Effect of Peritumoral Bupivacaine on Primary and Distal Hyperalgesia in Cancer-Induced Bone Pain

Background: Cancer-induced bone pain (CIBP) is a debilitating chronic pain condition caused by injury to bone nerve terminals due to primary or metastasized bone tumors. Pain manifests as enhanced sensitivity, not only over the affected bone site but also at distal areas that share common nerve innervation with the tumor. In this study, we aim to understand how tumor-induced primary and distal pain sensitivities are affected by bupivacaine-induced block of bone nerve endings in a rat model of CIBP.

Methods: MRMT-1 breast cancer cells were injected into the proximal segment of tibia in female Sprague-Dawley rats. Radiograms and micro-CT images were obtained to confirm tumor growth. Bupivacaine was injected peritumorally at day 7 or day 14 post-tumor induction, and withdrawal thresholds in response to pressure and punctate mechanical stimulus were recorded from the knee and hind-paw, respectively. Immunohistochemical studies for the determination of ATF3 and GFAP expression in DRG and spinal cord sections were performed.

Results: Rats developed primary and distal hyperalgesia after MRMT-1 administration that was sustained for 2 weeks. Peritumoral administration of bupivacaine in 7-day post-tumor-induced (PTI) rats resulted in a reversal of both primary and distal hyperalgesia for 20-30 mins. However, bupivacaine failed to reverse distal hyperalgesia in 14 day-PTI rats. ATF3 and GFAP expression were much enhanced in 14 day-PTI animals, compared to 7 day-PTI group.

Conclusion: Results from this study strongly suggest that distal hyperalgesia of late-stage CIBP demonstrates differential characteristics consistent with neuropathic pain as compared to early stage, which appears more inflammatory in nature.

Keywords: bupivacaine; cancer-induced bone pain; distal hyperalgesia; epidermal nerve fiber; primary hyperalgesia.