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Characteristics And Treatment Of Diabetic Neuropathic Pain

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Introduction

Pain is an unpleasant sensory and emotional experience that can have a significant impact on a person’s quality of life, general health, psychological health, and social and economic well-being. The International Association for the Study of Pain (IASP 2011) defines: neuropathic pain as ‘pain caused by a lesion or disease of the somatosensory nervous system’. This is further delineated as central neuropathic pain ‘pain caused by a lesion or disease of the central somatosensory nervous system’, and peripheral neuropathic pain ‘pain caused by a lesion or disease of the peripheral somatosensory nervous system’. Neuropathic pain is very challenging to manage because of the heterogeneity of its aetiologies, symptoms and underlying mechanisms (Beniczky et al. 2005).

Examples of common conditions that have peripheral neuropathic pain as a symptom are painful diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia, and radicular pain, pain after surgery and neuropathic cancer pain (that is, chemotherapy-induced neuropathy and neuropathy secondary to tumour infiltration). Examples of conditions that can cause central neuropathic pain include stroke, spinal cord injury and multiple sclerosis. Neuropathic pain can be intermittent or constant, and spontaneous or provoked. Typical descriptions of the pain include terms such as shooting, stabbing, like an electric shock, burning, tingling, tight, numb, prickling, itching and a sensation of pins and needles. People may also describe symptoms of allodynia (pain caused by a stimulus that does not normally provoke pain) and hyperalgesia (an increased response to a stimulus that is normally painful) (McCarberg 2006)

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The neuropathic pain involves the maladaptive changes in the peripheral, central and autonomic system such as sensitization of nociceptors, abnormal ectopic excitability of affected neurons, pronociceptive facilitation at spinal dorsal, disinhibition of nociception at spinal inhibitory network, sympathetically mediated pain and CNS reorganization process. (1) Neuropathic pain is a chronic pain syndrome of unknown etiology that has been associated with drug disease or injury-induced damage or destruction to sensory afferent fibers of the peripheral nervous system which triggers the abnormal synaptic rewriting of Aβ, Aδ and C fibers at the level of the spinal cord creating a state of chronic pain. (2) The nociceptors are receptors with stimulus specific different modalities located at free nerve endings of unmylinated C fibers and lightly myelinated Aδ. An activation of the nociceptors by noxious, mechanical, thermal and chemical stimuli causes release of the endogenous peptides such as bradykinin, substance P, calcitonin gene-related peptide, prostaglandins, excitatory amino acids, neurokinin, serotonin, norepinephrine, histamine, growth factors, lysophosphatidic acid, etc which modify nociceptors causing degradation of axon and myelin sheath promoting the hyperalgesia and allodyania characteristic neuropathic pain.

In neuropathic pain, an abnormal ectopic excitability of afferent neurons caused by alteration in the sodium channels produces the positive symptoms of neuropathic pain such as paraesthesia and dysaesthesia due to spontaneous discharge of myelinated Aβ fibers as well as burning pain due to altered excitability of unmyelinated Aδ and C fibers. Glutamate is the major excitatory transmitter in CNS including pain system. An activation of the glutamate receptors such as NMDA receptors by noxious input in the dorsal horn causes stimulation of Aβ, Aδ and C fibers which increases excitability of nociceptive central neurons (Namaka et. al, 2004). Painful stimuli from peripheral thermoreceptors, mechanoreceptors, and nociceptors are transmitted via sensory afferent fibers to a collection of PNS sensory receptor cell bodies collectively termed the spinal ganglia, or dorsal root ganglia (DRG). Nociception begins when Aδ and C fibers respond to noxious stimulation and transmit this information via the dorsal root ganglia to the dorsal horn of the spinal cord.

These nerve fibers are activated by a host of biochemical products of tissue damage and inflammation including prostaglandins, cytokines, bradykinin, histamine, free radical, protons, purines, neurotrophins and others (Marco P. 2003). The pathomechanism of different types of pain have been studied with the aim of developing new pharmacotherapies for specific pain types. As pain is a subjective sensation, it is difficult to evaluate correctly in clinical trials(Ueda H. ,2006). The diagnosis of neuropathic pain is often be challenging and diagnostic criteria as it is commonly co-exist with other types of pain such as low back pain associated with both radiculopathy and musculoskeletal abnormalities (Upasani C. 2012). Assessment of neuropathic pain should focus on identifying and treating the underlying disease processes and peripheral or central nervous system lesions, response to prior therapies, and comorbid conditions that can be affected by therapy. (5) Neuropathic pain resulting from disordered neural processing within the nervous system is poorly recognized in animals and consequently is difficult to manage (Rusbridge C. , 2008). The most common precipitating cause of neuropathic pain is diabetes particularly where blood glucose control is poor.

Approximately 20 to 24% of diabetic patients experienced neuropathic pain. Diabetic neuropathic pain can occur either spontaneously as a result of exposure to normally mildly painful stimuli i. e. hyperalgesia or to stimuli that are not normally perceived as being painful i. e. allodyania. Diabetes is commonly associated with a peripheral neuropathy that often results in significant pain. The pain has been described as an “anching, burning, stabbing or tingling” sensation and often affects sleep. TCAs, certain anticonvulsants (e. g. gabapentin) and opioid analgesics are currently used to treat the neuropathic pain due to diabetic peripheral neuropathy but often are limited by efficacy or significant side effects. An uncontrolled hyperglycemia in diabetic patients leads to several complications including retinopathy, nephropathy, autonomic dysfunction and neuropathy.

Hyperglycemia has been reported to result in increased polyol pathway activity, oxidative stress, advanced glycation end product formation, nerve hypoxia / ischemia, increased activation of protein kinase c and impaired nerve growth factor support. Oxidative stress causes vascular impairment leading to endothelial hypoxia resulting in impaired neural function, reduced nerve conduction velocity and loss of neurotrophic support. Long term oxidative stress can mediate apoptosis of neurons and Schwann cells leading to nerve damage (Sayyad S. G. , 2006). The streptozotocin (STZ) which selectively destroys pancreatic β-cells rapidly induces diabetes in rodents. Prolonged hyperglycemia causes degeneration of neurons and slowing of nerve conduction velocity occurs in STZ induced diabetic animals as in patients with diabetic neuropathy. In addition, STZ-induced diabetic rat shows neuropathic pain characterized by mechanical and thermal allodyania, one of the symptoms of diabetic neuropathy. The management of neuropathic pain is still a major challenge to clinicians because of its unresponsiveness to most common painkillers.

The mechanisms responsible for neuropathic pain are not well established and therefore, treatment largely depends on empirical measures, previous drug efficacies and trial and error. Treatment for neuropathic pain is still not satisfactory for most of patients especially those with a severe conditions highlighting the need for novel and more efficacies therapy for pain relief (Camara C. , 2013). Recently changes in the ion channels have attracted attention as a possible aetiology of neuropathic pain. The treatment modulating targeted ion channels are based on the known reorganization of ion channels in nervous, dorsal root ganglia, spinal cord and brain after nerve injury. Na+ and Ca++ channels are known to be abnormally activated, up-regulated or both and thus blocking these channels offer the possibility of reducing neuropathic pain. (9)The current pharmacotherapy of neuropathic pain includes the use of unconventional agents such as topical capsaicin, TCAs, certain anticonvulsants, opioids, etc. however use of these agents is associated with suboptimal therapeutic efficacies and/or side effects.

Thus there has been a continuing search for novel drug molecules to alleviate neuropathic pain (Ueda H. , 2006). Because neuropathic pain is also characterized by neuronal hyperexcitability therefore the clinicians and researchers have reasoned and concluded that anticonvulsant drugs might alleviate or reduce the neuronal hyperexcitability. Use of antiepileptic drugs for treatment of neuropathic pain is an attractive option because of:

  1. Similar pathophysiology of neuropathic pain and epilepsy e. g. central sensitization.
  2. Common process of ectopic neuronal firing for both epilepsy and neuropathic pain and
  3. Both disorders are caused by central neuron system injury such as head trauma.

An effectiveness of antiepileptic drugs in treatment of neuropathic pain is due to sodium channel blockade, calcium channel blockade, enhancement of GABAergic transmission, inhibition of glutaminergic transmission, free radical scavenging activity, inhibition of nitric oxide formation and enhancement of serotonergic transmission properties (Sullivan M. D. et. al. , 2006).

Unfortunately, no specific pharmacological agent has demonstrated unequivocal efficacy in reversing neuropathy or preventing disease progression. The important discrepancies are observed on the effectiveness and potency of antiepileptics in acute nociception and sensitization due to inflammation and neuropathy. There is also some controversy in literature on whether antiepileptics are only active in central areas of nervous system or is also effective in periphery (Curros-Criado M. M. 2007). The global incidence of DM is increasing at an alarming rate and the studies indicate that to affect 366 million individuals by 2050 (Bodhankar et al. , 2012). Besides hyperglycemia, several other symptoms including hyperlipidemia are involved in the development of micro-vascular and macro-vascular complication of DM (Tang et al. , 2006). A frequent complication of DM is neuropathy. Up to 50% of diabetics will develop a neuropathy after 25 year of the disease (Galer et al. ,2000). Which are the major causes of morbidity and death (Tang et al. , 2006).

Oxidative Stress And DN

Oxidative stress is defined as “a state where oxidative forces exceed the antioxidant system due to loss of the balance between them” (Yoshikawa and Naito 2002). Oxidative stress occurs in a cellular system when the production of free radical moieties exceeds the antioxidant capacity of the system. If cellular antioxidants do not remove free radicals, radical attack and damage proteins, lipids and nucleic acids. The oxidized and nitrosylated products of free radical attack have decreased biological activity, leading to loss of energy metabolism, cell signaling, transport, and other major functions. These altered products also are targeted for proteosome degradation, decreasing cellular function. Accumulation of such injury ultimately leads a cell to die through necrotic or apoptotic mechanisms (Vincent et al. ,2004). Chemistry of oxidative stressSeveral free radicals species are normally produced in the body to perform specific functions.

Superoxide (O2), hydrogen peroxide (H2O2), nitric oxide (NO) are three free radical reactive oxygen species (ROS) that are essential for normal physiology, but are also believe to accelerate the process of aging and to mediate cellular degeneration in disease states. These agents together produced highly active singlet oxygen, hydroxyl radicals, and peroxynitrite that can attack proteins, lipids and DNA (Vincent et al. ,2004). a. Superoxide ( O2 – )O2 – is generated by the mitochondrial electron transfer chain during the oxidation of reduced nicotinamide adenine dinucleotide (NADH) to oxidized nicotinamide adenine dinucleotide (NAD+)and also by product of many enzymes that acts as an oxidases. Approximately 4% of electrons that enters the respiratory chain lead to the formation of O2. The beneficial effect of O2 – include regulation of vascular function, cell division, inflammation, apoptosis, and bactericidal activity of neutrophils. If decreased level of O2- can lead to an increased susceptibility to bacterial infections, as illustrated in Down’s syndrome patients with elevated cytoplasmic superoxide dismutase (SOD).

Excess O2- is removed through the activity of a family of SOD enzymes that convert O2– to H2O2 and oxygen. (Vincent et al. ,2004). b. Hydrogen peroxide (H2O2)H2O2is produced after the spontaneous or SOD- catalyzed dismutation of O2- as well as so many other enzymatic reactions. Unlike O2-, which remains at the site of production, H2O2 can diffuse across the membranes and through the cytosol. This ROS is another component of leukocyte-mediated defense against bacteria. Because of H2O2 is powerful oxidizing agent, cells express abundant catalase, glutathione (GSH), and thioredoxin that convert H2O2to water. When H2O2 reacts with free Fe2+, the iron is oxidized and hydroxyl radical production, including loss of vasodilation that can lead to endothelial injury and tissue hypoxia. (Vincent et al. , 2004)c. Nitric oxide (NO) NO is generated through the activity of a cytosolic enzyme known as NO synthase (NOS). There are both constitutively expressed, calcium dependent isoform of NOS and an inducible isoform that is associated with inflammation and cell activation. NO modulates cellular respiration through direct inhibition of cytochrome oxidase by competitively occupying the oxygen – binding site. The inducible form of NOS is increased in the arteries of diabetic rats. Damaged neurons recover more slowly in the presence of NO, and conversely, NOS inhibitors promote neuronal recovery from injury. (Vincent et al. , 2004).

Hyperglycemia activates many signaling mechanisms in cells. Four major pathways that can lead to cell injury downstream of hyperglycemia are illustrated. 1) Excess glucose shunts to the polyol pathway that depletes cytosolic NADPH and subsequently GSH. 2) Excess glucose also undergoes autooxidation to produce AGEs that impair protein function and also activate RAGEs that use ROS as second messengers. 3) PKC activation both further increases hyperglycemia and also exacerbates tissue hypoxia. 4) Overload and slowing of the electron transfer chains leads to escapes of reactive intermediates to produce O2-. As well as activation of NADH oxidase that also produces O2-. A unifying mechanism of injury in each case is the production of ROS that impair protein and gene function.

The enzyme aldose reductase (AR) reduces glucose to sorbitol and sorbitol dehydrogenase (SDH) Oxidised sorbitol to fructose (Vincent et al. ,2004). AR that causes accumulation of sorbitol at the cellular level in various diabetic conditions. Sorbitol accumulation directly leads to tissue damage and promotes the macrovascular and microvascular complications of diabetes because excess intracellular sorbitol levels decrease the concentration of various protective organic osmolytes. This is seen in the animal model of cataracts that contain decreased levels of taurine, a potent antioxidant and free-radical scavenger. Interestingly, inhibitors of aldose reductase have restored levels of protective osmolites and prevented diabetic complications by diminishing sorbitol reduction (Codario. , 2005). Since NADPH is consumed by aldose reductase-mediated reduction of glucose to sorbitol and NADPH is required for regeneration of reduced glutathione (GSH), this too contributes to oxidative stress. The second step in the polyol pathway oxidizes sorbitol to fructose via sorbitol dehydrogenase.

Formation of fructose promotes glycation as well as depletes NADPH, further augmenting redox imbalance. Activation of aldose reductase may also increase formation of diacylglycerol, which activates the deleterious PKC pathway. (Edward’s et al. , 2008).

Hexosamine pathway: The hexosamine pathway was implicated as an additional factor in the pathology of diabetes-induced oxidative stress and complications. Fructose-6 phosphate is a metabolic intermediate of glycolysis. However, during glucose metabolism some fructose-6 phosphate by is shunted from the glycolytic pathway to the hexosamine pathway. Here fructose-6 phosphate is converted to glucosamine-6 phosphate by glutamine fructose-6 phosphate amidotransferase. Glucosamine-6 phosphate is then converted to uridinediphosphate-N-acetyl glucosamine (UDPG1cNAc), a molecule that attached to the serine and threonine residues of transcription factors. Hyperglycemic conditions create additional flux through the hexosamine pathway, ultimately resulting in excess G1cNAc and abnormal modification of gene expression.

Specifically, hyperglycemic conditions and excess G1cNAc cause increased activation of Sp1, a transcription factor implicated in diabetic complication. Sp1 is responsible for the expression of many glucose-induced “housekeeping” genes including transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor -1 (PAI-1). Thus, increased flux through the hexosamine pathway has been causally implicated in multiple metabolic derangements in diabetes (Edwards et al. , 2008).

Protein kinase C pathway: The Protein kinase C (PKC) pathway is an additional mechanism by which hyperglycemia causes injury in complication-prone tissues. Elevated glucose levels stimulate diacylglycerol (DAG), which in turn activates PKC. Increased production of the PKC, PKC-β-isoform in particular has been implicated in over expression of the angiogenicprotein vascular endothelial growth factor (VEGF), PAI-1, NF-кB, TGF-β and the development of diabetic complication such as retinopathy, nephropathy, and cardiovascular disease (Codario. , 2005). Data on the effect of PKC-β and VGEF on diabetic neuropathy are less clear, but generally most support the concept that increased PKC pathway flux plays a role in neuropathy as well. The link of PKC to diabetic neuropathy is supported by studies in streptozotocin (STZ) induced diabetic rats, Where PKC inhibition normalizes both sciatic nerve blood flow and nerve blood flow and nerve conduction velocity. Over expression of PKC isoforms can also directly induce insulin resistance (Edward’s et al. , 2008).

Advanced glycation end products pathway: Non-enzymatic reactions between reducing sugars or oxaldehydes and proteins/lipids results in advanced glycation end products (AGEs). Three main pathways are responsible for the formation of reactive dicarbonyls (AGE precursor):

  1. Oxidation of glucose to form glyoxal.
  2. Degradation of Amadori products (fructose-lysine adducts), and
  3. Aberrant metabolism of glycoltic intermediates to methylglyoxal.

AGEs are heterogeneous modified intracellular and extracellular biomolecules. Inside cell, both protein and DNA adducts alter function and cellular transport. Methylglyoxal a highly reactive dicarbonyl is shown to induce sensitivity to vascular damage in endothelial cells (Edwards et al., 2008). Inflammatory responses, apoptosis, and mediators of various immune functions are also enhanced by the glycosylation end products, which bind to their receptor for advanced glycationendproducts (RAGE). The binding of AGE to their receptor sites enhances the expression of pro inflammatory and procoagulant molecules, enhancing vascular adhesion and thrombogenesis. This could explain the impaired wound healing and enhanced susceptibility to infection that is prominent in diabetic patients (Codario. , 2005).

Poly (ADP-ribose) polymerase pathway: PARP found in Schwann, endothelial cells, and sensory neurons is also implicated in glucotoxicity. PARP is a nuclear enzyme closely associated with oxidative-nitrosative stress, free radicals and oxidants stimulate PARP activation. PARP acts by cleaving nicotinamide adenine dinucleotide (NAD+) to nicotinamide and ADP-ribose residues attached to nuclear proteins. The result of this process include NAD+ depletion, changes in gene transcription and expression, increased free radical and oxidant concentration, and diversion of glycolytic intermediates to other pathogenic pathways such as PKC and AGE formation. (Edward’s et al. , 2008).

Current Therapy For DNP

The clinical management of DNP is often inadequate because of many reasons like inadequate diagnosis, inappropriate drug therapy, obscureness in the pathophysiological pathways leading to DN. The existing strategies for treatment of DNP can be broadly classified either as treatment based on pathogenetic concepts or based on the treatment (Kumar et al. , 2004). There are many agent belonging to different categories have been studied and used for the treatment of DN. The Major categories are opioids analgesic (Otari et al. , 2012), antidepressants (Hartemann et al. , 2011), anticonvulsants, NMDA antagonist, SSRIs, SNRIs, NSAIDS (Edward’s et al. , 2008), Topical treatments, Miscellaneous drugs.

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