We aimed to evaluate the antihyperalgesic efficacy of a combination of hydromorphone (HM) and bupivacaine (BP) delivered via controlled release from a biodegradable cylindrical rod. In vivo studies were performed using a rat model of thermal hyperalgesia induced by chronic constriction injury (CCI) of the sciatic nerve with loose ligatures. Poly(lactic-co-glycolic acid) (PLGA) rods (10 mm length, 1 mm diameter) loaded with HM (5 mg per rod), BP (5 mg per rod) or no drug (placebo) were implanted subcutaneously, in single or dual pairs, adjacent to the constriction injury, immediately after nerve ligation. We evaluated the efficacy of two dose levels for each drug, alone or in combination, in attenuating thermal hyperesthesia over a period of 12 days according to a prevention protocol. Plasma levels of drugs released from the rods and also released in an in vitro simulation were evaluated. In vitro studies demonstrated that drug release is maintained for at least 10 days. HM (5 mg) alone and BP (5 mg) alone did not attenuate hyperalgesia. Their combination provided a significant increase in the paw withdrawal latency as compared to single agents or placebo. When the dose in each group was doubled, implanting four rods, significant attenuation of hyperalgesia was observed. Analyses of rods retrieved after termination of experiments (after 12 days) revealed 30% residual HM and 70% residual BP content. Prolonged delivery of HM and BP alone or in combination via locally applied PLGA rods may offer a feasible alternative to provide long-lasting analgesia.