Hydrogen Sulfide in Analgesia: The Journey from Gas to Hybrids and Beyond

Hydrogen sulfide (H₂S), an endogenous gasotransmitter, plays a pivotal, yet complex, role in pain modulation. Although direct inhalation of H₂S for analgesic purposes faces obstacles, the administration of slow-release H₂S donors, particularly hybrid molecules formed by covalently linking H₂S-donating moieties with classic analgesics, has opened an attractive new therapeutic avenue. This hybridization strategy not only enables multimechanistic synergistic analgesia but also mitigates the toxic effects induced by existing analgesics through inherent cytoprotective and neuroprotective effects. We systematically delineate the development of H₂S-based analgesic therapies, tracing their evolution from H₂S gas to H₂S donors to combination therapies, presenting the most promising hybrids, and outlining future trends in this burgeoning field. This Perspective highlights the role of H₂S in pain management over the past two decades, with a focus on its mechanisms of action and therapeutic potential as an analgesic, to accelerate the development of novel H₂S-based therapies toward clinical translation.