Evaluation of the efficacy of a bioerodible bupivacaine polymer system on antinociception and inflammatory mediator release.

Pain due to tissue injury is often characterized by the presence of hyperalgesia and allodynia. It is hypothesized that these perceptual states are mediated by sensitization of peripheral terminals of primary afferent neurons together with several changes in the central nervous system. This provides a rationale for preemptive analgesia, whereby the blockade of primary afferent input prior to injury may result in a reduction of post-injury pain. One approach for prolonged blockade of primary afferent input is the use of bioerodible polymer systems providing regulated release of local anesthetics. Bioerodible polymer systems offer the theoretical advantage of controlled drug delivery maintained over prolonged periods. Local application of this system to the inflamed tissue compartment permits the use of smaller total drug doses. This may minimize systemic side effects, while maintaining prolonged peripherally-mediated antinociception. In the present study, we evaluated the effects of a bioerodible polymer/bupivacaine system (PLGA/bupivacaine) on several indices of inflammation and on hindpaw levels of the inflammatory mediators, substance P and bradykinin in the complete Freund's adjuvant model. We observed that PLGA/bupivacaine reduces inflammatory hyperalgesia, edema and hyperthermia in a temporal and dose-related fashion in awake animals. Moreover, we demonstrated that PLGA/bupivacaine has a prolonged inhibitory effect on the tissue levels of substance P and bradykinin in the inflamed hindpaws. The results of these studies clearly indicate the potential therapeutic utility of the PLGA bupivacaine system, with the single dose administration producing a prolonged suppression of hyperalgesia, edema and biochemical indices of inflammation.