Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model.
METHODS
The effects of a low, local dose of a tumor necrosis factor-alpha (TNF-alpha) 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.


BACKGROUND
TNF-alpha inhibitors reduce pain-associated behavior in experimental models of neuropathic pain. Moreover, systemic injections of TNF-alpha 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 microg/h etanercept delivered by poly(lactic-co-glycolic acid) (PLGA) millicylinders (1 mm diameter x 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 microg/h etanercept via PLGA millicylinder implanted next to the uninjured, contralateral sciatic nerve.


RESULTS
A low, local dose of etanercept (approximately 3 microg/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.


CONCLUSIONS
This preclinical study indicates that delivering TNF-alpha inhibitors by means of a locally administered polymeric formulation provides long-lasting analgesia in an inflammatory neuropathic pain model.
Zanella
John M
JM
Medtronic, Spinal and Biologics, Memphis, TN 38132, USA. john.zanella@medtronic.com
Burright
Eric N
EN
Hildebrand
Keith
K
Hobot
Chris
C
Cox
Mark
M
Christoferson
Laura
L
McKay
William F
WF
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D002908:Chronic Disease; D004195:Disease Models, Animal; D000068800:Etanercept; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy; D007074:Immunoglobulin G / Q000494:pharmacology*; D008297:Male; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D018124:Receptors, Tumor Necrosis Factor; D012585:Sciatica / Q000188:drug therapy*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept