Objective response to ethanol in essential tremor: results from a standardized ethanol challenge study.

BACKGROUND AND OBJECTIVES: Ethanol has been reported to improve tremor severity in approximately two thirds of patients with essential tremor (ET), but the accuracy of that proportion is not certain and the mechanism of action is unknown. The goal of this study was to investigate alcohol response on tremor by applying an a priori objective response definition and subsequently to describe the responder rate to a standardized ethanol dose in a cohort of 85 ET patients. A secondary analysis evaluated other tremor and nontremor features, including demographics, tremor intensity, breath alcohol concentration, nontremor effects of alcohol, self-reported responder status to ethanol, and prior ethanol exposure. METHODS: This was a prospective, open-label, single-dose challenge of oral ethanol during which motor and nonmotor measurements were obtained starting immediately prior to ethanol administration and subsequently every 20 min for 120 min. We defined tremor reduction as a 35% decline in power in the patient's tremor frequency recorded during spiral drawing 60 min after ethanol administration. RESULTS: In total, 80% of patients were considered alcohol responsive using our objective definition. Responder status and change in the objective tremor metrics were significantly correlated with the change in breath alcohol concentration levels after ethanol administration, but no other relationships to nontremor metrics were found. DISCUSSION: A high percentage of patients actually respond to acute ethanol. However, their self-reported response does not correlate well with their objective response. Objective response correlates with breath alcohol level but not with sedation, indicating a specific effect of ethanol on tremor.

Dose-escalation study of octanoic acid in patients with essential tremor.

BACKGROUND: Recently, 1-octanol has been shown to have efficacy in treating patients with essential tremor (ET). The primary metabolite of 1-octanol is octanoic acid (OA), which is now thought to be the active substance that mediates tremor suppression. Our aim was to describe the maximum tolerated dose (MTD) of oral OA in patients with ET and assess the pharmacokinetics (PK) and pharmacodynamics (PD) profile of OA. METHODS: The MTD was studied using an open-label, single-ascending 3 + 3 dose-escalation design. Predefined single doses ranged from 8 to 128 mg/kg, with grade 2 adverse events (AEs) defined as dose-limiting toxicity. Tremor was assessed using accelerometry, digital spiral analysis, and a standard clinical rating scale at baseline and up to 600 minutes after intake. Safety assessments and PK sampling were also performed. RESULTS: Dose-limiting toxicity was not reached. The most frequent AE was mild abdominal discomfort. Exposure (AUC) increased linearly with the dose. Secondary efficacy measures suggested a dose-dependent reduction of tremor. Accordingly, a single unified PK/PD model with an effect compartment and sigmoid maximum effect (Emax) response could be built that accounted well for the time profiles of plasma concentrations as well as effects on tremor severity across the 5 dose levels. CONCLUSION: Although our trial did not reach an MTD, a dose-dependent effect was demonstrated in the PK/PD model as well as in secondary efficacy outcomes. Future studies are needed to explore the safety in higher dose ranges and to confirm dose-dependent efficacy in a placebo-controlled design. TRIAL REGISTRATION: Clinicaltrials.gov NCT01468948FUNDING. NINDS Intramural Research Program; TG Therapeutics Inc.

Alcohol challenge and sensitivity to change of the Essential Tremor Rating Assessment Scale.

BACKGROUND: The ability of the Essential Tremor (ET) Rating Assessment Scale (TETRAS) to detect changes in tremor severity is unknown. METHODS: Fifteen adult ET patients received a single oral ethanol dose calculated to reach 0.05 g/dL breath alcohol content (brAC). Effects were investigated independently with accelerometry and TETRAS. RESULTS: Accelerometry data were log-transformed and a cumulative score logACC(R+L) was calculated. Correlation between logACC(R+L) and TETRAS was significant. TETRAS and accelerometry showed a significant effect of time point using repeated-measures analysis of variance. The difference between baseline and each of the following six time points as well as the correlation of TETRAS with brAC were significant. The calculated minimum detectable change of TETRAS was 8.9% and the effect size was d = 4.75 (95% confidence interval: 3.60-5.90). CONCLUSION: We demonstrated sensitivity to change of the TETRAS performance scale after a therapeutic intervention, which further establishes its potential for use in both clinical and research settings.

Octanoic acid in alcohol-responsive essential tremor: a randomized controlled study.

OBJECTIVE: To assess safety and efficacy of an oral, single, low dose of octanoic acid (OA) in subjects with alcohol-responsive essential tremor (ET). METHODS: We conducted a double-blind, placebo-controlled, crossover, phase I/II clinical trial evaluating the effect of 4 mg/kg OA in 19 subjects with ET. The primary outcome was accelerometric postural tremor power of the dominant hand 80 minutes after administration. Secondary outcomes included digital spiral analysis, pharmacokinetic sampling, as well as safety measures. RESULTS: OA was safe and well tolerated. Nonserious adverse events were mild (Common Terminology Criteria for Adverse Events grade 1) and equally present after OA and placebo. At the primary outcome, OA effects were not different from placebo. Secondary outcome analyses of digital spiral analysis, comparison across the entire time course in weighted and nonweighted accelerometry, as well as nondominant hand tremor power did not show a benefit of OA over placebo. The analysis of individual time points showed that OA improved tremor at 300 minutes (dominant hand, F = 5.49, p = 0.032 vs placebo), with a maximum benefit at 180 minutes after OA (both hands, F = 6.1, p = 0.025). CONCLUSIONS: Although the effects of OA and placebo at the primary outcome were not different, secondary outcome measures suggest superiority of OA in reducing tremor at later time points, warranting further trials at higher dose levels. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that a single 4-mg/kg dose of OA is not effective in reducing postural tremor in patients with ET at a primary outcome of 80 minutes, but is effective for a secondary outcome after 180 minutes.