Neuropathic Pain

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Neuropathic pain is pain that is caused by a lesion or disease of the somatosensory system. Typically disruption to the somatosensory system leads to loss of sensation, however in neuropathic pain there is paradoxical pain in the hypo-aesthetic area. As well as sometimes being difficult to diagnose, neuropathic pain is often severe, long-lasting, and resistant to treatment.

Definition

The IASP defines neuropathic pain as "pain that is caused by a lesion or disease of the somatosensory system". This definition deserves some discussion. Previously it was defined as "pain initiated or caused by a primary lesion or dysfunction in the nervous system." There are two key changes in the definition update. Dysfunction was replaced with disease, with disease referring to all types of abnormal conditions such as inflammation, autoimmune syndromes, and ion channel disorders. The term nervous system was replaced with somatosensory system in order to avoid confusion with other types of pain arising from the nervous system such as spasticity and rigidity of the muscles.

"Neurogenic pain" is an obsolete term. Neurogenic implied that the pain was generated in the peripheral nerve, however neuropathic pain is more complex than that.

Aetiology and Pathophysiology

Neuropathic pain includes multiple different conditions which differ in their aetiology and pathophysiology. In other words, different disorders of the somatosensory system may give rise to the same clinical picture but through different mechanisms.

There are two common ways of classifying neuropathic pain: by the underlying aetiology and by the affected level in the somatosensory system.

• The affected level can be anywhere from the brain down to the peripheral receptor. The most commonly affected sites are the peripheral nerves, nerve plexuses, dorsal roots, spinal cord, and thalamus.
• Causative conditions include metabolic diseases (e.g. diabetic neuropathy), infection (e.g. post-herpetic neuralgia), vascular disease (e.g. stroke), trauma (e.g. orofacial neuropathy), and cancer.

Classification of neuropathic pain based on location and aetiology

Peripheral	Spinal	Brain
Neuropathies	Multiple sclerosis	Stroke
Herpes zoster	Spinal cord injury	Multiple sclerosis
Nerve injuries	Arachnoiditis	Neoplasma
Amputations	Neoplasms	Syringomyelia
Plexopathies	Syringomyelia	Parkinson's disease (?)
Radiculopathies	Spinal stroke	Epilepsy (?)
Avulsions
Neoplasma
Trigeminal neuralgia

Pathophysiology

Another classification scheme is by pathophysiological mechanism, although many of these mechanisms are hypothetical. A single mechanism can be the cause of pain in different conditions, and also cause different symptoms; and furthermore different mechanisms may be involved in the same condition.

The pathophysiology involves a complex and redundant interplay of neural generators, circuits, and mediators. Neuroanatomical changes consist of both peripheral and central adaptive and maladaptive mechanisms. The adaptive processes include changes in pro-nociceptive and anti-nociceptive systems.

Nociceptors can be sensitised and silent nociceptors can be recruited. Increased afferent input can lead to sensitisation of the second order dorsal horn neurons. This "afferent barrage" can induce secondary sensitisation changes on second order neurons in the dorsal horn.

Neurogenic inflammation can play a role. In this setting there is an increase in excitatory neurotrasmitters and neuropeptides such as histamine, bradykinin, serotonin, and glutamate. Peripheral nerve fibres when injured can be "sensitised" - i.e. they bring about a intense and prolonged ectopic afferent activity to the central nervous system.

In normal sensory experience, a noxious stimulus applied to nociceptive sensory endings is transmitted to the brain. Inflammation can lead to nociceptive endings becoming hypersensitive causing inflammatory pain. When an injury or disease affects the peripheral nerves (neuropathy), sensory ganglia (ganglionopathy), or sensory roots (radiculopathy), then pain signals can occur in areas ectopically away from the sensory ending. Abnormal impulse discharge can then lead to neuropathic pain. A range of inciting events can lead to ectopic impulse discharge, such as trauma, nerve entrapment, infection, inflammatory, metabolic disturbance, malnutrition, vascular disease, toxins, radiation, and genetic. Most commonly ectopic impulse generation arises from the site of injury and the associated dorsal root ganglion. This abnormal impulse discharge can not only drive pain sensation (spontaneous or evoked), but also induce and maintain central nervous system pain amplification processes.

Another mechanism is a severe loss of small fibre input such as in diabetic neuropathy or small fibre neuropathy. This can lead to a sprouting of myelinated fibres into the superficial "nociceptive" laminae of the dorsal horn.

In some cases there is an increase of sympathetic activity. This can lead to further sensitisation of nociceptors.

Changes can be seen in the brain with altered central processing (altered modulation) and recruitment of areas that aren't involved in pain in normal states.

Hyperalgesia can be brought on in normal individuals with blockade of large-diameter afferent fibres. It is thought that mechanoreceptive afferent input from the larger delta and beta fibres suppress the afferent input form small Aδ and C fibres and have an inhibitory effect on the dorsal horn. In neuropathic pain this inhibitory function may be impaired. This is hyperpathia, seen along with heightened reflex excitability. Both sensory experiences and reflex action occur in distressing exaggeration when peripheral tissues have access to the central nervous system only by the smaller fibres.

Epidemiology

The prevalence of neuropathic pain has been estimated at 7-10%, but with marked variations between countries ranging from 1-18%. With the aging population it is expected that the prevalence of neuropathic pain will increase.

Clinical Features

Sensory Deficits

Partial or complete sensory deficit is a necessary part of neuropathic pain, but is insufficient to cause neuropathic pain on its own. There is a wide spectrum of sensory impairment seen with the changes in some patients only being detectable through quantitative sensory testing and not through standard bedside testing. All sensory functions may be impaired, however spinothalamic function loss appears to be required (cold, warmth, pinprick).

Allodynia and Hyperalgesia

Main article: Allodynia and Alloknesis

The morphological and functional nervous system changes lead to abnormal sensory signs. Hyperalgesia and allodynia are classic findings of neuropathic pain. Hyperalgesia is the lowering of the pain threshold with an increase in response to noxious stimuli. Allodynia is pain elicited by a stimulus that does not normally activate the nociceptive system. Hyperalgesia reflects sensitisation of receptors, while allodynia is a central phenomenon mediated by large myelinated fibres.

There are three types of mechanical hyperalgesia seen.

1. Static hyperalgesia: blunt gentle pressure on the skin elicits pain. This appears to be mediated by sensitised C nociceptors.
2. Punctate hyperalgesia: punctate stimuli (e.g. pin prick with a stiff von Frey hair) elicits pain. This is mediated by sensitised Aδ fibres
3. Dynamic hyperalgesia: light brushing elicits pain. This is mediated by Aβ fibres.

There are two types of thermal hyperalgesia

1. Cold hyperalgesia: cold stimuli elicits pain. This is possibly due to a loss of cold Aδ fibres leading to cortical reorganisation
2. Heat hyperalgesia: warm and heat elicit pain. This is possibly due to sensitisation of C fibres and their second order neurons.

Hyperpathia

THe IASP define hyperpathia as "a painful syndrome characterised by an abnormally painful reaction to a stimulus, as well as an increased threshold."

Hyperpathia may occur with allodynia, hyperaesthesia, hyperalgesia, or dysaesthesia. Some view it has a type of hyperaesthesia, or even equate the two terms. There is both an elevation of the threshold and central hyperexcitability.

There are four main features of hyperpathia.

1. Increased detection threshold: An increased threshold to noxious or non-noxious stimulation. This may be due to reduced afferent input.
2. Delay: An abnormal latent period in the perception of the stimulus. This may be due to reduced large fibre afferent input.
3. Summation: this refers to an increasingly painful sensation to a repetitive stimulus of steady intensity which unmasks hyperpathia. Summation can be seen as an explosive overshooting pain response that can occur with strong withdrawal movements and a vasomotor or vegetative reaction. There is a lack or insufficient relationship between the stimulus strength and sensation strength. There is poor localisation and the inability to identify the nature of the stimulus that elicited the pain, with a radiating sensation out from the point of sensation to wide adjacent areas. Summation may be due to afterdischarge in damaged sensory neurons, crossed afterdischarge in sensory neurons, coupling of adjacent nerves, and central sensitisation.
4. Aftersensation: there is a long aftersensation or pain after the stimulus has ceased. This can occur for seconds, minutes, or hours after only brief periods of stimulation.

Hyperpathia is a clinical feature seen in the presence of axonal loss i.e. peripheral or central de-afferentation. However, all of the causes of neuropathic pain can be associated with hyperpathia.

Paroxysms

Patients can experience shooting, burning, electric shock-like, or stabbing pain. The pain can occur spontaneously. However, more typically pain occurs with stimulation, and this is termed "paroxysms" of pain. Paroxysms can be elicited by innocuous stimuli. In some cases like trigeminal neuralgia only non-noxious stimuli, not noxious stimuli, elicit the paroxysms.

There is often a significant difference between morning and evening in symptoms. The exact picture can depend on the aetiology.

Paraesthesiae

Paraesthesiae can occur which are abnormal but nonpainful sensations. They can be spontaneous or evoked. Patients often describe them as pins and needles. It is thought that they reflect spontaneous activity of Aβ fibres.

Dysaesthesiae

Dysaesthesiae are abnormal, unpleasant, but not necessarily painful sensations. They can be spontaneuous or evoked. It is thought they dysaesthesia is mediated by sensitisation of C fibres.

Referred Pain and Spatial Summation

There can be an abnormal spread of pain. In painful myelopathic conditions a punctate stimulus can elicit a painful circular spreading sensation. There is a relationship between the area of spread and the intensity of pain. There is also a relationship between the intensity of deep pain and area of referred pain. Generally pain refers from deep to superficial structures.

This finding is thought to be mediated by changes in wide dynamic neurons in the dorsal horn. Wide dynamic neurons have small receptive zones that are excited by non-noxious stimuli. There is a surrounding much larger zone which responds to noxious stimuli. The larger receptive field zones overlap, and extend over several dermatomes. Therefore a noxious stimulus, but not a non-noxious one, activates several WDR neurons. Increasing the intensity of the stimulus results in further activation of WDR neurons in a cranial-caudal manner, and so there is progressive recruitment of WDR down the spinal cord. There may be a similar mechanism with sensory abnormalities in nerve injury, with spread to the contralateral side, as well as proximally and distally to the lesion.

Temporal Summation and Aftersensations

Temporal summation is an abnormally increasing painful sensation in response to repetitive stimulation of steady intensity. It is the clinical equivalent of wind-up.

High frequency repeated nociceptive stimulation produces a temporal summation of the nociceptive afferent impulses originating from the C fibres due to their relatively slow conduction velocities. This results in an increase in the perception of second pain without lessening the sensation of first pain, which is conducted rapidly by Aδ fibres. The accumulation of nociceptive activity within secondary neurons of the spinal cord is called windup. Windup is distinct from spinal sensitisation. Wind-up is an increase in frequency of C-fibre discharge. It is a transient phenomenon but can produce spinal sensitisation and become persistent.

Wind-up pain or abnormal temporal summation can be elicited by a variety of stimuli such as mechanical, thermal, and electrical. It can also occur in many types of tissues. This finding is seen in many chronic pain states, not just neuropathic pain.

Aftersensation is thought to be related to wind-up pain. It refers to the persistence of pain long after the noxious stimuli has terminated. This is another clinical feature of neuropathic pain. Examples are the persistent burning sensation in post-herpetic neuralgia after light touch, and the exaggeration of pain following exercise.

Psychosocial Impact

There is often a significant negative impact on quality of life, daily function, and psychological wellbeing.

Treatment

The treatment options are often disappointing. There is no medication that exists that has been proven to have long-term efficacy or tolerability. The difference in aetiology and pathophysiology to nociceptive pain makes neuropathic pain particularly challenging to treat.

See Also

• Central Sensitisation
• Nociception

Literature Review

Literature Review

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