Neuropathy is a disease of the peripheral nervous system. Many people with diabetes eventually develop nerve damage.
The four major forms of nerve damage are: peripheral neuropathy, autonomic neuropathy, mononeuropathy, and polyneuropathy. The most common form is peripheral neuropathy, which mainly affects the feet and legs.
Besides diabetes, the common causes of neuropathy are herpes zoster infection, chronic or acute trauma (including surgery) and various neurotoxins. Neuropathic pain is common in cancer as a direct result of the cancer on peripheral nerves (e.g., compression by a tumor) and as a side effect of many chemotherapy drugs.
Neuropathy often results in numbness, abnormal sensations called dysesthesias and allodynias that occur either spontaneously or in reaction to external stimuli, and a characteristic form of pain, called neuropathic pain or neuralgia, that is qualitatively different from the ordinary nociceptive pain one might experience from stubbing a toe or hitting a finger with a hammer. Neuropathic pain is usually perceived as a steady burning and/or "pins and needles" and/or "electric shock" sensations. The difference is due to the fact that "ordinary" pain stimulates only pain nerves, while a neuropathy often results in the firing of both pain and non-pain (touch, warm, cool) sensory nerves in the same area, producing signals that the spinal cord and brain do not normally expect to receive.
Treatment of Neuropathic Pain
Neuropathic pain can be very difficult to treat; even strong opioid analgesics may provide only partial relief and are not approved by the FDA for neuropathic pain indications. Controlled studies of opioid analgesics that have shown pain relief have not shown any consistent improvement in quality of life indicators. However, several classes of medications not normally thought of as analgesics are often effective, alone or in combination with opioids and other treatments. These include tricyclic antidepressants such as amitriptyline (Elavil®), anticonvulsants such as gabapentin (Neurontin®) and pregabalin (Lyrica®) and serotonin norepinephrine reuptake inhibitors ((SSNRI such as duloxetine (Cymbalta®).
In animal models of neuropathic pain, compounds that only block serotonin reuptake do not improve neuropathic pain. Similarly, compounds that only block norepinephrine reuptake also do not improve neuropathic pain. Compounds such as dulexetine, venlafaxine, and milpaciprap that block both serotonin reuptake and norepinephrine reuptake do improve neuropathic pain. Antidepressants usually reduce neuropathic pain more quickly and with smaller doses than they relieve depression. Antidepressants therefore seem to work differently on neuropathic pain than on depression, perhaps by activating descending norepinephrinergic and serotonergic pathways in the spinal cord that block pain signals from ascending to the brain.
The newer anticonvulsants gabapentin and pregabalin appear to work by blocking calcium channels in damaged peripheral neurons. Tricyclic antidepressants may also work on sodium channels in peripheral nerves. The anticonvulsants carbamazepine (Tegretol®) and oxcarbazepine (Trileptal®), especially effective on trigeminal neuralgia, are thought to work principally on sodium channels.
In general, the antidepressants seem to be most effective on continuous burning pain, while the anticonvulsants seem to work best on sudden, lancinating, "shock-like" pains that appear to involve large numbers of peripheral nerves improperly firing together.
In some forms of neuropathy, especially post-herpes neuralgia, the topical application of local anesthetics such as lidocaine can provide relief. A transdermal patch containing 5% lidocaine is available. Ketamine in a transdermal gel is also frequently effective when the neuropathy is localized.
In some neuropathic pain syndromes, "crosstalk" occurs between descending sympathetic nerves and ascending sensory nerves. Increases in sympathetic nervous system activity result in an increase of pain; this is known as sympathetically-mediated pain. Reducing the sympathetic nerve activity in the painful region with local nerve blocks or systemic medications such as clonidine may provide relief.
The NMDA receptor seems to play a major role in neuropathic pain and in the development of opioid tolerance, and many experiments in both animals and humans have established that NMDA antagonists such as ketamine and dextromethorphan can alleviate neuropathic pain and reverse opioid tolerance. Unfortunately, only a few NMDA antagonists are clinically available and their use is usually associated with unacceptable side effects.
Several opioids, particularly methadone, have NMDA antagonist activity in addition to their μ-opioid agonist properties that seems to make them effective against neuropathic pain, although this is still the subject of intensive research and clinical study. Methadone has this property because it is a racemic mixture; one stereo-isomer is a μ-opioid agonist; the other is a NMDA antagonist.
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