations, or continuous levodopa delivery.

In the paper, the authors cited the addition of 2 rescue therapies, inhaled levodopa powder and sublingual apomorphine, as well as the adjunctive treatments opicapone and safinamide, which work to reduce the amount of time spent in an off state. They also reviewed other therapies, including longer-acting levodopa formulations as well as possible dopaminergic delivery mechanisms under study.

Inhaled levodopa, approved by the FDA in 2018, has a mean time to action of 10 minutes, according to the pivotal phase 3 trial, which also showed the maintenance of the effect stretched to 60 minutes in 58% of the treatment group, compared with 36% of the placebo group (P = .0027). Results also showed a statistically significant 30 minute post-dose least-squares mean difference in Unified Parkinson’s Disease Rating Scale (UPDRD) motor scores of −9.8 in the treatment group vs −5.9 in the placebo group.

However, it did not reduce the time spent in the off state as compared with placebo.

The most frequent treatment-emergent adverse event (TEAE) (15% in both treatment groups) were mild to moderate and were not dose dependent.

In sublingual apomorphine, the reduction in the UPDRS motor score was –11.1 vs –3.5 in the placebo group. Mean time to take effect was 21.2 minutes (the placebo range began at 43 minutes). Five dose strengths were tested for tolerability and efficacy with a necessary initiation and titration phase to find the participant-specific beneficial dose without trigggering TEAEs, which led to discontinuation for 37% of the treatment group participants vs 9% of those on placebo.

The decision about which to prescribe—inhaled levodopa or sublingual apomorphine—is largely determined by the side effect profile, delivery mechanism, and patient choice.

Two other recent adjunctive therapy additions are once-daily dosing of dopamine-augmenting safinamide and opicapone. However, while they have few TEAE, they only reduce off periods by about 1 hour a day.


Larson D, Simuni T. New dopaminergic therapies for PD motor complications. Neuropharmacology. 2022;204:108869. doi:10.1016/j.neuropharm.2021.108869

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