Gabapentin Enacarbil Lowers Nighttime Agitation in Dementia Patients With Restless Legs Syndrome
Key Clinical Summary
- Gabapentin enacarbil (GEn) significantly reduced nighttime agitation in older adults with Alzheimer disease–related dementia (AD-D) and restless legs syndrome (RLS).
- Treatment led to improved total sleep time and fewer nighttime wake episodes by week 8.
- Adverse events were common in both groups, with a trend toward more falls in the GEn group.
A randomized, double-blind, placebo-controlled trial examined whether treating RLS with GEn (Horizant) could reduce nighttime agitation in older adults with Alzheimer disease–related dementia (AD-D). Investigators sought to determine whether addressing RLS—an underrecognized driver of nocturnal distress—could improve sleep and behavioral symptoms.
Study Findings
The study enrolled 147 older adults (mean age of 83.4 years) with AD-D, RLS, and nighttime agitation living in long-term care facilities or home settings. Participants were randomized to receive GEn or placebo for 8 weeks. Most were female (72%), White (92.3%), non-Hispanic (84.6%), and resided in nursing homes (76.9%).
The primary endpoint, change in nighttime agitation from baseline to week 8 (5 pm to 7 am), showed statistically significant improvement with GEn. Investigators found a treatment effect estimate of −1.67 (P = .003) at week 8 and an earlier effect at week 2.
Sleep outcomes also improved. Total sleep time measured by actigraphy increased significantly in the GEn group by week 8 (estimate, 48.45; P = .026). Nighttime wakefulness decreased both at week 2 (−12.54; P = .006) and week 8 (−11.12; P = .015).
By the observation period, agitation between 10 pm and 7 am showed clinically meaningful and statistically significant reductions. However, agitation between 5 pm and 10 pm and the frequency of RLS behaviors were not significantly reduced. Authors suggested potential delayed drug absorption in older adults and the timing of administration (5 pm) as contributing factors.
Safety findings showed adverse events in 81.1% of GEn recipients and 68.5% of placebo recipients. Serious adverse events were similar (10 with GEn, 12 with placebo). A trend toward more falls in the GEn group (P = .066) warrants further evaluation.
Clinical Implications
For long-term care clinicians, these findings highlight a promising, mechanistically targeted approach to nighttime agitation. By identifying and treating RLS, practitioners may reduce nocturnal motor restlessness and associated agitation, thereby improving sleep quality for residents and reducing caregiver strain.
Because GEn improved agitation primarily after 10 pm, clinicians should consider the timing of medication, the potential for delayed absorption in older adults, and individual safety risks, including falls. The results also underscore the importance of RLS screening in dementia, as symptoms may present as agitation rather than classical discomfort sensations.
Nonpharmacologic strategies remain essential, and deprescribing medications that worsen RLS, correcting iron deficiency, and monitoring polypharmacy-related risks are key components of care. Larger, longer trials are needed to clarify dosing, timing, and long-term safety.
Conclusion
This trial introduces a novel, evidence-based avenue for addressing nighttime agitation in dementia by focusing on RLS assessment and treatment. Further research will help refine dosing strategies, explore nonpharmacologic interventions, and validate long-term outcomes in broader populations.
Reference
Richards KC, Fry LM, Lozano AJ, et al. Treatment of restless legs syndrome improves agitation and sleep in persons with dementia: a randomized trial. J Am Med Dir Assoc. 2025;26(5):105485. doi:10.1016/j.jamda.2025.105485
