Eric N. Burright

Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model.

Study Design. The effects of a low, local dose of a tumor necrosis factor-alpha (TNF-&agr;) inhibitor on neuropathic pain behaviors in a rat chronic constriction injury model were evaluated. Objective. To investigate whether a peripherally implanted polymer drug depot can deliver a dose of etanercept sufficient to reduce thermal hyperalgesia and mechanical allodynia in a rat model of neuropathic pain. Summary of Background Data. TNF-&agr; inhibitors reduce pain-associated behavior in experimental models of neuropathic pain. Moreover, systemic injections of TNF-&agr; inhibitors have suggested some efficacy in treating sciatic pain in limited, off-label clinical studies. Improvements in these results may be obtained by optimal dosing via targeted, sustained delivery at the site of disc-induced inflammation. Methods. Unilateral chronic constriction injury was applied to the sciatic nerve of 56 male, Wistar rats. Four groups of animals (n = 7) received 0.5 mL phosphate-buffered saline every 3 days, 0.3 or 3 mg/kg etanercept every 3 days, or gabapentin (60 mg/kg) 1 hour before each behavioral test all via subcutaneous injection. Two groups of animals received 1.5 or 3.0 &mgr;g/h etanercept delivered by poly(lactic-co- glycolic acid) (PLGA) millicylinders (1 mm diameter × 10 mm long) implanted near the injured sciatic nerve. One group received a PLGA millicylinder implanted near the injured sciatic nerve. The final group received 3.0 &mgr;g/h etanercept via PLGA millicylinder implanted next to the uninjured, contralateral sciatic nerve. Results. A low, local dose of etanercept (∼3 &mgr;g/h) delivered by a polymer depot significantly reduced (P < 0.05) thermal hyperalgesia for 57 days as compared to polymer depot without drug or an etanercept-loaded depot implanted near the contralateral sciatic nerve, and equivalent to a 10-fold higher dose delivered by repeat subcutaneous injection. Conclusion. This preclinical study indicates that delivering TNF-&agr; inhibitors by means of a locally administered polymeric formulation provides long-lasting analgesia in an inflammatory neuropathic pain model.