Neuropathic+pain+and+treatment

= __**Overview**__ = toc

= = Unlike other types of pain caused by stimulation of pain receptors, neuropathic pain is a type of chronic pain caused by damaged or dsyfunctional nervous system that normally signals pain. Patients with neuropathic pain may experience intermittent or unremitting pain associated with conditions such as alldoynia, dsythesia and hyperpathia. It can also arise some unpleasant emotional conditions such as hypersensitivity, sleep disturbance and incrased arousal level. Although systemic medications with specific guidelines are available for the treatment of neuropathic pain, many patients do not fully recover or experience the intolerable adverse effects associated with effective medication. Recent resesarch suggests that the noninvasive pain management procedures such as transcranial direct current stimulation (tDCS) and repeated transcranial magnetic stimulation (rTMS) can produce long lasting analgesic effects in patients suffering from different types of neuropathic pain such as phantom limb pain. Major focus of this page is to emphasize the relation between causes and mechanisms of neuropathic pain as well as its associated symptoms and how repeated electrical stimulation on the brain can induced neuronal plasticity to relieve neuropathic pain with only minimum adverse effects. It also discuss about the clinical protocol and the challenges of this treatment.

Neuropathic pain is often derived from the continuation of previous disease or physical trauma that causes damage or lesion in the nervous system. Although many neuropathic cases still considered idiopathic, some possible causes are known.

__**1.1 Diabetes**__
Degeneration of the peripheral nervous system is most common secondary complication of diabetes. Hyperglycaemia,characteristic to diabetes, exerts increased polyol pathway through enzyme aldose reductase resulting the accumulation of sorbitol and latter to fructose in the nerve and non-enzymatic glycosylation of structural nerve proteins. Hyperglycaemia also linked to oxidative stress as well as increase in cytokines release which causes vascular inflammation. [8] As a result of increased vascular dysfunction and reduced blood flow in the nerve, endoneural hypoxia is triggered. Hypoxia can causes the interference in axonal transport and impairment of nerve conduction. Progressive nerve fiber loss, another characteristic of diabetes, causes lesion in peripheral nerves and may contributes to painful diabetic neuropathy.



**__1.2 Alcoholism__**
It is believed that long-term abuse of alcohol has detrimental effects on the nervous system and may lead to the diagnosis of neuropathic pain. Alcoholic neuropathy is well-characterized by axonal degeneration and demyelination of neuronal fibers. Chronic alcohol consumption decrease thiamine absorption and hepatic thiamine storage. Development of thiamine deficiency leads to neuronal damage in central nervous system through several mechanisms including mitochondrial damage and apoptosis. Ethanol also shows neurotoxic effect on spinal cord and neuronal organelles. Acetaldehyde, metabolite of ethanol, promote DNA damage and mutation, and increase in reactive oxygen species (ROS) which puts oxidative stress on neurons and impairs fast axonal transport. A recent study suggests that alcohol affects myelinated and unmyelinated small fiber loss in normal thiamine level, supporting the view of direct neurotoxic effect of alcohol.

**__ 1.3 Nutritional deficiencies __**
Nutritional imbalance and vitamin deficiencies may also cause neuropathic pain. Vitamin B12, also called cobalamin, is a key factor in the normal function of nervous system and its deficiency may causes wide range of neurological manifestations including myelopathy, peripheral neuropathy and other neuropsychiatric disorders. Cobalamin-deficient neuropathy is common among the elderly and best characterized by the demyelination of the posterolateral columns of the spinal cord. The myelination process in CNS is heavily dependent on the ratio between between S-adenosylmethionine (SAM) and its product, S-adenosylhomocysteine (SAH) —myelination ratio. Inhibition of the vitamin B12 dependent enzyme, methionine synthase, causes rapid elevation of SAH and fall of SAM level which leads to inversion of the myelination ratio and Inhibition of //S//-adenosylmethionine-dependent methylation. This defective myelination or demyelination mainly seen in the posterlateral columns of spinal cord but can also be found in cerebral white matter. Another possible cause of neurologic manifestation is the conversion of L-methylmalonyl CoA to succinyl CoA where adenosylcobalamin, active form of cobalamin, act as cofactor. When amount of cobalamin is minimised, instead of succinyl CoA, L-methylmalonyl-CoA converts itself into D- methylmalonyl CoA and then hydrolyzed to methylmalonic acid(MMA). Increase in methylmalonic acid leads to abnormal odd chain and branched chain fatty acids with defective myelination or demyelination which might contribute to dysfunctional nerve transmission. Vieira-Makings E, Chetty N, Reavis SC, Metz J.  (1991). Methylmalonic acid metabolism  and nervous-system fatty acids  in cobalamin-deficient fruit bats receiving supplements  of <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">methionine <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">, <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">valine <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;"> and <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">isoleucine <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">. <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;"> Biochem J. <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">275 ( Pt 3):585-90.

__** 1.4 Multiple sclerosis **__
Multiple sclerosis is a chronic inflammatory disorder characterized by relapsing lesions in the central nervous system. It is also known as autoimmune disease that attacks myelinated axons. In early stage, specific T cells, CD4+ lymphocytes, interact with adhesion molecules on endothelial cells and penetrate through the blood brain barrier into the CNS. <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">Smith KJ, McDonald WI. <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">(1999). <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">The <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">pathophysiology <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;"> of <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">multiple <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">sclerosis <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">: the <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">mechanisms <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">underlying <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;"> the <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">production <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;"> of <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">symptoms <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;"> and the <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">natural <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">history <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;"> of the <span class="highlight" style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">disease <span style="font-family: 'Calibri','sans-serif'; font-size: 14.66px;">. Philos Trans R Soc Lond B Biol Sci. 354(1390):1649-73. After the entry, CD4+ binds to specific myelin epitopes and initiate chronic inflammation response in the CNS. As a result, macrophages and other relevant antibodies will damage the myelin sheath, slowing or blocking axonal conduction. [31] Also, free radicals released by macrophages induce oxidative stress,causing a damage to DNA and other neuro- proteins. This lesion in spinal cord might triggers peripheral sensitization or hypersensitivity of specific neurons and reduces the threshold for nociceptive pain which eventually leads to chronic neuropathic pain.

**__1.5 Autoimmune disease__**
Guillain-Barré syndrome is a type of peripheral nerve disorder characterized by progressive motor weakness, sometimes to complete paralysis of more than one limb. All forms of Guillain-Barré syndrome are considered autoimmune disease triggered by infection agents. Current hypothesis suggests that all infectious molecules stimulate the autoimmunity through the phenomenon called molecular mimicry. For example, infectious agent called //Campylobacter jejuni// share homologus epitopes with peripheral nerves triggering immune system reacton such as antiganglioside antibodies. The autoimmunity response often results the direct damage to the myelin or demyelination, leading to complete or partial muscle paralysis and latter possible neuropathy.



**__1.6 Others__**
**Others include:**


 * Toxic exposure(heavy metals, certain medications and cancer treatment such as vincristine )
 * Trauma (surgery, amputation)
 * Carpal Tunnel Syndrome
 * Inherited disorders (Charcot-Marie-Tooth diseases and amyloid polyneuropathy)
 * Tumors and cancer treatment
 * Parkinson’s disease
 * Stroke
 * Kidney disease
 * Liver diseases
 * Lyme disease
 * HIV/AIDs
 * hypothyroidism

**__2.1 Peripheral sensitization__**
Peripheral sensitization refers to reduced threshold and heightened responses of peripheral ends of nociceptors due to the nerve injury. Peripheral sensitization is caused by multiple pathophysiological mechanisms. After the nerve injury or neurogenic inflammation occurs, immune cells release inflammatory mediators such as endothelin, prostaglandin E2 (PGE2), cytokines that may sensitize the nociceptor. For example, peripheral inflammation upregulates spinal Cyclo-oxygenase (COX-2), which converts arachidonic acid to prostaglandin (PGE2). Increased PGE2 sensitizes sensory neurons in spinal dorsal horn by activating the EP1 receptors and allowing increase in intracellular [Ca2+] level, consequently resulting increased responsiveness of peripheral ends of nociceptor and possible development ofhyperalgesia and allodynia. A number of animal models show a cluster of sodium channels (i.e Nav 1.3, Nav 1.7 and Nav 1.8) at the site of nerve lesion as well as in the dorsal root ganglion. This abnormal sodium channel expression causes ectopic neuropacemaker activity which play a key role in lowering threshold and increase in firing frequency, leading to hyperexcitability of nociceptor terminals.

**__2.2a Central sensitization__**
Central sensitization refers to increase in the central neuron excitability to normal stimuli, usually results from peripheral nerve damage or repeated nerve stimulation, but it can also form in absence of injury. Continuous firing of Aδ and C-fiber noicieptor caused by nerve inflammation, leads to glutamate release which then activate glutamate receptors (i.e AMPA, NMDA) in the spinal cord. Activation of NMDA receptors causes increase in the intracellular [Ca2+] level and cAMP in which subsequently trigger the release of calmodulin-dependent protein kinase II (CaMKII), a key mediator of long term potentiation. Protein kinases consist of the signalling cascade that modulates gene transcription to sensitize the dorsal horn (i.e low activation thresholds, expansion of receptive fields and ectopic discharges).

**__2.2b Deafferentation hypersensitivity__**
Neuropathic pain can also rise from complete or partial loss of sensory input to the central nervous system. Although the exact mechanism behind it is unknown, it is likely due to abnormal hypersensitivity of central neurons and alteration of axonal pathway. Deafferentation patients have several spontaneous pain like other neuropathic patients but they do not experience hyperalgesia or allodynia. [49]

**__2.3 Mechanism based symptoms__**
Patients with neuropathic pain often describe their pain as “burning” sensation. Research studies show that spontaneous burning pain is largely due to abnormal sensitivity of peripheral ends of nociceptor and hyperactivity of central neurons. Allodynia is one of the common feature of neuropathic pain in which pain caused by normal stimulus. Current view on mechanism of allodynia is still controversial. However, recent findings suggest that both spontaneous firing of damaged nociceptive afferents and central sensitization lead to hypersensitive reaction to normal stimulus such as light touch. [53] Similarly, hyperalgesia, another characteristic of neuropathy, initially thought to be formed by sensitization of nociceptive nerve endings. However, recent evidences show that central sensitization is equally important.

**__3. Noninvasive pain treatment approach__**
Many treatments or therapies are currently available, however, only approximately 50% of patients reports considerable pain relief. Many cases of neuropathic pain caused by multiple mechanisms thus finding appropriate treatment often very challenging. Recent studies suggest non-invasive treatment such as tDCS and rTMS as possible high pain relief treatment with no adverse side effects.

**__3.1 Transcranial direct current stimulation__**
Transcranial direct current stimulation is a brain stimulation technique that applies low current directly to specific cerebral cortex area using small electrodes. This technique uses two electrode: anodal electrode (positively charged) and cathodal electrode (negatively charged). Current injected will flow from one electrode to another, generating bidirectional circuit. Stimulation with anode will increase cortical excitability whereas stimulation with cathode will diminish excitability. Exact mechanisms is not yet clear but it is believed to be somewhat similar to long-term potentiation and long-term depression. A key feature of tDCS is its outlasting effects beyond the stimulation period. For example, a group of patients with chronic neuropathic pain have shown persisting excitability changes at the site of stimulation and lower pain intensity even after 12 weeks of treatment. The effect of stimulation seems to be involved with the duration of stimulation and the strength of electrical current. Another benefit of this technique is about the safety and minimum side effects. Some side effects of tDCS includes mild headache, skin irritation, dizziness however most of them usually disappeared after the end of session and left no significant distress. [60]



**__3.2 Repeated magnetic transcranial stimulation__**
Repeated transcranial magnetic stimulation is another brain stimulation technique that changes neuronal activity in the selected cortex. Instead of using electrodes, rTMS uses large, rapidly changing magnetic field to induce electric current in the brain of interest. Similar to tDCS, this technique shows outlasting effects after the stimulation and can increase or decrease cortical excitability by changing the intensity of stimulation, electric coil orientation and frequency. In terms of clinical use, rTMS has stronger effect on the brain of interest than tDCS but has greater risks as well. Most prominent side effects of rTMS includes seizures ,fainting and syncope. media type="youtube" key="ycSGgkndRJU" height="251" width="448"

__See Also__
Pain-induce synaptic plasticity in anterior cingulate cortex Mechanisms of Neuropathic Pain Causes and Genetic Variability in Neuropathic Pain Signs, Symptoms, Diagnosis, and Comorbidities Treatment and Therapy of Neuropathic Pain