Hydrogel-Based Delivery Systems for Non-Opioid Analgesics: Advances, Challenges, and Clinical Prospects.

This review focuses on hydrogel-based systems specifically designed for non-opioid analgesics, aiming to improve efficacy, safety, and translational applicability. The opioid crisis has intensified the need for safer and more effective alternatives in pain management. Non-opioid analgesics including NSAIDs, acetaminophen, gabapentinoids, antidepressants, anticonvulsants, NMDA receptor antagonists, topical agents, and cannabinoids offer promising options but are limited by rapid clearance, short half-lives, and off-target effects. Hydrogel-based drug delivery systems present a novel solution by enabling controlled, localized, and sustained release of analgesics, thus improving therapeutic efficacy and minimizing systemic toxicity. Advances in stimulus-responsive, self-healing, mechanically robust, and hybrid or nanocomposite hydrogels have broadened their biomedical applications and clinical relevance. This narrative review summarizes key hydrogel technologies and their integration with non-opioid analgesic agents. We explore encapsulation strategies, drug release mechanisms, and emerging clinical data, while also addressing critical challenges such as biocompatibility, mechanical durability, and translational scalability. Interdisciplinary collaboration between material scientists, clinicians, and regulatory experts is essential to advance hydrogel-based therapies from bench to bedside. Overall, hydrogel platforms hold transformative potential in optimizing non-opioid analgesic delivery and redefining the future of pain management.