(M1130-09-53) Thermoresponsive Polymeric Prodrug of Hydromorphone (ProGel-HMP) Provides Sustained Relief to Skeletal Pain in a Rodent Model of Femur Fracture

Purpose: While many alternative approaches have been taken, opioids are still the mainstay analgesic for peri-surgical musculoskeletal pain management. Given the current opioid epidemic, there is an urgent need for the development of potent and non-addictive analgesics. To address this challenge, we seek to develop a thermoresponsive polymeric hydromorphone prodrug formulation (ProGel-HMP), which can provide potent and sustained local analgesia for musculoskeletal pain with minimal adverse opioid side effects and a low risk of developing dependency or addiction.

Methods: ProGel-HMP (M_w=5,500 Da, HMP content = 20.44 w/w%) was synthesized and characterized as reported previously¹. The femur close fracture model was established on female CD-1 mice (12-week) using a modified method described by Bonnarens and Einhorn with a three-point bending device². ProGel-HMP (6, 12, 24 mg/kg, HMP dose equivalent), HMP (6 mg/kg) and Saline were administered into the fracture site immediately after the femur fracture. Age-matched healthy mice and Sham-operated mice were used as controls. The pain behavior analysis was performed on an Incapacitance Tester Librae from Ugo Basile^®. The nociceptive threshold was assessed using a Tail Flick Unit also from Ugo Basile^®.

Results: ProGel-HMP-treated mice with femur fracture showed complete and sustained pain relief at all dosing levels for three weeks. For the HMP-treated mice, however, fracture-associated pain returned within two days. The Tail Flick test results suggest that the HMP dosed at 6 mg/kg showed the strongest systemic analgesia (~ 100 % MPE, 4 hours), which lasted for 2 days. The systemic analgesic effect of ProGel-HMP, on the other hand, was much weaker and dose dependent, with ProGel-HMP (6 mg/kg HMP dose equivalent) showing only a weak transient systemic analgesia at 2 hours with ~ 25% MPE.

Conclusion: These experimental findings on the acute skeletal trauma pain model support ProGel-HMP as a peripheral-restricted opioid prodrug. When injected locally at the site of pathology, it provides potent and sustained pain relief with minimal systemic analgesia detectable.

References: 1. Jia, et al. Mol. Pharm. 2024, 21(4):1838-1847.
2. Bonnarens, et al. J. Orthop. Res.1984, 2(1):97-101.

Acknowledgements: This study was supported in part by the National Institutes of Health (R01 AR080500). The analgesic efficacy and safety of ProGel-HMP were evaluated in vivo according to procedures approved by the Institutional Animal Care and Use Committee (IACUC) of University of Nebraska Medical Center. Dong Wang is a co-inventor of a PCT patent application covering ProGel technology.

Incapacitance test of mice receiving a single local injection of ProGel-HMP at the fracture site (Femur). ****, P ≤ 0.0001 HMP·HCl vs Healthy; ***, P ≤ 0.001 HMP·HCl vs Healthy; ####, P ≤ 0.0001 HMP·HCl vs Sham; ###, P ≤ 0.001 HMP·HCl vs Sham; &&&&, P ≤ 0.0001 HMP·HCl vs Saline; @@@@, P ≤ 0.0001 Saline vs Healthy; §§§§, P ≤ 0.0001 Saline vs Sham; §§§, P ≤ 0.001 Saline vs Sham; §§, P ≤ 0.01 Saline vs Sham; %%%%, P ≤ 0.0001 ProGel-HMP 6 mg/kg vs HMP·HCl; %%%, P ≤ 0.001 ProGel-HMP 6 mg/kg vs HMP·HCl; %%, P ≤ 0.01 ProGel-HMP 6 mg/kg vs HMP·HCl; ††††, P ≤ 0.0001 ProGel-HMP 6 mg/kg vs Saline; †††, P ≤ 0.001 ProGel-HMP 6 mg/kg vs Saline; ††, P ≤ 0.01 ProGel-HMP 6 mg/kg vs Saline; $$$$, P ≤ 0.0001 ProGel-HMP 12mg/kg vs HMP·HCl; $$$, P ≤ 0.001 ProGel-HMP 12mg/kg vs HMP·HCl; $, P ≤ 0.05 ProGel-HMP 12mg/kg vs HMP·HCl; ‡‡‡‡, P ≤ 0.0001 ProGel-HMP 12 mg/kg vs Saline; ‡‡‡, P ≤ 0.001 ProGel-HMP 12 mg/kg vs Saline; ! ! ! !, P ≤ 0.0001 ProGel-HMP 24mg/kg vs HMP·HCl; !, P ≤ 0.05 ProGel-HMP 24mg/kg vs HMP·HCl; ∆∆∆∆, P ≤ 0.0001 ProGel-HMP 24 mg/kg vs Saline; ∆∆∆, P ≤ 0.001 ProGel-HMP 24 mg/kg vs Saline.

Tail flick test of the femur fracture mice post ProGel-HMP treatments. The maximum latency time was set as 15 s. ****, P ≤ 0.0001 HMP·HCl vs Healthy; ####, P ≤ 0.0001 HMP·HCl vs Sham; &&&&, P ≤ 0.0001 HMP·HCl vs Saline; %%%%, P ≤ 0.0001 ProGel-HMP 6 mg/kg vs HMP·HCl; $$, P ≤ 0.01 ProGel-HMP 12 mg/kg vs HMP·HCl; !, P ≤ 0.05 ProGel-HMP 24 mg/kg vs HMP·HCl; #, P ≤ 0.05 HMP·HCl vs Sham.