title: Trial of dextromethorphan/quinidine to treat levodopa-induced dyskinesia in Parkinson's disease.
abstract: 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.
  
  
  
  PD patients were randomized to dextromethorphan/quinidine (45 mg/10 mg 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.
  
  
  
  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.
  
  
  
  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. © 2017 International Parkinson and Movement Disorder Society.
authors.affiliation: The Edmond J Safra Program in Parkinson's Disease, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fox
authors.affiliation: Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Leonard Verhagen
authors.initials: LV
authors.lastname: Metman
authors.affiliation: Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Nutt
authors.affiliation: Oregon Health and Science University, Portland, Oregon, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Brodsky
authors.affiliation: Emory University, Atlanta, Georgia, USA.
authors.forename: Stewart A
authors.initials: SA
authors.lastname: Factor
authors.affiliation: The Edmond J Safra Program in Parkinson's Disease, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Lang
authors.affiliation: Avanir Pharmaceuticals, Inc, Aliso Viejo, California, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Pope
authors.affiliation: Avanir Pharmaceuticals, Inc, Aliso Viejo, California, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Knowles
authors.affiliation: Avanir Pharmaceuticals, Inc, Aliso Viejo, California, USA.
authors.forename: João
authors.initials: J
authors.lastname: Siffert
mesh_terms: D000368:Aged; D000978:Antiparkinson Agents / Q000009:adverse effects*; D018592:Cross-Over Studies; D003915:Dextromethorphan / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy* / Q000209:etiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007980:Levodopa / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010300:Parkinson Disease / Q000188:drug therapy*; D010865:Pilot Projects; D011802:Quinidine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D000978:Antiparkinson Agents; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007980:Levodopa; D003915:Dextromethorphan; D011802:Quinidine
keywords: AVP-923; Parkinson's disease; Unified Dyskinesia Rating Scale; dextromethorphan/quinidine; levodopa-induced dyskinesia