Besides peripheral nerve injury, the acute inflammation is one of the pathological features of tissues after surgery, which exacerbates the postoperative pain, especially in the first 48 h after the surgery. Multimodal analgesia (MMA), such as the combination of non-steroidal anti-inflammatory drugs (NSAIDs) with local anesthetics, has shown enhanced potency compared with the usage of local anesthetics alone. However, rare formulations can provide long-term analgesia at a single dose. Herein, bupivacaine (BUP, a local anesthetic) loading poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPB) were coated with meloxicam (MLX, an NSAID) loading lipid bilayer (LPM), forming a core–shell nanosystem (NPB@LPM) to provide enhanced and long-term analgesia to treat postoperative pain. MLX was encapsulated in the lipid shell, which enabled high dose MLX to be released in the first 48 h after surgery to reduce the acute inflammation induced pain. BUP was encapsulated in the PLGA core to provide a long-term release for the nerve block. This nanosystem provided a 7-day (whole recovery cycle) effective analgesia in the Brennan’s plantar incision rat model. The tissue reactions of NPB@LPM are benign. This work will provide feasible strategies on designing drug delivery systems for postoperative pain management.

Reducing the drug administration times and prolonging the postoperative analgesia duration are important requirements of clinical local anesthesia. However, both local anesthetics currently used in the clinic and potentially new anesthetic drugs such as biological toxins have limited pharmaceutical effect. Biomaterials such as liposomes and polymeric microspheres can be designed to load local anesthetics to achieve a prolonged duration and on-demand drug release, accordingly satisfying clinical needs. In this review, we briefly summarized the recent developments in the design of drug delivery systems for controlled release of local anesthetics, and introduced the design principle, the function of several representative drug controlled release systems, and their applications in local anesthesia. We also discussed the challenges and future perspectives in this field.