Sodium Oxybate Shows Potential as Effective Therapy for Alcohol-Responsive Essential Tremor of Voice

Kristina Simonyan, MD, PhD

Findings from a recently published open-label phase 2 study (NCT01961297) demonstrated that 1.0 to 1.5 g of oral sodium oxybate (Xyrem) significantly reduced voice symptoms in patients with self-reported alcohol-responsive essential tremor of voice (ETv). The therapy was fast-acting but short-lived and thus, investigators concluded that it may require daily repeated intake on average every 4 hours for therapeutic benefits to be maintained.¹

"Significant neuromodulatory effects of sodium oxybate involve the normalization of pathophysiological cerebellar and parietal-prefrontal cortical activity, which may be an underlying mechanism of sodium oxybate in ETv," senior investigator Kristina Simonyan, MD, PhD, director of laryngology research, Mass Eye and Ear, Harvard Medical School, and colleagues, wrote.

The proof-of-concept trial featured 17 patients with ETv and 15 healthy controls who received 1.0 to 1.5 of oral sodium oxybate and underwent brain MRI imaging. After recruitment, 3 patients were found ineligible because of unclear diagnosis (n = 1), profound hearing loss (n = 1), and the presence of a history of a brain lesion unrelated to tremor (n = 1). The cohort had an average ETv duration of 8.6 (±5.9) years with an average age of symptom onset of 53.9 (±15.3) years.

Published in Movement Disorders, the study’s primary end point was the number of patients with reduced ETv symptoms by at least 10% at about 40 to 45 minutes after sodium oxybate intake based on the combined visual analog scale score of ETv symptom severity. At the conclusion of the analysis, sodium oxybate met its primary end point of significant effect on ETv severity (corrected Z = –3.2; P = .001) at 40 to 45 minutes after intake. Specifically, 13 of 14 patients (92.9%) with ETv showed an average of 40.8% (±18.4) reduction in their symptoms, ranging from 12.5% to 66.7%, after receiving treatment. Based on patients’ reports and investigator observations during the monitoring period, symptom improvement lasted on average of 3.5 hours, gradually wearing off by the end of the fifth hour.

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Coming into the study, patients with ETv demonstrated increased activity in the left primary sensorimotor cortex, supplementary motor area, middle occipital gyrus, cerebellar lobule Vlla, right inferior frontal gyrus and inferior parietal lobule, bilateral superior parietal lobule, and middle orbital gyrus. Nearly 1 hour after initiating sodium oxybate treatment, investigators observed decreased activity in the right inferior frontal gyrus, insula, IPL, middle occipital gyrus, cerebellum, and bilateral SPL compared with their individual baseline, thus meeting the secondary end point.

"In developing novel treatments for ETv, the considerations of disorder pathophysiology are of critical importance," the study authors wrote. "Our current findings of changes in brain activity during symptomatic speech production in ETv patients compared to healthy controls replicate the results of the previous studies and provide the foundation for examining the effects of sodium oxybate on brain function."

The therapy was well tolerated, with no major adverse events (AEs) reported, no drug-induced suicidal ideations, and no rebound effects seen at the 5th hour after drug intake or on the next day after the study. Nearly two-third (64.3%; 9 of 14) of the cohort experienced transient minor AEs, which included lightheadedness (100%; n = 9) or dry mouth (11.1%; n = 1), both of which were present regardless of drug efficacy. All AEs seen in these patients were resolved within 45 to 60 minutes after administering sodium oxybate.

After 1 year of completing the 12-month study period, 4 (28.6%) of the 14 patients with ETv were lost to follow-up. Of the remaining 10, half (50%) were successfully receiving sodium oxybate by their treating physician outside of the study, 4 patients (40%) were interested in the treatment but unable to fill the prescription because of medical insurance reimbursements, and 1 patient (10%) was not interested in the treatment.

REFERENCE
1. O’Flynn LC, Frucht SJ, Simonyan K. Sodium oxybate in alcohol-responsive essential tremor of voice: an open-label phase 2 study. Mov Disord. 2023;38(10):1936-1944. doi:10.1002/mds.29529