Systemic Diclofenac Sodium Reduces Post-Operative rhBMP-2 Induced Neuroinflammation - a Rodent Model Study.

STUDY DESIGN: This is a basic science, animal research study.

OBJECTIVE: This study aims to explore, in rodent models, the effectiveness of systemic non-steroidal anti-inflammatory drugs (NSAIDs) in reducing recombinant human bone morphogenetic protein-2 (rhBMP-2) induced neuro-inflammation.

SUMMARY OF BACKGROUND DATA: rhBMP-2 is increasingly used to augment fusion in lumbar interbody fusion surgeries, although it can cause complications including post-operative radiculitis.

METHODS: Eighteen 8-week-old Sprague-Dawley rats underwent Hargreaves testing to measure the baseline thermal-withdrawal threshold before undergoing surgical intervention. The L5 nerve root was exposed and wrapped with an Absorbable Collagen Sponge containing rhBMP-2. Rats were randomized into three groups: low dose (LD), high dose (HD) diclofenac, and saline, receiving daily injection treatment. Hargreaves testing was performed post-operatively on Day 5 and 7. Seroma volumes were measured by aspiration and the nerve root was then harvested for Hematoxylin and Eosin (H&E), immunohistochemistry (IHC), Luxol Fast Blue (LFB) staining and RT-qPCR. The Student's t-test was used to evaluate the statistical significance between groups.

RESULTS: The intervention groups showed reduced seroma volume, and a general reduction of inflammatory markers (MMP12, MAPK6, GFAP, CD68 and IL18) compared to controls, with the reduction in MMP12 being statistically significant (p = 0.02). H&E and IHC of the nerve roots showed the highest macrophage density in the saline controls and lowest in the HD group. LFB staining showed the greatest extent of demyelination in the LD and saline groups. Lastly, Hargreaves testing, a functional measure of neuroinflammation, of the HD group demonstrated a minimal change in thermal withdrawal latency (TWL). In contrast, TWL of the LD and saline groups showed a statistically significant decrease of 35.2% and 28.0%, respectively (p<0.05).

CONCLUSION: This is the first proof-of-concept study indicating that diclofenac is effective in alleviating rhBMP-2 induced neuroinflammation. This can potentially impact clinical management of rhBMP-2 induced radiculitis. It also presents a viable rodent model for evaluating the effectiveness of analgesics in reducing rhBMP-2 induced inflammation.