Cortical spectral rebalancing underlies pregabalin’s efficacy in restless legs syndrome

Restless legs syndrome afflicts nearly half of all patients with end-stage renal disease, imposing profound burdens through relentless insomnia and functional decline. Dopaminergic agents—the established first-line therapy—trigger augmentation, a paradoxical intensification of symptoms that leaves patients worse than when they began treatment. The resultant therapeutic impasse has left a vulnerable population without effective recourse. Here we demonstrate that pregabalin, an α2δ calcium channel ligand with established renal safety, provides robust and sustained symptom relief in a randomized, placebo-controlled trial of dialysis patients with uremic restless legs syndrome. Clinical benefits emerged rapidly and intensified over three months, with pregabalin-treated patients showing more than twofold greater likelihood of categorical improvement in disease severity. In complementary animal electrophysiology experiments, pregabalin distinctively suppressed cortical hyperarousal—a hallmark of restless legs syndrome—by rebalancing low- and high-frequency oscillatory activity patterns, particularly in motor regions. This neural signature closely resembled that of gabapentin, another therapeutically effective α2δ ligand, suggesting convergent mechanisms. Beyond establishing pregabalin as an urgently needed alternative to dopaminergic therapy, our results demonstrate that cortical oscillatory profiling can reveal mechanistic convergence among candidate therapeutics, offering a rational preclinical screening strategy for neurological disorders before exposure of high-risk patient populations to experimental interventions. This framework may accelerate therapeutic discovery while reducing clinical trial risks in vulnerable populations.