Dextromethorphan-Quinidine Combination Reduces Inappropriate Emotional Episodes in MS

Paula Moyer, MA

April 18, 2005

April 18, 2005 (Miami Beach) — A dextromethorphan-quinidine cocktail (Neurodex) effectively addresses the inappropriate laughing and crying episodes experienced by some patients with multiple sclerosis (MS), according to investigators who presented their findings here at the 57th annual meeting of the American Academy of Neurology.

The incongruous laughing and crying episodes, also called "emotional incontinence," are due to pseudobulbar affect (PBA). Dextromethorphan, the active ingredient in most over-the-counter cough suppressant syrups, also binds to the sigma-1 and N-methyl-D-aspartate neuroreceptors and therefore had the potential to address PBA.

"If we gave patients a sufficient dose of dextromethorphan alone to penetrate the central nervous system, the trade-off would be nausea and vomiting," principal investigator Hillel Panitch, MD, said during a press briefing. "However, because quinidine prevents systemic metabolism of dextromethorphan, we can use less dextromethorphan that is yet sufficient to address PBA." Dr. Panitch is a professor of neurology at the University of Vermont College of Medicine in Burlington, where he is the director of the Multiple Sclerosis Center at Fletcher Allen Health Care.

The investigative formulation, also known as AVP-923, consists of 30 mg each of dextromethorphan and quinidine sulfate. In a double-blind, placebo-controlled study, the investigators recruited 150 patients with MS at 22 community and university-based centers to be treated either with the study drug or placebo every 12 hours for 12 weeks. The patients completed a diary and recorded the number of episodes of inappropriate laughing, crying, or both that occurred each day and indicated the medications they took, the times they took them, and any adverse events. The patients had scored at least 13 on a validated self-assessment tool used to evaluate PBA.

The investigators saw the patients in follow-up clinic visits on days 15, 29, 57, and 85. At those times, they obtained patients' clinical chemistry, vital signs, physical examinations, and electrocardiograms. The investigators compared the change in self-assessment score between the treated and placebo patients and also assessed individual change from baseline to the date of each study visit. They also compared the number of laughing and crying episodes and used separate visual analog scale scores for overall quality of life, quality of relationships, and pain intensity.

Treated patients had a clinically and statistically greater reduction in their self-assessment scores than did those who received the placebo (P < .0001). Treated patients also had fewer laughing and crying episodes (P = .0002), a higher quality of life and relationships (P < .0001 and P = .0001, respectively), and less pain (P = .027).

When the investigators evaluated response rates, they found that 84% of treated subjects responded to treatment compared with 49% of placebo patients (P < .0010). The number of emotionally inappropriate episodes per week was 46% lower in the treated group than in the placebo group, with treatment effects observed the first week of treatment.

The rate and severity of adverse events were similar in the two groups, although more patients in the treated group reported dizziness (P = .01). Eleven treated patients (14%) discontinued treatment due to adverse events, as did eight placebo patients (11%). The investigators documented no clinically significant changes in other safety measures.

"I treat many patients with MS and it's refreshing to see a new treatment strategy that appears to have a low rate of side effects," said Michael E. Batipps, MD, who commented on the presentationin an interview seeking outside comment. "We've seen many drugs developed for MS that eventually have been found to have substantial side effects. PBA is a concerning development that we would like to prevent from happening, and the potential to treat it is encouraging. However, although the dextromethorphan-quinidine combination appears to show promise in a subset of MS patients, we will need to see whether these results are confirmed in further studies." Dr. Batipps is a neurologist in private practice in Washington, D.C., with a focus in MS.

The study was funded by Vainer Pharmaceuticals, the maker of Neurodex.

AAN 57th Annual Meeting: Abstract S46.001. Presented April 14, 2005.

Reviewed by Gary D. Vogin, MD

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