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Thursday, May 18, 2017

Parkinson-Related Dyskinesia May Respond to Dextromethorphan, Quinidine Combo

Shannon Aymes, MD May 18, 2017

Levodopa-induced dyskinesia can have an impact on quality of life in Parkinson disease.

A small, proof-of-concept study suggests dextromethorphan with quinidine may be a future treatment option for levodopa-induced dyskinesia (LID) in patients with Parkinson's disease (PD). The results were published in Movement Disorders.1
Chronic levodopa therapy for PD may lead to LID. LID is associated with poorer quality of life and higher healthcare use. Potential therapeutic targets include serotonergic pathways, N-methyl-D-aspartate receptors (NMDA), and sigma-1 receptors. Of note, dextromethorphan is thought to have an impact on all three of these pathways, and combining dextromethorphan with quinidine increases the bioavailability of dextromethorphan by inhibiting CYP2D6.

Susan H. Fox, MB ChB, MRCP(UK), Ph, associate director of the movement disorders clinic at the University Health Network in Toronto, Canada, and colleagues sought to examine the efficacy and safety of dextromethorphan with quinidine for LID.  
The investigators conducted a proof-of-concept, randomized, placebo-controlled, double-blind, crossover study of patients with PD. The participants were randomly assigned to receive either dextromethorphan 45 mg plus quinidine 10 mg twice daily or placebo during 2 2-week crossover treatment periods. After a 2-week washout period, intravenous levodopa infusions over 2 hours were administered to the participants who were then monitored for dyskinesia severity.
In the 13 efficacy-evaluable participants, there was no significant difference in dyskinesia-severity for dextromethorphan with quinidine compared with placebo (area under the curve [AUC] 966.5 vs 1048.8, P =.191). However, in efficacy-evaluable participants who had 80% or more compliance with the study drug, the investigators reported lower dyskinesia-severity with post-hoc sensitivity analysis for infusion start time to 4 hours post-infusion (AUC 1585.0 vs 1911.3, P =.024). Further, 9 participants reported “much/very much improved” dyskinesia symptoms on the study drug.
Adverse events were reported in 11 out of the 13 participants (78.6%) while on the study drug. The most common adverse events were fatigue and somnolence and most were rated as mild to moderate.
“In conclusion, this proof-of-concept study provides preliminary evidence of a clinical benefit with DM 45 mg/Q 10 mg BID [twice a day] for treatment of LID in patients with PD,” the researchers wrote. The results will need to be confirmed in larger studies. 
Disclosures: The study was funded by a grant from the Michael J. Fox Foundation for Parkinson's Research given to Avanir Pharmaceuticals. Avanir Pharmaceuticals provided the clinical and medical monitoring, statistical analysis, and data management. Co-investigators SA Factor, LE Pope, N Knowles, and J Siffert report relationships with Avanir Pharmaceuticals.


Fox SH, Metman LV, Nutt JG, et al. Trial of dextromethorphan/quinidine to treat levodopa-induced dyskinesia in Parkinson's disease [published online March 30, 2017]. Mov Disord. doi:10.1002/mds.26976

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