A Gel/Fiber composite formulation achieves sequential delivery based on multimodal analgesia reducing chronic pain

Pain management plays an essential role in medical care. Previous studies showed that pain is a dynamic process involving multiple mechanisms, which inspired the concept of multimodal analgesia. Therefore, a drug delivery system loaded with a single analgesic may be insufficient for pain control. In this study, an implantable thermogel/electrospun fiber (Gel/Fiber) system loaded with bupivacaine hydrochloride (BUP-HCl) and acetaminophen (APAP) was synthesized. In the composite, BUP-HCl was preferentially released from the hydrophilic thermogel to relieve nociceptive pain, followed by the release of APAP in a more sustained manner from hydrophobic fibers to reduce the inflammatory reaction. Pain behavioral study and activation assay of spinal glial cells in the chronic constriction injury (CCI) model demonstrated the superior analgesic efficacy and chronic pain prevention property of the Gel/Fiber system. Furthermore, the composite exhibited satisfactory biocompatibility, as shown by histological and pharmacokinetic analysis. These results indicate that the successful sequential BUP-HCl/APAP release by a Gel/Fiber system alleviates chronic pain with good biocompatibility.Our study may pave the way for the future application of extended-delivery systems.