Understanding Tremors and the Need for New Therapies
Essential tremor (ET) is the most prevalent type of tremor, characterized by involuntary, rhythmic shaking, most commonly in the hands [1.2.2]. This condition can significantly impact a person's quality of life, making everyday tasks like writing, drinking from a cup, or dressing difficult [1.8.2]. The prevalence of ET increases with age, affecting approximately 5% of adults over the age of 60 [1.9.2]. For decades, the mainstays of treatment have been two medications originally developed for other conditions: propranolol, a beta-blocker, and primidone, an anti-seizure drug [1.10.2, 1.10.3]. While these can be effective for some, they only reduce tremor amplitude by about 50% in 40% to 60% of patients and can come with significant side effects like fatigue, depression, and confusion [1.4.5, 1.10.1]. This efficacy gap highlights the urgent need for new, targeted medications for tremors.
The Landscape of Traditional Medications
Historically, pharmacological options for essential tremor have been limited. Propranolol is the only medication specifically approved by the FDA for ET, a status it has held for decades [1.4.5, 1.10.3]. It works as a nonselective beta-blocker [1.10.3]. Primidone, an anticonvulsant, is another first-line treatment with comparable efficacy to propranolol [1.10.3].
Other medications are used off-label with varying degrees of success and evidence [1.4.4]. These include:
- Other Beta-Blockers: Nadolol and atenolol may be options [1.10.3].
- Anti-seizure drugs: Gabapentin and topiramate are sometimes prescribed but can have a high rate of adverse effects [1.10.3, 1.10.4].
- Benzodiazepines: Alprazolam and clonazepam may help, particularly with anxiety-induced tremors, but carry a risk of dependency and sedation [1.10.3, 1.10.4].
- Botulinum Toxin (Botox): Injections can be useful for head and voice tremors, and sometimes hand tremors, but can cause muscle weakness [1.10.4].
The limitations of these existing therapies—including partial efficacy and undesirable side effects—have driven researchers to explore novel mechanisms of action and develop the next generation of tremor treatments.
Emerging Medications: A New Frontier
Recent years have seen a surge in research targeting the underlying neurological pathways of tremor. Several investigational drugs are in the pipeline, focusing on novel targets like T-type calcium channels and GABA-A receptors [1.4.4]. These channels are believed to play a role in the abnormal neuronal burst firing in the brain circuit (Cerebello-Thalamo-Cortical circuit) that correlates with tremor activity [1.4.4, 1.5.1].
Ulixacaltamide (PRAX-944)
Ulixacaltamide, developed by Praxis Precision Medicines, is a highly selective T-type calcium channel inhibitor [1.5.1]. It's designed to block the abnormal nerve signals that cause tremors [1.5.1]. Phase 2 studies showed that Ulixacaltamide improved Activities of Daily Living (ADL) scores for patients and had favorable tolerability [1.5.4]. The drug is currently in late-stage Phase 3 clinical trials [1.5.1, 1.5.3]. Despite a recommendation from an independent committee to halt one study after an interim analysis suggested it was unlikely to succeed, the company is continuing its Phase 3 program and plans to make a decision on FDA submission after final analysis [1.5.2].
Other Investigational Drugs
- Suvecaltamide (SAGE-324/BIIB124): This is a positive allosteric modulator of the GABA-A receptor [1.6.5]. However, in July 2024, Sage Therapeutics and Biogen announced that a Phase 2 study did not meet its primary endpoint, failing to show a statistically significant reduction in tremor compared to placebo. Consequently, the companies announced they would not pursue further clinical development of this drug for essential tremor [1.6.1, 1.6.2, 1.6.4].
- CX-8998: Another T-type calcium channel blocker, CX-8998 showed some promise in improving motor performance in clinical trials but did not meet all its primary endpoints [1.2.1, 1.4.4].
- CAD-1883 (Rimtuzalcap): This compound is a positive allosteric modulator of the small-conductance calcium-activated potassium channel and has been in clinical trials [1.4.4].
Comparison of Tremor Medications
| Medication/Class | Mechanism of Action | Status | Common Side Effects |
|---|---|---|---|
| Propranolol | Nonselective beta-blocker | FDA Approved | Fatigue, lowered heart rate, depression, lightheadedness [1.10.1, 1.10.4] |
| Primidone | Anticonvulsant | Used as first-line | Sedation, nausea, confusion, loss of balance [1.10.1, 1.10.2] |
| Ulixacaltamide | T-type calcium channel inhibitor | Investigational (Phase 3) | Fatigue, dizziness, headache, constipation [1.5.5] |
| Suvecaltamide | GABA-A receptor modulator | Development for ET halted | Somnolence, fatigue, dizziness, balance disorder [1.6.2] |
Beyond Medication: Non-Pharmacological Treatments
For patients whose tremors do not respond to medication, several non-drug options exist. These have seen significant technological advancement.
- MR-guided Focused Ultrasound (HIFU): This non-invasive procedure uses focused sound waves guided by MRI to create a tiny lesion in the thalamus, the part of the brain causing the tremor [1.11.2]. The effect is often immediate [1.10.2]. The FDA first approved it for treating one side of the body in 2016 and expanded approval in late 2022 to allow for a staged treatment of the second side after nine months [1.2.5, 1.4.3]. Five-year data shows a durable tremor reduction of over 70% [1.8.3].
- Deep Brain Stimulation (DBS): This surgical procedure involves implanting an electrode in the thalamus, which is connected to a neurostimulator in the chest [1.11.2]. The device sends electrical pulses to disrupt the signals causing the tremor [1.11.1]. It is an effective treatment for both sides of the body [1.11.1].
- Lifestyle and Adaptive Devices: Physical and occupational therapy can improve muscle control and help patients adapt [1.11.2]. Strategies include avoiding caffeine, using weighted utensils, and nerve stimulation wristbands like the Cala Trio [1.11.1, 1.11.2].
Conclusion: The Future of Tremor Management
While propranolol and primidone remain the cornerstone of medical therapy for essential tremor, the treatment landscape is evolving. The pursuit of a new medication for tremors has led to promising investigational drugs like Ulixacaltamide, which targets the underlying neuro-circuitry with greater precision. Although some candidates like Suvecaltamide have not succeeded in late-stage trials, the research has advanced the understanding of ET's pathophysiology. Alongside these pharmacological developments, non-invasive procedures like focused ultrasound offer powerful alternatives for medication-refractory patients. The future of tremor management looks to be a combination of more targeted drugs, advanced neuro-modulating procedures, and personalized therapeutic strategies, offering new hope for millions affected by this condition.
For more information on research and support, consider visiting an authoritative source such as the International Essential Tremor Foundation.
