Neuropathic Pain

This article or area is currently under construction and may only be partially complete. Please come back soon to see the finished work! (19/08/2023)

Original Editor - Kerstin McPherson

Top Contributors - Andeela Hafeez, Melissa Coetsee, Kerstin McPherson, Vanessa Rhule, Riccardo Ugrin, Lucinda hampton, Kim Jackson, Admin, Evan Thomas, Chrysolite Jyothi Kommu, Temitope Olowoyeye, Jo Etherton, WikiSysop, Vidya Acharya, Kapil Narale, Lauren Lopez, Oyemi Sillo, Amanda Ager, 127.0.0.1, Wendy Walker and Carina Therese Magtibay

Introduction

The International Association for the Study of Pain (2011) defines neuropathic pain as ‘pain caused by a lesion or disease of the somatosensory nervous system’. It is a complex, chronic pain state that presents a challenge to patients and clinicians.

It is the result of disease or damage anywhere along the neuraxis of the peripheral or central (spinal and supraspinal) nervous system.

1. Central neuropathic pain is defined as ‘pain caused by a lesion or disease of the central somatosensory nervous system’.
2. Peripheral neuropathic pain is defined as ‘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.

Aetiology

Conditions frequently associated with neuropathic pain can be categorised into two major groups: pain due to damage in the central nervous system (CNS) and pain due to damage to the peripheral nervous system (PNS).

Conditions associated with neuropathic pain

CNS	PNS
Strokes: Cortical and subcortical	Nerve compression/ entrapment neuropathies (carpal tunnel syndrome, thoracic outlet syndrome, nerve root compression
Spinal cord injuries	Post-traumatic neuropathy (following surgical procedures or acute injury)
Syringomyelia and syringobulbia	Post-amputation stump and phantom limb pain
Trigeminal and glossopharyngeal neuralgias	Postherpetic neuralgia
Neoplastic and other space-occupying lesions	Disease related neuropathies: Diabetic neuropathy, cancer-related neuropathies and HIV-related neuropathy
Central pain in Multiple Sclerosis	Complex regional pain syndrome (CRPS) type 2

Also see Neuropathies

Epidemiology

The estimated prevalence of neuropathic pain is about 5%, but due to the difficulty in accurately diagnosing neuropathic pain, this number is likely an underestimation. Neuropathic pain is not an inevitable consequence of neural lesion, and the progression from acute to chronic neuropathy occurs only in a minority and is influenced by a huge number of factors

The following risk factors could predispose an individual to the development of neuropathic pain:

• Age 50-64 years
• Being female
• Sociodemographic status: there is some evidence that unemployment and lower educational levels is associated with a higher incidence of neuropathic pain
• Injury sites: some anatomical sites are more prone to developing neuropathic pain
• Emotional and cognitive well-being: can influence how neuropathic pain is experienced

Pathophysiology

Neuropathic pain is the result of disease or lesion of the somatosensory nervous system which results in altered and disordered transmission of sensory signals. Changes in nerve function occur both at the site of the injury and areas around the injury. Peripheral, spinal and central changes result in increases excitability and facilitation of signals, and a loss of inhibition. With increasing chronicity, there is increased involvement of central changes. The pathophysiology is complex and still not fully understood. For more detail see the additional reference:

Pathophysiology in Neuropathic pain

	Peripheral changes	Spinal cord changes	Cortical changes
Spontaneous pain	Ectopic impulses along Aβ, Aδ, and C fibres of neuromas, nerve ends and nerve roots	Ectopic impulses at the dorsal root ganglia	Ectopic impulses at the thalamus
Sensitisation	Alterations in ion-channels: increased function of sodium channels leading to increased excitability, loss of potassium channels to modulate nerve activity	Increased expression and function of calcium channels leading to increased transmitter release and enhanced excitability of spinal neurons; expanded receptor fields through NMDA-receptor activation; A-fibre sprouting into laminae I and II of the dorsal horn, which can result in allodynia	Altered descending inhibition at the brain-stem (modulated by the cingulate cortex and amygdala); Limbic areas drive anxiety, depression and sleep problems; cortical reorganisation

Central Sensitisation

The term central sensitisation (CS) is often incorrectly used synonymously with neuropathic pain. CS is however a mechanism that can occur independent of nerve lesions, but is often at play in chronic neuropathic pain. Central sensitisation is a state where spinal excitability increases due to repeated painful inputs. CS results in decreased thresholds and increased response to nociceptive input

• Following a peripheral origin, central sensitisation may develop as a result of ectopic neuronal activity in the spinal cord dorsal horn, implying a potential autonomous pain-generating mechanism. This leads to an increase in the size of the sensory receptive field, a reduced threshold for nociception, and hypersensitivity to various innocuous stimuli.
• First order neurons may increase their firing if they are partially damaged and increase the number of sodium channels.
• Ectopic discharges are a result of enhanced depolarization at certain sites in the fiber, leading to spontaneous pain and movement-related pain.
• Inhibitory circuits may be impaired at the level of the dorsal horn or brain stem (or both) allowing pain impulses to travel unopposed. See Pain Facilitation and Inhibition
• In addition, there may be alterations in the central processing of pain when. Second- and third-order neurons develop a “memory” of pain and become sensitized. There is then heightened sensitivity in spinal neurons and reduced activation thresholds.

Abnormal Impulse Generating Sites (AIGS)

• Abnormal Impulse Generating Sites (AIGS) are defined as the unmyelinated sites along the damaged axon in which the number, kind and excitability of ion channels are altered. This change in ion channel distribution make the site susceptible to non-noxious stimuli such as mechanical, chemical, or thermal stimuli.
• The high density of ion channels may result in a resting potential close to the threshold, leading to spontaneous ectopic impulses.
• AIGS fires antidromically and orthodromically, resulting in constant noxious stimulus into the central nervous system and neurogenic inflammation in the tissues. For this reason AIGS can persist even though the primary injury on the axon is completely healed.
• Where axons are disconnected from their distal targets (eg. amputation), inflammation and sprouting occur in the resulting and neuromas can form. A neuroma may become an anatomical site for generating nociceptive impulses.
• Together, neuromas, AIGS and dorsal root ganglion changes in receptors can be the peripheral nervous system cause of the phantom limb pain.

Clinical Presentation

Neuropathic pain is typically characterised by pain that is associated with sensory symptoms/deficits. The coexistence of both positive and negative somatosensory signs is a key diagnostic feature:

	Positive signs	Negative signs
Features	Paraesthesia: crawling/tingling sensation Spontaneous pain: burning, shooting, electric-like sensations Hyperalgesia: increased sensitivity to noxious stimuli Allodynia: pain in response to non-noxious stimuli Summation: progressive worsening of pain with repetitive stimulation	Hyposthesia: sensory loss and numbness Sensory loss is in the distribution of the damaged nerve or in the areas that correspond to the spinal/cortical region that has been damaged

History: Patients will often report spontaneous pain and sensations of ‘pins and needles,’ shooting, burning, stabbing, crawling, and paroxysmal pain (electric-shock like). These sensations affect not only the patient’s sensory system, but also the patient’s well-being, mood and focus. The onset of pain may be delayed, as is often the case in central post-stroke pain, or the phantom limb pain where neuropathic symptoms may start months or years after the primary event of injury.

Clinical findings: There may be decreased reflexes, weakness and autonomic changes. Sensation testing will reveal abnormalities - if sensation is normal, it is highly likely that the pain experienced is of neuropathic origin.

Neuropathic pain is often mixed with other pain mechanisms (nociceptive, central sensitisation), which may result in a mixed clinical presentation.

Diagnosis and Assessment

One of the challenges of neuropathic pain, is the ability to assess it. Assessing quality, intensity and improvement, as well as accurately diagnosing neuropathic pain is often complex.

There are, however, some diagnostic tools that may assist clinicians in evaluating neuropathic pain. eg nerve conduction studies and sensory-evoked potentials can identify and quantify the extent of damage to sensory (but not nociceptive) pathways by monitoring neurophysiological responses to electrical stimuli.

It is also very important to perform a thorough neurological evaluation to identify motor, sensory and autonomic dysfunctions.

Grading System for Neuropathic Pain (NP)

Possible NP	Probable NP	Confirmed NP
History of relevant neurological lesion or disease; pain distribution neuroanatomically plausible	Pain associated with sensory signs in the same neuroanatomically plausible distribution on clinical examination	Diagnostic test confirming a lesion or diseae of the somatosensory nervous system explaining the pain
History and pain and sensory descriptors are compatible with a lesion in the nervous system and not an inflammatory or non-neurological condition	The area of sensory changes may extend beyond, be within, or overlap the area of pain	Requires that other types of pain are excluded or highly unlikely to entirely explain the pain condition

Quantitative Sensory Testing

QST is often time consuming and involved expensive equipment, which limits is application in clinical practice. There are however simplified bedside QST tests that can be useful to gain improved understanding related underlying pain mechanisms.

Mechanical sensitivity to tactile stimuli is measured with von Frey hairs, pinprick with weighted needles, vibration sensitivity with vibrometers and thermal pain with thermodes.

Outcome Measures

The following tools can be used to screen for neuropathic pain and to monitor neuropathic pain over time

• DN4 - a well validated screening tool to rank the probability that of peripheral or central neuropathic mechanisms are involved in chronic pain
• LANSS
• PainDETECT

Management

Neuropathic pain often responds poorly to standard pain treatments and occasionally may get worse instead of better over time. For some people, it can lead to significant disability. Since the cause of neuropathic pain can often not be treated, the focus of its management is on alleviating the symptoms which requires an multidisciplinary approach that combines therapies:

TENS therapy

1. Medical management and the use of pharmacological agents
2. Physiotherapy
3. Low impact general physical activities
4. Counselling
5. Relaxation therapy
6. Massage therapy
7. Acupuncture

Pharmacological Management

A number of pharmacological treatments can be used to manage neuropathic pain outside of specialist pain management services. However, there is considerable variation in how treatment is initiated, the dosages used, the order in which drugs are introduced, whether therapeutic doses are achieved and whether there is correct sequencing of therapeutic classes. A further issue is that a number of commonly used treatments are unlicensed for treating neuropathic pain, which may limit their use. These factors may lead to inadequate pain control, with considerable morbidity. The goal of pharmacotherapy is to selectively block the production and/or transmission of pain-producing afferent activity in the periphery, and to engage mechanisms of endogenous inhibition in the CNS.

For commonly used pharmacological treatments see Neuropathic Pain Medication .

First line treatment generally includes:

• Tricyclic anti-depressants (TCAs)
• Serotonin- noradrenaline reuptake inhibitors (SNRIs)
• Pregabalin, Gabapentin
• Carbamazepine is however regarded as the first-line treatment for trigeminal neuralgia.

It is very important to identify concomitant underlying pain mechanisms, as this could improve the effectiveness of pharmacological management by targeting additional mechanisms with different analgesic agents.

Other Medical Interventions

For some individuals with refractory neuropathic pain, interventional treatments—which deliver medications to specific regions or modify particular brain structures—offer alternative therapy options.

Some of the interventional treatments include:

1. Spinal cord stimulation: Requires the application of a monophasic square-wave pulse (at a frequency in the 30–100 Hz range) that results in paraesthesia of the painful part
2. Cortical stimulation: Using either invasive epidural or transcranial non-invasive procedures (such repetitive transcranial magnetic stimulation (TMS) and transcranial direct current stimulation), cortical stimulation entails stimulating the pre-central motor cortex below the motor threshold.
3. Deep brain stimulation: The internal capsule, various nuclei in the sensory thalamus, periaqueductal and periventricular grey, motor cortex, septum, nucleus accumbens, posterior hypothalamus, and anterior cingulate cortex are potential targets for pain relief in deep brain stimulation.
4. Intrathecal treatments: In individuals with persistent pain that is severe and otherwise resistant to treatment, this offers a targeted drug delivery option to the painful part.

Physiotherapy Management

Physiotherapy modalities and rehabilitation techniques are important options and must be considered when pharmacotherapy alone is not sufficient . Physiotherapy aims to addressinflammation, stiffness, and pain with exercise, mobilisation and electrotherapy modalities. Treatment aims to help the body heal itself by encouraging the production of the body's natural pain-relieving chemicals.

1. Acute pain relief: for patients who have severe pain, start with contrast baths, desensitisation techniques, and oedema control
2. Electrotherapy: TENS therapy has low quality evidence for being effective in the treatment of painful peripheral neuropathy. Low level laser therapy may provide pain relief for neuropathic pain .
   

   Laser therapy
3. Therapeutic Exercise: Gentle ROM exercises and isometric strengthening can be useful to reorganise sprouting and cortical body representation, and to restore functional ROM and strength .
4. 

   Mirror therapy
   Graded motor imagery: Mirror therapy and graded motor imagery are movement representation techniques and have been suggested to be beneficial in neuropathic pain management - especially for phantom limb pain , CRPS and stroke pain.
5. Aerobic Exercise: regular aerobic exercise has been shown to help manage chronic pain. There are studies showing that exercise may be an important part of the treatment and prevention of neuropathic pain after chemotherapy. Aerobic exercise resulted in improved mechanical allodynia and heat hyperalgesia in animal models of neuropathic pain.

Please watch the following video for relevant about neuropathic pain.

Management of Neuropathic Pain