A Study on Neuropathic Pain: Causes, Grading System, Mechanism- A Review

 

S. Akilashree., Brindha Devi. P*

Department of Bio-Engineering, School of Engineering, Vels Institute of Science, Technology and Advanced Studies

 

ABSTRACT:

Neuropathic pain, the type of pain condition which is caused by the specific nociceptors and is very different from the regular pain. The pain caused is highly intolerable to patients as the pain can be evoked by gentle touch, wind, clothes pressure and puts a great challenge to proceed with day to day activities. The treatments for the neuropathic pain reduces the production of neurotransmitters to some extent which be the cause of intolerable pain, but the faster disease progression is the main concern which can be sorted out by earlier prediction. The efficient grading system is required to differentiate the neuropathic pain condition and to initiate the treatment quickly after the onset of disease. The grading factors give the actual cause, location and the progression of pain. Understanding the mechanism behind the neuropathic pain is very important to carry out the drug formulation, effects of drugs, and distinguishing neuropathic pain from the regular induced pain. It is also required to initiate the treatment shortly after the onset of disease. Here, this review explains about the grading system of neuropathic pain, causes of pain, mechanism and the wide range of drugs involved in the treatment of neuropathic pain.

 

 

 

1. INTRODUCTION:

Truthfully, pain is not unpleasant when the real phenomena are understood (i.e) it is a signal and plays a protective role by warning us about the tissue damage after which it minimizes the damage by the coordinated reflex and behavioral responses based on the level of tissue damage. Changes in the peripheral and central nervous system (PNS and CNS) establish pain due to certain tissue damage in specific location which leads to enhance the rate of wound repair because any interaction to the injured part is avoided until the pain disappear and by which we can come to the conclusion that pain plays a vital role in protection and reversing the damages (Woolf and Mannion, 1999).

 

 

Commonly, Pain is caused by the nociceptive afferents arising from the damaged tissue at a specific location and it is the “common pain” due to the potential damage and lies as the physiological condition (Treede et al., 2008). Still, pain can occur without the simulations from peripheral sensory endings and that is said to be Neuropathic pain caused by damage in the somatosensory system (Baron, 2006) and there are several neuropathic pain disorders like painful neuropathies, syringomyelia, and central post-stroke pain (Treede et al., 2008, Merskey, 1994)

 

2.    NEUROPATHIC PAIN:

In Order to differentiate nociceptive pain from the common pain for the ease of diagnosis, The International Association for the Study of Pain (IASP) established neuropathic pain by means of “pain initiated or triggered by a primary lesion or dysfunction in the nervous system.” (Hansson, 2008, Dworkin at al., 2003, Jensen et al., 2002, Backonja, 2003, Cruccu et al., 2004). Firstly, Neuropathic pain needs to be distinguished from pain caused by neuroplastic changes from nociceptive stimulation and from the pain caused by neurological disorders. Initially, there were no diagnosis, proper anatomical features of the disease and treatment for the neuropathic pain conditions. Neuropathic pain is the kind of painful condition which results as a result of a lesion or disease affecting the somatosensory system (Cervero and Laird, 1991, Treede et al, 1992; Carter and Galer, 2001; Baron et al., 2010; Baron, 2006). This pain is not the same as the regular induced pain instead the pain can be evoked by a gentle touch, wind, pressure of clothes which can be witnessed in neuropathic pain disorder patients. Central sensitization is one of the causes of the neuropathic pain where it involves the changes in the CNS based on the amount of pain experienced and the patient becomes more sensitive and less provocative.

 

Neuropathic pain is classified into two; peripheral and central neuropathic pain based on the site of lesion and this site is important during the disease diagnosis (Hansson, 2001; Jensen and Gottrup, 2003). Peripheral neuropathic pain is an idiopathic condition (causes is unknown) but the pain is neuropathic (pain from nerve damage). The presence of peripheral neuropathic pain makes the patient’s medical condition more complex (Devi and Venkatesan, 2018)

 

Nevertheless, pain is still a pain when a patient experiences, so how to differentiate the neuropathic pain from other conditions like musculoskeletal pain?

 

There are 2 requirements to satisfy the neuropathic pain conditions, they are the pain distribution throughout the body part of CNS or to the nerves, roots, fascicles and the location of the lesion affecting the peripheral and somatosensory system. The cases of the neuropathic pain experience immediate pain onset within a short period after injury (Treede et al., 2008; Andersen et al., 1995, Kehlet et al., 2006). When these requirements are fulfilled, the condition can be a neuropathic pain in most of the cases.

 

2.1.  Causes:

The causes of neuropathic pain comprise infection, surgery, tumor infiltration, chemotherapy, nerve compression neurotoxins, inflammation, and trauma. The lesions in the nervous system with the capability to affect the somatosensory system can cause neuropathic pain (Carter and Galer, 2001, Backonja, 2003). The injuries which are responsible for the neuropathic pain condition may heal with the time but the damage caused in the nervous system remain the same. Accidents and injuries which affect the spinal cord or other parts of the nervous system can also be the cause of the pain. Spinal cord compression and Herniated disks may contribute to neuropathic pain conditions. The other causes include Alcoholism, Diabetes, AIDS, Amputation surgeries, Multiple sclerosis, Syphilis, thyroid problems. The causes of neuropathic pain and symptoms are depicted in the figure 2.1A.

 

Figure 2.1A: Causes of Neuropathic Pain

 

2.2.  Neuropathic pain grading system:

Organizing certain tests which confirms the neuropathic pain in an individual is highly required to avoid misinterpretation with other conditions. Hence, the grading system available facilitates the validation of tests. There are 4 criteria’s under the grading system and to avoid confusion, often 2 or more experts predictions are taken into account. The neuropathic pain diagnostics does not depend on the single findings and require further investigation for the confirmation.

 

 

2.2.1.         Pain with a discrete neuroanatomical plausible distribution:

This criterion is about the pain distribution in the innervation territories of nerves, roots, fascicles. In peripheral neuropathic pain, the pain distribution has to confirm the innervation territories of the nerve segments. Nevertheless, the distribution of pain need not be identical but should be in a consistent manner for the neuropathic pain condition (Treede et al., 2008). In central neuropathic pain, the pain distribution should be throughout the body part of CNS, detailed medical history of the patient is highly required for drawing into conclusions when diagnosing for neuropathic pain. Assessing the duration of the pain, initiation of pain after injury, the intensity of pain has to be obtained from the patient. This can be done using neuropathic pain scales from 0 to 10 for easy assessment (Dworkin, 2002; Krause and Backonja, 2003).

 

2.2.2.         A history of a relevant lesion or disease affecting the central or peripheral somatosensory System:

The experienced lesion or the disease should be capable of causing an effect on the somatosensory system, hence this criteria has to be analyzed at the first stage of grading neuropathic pain and these lesions or disease be the evidence for the cause of pain and neural damage which is absent in other native lesions.

 

2.2.3.         Confirmatory tests for the pain distribution:

This criterion consists of the examination of neurologic signs which acts as the evidence for the lesions and the pain distribution. This criterion is not for all the patients as the neurologic signs often do not accompany with the neuropathic pain disorders. Verbal questionnaires, biopsies, neuroimaging are the tests for the preliminary testing (Bouhassira et al., 2004, Bouhassira et al., 2005, Marchettini, 2005) for neuropathic pain and confirmed by nerve conduction studies, skin biopsy, laser-evoked potentials, masseter inhibitory reflex, blink reflex, RIII component of the withdrawal reflex, and electromyography (Treede et al., 2008; Cruccu et al., 2004).

 

2.2.4. Confirmatory tests for the lesions or disease causing the pain:

This relates to the diagnostic test for the lesion or disease which affects the somatosensory system and this criterion can be matched with the tests like CT, MRI, nerve biopsy to directly visualize the nerve fibers, for the confirmation of neuropathic pain ((Treede et al., 2008;).

 

2.3.  Physical examination tests:

Quality of life (QOL) indicator is a significant tool for assessing any medical condition which is based on the patient’s assessment of their own health (Amanova et al., 2018). Diagnostic tests for the neuropathic pain is very difficult as it often confuses with the other conditions, hence need better attention during the tests. This is the preliminary tests which are examined by physicians under various criteria for the confirmation of neuropathic pain and the patients are advised to describe their symptoms correctly in order to avoid confusion and severity of the disorders (Backonja and Galer, 1998). Pinprick sensitivity (hyperalgesia), light touch, brushing with swabs (allodynia), pressure with the finger are all the tests for the detection of sensory deficits. Each test is carried out first in the unaffected area and then to the affected area for the comparison of sensitivity and the severity of disorders (Carter and Galer, 2001).

 

2.4.  Other studies:

The tests including electromyography, nerve conduction velocity tests are performed to assess the peripheral nervous system and thermal stimuli are provided to check the patient’s ability to differentiate the temperature. Anatomy function test can be performed by Magnetic Resonance Imaging (MRI) to study the integrity of regions like brainstem, cortex, and thalamus (Carter and Galer, 2001).

 

2.5.  Pathophysiological conditions:

Not one but many other causes leads to the neuropathic pain; more likely lesions which occur at any site of the nervous system can lead to the pain condition (Baron et al., 2010; Baron, 2006). Peripheral sensitization can be defined as the state of hyperexcitability in afferent nerves due to the initiation of rigorous repair mechanisms of neural tissues in reaction to injury. This leads to functional changes in CNS and causes the state of hyperexcitability called as central sensitization. This phenomenon, Peripheral and central sensitization lead to neuropathic pain conditions. Injuries in the nervous system can cause permanent dysfunctions in sensory processing, and in some cases leads to neuropathic pain (Carter and Galer, 2001).

 

3.    MECHANISM OF NEUROPATHIC PAIN:

3.1.  Stimulus independent pain:

There are two kinds of neuropathic pain based on stimulus and the firing of the sensory neuron as stimulus dependent and stimulus-evoked pain. Often the stimulus-dependent pain is regulated by the activity of sensory neurons and the firing of dorsal horn neurons in the spinal cord.

 

It is important to know the type of channels involved in the mechanism of neuropathic pain, there are 2 types of sodium channels are present in the sensory neurons where one type is sensitive to tetrodotoxin (all sensory neurons) and other is insensitive to the same (nociceptor sensory neurons) (Woolf and Mannion, 1999; Novakovic et al., 1998). It is also noted that ectopic discharges from the nerve injury also correlates with the neuropathic pain by the accumulation of both the type of sodium channels in the axon which results in hyperexcitability in the injured neurons (Sun et al., 2005, Lai et al., 2003). The pain sensation raised as stimulus-independent pain due to the alteration in sodium channels is depicted in figure 3.1A. The upregulated levels of sodium channels and intact fibers may lead to the reduced action potential until the ectopic discharge take place (Black et al., 2008, Siqueira et al., 2009). The shooting pain without any stimuli is caused by the ectopic discharge in the nociceptors and these discharges are noted by the microneurography in the primary afferents from the patients (Nyström et al., 1989; Ørstavik et al., 2006; Ørstavik et al., 2010). As the sodium channels are accountable for the neuropathic pain induction, the sodium channel-breakers are introduced and they often have side effects in the central nervous system and cardiovascular system as they are not selective enough to act on the sodium channels in the axon of the injured neurons (Woolf and Mannion, 1999, Rowbotham et al, 1998; Fields et al., 1998). Addition to the sodium channels, there are other ion channels which can be altered after the nerve injury like voltage-gated potassium channels (Ultenius, 2006). This alteration in the ion channels contributes to the hyperexcitability of nerves.

 

Figure 3.1A: Stimulus-independent pain

 

There is one more sector called sympathetically maintained pain where the action of sympathetic axons with dorsal root ganglia initiates. As the pain arises from the injury of the nerve fibers, both the injured as well as uninjured axons start to produce alpha-adrenoreceptors which makes the axons sensitive to noradrenaline and catecholamines produced by postganglionic terminals. Sympathetic activity induces the activity of sensory fibers after the nerve injury by the inducement of sympathetic axons into the dorsal root ganglia which forms the basket like structure around the sensory neurons (McLachlan et al., 1993).

 

The inhibitory pathways or the brain stimulators induced through the peripheral nerve injury influences the process of maintaining the stimulus-independent pain. After the peripheral nerve injury, loss of GABAergic interneurons occurs in the spinal horn (Moore et al., 2002). Hence the avoidance of the cell death of GABAergic interneurons leads to hyperalgesia which shows that disinhibition leads to neuropathic pain (Scholz et al., 2005). The input from the primary neurons is received by the neurons present in the dorsal horn of the spinal cord which process and transmit to the brain. The firing of neurons in the dorsal horn of the spinal cord is influenced by the excitatory inputs as well as the segmental inhibitory inputs, where an increase in inhibitory inputs leads to the reduction in the activity of neurons in the dorsal horn of spinal cord. Thus, there is an increase in inhibition and down-regulated inhibitory receptors (Willis and Coggeshall, 2012). Moreover, the interneurons which are as well inhibitory, die after the nerve injury by the excitotoxic mechanisms. Hence due to the down-regulated inhibitory receptors, disinhibition occurs and which leads to the spontaneous firing of dorsal horn neuron in response to the afferent signals (Willis and Coggeshall, 2012; Sugimoto et al., 1990). Opioid receptors and GABA receptors are reduced and the hormone-like cholecystokinin is increased in the injured neuron.

 

Paroxysmal extreme pain disorder and Erythromelalgia are some of the hereditary disorders of pain which have the influence of voltage-gated sodium channels in the mechanism of disorder and caused by the mutation occurred in the SCN9A gene, codes for Nav1.7 voltage-gated sodium channel (Dib-Hajj et al., 2009).

 

3.2.  Stimulus-evoked pain:

Myelinated afferent fibers are the cause of pain which is being experienced due to its tendency to carry the action potential. The fibers input leads to the firing of dorsal horn neurons and the increase and continuous input results in sensitization of dorsal horn neurons and makes them respond in an exaggerated way even for a normal stimulus which occurs in stimulus-evoked neuropathy. For example, brush-evoked hyperalgesia which occurs due to the continuous Aβ fiber inputs to the dorsal horn and leads to the sensitization of dorsal horn neurons. Thus, they respond in a most exaggerated way for the normal stimuli and by which the pain is experienced severely. The pain sensation raised as stimulus-evoked pain due to the central sensitization is depicted in figure 3.2A.

 

Figure 3.2A: Stimulus-evoked pain

 

The mechanism behind the stimulus-evoked pain is sensitization of dorsal horn neurons which is produced by the main neurotransmitter present in the primary neurons, glutamate. The amino acid glutamate neurotransmitter can act on various kinds of glutamate receptors to cause depolarization in the dorsal horn neurons. Once the depolarization reaches the maximum, discharge of action potential takes place.

 

The nociceptors activation causes the release of glutamate which binds with glutamate receptor amino-3-hydroxy-5-methylisoxazole-4-propionic acid and causes depolarization in the dorsal horn neurons and the discharge of action potential takes place once the threshold is reached. The other glutamate receptor is N-methyl-D-aspartate (NMDA) is often closed and does not activate even when the glutamate released binds with the receptor due to the magnesium ion blocking the channels and thus require NMDA receptor to get phosphorylated and to remove the magnesium ion blocks to increase the excitability (Chen et al., 1992; Ultenius et al., 2006). The phosphorylation of NMDA receptor occurs by the action of neuropeptides like substance P, present in nociceptor central terminals with glutamate, binds with the neurokinin 1 receptors leads to depolarization and up-regulation of calcium concentration. The phosphorylation of NMDA receptor at tyrosine residue can occur by the action of tyrosine kinase to increase the excitability. This process leads to the activation of protein kinase C, phosphorylates the NMDA receptors and the magnesium block gets removed to increase the excitability.

 

Hence, the input from the nociceptors to the dorsal horn neurons influences the excitability of neuronal membranes which is called as central sensitization (Rowbotham et al., 1998; Fields et al., 1998). This phenomenon influences the way the neurons respond to the further nociceptive inputs (Woolf, 1983). The central sensitization phenomenon can be understood by the range of the inputs and the followed excitability of neuronal membranes. This process can be demonstrated in three ways, like an upregulated response to the suprathreshold input; enlargement of the area where stimulus activates the neurons; and by the subthreshold inputs reach the threshold to increase the discharge of action potential. These changes induce pain which moves and spreads from the site of neuron injury and includes Aβ-fibre-mediated hyperalgesia (Treede et al., 1992; Gracely et al., 1992). The spreading of pain from the location of injury to other places is due to central sensitization phenomenon. In order to block central sensitization, NMDA antagonists are introduced and which have put an end to the pain in patients with neuropathic pain (Nelson et al., 1997). Brush-evoked hyperalgesia shows the activity of conducting myelinated axons where the electrical stimulation along the A fibers causes pain in these patients. The A fiber conduction blocks can put an end to the allodynic symptoms in the patients (Ochoa and Yarnitsky, 1993). Hence, introducing local anesthetic blockers to dismantle the constant and rigorous activity of nociceptors, can put an end to the allodynic features in the patients. The continuous input to the A fibers is required to maintain the increase in excitability in the patients with the pain caused due to the central sensitization phenomena (Gracely, et al., 1992; Koltzenburg et al., 1994).

 

 

There are some cases where the continuous input from the nociceptors is not required for the A fiber mediated pain mechanism. These cases include the other mechanisms such as a fiber phenotypic switching after peripheral nerve injury, fiber sprouting in the spinal cord and disinhibition.

 

Peripheral nerve injury is the cause for the sprouting of Alpha fiber central terminals in lamina II, specific laminae in the dorsal horn which receives C fibers whereas other laminae in the dorsal horn have A fiber central terminals (Woolf et al., 1992). The injury in the peripheral axons of C fibers is the cause of the sprouting mechanism (Mannion et al., 1996). Hence, the neurotrophic factors mimicking as C fibers introduced through spinal theca can put an end to the sprouting of a fiber due to injury (Gracely et al., 1992). The lamina II which receives C fibers that is the nociceptor inputs starts to receive the non-noxious stimuli which are being misinterpreted by the nervous system and leads to allodynic features in the patients (Woolf and Doubell, 1994).

 

The neuropeptides like substance P, calcitonin gene-related peptide are down-regulated after the peripheral nerve injury where these neuropeptides are normally expressed in the C fibers, A-delta fibers an involved in sensory transmission. Nevertheless, Aβ fibers start to express the neuropeptides due to the low threshold stimuli and results in the release of neuropeptides in dorsal horn to increase the excitability and falls as a phenotypic switch (Miki et al., 1997).

 

The other important mechanism of pain is the peripheral sensitization which occurs as a result of down-regulated activation of nociceptor peripheral terminals (Rowbotham et al., 1998; Fields et al., 1998). The release of neuropeptides like substance P, calcitonin-gene-related peptide occurs by the ectopic discharge. The release of these substances leads to the peripheral sensitization in both injured and uninjured nerve fibers (Amir et al., 2005; Wu et al., 2002; Bostock et al., 2005). The similar changes which occur after the central lesion lead to central neuropathic pain (Hains et al., 2007).

 

The changes which occur in the neuronal structure and its function after an injury, high threshold stimuli be the important characteristics in understanding neuropathic pain mechanisms. The changes in the brain can be experimentally measured using fMRI imaging, positron- emission tomography.  The alterations which contribute to the pain mechanism can be detected by the imaging processes (Flor et al., 1995).

 

4.    TREATMENT AND RECENT DRUG DISCOVERIES:

Decades ago, the tricyclic antidepressants were used as efficient drugs for the treatment of neuropathic pain and had a notable effect on the patients with pain (Sindrup and Jensen, 1999). In recent studies, it has been proved that the broad spectrum tetracycline antibiotic, Minocycline reduces the neuropathic pain in CCI hyperalgesia rats (Abbaszadeh et al., 2018). The ion channel blockers are often introduced to patients with diabetic neuropathy (Kastrup et al., 1987) which includes carbamazepine, phenytoin (Dray et al., 1997), lamotrigine and other drugs. The carbamazepine and phenytoin block the sodium channels and leads to the decrease level of neuronal excitability in the nociceptors. Lamotrigine, anticonvulsant acts as the sodium channel blockers and decreases the level of glutamate release by neuronal excitation (Canavero and Bonicalzi, 1996). The calcium channel blockers like Gabapentin, pregabalin reduces the transmission of neurotransmitters after the nerve injury and other pain conditions (O'Connor and Dworkin, 2009). The NMDA antagonists like dextromethorphan also involved in reduced the pain in the diabetic neuropathy conditions (Harati et al., 1998). Interestingly, the capsaicin compound which is found in chilies has the property to reduce the pain after the nerve injury and postherpetic neuralgia (Watson and Evans, 1992) by totally reducing the amount of substance P from the sensory neurons. Opioids are the general concern in the treatment of neuropathic pain as many opioid molecules are effectively helping in reducing certain types of neuropathic conditions like postherpetic neuralgia, allodynia. It is been stated that opioids also have controlled effects on the peripheral as well as central neuropathic pain (Norrbrink and Lundeberg, 2009). Intravenous supply of morphine reduced the pain caused by postherpetic neuralgia (Rowbotham et al., 1991) and Oxycodone with antidepressants decreases the steady pain. Tramadol which is an analgesic and introduced to diabetic polyneuropathy conditions (Harati et al., 1998). Recently, new treatments were developed to enhance the drug delivery in neuropathic patients with Amitriptyline HCl (AMT) and pregabalin (PGB) and has been found that it exerted anti depression and other beneficial effects. These drugs were exhibited as the effective combination therapy for the neuropathic pain by progressive release of drug (Purushothaman et al., 2017).

 

5.       CONCLUSION:

The mechanism behind the neuropathic pain disorders has been understood through various laboratory experiments for the molecular level study and by the examination of patients with pain disorders. The source of pain is first identified to classify the symptoms based on the level of understanding. Various drug therapies are being introduced to patients in order to identify the location of pain from where it is getting mediated from and various ranges of new drugs are in the stage of development. There is a different combination of treatment for the neuropathic pain ranging from opioids, channel blockers, antidepressants, and other drugs to reduce the pain caused by nerve injury or other sources of pain. One of the main concern is that neuropathic pain disorder is often misinterpreted with the normal pain and does require very conscious diagnosing through the grade systems to avoid confusion. Assessing the disorder with proper care be the initial step as it influences the rate of progression of the disease in the body. The severity of pain varies from one individual to another and often occurs as a most shooting pain in the body. The physician has to choose the appropriate treatment for the patients after the assessment based on the source of pain, symptoms, intensity of pain and other parameters. There should be very specific methods for diagnosis to avoid misinterpretation with the other disorders and to start the treatment right after the onset of disease which is very essential.

 

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Received on 17.12.2018           Modified on 05.02.2019

Accepted on 10.03.2019         © RJPT All right reserved