Neuropathic Pain 1

By Prof. Tissa Wijeratne and Prof. Robert D Helme

 

Introduction

     Chronic pain can be divided into neuropathic and nociceptive pain. The International Association for the Study of Pain (IASP) defines neuropathic pain as “pain initiated or caused by a primary lesion or dysfunction in the nervous system”. This includes lesions or diseases affecting the central or peripheral nervous system. Post herpetic neuralgia, painful small fibre neuropathy, painful polyneuropathy (especially that due to diabetes), pain in multiple sclerosis and central post stroke pain are examples of neuropathic pain. Neuropathic pain can be spontaneous or evoked.  Diagnosis and treatment of neuropathic pain is complex needing thorough clinical evaluation, and treatment often is difficult and incomplete.  Better understanding of the clinical symptoms and signs, pathophysiology and current treatment approach to neuropathic pain leads to the optimum management of neuropathic pain among patients.

 

Epidemiology

     Pain is the most common symptom in day to day practice of a medical practitioner. It is estimated that twenty per-cent (one in five) of the adult population suffers from pain according to epidemiological studies in the west. The diagnosis of long term pain associated with lesions in the nervous system probably plays an important role in neurological disorders in human being. However, information on the prevalence of neuropathic pain in the community is limited. Published information comes from specialised cohorts such as people with chronic back pain, nerve entrapment syndromes, multiple sclerosis and diabetes or people who attend specialised pain clinics. These reports are unlikely to be generalizable to the community population.

     Recent community studies have assessed the prevalence of neuropathic pain using survey tools such as the Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) or self-reported tools such as the Berger criteria. A recent survey analysing 6,000 adults from the primary health systems of the United Kingdom, found a prevalence of 8.2 % of patients with pain having predominant neuropathic features.

     Yawn and colleagues conducted a mailed survey (n= 3575 community respondents), telephone interview (n= 905), and clinical examination (n=205) to estimate the population prevalence of neuropathic pain. Using the clinical examination as the gold standard, estimates from several screening tools were developed and adjusted to the Olmsted County, Minnesota adult population. The estimated community prevalence of neuropathic pain from the gold standard (neurological examination) was 9.8%. Prevalence rates based on self-reported nerve pain was 12.4%. Most other estimates were lower, including a 3.0% population prevalence using the Berger criteria and 8.8% using the S-LANSS. Neuropathic pain occurred in about 1 in every 10 adults over 30 according to another study.

 

Grading system for neuropathic pain

     A neuropathic pain grading system may be used to decide the level of certainty of the diagnosis of neuropathic pain (NP). Treede et al (2008) have devised such a scale which allows for three levels of certainty:

Definite neuropathic pain

Probable neuropathic pain

Possible neuropathic pain

 

     The levels definite and probable neuropathic pain indicates that the presence of neuropathic pain is established.  A patient with a definite neuropathic pain will have a pain with a distinct neuroanatomically plausible distribution (demonstration of this by at least one confirmatory test is necessary) with a history of a relevant lesion affecting the peripheral and central somatosensory system (demonstration of a relevant lesion or disease by at least one confirmatory test is necessary).  A patient with a probable neuropathic pain should have a pain with a distinct neuroanatomically plausible distribution and history of a relevant lesion or disease affecting the peripheral or central somatosensory system (with demonstration of any one of these by a confirmatory test).

     Possible neuropathic pain indicates that the presence of neuropathic pain is yet to be established.

 

Diagnosis

     In recent years several screening tools that can help to identify neuropathic pain have been introduced. These tools are based on verbal description of pain with or without limited bedside examination of the patient. The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale and DN4 questionnaire (Douleur Neuropathique en 4 Questions) use  interview questions on symptom items and physical tests ( pinprick and touch hypoesthesia) and demonstrate higher sensitivity and specificity than the screening tools with only interview questions. The Neuropathic Pain Questionnaire (NPQ) consists of 12 items (10 related to sensory responses or sensations and 2 related to affect). The NPQ demonstrated 66% sensitivity and 74% specificity compared to clinical examination that confirmed the diagnosis of neuropathic pain in a validation sample.

     ID-Pain has five sensory descriptor items and one item relating to joint pain. In the validation study 22% of the nociceptive group, 39% of the neuropathic and nociceptive group and 58% of the neuropathic group scored above 3, the recommended cut off score for neuropathic pain.

     Pain DETECT is an easy to use self-report questionnaire with nine items (seven sensory descriptor items and two items relating to the radiating and temporal characteristics of the individual pain pattern. Pain DETECT demonstrated 83% sensitivity and 80% specificity in the validation sample. Currently these instruments should not be used alone in determining the presence of neuropathic pain during routine clinical management.

     At the bed side examination, abnormal sensory findings should be neuroanatomically logical, that is be compatible with a definite lesion site. Location, quality, and intensity of pain should be assessed. Accurate assessment requires a clear understanding of the possible types of negative (e.g., sensory loss) and positive (e.g., pain and paresthesias) symptoms and signs. Neuropathic pain can be spontaneous (present without any precipitating or on-going cause being apparent) or elicited by a stimulus (evoked pain). Spontaneous pain is often described as a constant burning sensation, but may also be intermittent or paroxysmal, and includes dysesthesias. Paresthesias may also be present. Evoked pain (e.g., hyperalgesia, hyperpathia and allodynia by clinical examination) are elicited by mechanical, thermal, or chemical stimuli.

     Neurological examination in suspected neuropathic pain should also include thorough assessment of motor, sensory, and autonomic phenomena in order to identify all signs of neurological dysfunction. Sensory disorders should be recorded in detail, preferably on body sensory maps which provides valuable information. Tactile sense is best assesses with a piece of cotton wool, pinprick sense with a wooden tooth pick , thermal sense with warm and cold objects (e.g., metal rollers), and vibration sense with a 128-Hz tuning fork. Autonomic dysfunction is more difficult to detect but careful inspection may reveal sweating, colour and temperature asymmetries as well as skin and nail dystrophy.

     Quantitative sensory testing (QST) analyses perception in response to external stimuli of controlled intensity. Detection and pain thresholds are determined by applying stimuli to the skin in an ascending and descending order of magnitude.

     Mechanical sensitivity for tactile stimuli is measured with filaments that produce graded pressures, such as the von Frey hairs, pinprick sensation with weighted needles, and vibration sensitivity with an electronic vibrameter. Thermal perception and thermal pain are measured using a thermode, or other device that operates on the thermoelectric effect.

     QST has been used for the early diagnosis and follow-up of small-fibre neuropathy, and has proved useful in the early diagnosis of diabetic neuropathy. QST is also suitable for quantifying mechanical and thermal allodynia and hyperalgesia in painful neuropathic syndromes, and has been used in pharmacological trials to assess treatment efficacy on evoked pains. QST may show abnormal findings   in non-neuropathic pain states, such as rheumatoid arthritis and inflammatory arthromyalgias.

     Large-size, non-nociceptive afferent nerve fibres have a lower electrical threshold than small-size, nociceptive afferents. Unless special techniques are used, i.e., experimental blocks or stimulation of special organs (cornea, tooth pulp), electrical stimuli also excite large afferents, thus hindering nociceptive signals. Hence standard neurophysiological responses to electrical stimuli, such as nerve conduction studies (NCS), can identify, locate, and quantify damage along the peripheral or central sensory pathways, but they do not assess nociceptive pathway function.

     Researchers have tried numerous techniques for selectively activating pain afferents. One of the preferred approaches uses laser stimulators to deliver radiant-heat pulses that selectively excite the free nerve endings (Aδ and C) in the superficial skin layers. Late LEPs are amongst the neurophysiological tools for assessing nociceptive pathway function and are diagnostically useful in peripheral and central neuropathic pain. In clinical practice, their main limitation is that they are currently available in too few centres. Ultralate LEPs (related to C-fibre activation) are technically more difficult to record, and few studies have assessed their usefulness in patients with neuropathic pain.

     Contact heat-evoked potentials are a recent development that still needs clinical validation. Painful neuropathies typically and preferentially involve small nerve fibres. Nerve biopsy may be unrewarding in the early detection of small-fibre neuropathy because small-fibre assessment is difficult and requires electron microscopy. Punch skin biopsy can quantify Ad and C nerve fibres by measuring the density of intra-epidermal nerve fibres (IENF). IENF loss has been shown in various neuropathies characterized by small-fibre axonal loss. Punch skin biopsy is easy to do, minimally invasive, and optimal for follow-up. Despite these advantages, it is of no value in central pain and demyelinating neuropathy.

 

Pathophysiology

     Both basic and human research indicates that a lesion of afferent pathways is a requirement for the development of neuropathic pain. There are, however, different mechanisms of symptom generation in neuropathic pain, and different pain qualities appear to utilise overlapping mechanisms. Nevertheless, it is clinically important to try and identify the different mechanisms of neuropathic pain among patients as well as within the individual patients, especially in research settings. Different treatment regimens may eventually be needed for the different pain conditions, but this has yet to be achieved.

 

Central sensitisation

     Allodynia and hyperalgesia in and adjacent to, the area of supply   of the lesioned nerves requires CNS involvement. Central sensitisation might develop as a consequence of ectopic activity in primary nociceptive afferent fibres (there are several mechanisms, not only ectopic activity, eg wind up, long term potentiation, loss of inhibitory pathways, apoptosis, cytokine activation). This could occur without the evidence of structural damage within the CNS.

     Physiologically ongoing discharges within the dorsal horn of the spinal cord eventually lead to phosphorylation of NMDA and AMPA receptors or expression of voltage gated sodium channels in the post synaptic second order neurons.  These result in neuronal hyper excitability. This causes low-threshold mechanosenstive Aβ and Aδ afferent fibres to activate second-order nociceptive neurons.  As a result of these changes light brushing or light pricking of skin become significantly painful.

 

Ectopic nerve activity

     Injured axons of the nociceptive pathways may develop spontaneous and repetitive firing known as ectopic activity. This can cause spontaneous pain and paroxysmal shooting pain in the absence of any external stimulus. Ectopic activity has been recorded by miconeurography in afferent fibres from a neuroma in patients with stump and phantom pain, as well as in patients with painful diabetic neuropathy.

     After a peripheral nerve lesion, spontaneous activity is evident in both injured and neighbouring uninjured nociceptive afferents. Increasing levels of mRNA for voltage-gated sodium channels has been shown to correlate with ectopic activity. Increased expression of sodium channels in lesioned and intact fibres might lower action potential threshold until ectopic activity takes place.

     Lesions in the central components of the somato sensory systems have also shown to have similar changes within second-order nociceptive neurons, leading to central neuropathic pain according to some studies.

     Microneurographic recordings have indicated ongoing ectopic activity of nociceptive afferents in these patients after raised membrane excitability: this is thought to be caused by underlying pain channelopathies.

     Several other ion channels probably undergo alterations after a nerve lesion, such as voltage-gated potassium channels, which may also results in changes in membrane excitability of nociceptive nerves.

     Nerve lesions induces up-regulation of various receptor proteins such as the transient receptor potential V1 (TRPV1). This is located on subtypes of peripheral nocicepive endings. TRPV1 is physiologically activated by noxious heat at about 41°C. After a nerve lesion, TRPV1 is down regulated on injured nerve fibres but up regulated on uninjured C-fibres.

     Clinically, patients with such underlying pain mechanisms can also be characterised by the presence of heat hyperalgesia in addition to ongoing burning pain.