Neuropathic Pain

Figure 1. Aetiology, mechanisms, and symptoms
Image Unavailable
Image source: Medscape adapted from Woolf & Mannion (1999)

Pain is commonly thought as a symptom of diseases but, with neuropathic pain, it is often regarded as the primary diagnosis of the disease state. Neuropathic pain is uniquely distinguished from nociceptive pain because it does not require continuous noxious stimuli in order for the pain to persist. Nociceptive pain is usually caused by an external stimulus and stops when the stimulus is removed because the production of abnormal afferent signals ceases. With neuropathic pain, however, there is no cessation as it is pain that does not originate from an external stimuli[1]. Neuropathic pain is normally caused by traumas, lesions, diseases, or cellular malformations in the central or peripheral nervous system which is, more often than not, more difficult to diagnose and treat. It is not uncommon for neuropathic pain to last months or even years. Mechanisms of neuropathic pain indicate independency from etiological factors and pathophysiological treatment of neuropathic pain appear to be more effective than disease driven treatments[2]. Mechanism dependent treatment is often challenging as it is diagnostically difficult to isolate. Pharmacological treatments such as opioids, anticonvulsants, and antidepressants, are often used for trauma or cellular malformations to block sensory fibres[3]. Electrotherapy and neurostimulation therapy is shown to provide significant relief for neuropathic pain but current techniques can be invasive and is extremely risky for older patients[4].

1. Symptoms

Neuropathic pain manifests via normal pain pathways so the symptoms are similar to physiological nociceptive pain. These symptoms may also be paradoxical as an individual may experience both positive and negative symptoms concurrently[5]. A study conducted by Freeman et al.[6], attempted to profile neuropathic pain symptoms caused by specific disorders such as HIV, central post-stroke pain, and diabetic peripheral neuropathy and found that there is no consistent cluster of pain in regards to the diseases. This study supports the hypothesis that neuropathic pain is a multidimensional property which involve physiological and emotional mechanisms.

1.1. Positive symptoms

Figure 2. Baseline and diabetic pain activity in the spinothalamic tract
Image Unavailable
Image source: Pathophysiological mechanisms of neuropathic pain (Leone et al., 2011)

Positive symptoms are often spontaneous and can be conceptualized as an increase in the pain experience. This includes the perceived manifestation of physiological pain but no stimuli is present or an enhanced experience to pain.

Dysesthesia is often referred to as an episode where pain is experienced and includes the many types of pain such has tingling, shooting, burning, stabbing, dull, etc. Paraesthesia describes the same sensations as dysesthesia but the sensations are not yet perceived as painful.
Hyperalgesia describes an increased sensitivity to pain and may be caused by many mechanisms that lower the individual pain threshold. This is often tested by pricking a person with a pin and the pain is experienced as more intense than it normally should. An extreme type of hyperalgesia is allodynia where previously innocuous stimuli, such as touch or certain temperature ranges, produce pain[7].

1.2. Negative symptoms

Negative symptoms, in contrast to positive symptoms, are sensory deficits. Neuropathic pain manifesting through negative symptoms are paradoxical by definition as the sufferer’s threshold for pain is increased. The sufferer may experience hypoesthesia or anesthesia which are describe the partial or complete loss of sensation respectfully. A normally painful stimuli would be left untreated and unnoticed and can have detrimental consequences.

2. Mechanisms

Physiological mechanisms underlying neuropathic pain symptoms are less predictable and often difficult to isolate. A number of different mechanisms can be the cause for one symptom and one symptom can be the product of many different mechanisms. For this reason, treatment for neuropathic pain based on physiological symptoms are often inconsistent and ineffective. There are three major categories of mechanisms which broadly covers the entire physiological aspects of a person. Central and peripheral processes obviously involve changes to the central and peripheral nervous system. Cellular mechanisms involve cellular responses and molecules that enhance or impair the pain process. It is important to note that these mechanism are not distinct and syndromes are often the result of a combination of mechanisms.

2.1. Central nervous system

Central mechanisms of neuropathic pain involve abnormal expression at the spinal column or involve the structure of the brain itself. Abnormalities to these sites are usually disease driven as they are usually protected by the spinal column and skull.

Normally, afferent pain fibres from the peripheral nervous system terminate at neurons located in the spinal column. These neurons, located in the dorsal horn, are AMPA receptor dependent and are involved in the expression of pain. Damage to the dorsal horn may cause upregulation of AMPA receptors and so nociceptive input may trigger a greater than normal response. Pronociceptive facilitation at the spinal dorsal horn decreases the pain threshold and so previously innocuous stimuli will trigger a pain response[8].

Cortical plasticity plays an important role in the perception of pain. Studies from sufferers of phantom limb syndrome and experimental studies using rat models reveal that increased cortical reorganization positively correlates with experiences of neuropathic pain. These studies suggests that areas of the brain that are active during pain expands into other areas but this expansion does not lead to consistent positive, negative, or specific syndromes[9].

2.2. Peripheral nervous system

Injury to the peripheral nervous system can drastically affect the afferent nerve fibres involved in the pain pathway. Ectopia (abnormal expression) of injured neurons have been suggested as one of the causes of neuropathic pain. Spontaneous discharge of the Aβ fibres are mainly found in the injury site of the peripheral nervous system and although these fibres are normally involved in non-painful paresthesias, Devor[10] suggests that phenotypic switching upon neuronal injury may be the cause of the fibre’s ability to signal pain.

Sympathetically maintained pain is a phenomenon by which abnormalities to the sympathetic trunk may generate or enhance pain. These abnormalities may be the result of traumas, lesions, or diseases and exacerbations of these abnormalities is positively correlated with the amount of pain experienced. Evidence from animal models have shown that sympathectomy (surgically severing the sympathetic trunk) relieves the animal of pain. Furthermore, electrical stimulation of the sympathetic trunk after a sympathectomy results in hyperalgesia[11].

2.3. Cellular mechanisms

The mechanisms above attempt to describe neuropathic pain by their physiological location but they are dependent on cellular and molecular changes. Obviously any changes in the biochemical molecules involved in the pain pathway or in the areas of the brain that perceive pain will alter how an individual experiences stimuli.

Continuous input of noxious stimuli on the nerve endings will decrease the affinity of the magnesium block on the NMDA receptor and upregulation of AMPA receptors will be more likely to occur with low level or minimal stimulation. Increased expression of AMPA receptors on the cell surface will obviously lead to increased expression sodium receptors on the cell surface. A direct consequence of increasing the density of sodium channels is hyperexcitability which causes ectopic generation of action potentials[7].

Nerve injury also releases signalling chemicals that cause a two to four-fold increase of microglia that moves directly to site of injury[12]. Microglial activation causes the release of cytokines such as TNFα, IL1β, IL-6 which has a proinflammatory effect on the cell. These cytokines can directly activate the nociceptors on the cell and, over a long period of time, induce pain hypersensitivity[13].

3. Treatment and Therapy

3.1. Pharmacological therapy

Pharmacological therapies are often difficult to administer because the symptoms of neuropathic pain can be cause my many different mechanisms. Placebo studies involving pharmacological therapies for neuropathic pain all suggest that antidepressants should be involved in the treatment for neuropathic pain[14]. These include tricyclic antidepressants and SNRIs. These drugs act as serotonin and norepinephrine reuptake inhibitors which causes the levels of both neurotransmitters to remain constant or increased in the nervous system. In addition, they also work as sodium channel blockers at the peripheral site of injury[3]. These drugs treat neuropathic pain by managing the ectopic discharges of pain pathway fibres.

3.2. Neurostimulation and electrotherapy

Neurostimulation and electrotherapy have also been shown to treat neuropathic pain and is usually presented as an option when pharmacological treatments are ineffective. Efficacy to pharmacological agents may be reduced as tolerance to the agents build over time or due to idiosyncratic factors. Neurostimulation has been also shown to reduce the amount of analgesics required to modulate neuropathic pain[15]. The affected areas of the brain may be too deep and thus electrotherapy may be impossible to conduct. The procedure is often invasive and thus is not suitable for many sufferers of neuropathic pain. Another case study conducted by Chodakiewitz, Bicalho, & Chodakiewitz[16] discusses the efficacy of neuromodulation using a combination of electrotherapies targeting the periventricular gray area and spinal cord stimulation to treat chronic lumbar pain which led to the complete relief of the condition.

1. Belfer, I., & Dai, F. Phenotyping and genotyping neuropathic pain. Current Pain and Headache Reports 14, 203-212 (2010)
2. Scholz, J., Mannion, R.J., Hord, D.E., Griffin, R.S., Rawal, B., Zheng, H., Scoffings, D., Phillips, A., Guo, J., Laing, R.J., Abdi, S., Decosterd, I., & Woolf, C.J. A novel tool for the assessment of pain: validation in low back pain. PLoS Medicine 6 (2009)
3. Bonezzi, C., Allegri, M., Demartini, L., & Buonocore, M. The pharmacological treatment of neuropathic pain. European Journal of Pain Supplements 3, 85-88 (2009)
4. Lefaucheur, J., Drouot, X., Cunin, P., Bruckert, R., Lepetit, H., Créange, Wolkenstein, P., Maison, P., Keravel, Y., & Nguyen, J. Motor cortex stimulation for the treatment of refractory peripheral neuropathic pain. Brain 132, 1463-1471 (2009)
5. Baron, R., Binder, A., & Wasner, G. Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurology 9, 807-819 (2010)
6. Freeman, R., Baron, R., Bouhassira, D., Cabrera, J., & Emir, B. Sensory profiles of patients with neuropathic pain based on the neuropathic pain symptoms and signs. Pain 155, 367-376 (2014)
7. Woolf, C. J., & Mannion, R. J. Neuropathic pain: Aetiology, symptoms, mechanisms, and management. Lancet 353 1959-1964 (1999)
8. Jensen, T. S., & Finnerup, N. B. Neuropathic pain: Peripheral and central mechanisms. European Journal of Pain Supplements 3 33-36 (2009)
9. Gustin, S. M., Peck, C.C. Cheney, L. B., Macey, P. M., Murray, G. M. & Henderson, L. A. Pain and plasticity: is chronic pain always associated with somatosensory cortex activity and reorganization? The Journal of Neuroscience 32, 14874-14884 (2012)
10. Devor, M. Ectopic discharge in Aβ afferents as a source of neuropathic pain. Experimental Brain Research 196, 115-128 (2009)
11. Nickel, F. T., Seifert, F., Lanz, S., & Maihöfner, C. Mechanisms of neuropathic pain. European Neuropsychopharmacology 22, 81-91 (2012)
12. Inoue, K., & Tsuda, M.. Microglia and neuropathic pain. Glia 57, 1469-1479 (2009)
13. Lees, J.G., Duffy, S.S., & Moalem-Taylor, G. Immunotherapy targeting cytokines in neuropathic pain. Frontiers in pharmacology 4, (2013)
14. Jefferies, K. Treatment of Neuropathic Pain. Seminars in Neurology 30, 425-432 (2010)
15. Reverberi, C., Bonezzi, C., & Demartini, L. Peripheral subcutaneous neurostimulation in the management of neuropathic pain: Five case reports. Neuromodulation 12, 146-155 (2009)
16. Chodakiewitz, Y., Bicalho, G., & Chodakiewitz, J. Multi-target neurostimulation for adequate long-term relief of neuropathic and nociceptive chronic pain components. Surgical Neurology International 4, 170-175 (2013)

Add a New Comment
Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License