From single targets to circuits diversified discovery and development strategies towards new paradigms for non-opioid analgesics.

The long-term use of opioids for analgesia is associated with serious adverse effects such as addiction and respiratory depression, as well as a potential increased risk of all-cause mortality, necessitating the development of safer alternative therapies. This review systematically elaborates on the latest advances in non-opioid analgesic research, covering diverse target strategies ranging from peripheral ion channels and GPCRs to central neuro-immune inflammation and specific neural circuits. It also discusses the advantages of multi-target ligands in overcoming signal redundancy. Concurrently, the review highlights how cutting-edge technologies-such as multi-omics analysis, artificial intelligence (AI) and computational pharmacology, and human induced pluripotent stem cell (iPSC) and organoid models-are revolutionizing target discovery, drug screening, and preclinical assessment. Despite significant ongoing challenges in target clinical translation, safety balance, and personalized treatment, the integration of these systematic interventional strategies with precise technological approaches holds promise for advancing the development of next-generation non-opioid analgesics. This progress aims to ultimately provide safer and more effective therapeutic options for patients with chronic pain, thereby addressing the opioid crisis.