The fixed combination of dextromethorphan hydrobromide and quinidine sulfate (dextromethorphan/quinidine; commercially available as Nuedexta) is used in the treatment of pseudobulbar affect (PBA) in adults. PBA occurs secondary to various otherwise unrelated neurologic conditions (e.g., amyotrophic lateral sclerosis [ALS], multiple sclerosis [MS], dementia of the Alzheimer's type [ Alzheimer's disease] or other dementia, parkinsonian syndrome, stroke, traumatic brain injury) and is characterized by involuntary, sudden, uncontrollable, and frequent episodes of laughing and/or crying. These episodes typically occur out of proportion or incongruent to the underlying emotional state. PBA episodes often cause severe embarrassment and social dysfunction, which can lead to social isolation, impaired function, and reduced quality of life.
Efficacy and safety of the fixed-dose combination of dextromethorphan hydrobromide and quinidine sulfate (Nuedexta) were principally demonstrated in the Safety, Tolerability, and Efficacy Results Trial of AVP-923 in PBA (the STAR trial), which was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 326 adults with clinically important PBA and underlying ALS or MS. Patients in the STAR trial were randomized to receive dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg, dextromethorphan hydrobromide 30 mg/quinidine sulfate 10 mg, or placebo for 12 weeks; medication was administered once daily for the first week, then twice daily during weeks 2 through 12. The primary outcome measure, the number of PBA (laughing and crying) episodes, was substantially lower in both dextromethorphan/quinidine treatment groups compared with the placebo group, with a mean reduction in daily PBA episode rate of 49% in patients receiving dextromethorphan hydrobromide 20 mg/quinidine sulfate 10 mg. The secondary end point in this trial was the Center for Neurologic Studies Lability Scale (CNS-LS; a 7-item self-report questionnaire assessing crying [3 items] and laughter [4 items]) score difference between day 84 and baseline. This secondary end point also was substantially lower in both dextromethorphan/quinidine groups compared with the placebo group. No clinically important differences were observed between the 2 dextromethorphan/quinidine groups. In addition, the fixed combination of dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg was found to be generally well tolerated in this trial.
Two additional randomized, double-blind, controlled studies using higher dosages of dextromethorphan/quinidine (dextromethorphan hydrobromide 30 mg and quinidine sulfate 30 mg twice daily) provide supportive evidence for use of the drug combination in the treatment of PBA. CNS-LS scores and number of laughing and crying episodes both were substantially decreased in patients receiving dextromethorphan/quinidine compared with patients receiving higher dosages of either dextromethorphan or quinidine alone in a 4-week study in patients with PBA and underlying ALS and in a 12-week study comparing dextromethorphan/quinidine with placebo in patients with PBA and underlying MS.
The clinical studies evaluating dextromethorphan and quinidine in the treatment of PBA have been conducted in patients with underlying ALS or MS. Although dextromethorphan/quinidine potentially may be effective in reducing PBA symptoms in other brain disease and injury states (since the pathophysiologic mechanisms causing PBA are likely to be similar), the manufacturer states that the efficacy and safety of dextromethorphan/quinidine have not been established in patients with other types of emotional lability that commonly occur, such as in patients with Alzheimer's disease and other dementias. Further clinical studies specifically evaluating the efficacy and safety of the fixed combination in the treatment of PBA in patients with various other neurologic disorders are therefore needed.
Dextromethorphan/quinidine is the first treatment approved by the US Food and Drug Administration (FDA) for the treatment of PBA. Other agents that have been used to treat PBA include tricyclic antidepressants and selective serotonin-reuptake inhibitors (SSRIs); however, clinical studies evaluating these agents in the treatment of PBA have had limitations, including small numbers of patients and methodologic problems in definitions of PBA improvement. Clinical studies comparing dextromethorphan/quinidine with other agents used off-label in the treatment of PBA have not been performed to date.