Mechanisms and treatment of neuropathic pain.

Neuropathic pain (pain associated with lesions or dysfunction of nervous system) is relatively common, occurring in about 1% of the population. Studies in animal models describe a number of peripheral and central pathophysiological processes after nerve injury that would be the basis of underlying neuropathic pain mechanism. A change in function, chemistry, and structures of neurons (neural plasticity) underlie the production of the altered sensitivity characteristics of neuropathic pain. Peripheral sensitization acts on the nociceptors, and central sensitization takes place at various levels ranging from the dorsal horn to the brain. In addition, abnormal interactions between the sympathetic and sensory pathways contribute to mechanisms mediating neuropathic pain. Despite recent advances in identification of peripheral and central sensitization mechanisms related to nervous system injury, the effective treatment of patients suffering from neuropathic pain remains a clinical challenge. Although numerous treatment options are available for relieving neuropathic pain, there is no consensus on the most appropriate treatment. However, recommendations can be proposed for first-line, second-line, and third-line pharmacological treatments based on the level of evidence for the different treatment strategies. Beside opioids, the available therapies shown to be effective in managing neuropathic pain include anticonvulsants, antidepressants, topical treatments (lidocaine patch, capsaicin), and ketamine. Tricyclic antidepressants are often the first drugs selected to alleviate neuropathic pain (first-line pharmacological treatment). Although they are very effective in reducing pain in several neuropathic pain disorders, treatment may be compromised (and outweighed) by their side effects. In patients with a history of cardiovascular disorders, glaucoma, and urine retention, pregabalin and gabapentine are emerging as first-line treatment for neuropathic pain. In addition these anti-epileptic drugs have a favourable safety profile with minimal concerns regarding drug interactions and showing no interference with hepatic enzymes. Despite the numerous treatment options available for relieving neuropathic pain, the most appropriate treatment strategy is only able to reduce pain in 70% of these patients. In the remaining patients, combination therapies using two or more analgesics with different mechanisms of action may also offer adequate pain relief. Although combination treatment is clinical practice and may result in greater pain relief, trials regarding different combinations of analgesics are lacking (which combination to use, occurrence of additive or supra-additive effects, sequential or concurrent treatment, adverse-event profiles of these analgesics, alone and in combination) are lacking. Additionally, 10% of patients still experience intractable pain and are refractory to all forms of pharmacotherapy. If medical treatments fail, invasive therapies such as intrathecal drug administration and neurosurgical interventions may be considered.