Episodes of involuntary laughing and crying, known as pseudobulbar affect, were safely and effectively treated with dextromethorphan and quinidine.
TORONTO—A combination of dextromethorphan and quinidine appears to be an effective, safe, and well-tolerated treatment for pseudobulbar affect, said Erik P. Pioro, MD, at the 62nd Annual Meeting of the American Academy of Neurology.
Pseudobulbar affect—common among patients with multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other neurologic conditions—involves involuntary, sudden, and frequent episodes of laughing or crying.
“These episodes are very exaggerated and are often incongruent or inconsistent with what the individual may be feeling inside,” said Dr. Pioro, Director of the Section for ALS and Related Disorders at the Cleveland Clinic. “Some patients whom I’ve followed have been at a funeral and, instead of crying or being sad, suddenly started giggling or laughing. So one can imagine how socially paralyzing and incapacitating this condition can be.”
At present, there is no FDA-approved treatment for the condition. “Primarily, antidepressant medications are the mainstay now that they are being used off-label for treating pseudobulbar affect,” said Dr. Pioro. “Sometimes the antidepressants work reasonably well; other times, not so well. It’s quite variable.… In addition, the side-effect profiles of some of the antidepressants are really quite poor.”
Dextromethorphan and Quinidine Treatment
Dr. Pioro and colleagues tested the dextromethorphan and quinidine treatment in a 12-week, placebo-controlled, double-blind trial and a 12-week open-label extension. The treatment showed better results than placebo during the double-blind phase, continued benefits during the open-label phase, and a “very low” incidence of serious adverse events, according to Dr. Pioro.
Avanir Pharmaceuticals (Aliso Viejo, California) hopes to gain FDA approval for the treatment in the fourth quarter of 2010 and to make it available to pseudobulbar affect patients in the first quarter of 2011. The company plans to offer two doses: a combination of dextromethorphan 30 mg with quinidine 10 mg and a combination of dextromethorphan 20 mg with quinidine 10 mg.
The medication would be available in capsules taken orally twice daily in single-tablet form, according to Dr. Pioro. For elderly or more fragile patients with pseudobulbar affect, he said, “one may choose to start with the lower 20 mg/10 mg dosing first, see how they do, and if they don’t improve or they could use more improvement, to titrate up from there.”
The company had previously requested FDA approval for a combination of dextromethorphan 30 mg and quinidine 30 mg, but the FDA expressed concerns about that treatment’s tolerability and potential to cause cardiac arrhythmias in situations such as dosing errors or drug interactions, according to Dr. Pioro. Dextromethorphan is an NMDA receptor antagonist, and quinidine is a CYP2D6 inhibitor that increases concentrations of dextromethorphan in the plasma. Quinidine has the potential to be pro-arrhythmic at doses 60 to 100 times higher than the amount contained in the new combination.
The company agreed to reformulate to reduce the amount of quinidine in the combination by 67% and conduct a confirmatory Phase III trial to demonstrate safety, tolerability, and efficacy to support approval.
Double-Blind Efficacy
A total of 326 patients, all of whom had pseudobulbar affect and MS or ALS, entered the double-blind trial. To be eligible, the subjects had to have a score of at least 13 on the Center for Neurologic Study–Lability Scale (CNS–LS), a validated indicator of pseudobulbar symptom severity. CNS–LS scores range from 7 to 35, with higher scores indicating more severe symptoms; 13 is considered to correspond with the threshold for the clinical manifestation of symptoms.
At screening, the patients were randomized (1:1:1) into three groups: 110 received dextromethorphan 30 mg and quinidine 10 mg, 107 received dextromethorphan 20 mg and quinidine 10 mg, and 109 received placebo once daily for the first week and twice daily for the remaining 11 weeks. Patient data, including number of daily laughing or crying episodes, CNS–LS scores, and electrocardiograms, were collected during visits at baseline and weeks two, four, eight, and 12. However, beginning one week prior to randomization, patients began recording the number of daily episodes they experienced, which served as the “pre-treatment” baseline values.
The results indicated that treatment was associated with a reduction in laughing and crying episodes—the trial’s primary end point. Each treatment group had about a 47% to 48% benefit over placebo in reducing episode rates over the 12-week study course.
Treatment also was associated with a reduction in CNS–LS scores—the trial’s secondary end point. At baseline, those scores were 19.8 for the dextromethorphan 30-mg group, 21.0 for the dextromethorphan 20-mg group, and 19.9 for the placebo group. At week two, they had decreased to 13.1 for the dextromethorphan 30-mg group, 14.6 for the dextromethorphan 20-mg group, and 15.4 for the placebo group. And at week 12, the scores were 11.8 for the dextromethorphan 30-mg group, 12.8 for the dextromethorphan 20-mg group, and 14.3 for the placebo group.