Trial of dextromethorphan/quinidine to treat levodopa-induced dyskinesia in Parkinson's disease

Susan H. Fox, Leonard Verhagen Metman, John Nutt, Matthew Brodsky, Stewart A. Factor, Anthony E. Lang, Laura E. Pope, Nadine Knowles, João Siffert

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Background: Nondopaminergic pathways represent potential targets to treat levodopa-induced dyskinesia in Parkinson's disease (PD). This pilot-study (NCT01767129) examined the safety/efficacy of the sigma-1 receptor-agonist and glutamatergic/monoaminergic modulator, dextromethorphan plus quinidine (to inhibit rapid dextromethorphan metabolism), for treating levodopa-induced dyskinesia. Methods: PD patients were randomized to dextromethorphan/quinidine (45mg/10mg twice daily)/placebo in two 2-week double-blind, crossover treatment periods, with intervening 2-week washout. After 14 days, a 2-hour intravenous levodopa-infusion was administered. Patient examinations were videotaped before infusion ("off" state) and every 30 minutes during and afterwards until patients returned to "off." The primary endpoint was dyskinesia-severity during infusion measured by Unified Dyskinesia Rating Scale part 3 area-under-curve scores (blinded expert rated). Additional endpoints included other dyskinesia/motor assessments, global measures of clinical-change, and adverse-events. Results: A total of 13 patients were randomized and completed the study (efficacy-evaluable population). Dyskinesia-severity was nonsignificantly lower with dextromethorphan/quinidine than placebo during infusion (area-under-curve 966.5 vs 1048.8; P=.191 [efficacy-evaluable patients]), and significantly lower in a post-hoc sensitivity analysis of the per-protocol-population (efficacy-evaluable patients with≥80% study-drug-compliance, n=12) when measured from infusion start to 4-hours post-infusion completion (area-under-curve 1585.0 vs 1911.3; P=.024). Mean peak dyskinesia decreased significantly from infusion-start to return to "off" (13.3 vs 14.9; P=.018 [efficacy-evaluable patients]). A total of 9 patients rated dyskinesia "much/very much improved" on dextromethorphan/quinidine versus 1-patient on placebo. Dextromethorphan/quinidine did not worsen PD-motor scores, was generally well tolerated, and was associated with more frequent adverse events. Conclusion: This study provides preliminary evidence of clinical benefit with dextromethorphan/quinidine for treating levodopa-induced dyskinesia in PD. Larger studies with a longer treatment duration need to corroborate these early findings.

Original languageEnglish (US)
JournalMovement Disorders
DOIs
StateAccepted/In press - 2017

Keywords

  • AVP-923
  • Dextromethorphan/quinidine
  • Levodopa-induced dyskinesia
  • Parkinson's disease
  • Unified Dyskinesia Rating Scale

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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    Fox, S. H., Metman, L. V., Nutt, J., Brodsky, M., Factor, S. A., Lang, A. E., Pope, L. E., Knowles, N., & Siffert, J. (Accepted/In press). Trial of dextromethorphan/quinidine to treat levodopa-induced dyskinesia in Parkinson's disease. Movement Disorders. https://doi.org/10.1002/mds.26976