Neuropathic pain

After a peripheral nerve lesion, aberrant regeneration may occur. Neurons become unusually sensitive and develop spontaneously pathological activity and abnormal excitability. This phenomenon is called "peripheral sensitization".

The (spinal cord) dorsal horn neurons give rise to the spinothalamic tract (STT), which constitutes the major ascending nociceptive pathway. As a consequence of spontaneous activity arising in the periphery, STT neurons develop increased background activity, enlarged receptive fields and increased responses to afferent impulses, including normally innocuous tactile stimuli. This phenomenon is called central sensitization. Central sensitization is an important mechanism of persistent neuropathic pain.

Other mechanisms may take place at the central level after peripheral nerve damage. The loss of afferent signals induces functional changes in dorsal horn neurons. A decrease in the large fiber input decreases the activity of interneurons inhibiting nociceptive neurons i.e. loss of afferent inhibition. Hypoactivity of the descending antinociceptive systems or loss of descending inhibition may be another factor. With the loss of neuronal input (deafferentation) the STT neurons begin to fire spontaneously, a phenomenon designated "deafferentation hypersensitivity."

Neuroglia ("glial cells") may play a role in central sensitization. Peripheral nerve injury induces glia to release proinflammatory cytokines and glutamate—which, in turn influence neurons.[9]

The phenomena described above are dependent on changes at the cellular and molecular levels. Altered expression of ion channels, changes in neurotransmitters and their receptors as well as altered gene expression in response to neural input are at play.[10] Neuropathic pain is associated with changes in sodium and calcium channel subunit expression resulting in functional changes.  In chronic nerve injury, there is redistribution and alteration of subunit compositions of sodium and calcium channels resulting in spontaneous firing at ectopic sites along the sensory pathway.[6]

Pregabalin and gabapentin may reduce pain associated with diabetic neuropathy.[14][12][15][16] The anticonvulsants carbamazepine and oxcarbazepine are especially effective in trigeminal neuralgia. Gabapentin may reduce symptoms associated with neuropathic pain or fibromyalgia in some people.[12] There is no predictor test to determine if it will be effective for a particular person. A short trial period of gabapentin therapy is recommended, to determine the effectiveness for that person. 62% of people taking gabapentin may have at least one adverse event, however the incidence of serious adverse events was found to be low.[12]

Lamotrigine does not appear to be effective for neuropathic pain.[17]

Dual serotonin-norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, and milnacipran, as well as tricyclic antidepressants such as amitriptyline, nortriptyline, and desipramine are considered first-line medications for this condition.[13] While amitriptyline and desipramine have been used as first-line treatments, the quality of evidence to support their use is poor.[18][19]

Bupropion has been found to have efficacy in the treatment of neuropathic pain.[20][21][22]

Local intradermal injection of botulinum toxin is helpful in chronic focal painful neuropathies.[23]

There is little evidence that cannabis helps treat chronic neuropathic pain,[24] and benefits are likely outweighed by psychotomimetic effects.[25]

There is no good evidence that herbal products (nutmeg or St John's wort) are useful for treating neuropathic pain.[26]

A 2007 review of studies found that injected (parenteral) administration of alpha lipoic acid (ALA) was found to reduce the various symptoms of peripheral diabetic neuropathy.[27] While some studies on orally administered ALA had suggested a reduction in both the positive symptoms of diabetic neuropathy (dysesthesia including stabbing and burning pain) as well as neuropathic deficits (paresthesia),[28] the meta-analysis showed "more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone".[27] There is some limited evidence that ALA is also helpful in some other non-diabetic neuropathies.[29]

Benfotiamine is an oral prodrug of Vitamin B1 that has several placebo-controlled double-blind trials proving efficacy in treating neuropathy and various other diabetic comorbidities.[30][31]

Neuromodulation is a field of science, medicine and bioengineering that encompasses both implantable and non-implantable technologies (electrical and chemical) for treatment purposes.[32]

Implanted devices are expensive and carry the risk of complications. Available studies have focused on conditions having a different prevalence than neuropathic pain patients in general. More research is needed to define the range of conditions that they might benefit.

The best long-term results with deep brain stimulation have been reported with targets in the periventricular/periaqueductal grey matter (79%), or the periventricular/periaqueductal grey matter plus thalamus and/or internal capsule (87%).[33] There is a significant complication rate, which increases over time.[34]

Stimulation of the primary motor cortex through electrodes placed within the skull but outside the thick meningeal membrane (dura) has been used to treat pain. The level of stimulation is below that for motor stimulation. As compared with spinal stimulation, which is associated with noticeable tingling (paresthesia) at treatment levels, the only palpable effect is pain relief.[35][36]

Spinal cord stimulators use electrodes placed adjacent to but outside the spinal cord. The overall complication rate is one-third, most commonly due to lead migration or breakage but advancements in the past decade have driven complication rates much lower. Lack of pain relief occasionally prompts device removal.[37]

Intrathecal pumps deliver medication directly to the fluid filled (subarachnoid) space surrounding the spinal cord. Opioids alone or opioids with adjunctive medication (either a local anesthetic or clonidine) or more recently ziconotide[38] are infused. Complications such as serious infection (meningitis), urinary retention, hormonal disturbance and intrathecal granuloma formation have been noted with intrathecal infusion.

There are no randomized studies of infusion pumps. For selected patients 50% or greater pain relief is achieved in 38% to 56% at six months but declines with the passage of time.[39] These results must be viewed skeptically since placebo effects cannot be evaluated.

The N-methyl-D-aspartate (NMDA) receptor seems to play a major role in neuropathic pain and in the development of opioid tolerance. Dextromethorphan is an NMDA antagonist at high doses. Experiments in both animals and humans have established that NMDA antagonists such as ketamine and dextromethorphan can alleviate neuropathic pain and reverse opioid tolerance.[40] Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by a very short half life (ketamine), weak activity (memantine) or unacceptable side effects (dextromethorpan).

Opioids, while commonly used in chronic neuropathic pain, are not a recommended first or second line treatment.[41] In the short and long term they are of unclear benefit.[42] In the intermediate term evidence of low quality supports utility.[42]

Several opioids, particularly levorphanol, methadone and ketobemidone, possess NMDA antagonism in addition to their µ-opioid agonist properties. Methadone does so because it is a racemic mixture; only the l-isomer is a potent µ-opioid agonist. The d-isomer does not have opioid agonist action and acts as an NMDA antagonist; d-methadone is analgesic in experimental models of chronic pain.[43]

There is little evidence to indicate that one strong opioid is more effective than another. Expert opinion leans toward the use of methadone for neuropathic pain, in part because of its NMDA antagonism. It is reasonable to base the choice of opioid on other factors.[44] It is unclear if fentanyl gives pain relief to people with neuropathic pain.[45]

In some forms of neuropathy, especially post-herpetic neuralgia, the topical application of local anesthetics such as lidocaine is reported to provide relief. A transdermal patch containing lidocaine is available commercially in some countries.

Repeated topical applications of capsaicin are followed by a prolonged period of reduced skin sensibility referred to as desensitization, or nociceptor inactivation. Capsaicin not only depletes substance P but also results in a reversible degeneration of epidermal nerve fibers.[46] Nevertheless, benefits appear modest with standard (low) strength preparations,[47] and topical capsaicin can itself induce pain.[46]

In some cases a nerve block can be used to treat.

Carbamazepine acts by inhibiting voltage-gated sodium channels, thereby reducing the excitability of neural membranes. Carbamazepine has also been shown to potentiate gamma aminobutyric acid (GABA) receptors made up of alpha1, beta2, and gamma2 subunits. This may be relevant to its efficacy in neuropathic pain.[48] Carbamazepine is commonly used to help with pain attacks during night.