Anticytokine therapy in neuropathic pain management

Cytokine activation or dysregulation is implied in a variety of painful disease states. Numerous experimental studies provide evidence that proinflammatory cytokines induce or facilitate neuropathic pain. Cytokine levels are rapidly and markedly upregulated in the peripheral nerves, dorsal root ganglia, spinal cord and in particular regions of the brain, after peripheral nerve injuries. Direct receptor-mediated actions on afferent nerve fibers as well as cytokine effects involving further mediators have been reported. Whereas direct application of exogenous proinflammatory cytokines induces pain, blockade of these cytokines or application of anti-inflammatory cytokines reduces pain behavior in most experimental paradigms. Cytokine measurements may identify patients at risk of developing chronic pain associated with their neuropathic conditions, as in the examples of peripheral neuropathies and postherpetic neuralgia. Anticytokine agents currently on the market are effective for the treatment of mostly inflammatory pain conditions, and are starting to be introduced for neuropathic pain states; however, their use is limited by potential life-threatening complications. Owing to the pleiotropy and redundancy of the cytokine system, the successful approach may not be inhibition of one particular cytokine but strategies shifting the balance between pro- and anti-inflammatory cytokines in properly selected patients. Agents that specifically target downstream signaling molecules may provide hope for safer and more specific therapies.