Different pathophysiological mechanisms are thought to operate in chronic sciatica. Nociceptive and neuropathic pain components can be distinguished. Neuropathic pain may be caused by lesions of nociceptive sprouts within the degenerated disc (local neuropathic), mechanical compression of the nerve root (mechanical neuropathic root pain), or by action of inflammatory mediators (inflammatory neuropathic root pain) originating from the degenerative disc even without any mechanical compression. Since different pain-generating mechanisms possibly underlie sciatic pain, the term mixed pain syndrome was established. The incidence of each pain component in chronic sciatica as well as validated diagnostic tools to identify them remain unknown. Current analgesic therapeutic first-line strategies for chronic sciatica rely on NSAIDs that are known to relieve nociceptive pain only. In neuropathic pain, different therapeutic approaches are effective, i.e., antidepressants such as amitriptyline and anticonvulsants such as gabapentin, carbamazepine, and pregabalin. Therefore, the combination of these analgesic compounds with NSAID could be useful in patients with sciatic pain who do not respond to NSAID.