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This study aimed to assess potential efficacy and safety of dextromethorphan/quinidine (DMQ) in prophylactic treatment of migraine in patients with multiple sclerosis (MS) with superimposed pseudobulbar affect (PBA).Multiple sclerosis patients with superimposed PBA and comorbid migraine were enrolled into this open-label observational study at the University of Southern California Comprehensive MS Center. The baseline characteristics included, among other data, frequency and severity of acute migraine attacks and use of migraine relievers. The DMQ was used exclusively per its primary indication — PBA symptoms control — 20/10 mg orally, twice a day for the mean of 4.5 months (the shortest exposure registered was 3 months and the longest, 6 months). To determine whether treatment caused an effect on migraine frequency and severity, the baseline and posttreatment values were compared using nonparametric sign test.Thirty-three MS subjects with PBA, who also suffered from migraines, were identified. Twenty-nine subjects had improvement in headache frequency, 4 had no change, and none had worsening (P < 0.001 as compared with the baseline). Twenty-eight subjects had improvement in headache severity, 5 had no change, and none had worsening (P < 0.001).Our pilot study results provide evidence that DMQ shows promise as a candidate for larger clinical studies evaluating its efficacy for the prevention of migraine headaches.