Is Crisugabalin Signaling the Arrival of a Third Generation of α2δ Ligands?

Neuropathic pain continues to pose major therapeutic challenges, with current α2δ ligands offering only modest efficacy and limited tolerability for many patients. Crisugabalin (HSK16149) has emerged as a structurally novel candidate within this class, designed to enhance α2δ1 selectivity, reduce central nervous system penetration, and improve pharmacokinetic predictability. Preclinical studies show markedly higher affinity for α2δ1, reduced motor impairment, and no clear signals of abuse potential in preclinical models. Phase III trials in diabetic peripheral neuropathy and postherpetic neuralgia demonstrate consistent analgesic efficacy, signals of relatively rapid onset, and a favorable tolerability profile, particularly at 40 mg/day. Although current evidence is geographically limited and comparative data with established α2δ ligands are lacking, crisugabalin represents a potential evolutionary refinement that may contribute to the future development of the α2δ class. Its clinical role will depend on broader validation and real-world performance.