Restless Legs Syndrome Patients with Early Onset Disease or a Relevant Family History Associated with Pramipexole Ineffectiveness but Not Pregabalin.

Abstract

Background: Restless legs syndrome (RLS) is a complex condition characterized by significant heterogeneity. Factors that affect medication efficacy remain unclear; different RLS subtypes may respond differently to various drugs.

Objective: To identify factors associated with the ineffectiveness of pramipexole and pregabalin in patients with various subtypes of RLS.

Methods: This retrospective nested case-control study enrolled 257 RLS patients prescribed pramipexole or pregabalin between March 2019 and April 2024 at the sleep center of Sir Run Run Shaw Hospital. All patients completed a semi-structured questionnaire, underwent polysomnography and laboratory evaluations, and participated in a telephone survey. To represent iron-storage status, one principal component score that included five indicators of peripheral iron metabolism was extracted by principal component analysis. Treatment effectiveness was assessed using the Clinical Global Impression-Improvement (CGI-I) scale, with scores of 1-3 indicating effective treatment and higher scores reflecting ineffective treatment. Multivariate logistic regression was employed to assess the risk factors (or RLS subtypes) of medication ineffectiveness.

Results: Of patients treated with pramipexole, 42.7% (70/164) reported poor outcomes. Early onset RLS (OR = 5.076; 95% CI, 1.836-14.033) and relevant family history (OR = 4.537; 95% CI, 1.556-13.437) increased pramipexole ineffectiveness risk. Among pregabalin users, 34.4% (32/93) reported ineffectiveness, which was associated with hemoglobin levels (OR = 1.039; 95% CI, 1.001-1.079).

Conclusion: These findings suggest that RLS patients with familial or early-onset characteristics may represent a distinct subtype that responds preferentially to α2δ ligands over dopamine agonists, supporting personalized treatment approaches based on clinical phenotyping.