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Sodium oxybate (Xyrem), a drug approved to treat people with narcolepsy, provided temporary relief for laryngeal dystonia patients whose symptoms were alcohol-responsive, a phase IIb, double-blind, crossover trial showed.

The primary outcome measure was the change from baseline in laryngeal dystonia symptom severity 40 minutes after sodium oxybate intake compared with placebo.

At 40 minutes, sodium oxybate was superior in patients who had responded positively to an alcohol challenge test (P=0.008) but not in patients who weren't alcohol-responsive (P=0.42), said Kristina Simonyan, MD, PhD, DrMed, of Massachusetts Eye and Ear in Boston, and co-authors.

More alcohol-responsive patients had at least 16% symptom improvement with sodium oxybate compared with placebo (OR 2.09, 98.75% CI 0.75-5.80, P=0.036), the researchers reported in . The average benefit was 40.81% (98.75% CI 34.7-48.6).

Efficacy didn't differ among patients with various degrees of symptom severity or in those who had voice tremor. The drug's effects waned by 5 hours after intake without a rebound.

"We hear many stories of broken lives and careers from patients with laryngeal dystonia and they have been desperate for new treatments," Simonyan said in a statement. "Our trial gives us hope for a new, effective treatment that can be offered to some of these patients."

Laryngeal dystonia causes involuntary spasms in laryngeal muscles, leading to a strained, hoarse voice and a chronically impaired ability to communicate. Some 50,000 people in the U.S. and Canada have laryngeal dystonia, sometimes referred to as spasmodic dysphonia. Public figures like Robert F. Kennedy Jr. and journalist and former public radio talk show host have been open about their diagnoses.

About 57% of laryngeal dystonia patients are treated with botulinum neurotoxin injections, but 40% don't benefit from them, Simonyan and colleagues noted.

"On a trial-and-error basis, approximately 6% of patients receive off-label oral medications such as propranolol, primidone, or clonazepam, which provide only mild, if any, benefits," the researchers wrote. "None of these therapies directly target the underlying disorder pathophysiology, leaving patients to rely on short-term, often suboptimal management of their symptoms or remain untreated."

The of sodium oxybate evolved from patient reports of symptom improvement after drinking alcohol, which led to an in 2017.

Sodium oxybate is a centrally acting oral drug chemically identical to gamma-hydroxybutyric acid (GHB), an inhibitory neurotransmitter that mimics some of alcohol's effects. Due to central nervous system depression risk and the drug's potential for abuse and misuse, only through a Risk Evaluation and Mitigation Strategy (REMS) program.

The double-blind trial was conducted at Massachusetts Eye and Ear from January 2018 to December 2021. It involved 106 patients with alcohol-responsive and non-responsive laryngeal dystonia: 53 were randomized to receive 1.5 g of sodium oxybate first, and 53 to receive matching placebo first. Half the study sample was alcohol-responsive.

Alcohol responsiveness was determined by a challenge test using 40-proof vodka. Responsiveness was assessed by counting the number of characteristic voice breaks in a sentence and assessing voice harshness or strain, breathiness, and tremor using a visual analog scale at baseline and at four time points after drinking alcohol. Patients with 10% or greater symptom improvement from baseline were considered alcohol-responsive.

The cohort included 74 women and 32 men with a mean age of about 59. Of these, 53 patients had isolated focal laryngeal dystonia and 53 had co-occurring dystonic tremor of voice. Eight patients reported a family history of dystonia.

The safety profile of 1.5 g of sodium oxybate was consistent with findings from previous studies, Simonyan and co-authors reported. There were no statistically significant changes in cognitive function, suicidality, or vital signs.

A phase III clinical trial is warranted to provide more safety data on sodium oxybate in people with alcohol-responsive laryngeal dystonia, the researchers said. "In the meantime, sodium oxybate should be taken in accordance with the safety measures of its FDA-approved package insert, including the contraindications, warnings, and precautions," they noted.

Some clinicians may hesitate to use sodium oxybate because of its perceived association with illicit GHB, Simonyan and colleagues observed. "However, empirical research has consistently shown that risks of misuse, abuse, and cognitive impairment are greater with the use of illicit GHB than pharmaceutical product because of the differences in the accessibility, purity, and dosing between these formulations," they wrote.

The known rates of substance abuse, dependence, and diversion of pharmaceutical sodium oxybate have been extremely low, partly due to the REMS program, which requires enrollment and certification by prescribers and patients, drug dispensing only from a REMS-certified pharmacy, and extensive screening and counseling of patients, they added.

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