Non-surgical treatment of essential tremor: What's in store?

Non-surgical therapy is the mainstay of treatment for Essential Tremor (ET). Traditional pharmacological treatments were found to provide variable tremor reduction, with limited tolerability and high discontinuation rates. This narrative review analyzed studies on adults with ET, focusing on current and emerging non-surgical therapies, with priority given to efficacy and safety. While ACP-711 is a newly investigated positive allosteric modulator (PAM) of GABA-A receptors, other PAMs (SAGE-324 and PRAX-114) have been withdrawn after failure to demonstrate statistically significant effects in clinical trials. This has also extended to include highly selective Cav3 antagonists (T-type calcium channel blockers): suvecaltamide (JZP385) and NBI-827104/ACT-7099478. By contrast, ulixacaltamide (PRAX-944) has been recently found to be effective and safe in a large phase 3 trial. ES-481, a novel selective antagonist of transmembrane AMPA receptor regulatory protein (TARP)-γ8-dependent AMPA receptors, has been tested in a small trial in Canada, complicated by early participant drop-out. Non-pharmacological techniques such as transcranial neuromodulatory devices (e.g. transcranial ultrasound) have been investigated. While peripheral neuromodulatory devices (transcutaneous afferent patterned/peripheral nerve stimulation) have been FDA-cleared, other devices (e.g. orthotics) have presented promising results with improved tremor control and minimal side effects. In conclusion, emerging non-surgical treatment strategies may enhance effectiveness, tolerability, and patients' adherence. Although many compounds have failed during advanced clinical development, others remain in the pipeline. This renewed interest in the treatment of ET, along with a better understanding of its pathophysiology and clinical trial design, could ultimately lead to newer first-line agents specifically designed for ET.