Objective: To determine if modafinil could improve gait and freezing in people with Parkinson’s disease (PwPD)with freezing of gait (FOG).

Background: FOG is a debilitating complication in PwPD with limited treatment options if it does not respond to levodopa. Modafinil is an atypical stimulant that modulates beta and gamma band activity in the pedunculopontine nucleus (PPN)[1]. Stimulation of the PPN at these frequencies has been shown to improve FOG in PwPD[2].  We therefore hypothesized that Modafinil would improve gait in PwPD.

Method: PwPD with FOG were randomly assigned to an early start (24 weeks modafinil) or delayed start (12 weeks placebo followed by 12 weeks modafinil) of oral modafinil 100mg. Primary outcomes were change in stride-length and freezing of gait questionnaire (FOG-Q) scores. Secondary outcomes were change in UPDRS-III, Parkinson’s Disease Questionnaire-39, Epworth Sleepiness scale and REM sleep behavior disorder questionnaire (NCT03083132, FDA IND: 135059, UAMS IRB#206341).

Results: Participants in the early (n=12) and delayed-start (n=9) groups were well matched for age, Hoehn and Yahr staging, OFF-state motor and total UPDRS scores, FOG-Q scores, and cognitive function. All participants reported at least one side effect during the randomized portion of the study, the majority of which could be attributed to fluctuating PD symptoms and not modafinil. Primary and secondary outcomes did not reach statistical significance. Exploratory outcomes including objective turn measures showed a tendency toward improvement. For example, those on modafinil increased their turn width 8.2 cm more than the placebo group [95% CI: (-1.1 cm, +17.5 cm); p=0.081]. Freezing episodes were not significantly reduced between the early and delayed start groups at week 12. However, post-hoc analysis combining them into a single group showed that in 14 PwPD with freezing episodes on initial continuous gait evaluation, there was a small but significant reduction in total (28.5 vs 20.7 s, p=0.03) and percent freezing time (18% to 16%, p=0.02) after 12 weeks of treatment with modafinil 100mg.

Conclusion: Although primary outcomes for early vs delayed start modafinil did not reach significance, post-hoc analysis suggests that larger studies of modafinil for the treatment of FOG are still indicated.

References: [1] Virmani T, Urbano FJ, Bisagno V, Garcia-Rill E (2019) The pedunculopontine nucleus: From posture and locomotion to neuroepigenetics. AIMS Neurosci 6, 219-230.
[2] Thevathasan W, Debu B, Aziz T, Bloem BR, Blahak C, Butson C, Czernecki V, Foltynie T, Fraix V, Grabli D, Joint C, Lozano AM, Okun MS, Ostrem J, Pavese N, Schrader C, Tai CH, Krauss JK, Moro E, Movement Disorders Society PPNDBSWGcwtWSfS, Functional N (2018) Pedunculopontine nucleus deep brain stimulation in Parkinson’s disease: A clinical review. Mov Disord 33, 10-20.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-pilot-randomized-placebo-controlled-double-blinded-delayed-start-trial-of-modafinil-for-the-treatment-of-freezing-of-gait-in-parkinsons-disease/