ABSTRACT Musculoskeletal disorders are among the most common causes of acute and chronic pain. Extensive use of opioids for these conditions has made a substantial contribution to the current opioid epidemic. There is an urgent need to develop potent analgesics that are as effective as opioids but avoids the side effects, including the risk of dependency and addiction. To address this challenge, we have developed a macromolecular prodrug (P-HMP) of hydromorphone (HMP) based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers. When HMP content increased to ³ 16 wt%, the aqueous solution of P-HMP becomes thermoresponsive and transitions from a liquid at 4°C to a hydrogel at ³ 30°C. The hydrogel, which was designate as ProGel-HMP, allows the sustained retention of the opioid prodrug at sites of pathology. When tested in the destabilization of the medial meniscus (DMM) model of osteoarthritis (OA), ProGel-HMP provided potent and sustained (³ 16 days) pain relief without spinal cord analgesia. Once locally administration, P-HMP slowly dissolves from ProGel-HMP and is processed subcellularly by phagocytic cells to release HMP for sustained local pain relief. The P-HMP that is not sequestered by cells drains into the circulation and rapidly clears via the kidney, effectively limiting systemic exposure. Importantly, the absence of spinal cord analgesia, indicates that the thermoresponsive P-HMP does not permeate the blood-brain or spinal cord barriers, which circumvents the risks of eliciting centrally mediated drug-dependency and addiction associated with conventional opioids. Based on these preliminary findings, we hypothesize that (1) that ProGel-HMP can provide sustained and effective local post-operative analgesia and pain amelioration at sites of musculoskeletal trauma, independent of CNS-mediated effects; (2) that the formulation parameters of ProGel-HMP can be modified to regulate the duration and efficacy of local analgesia to meet the specific needs for pain management in different musculoskeletal conditions. To test these hypotheses, we propose to first establish the dimensions within which the ProGel-HMP formulation parameters can be adjusted to regulate the duration and efficacy of local analgesia (Aim 1). Three pain-causing conditions will then be simulated in mice to allow in vivo assessment of ProGel-HMP. The DMM mice will be used to identify optimal ProGel-HMP formulations for both short-term amelioration of post-operative pain and sustained amelioration of chronic OA pain. In addition to testing efficacy and safety, pharmacokinetics/biodistribution (PK/BD) and functional physiological studies will be performed to dissect ProGel-HMP’s mechanism of action (Aim 2). The final studies will employ a murine closed fracture model to screen for an optimal ProGel-HMP formulation that provides medium-term pain relief in skeletal trauma through the stages of tissue inflammation and early skeletal repair. Efficacy, safety and mechanistic studie...