What Is Neuropathic Pain?
Neuropathic pain is chronic pain that is caused by injury, damage or disease of the somatosensory system. The somatosensory system lets us perceive pain, touch, temperature, pressure, position, movement and vibration. It is comprised of afferent nerves in the skin, muscles, joints, and fascia with specific receptors that sense the different types of stimuli. These nerves send the information to the spinal cord and ultimately to the brain for additional processing. Sensory signals going into the spinal cord and the brain can be altered as a result of injury or disease of the somatosensory system. There are several common conditions associated with neuropathic pain. They include postherpetic neuralgia, trigeminal neuralgia, painful radiculopathy, diabetic neuropathy, HIV infection, leprosy, amputation, peripheral nerve injury pain and stroke.
Patients with neuropathic pain experience burning and/or unusual tingling, crawling, or electrical-like sensations. They may also have pain resulting from non-painful stimuli like light touching. Symptoms tend to persist and become chronic. Patients may also become less responsive to pain medications.
How Common is Neuropathic Pain?
It is estimated that one in three Americans experience chronic pain. About a fifth of patients who have chronic pain are thought to have largely neuropathic pain. Neuropathic pain roughly affects 7 to 10% of the general population.
It is seen more frequently in women and in people over 50 years of age. It commonly affects the neck, lower back, lower and upper limbs.
How Is it Diagnosed?
There are several screening tools that have been developed to identify neuropathic pain conditions. These are simple to use questionnaires that allow patients to assess the characteristic neuropathic pain symptoms. Symptoms found in these questionnaires are burning, tingling, pain caused by light pressure, sensitivity to touch, electric shock-like pain, pain to cold or heat, and numbness. Examples of questionnaires include DN4, painDETECT.
In addition to these subjective screening tools, there are objective tests used to investigate somatosensory pathway function. They include bedside sensory assessment, neurophysiological techniques, and skin biopsy.
Bedside sensory assessment involves examining different sensory stimuli. These are touch, pinprick, pressure, cold, heat, vibration, temporal summation and after sensations. Patients are asked to describe the sensation after the stimulus is applied.
Laser-evoked potentials (LEPs) are considered the most reliable neurophysiological test to assess damage along the somatosensory pathways. Laser stimulations selectively activate different pain receptors in the superficial layer of the skin. The responses to these stimulations are recorded from the scalp. They consist of waveforms with different latencies. LEPs and be absent, reduced in amplitude or delayed in latency in patients with damage to the pain signalling pathway.
Skin biopsy is used to assess epidermal nerves. It is regarded as the most sensitive test for diagnosing small-fibre neuropathies.
What are the Causes?
There are two categories of neuropathic pain: central and peripheral. Central neuropathic pain is caused by damage or disease of the brain and/or spinal cord. Peripheral neuropathic pain involves the small unmyelinated C fibres and the myelinated A fibres (specifically, Abeta and Adelta). Both of which are pain afferents.
Neuropathic pain may arise from changes in the pain signalling pathway. These changes can occur in the periphery (outside the brain and spinal cord) and/or in the central nervous system (CNS, which includes the brain and spinal cord). There is an apparent gain of excitation and a loss of inhibition. This shifts the sensory pathways to a hyperexcitable state, or a state of enhanced activity. This results from changes in ion channel function and expression, pain transmitting neuronal function and inhibitory interneuronal function.
Ion Channels Changes
There is increased expression and function of sodium channels (possibly Nav1.3, Nav1.7, and Nav1.8) as well as calcium channels (alpha2delta) in sensory nerves that lead to enhanced excitability. Simultaneously, there is a loss of potassium channels that normally help to control neural activity.
After nerve damage, transient receptor potential V1 (TRPV1) is reduced on injured nerve fibres but is increased on uninjured afferent fibres. This new expression of TRPV1 channels, plus sensitization to heat due to intracellular signal transduction, might result in spontaneous nerve activity induced by normal body temperature. This may occur if the threshold of TRPV1 is decreased to below 38oC.
Pain Transmitting Neuronal Changes
Enhanced excitability of spinal neurons enables low-threshold afferent fibres to activate pain transmitting neurons that send sensory information to the brain. It also expands their receptive fields so that a given stimulus excites more pain transmitting neurons, something referred to as "central sensitization." In other words, central sensitization is the increased responsiveness of pain neurons in the CNS to normal or low threshold sensory input. Specifically, continual discharge of peripheral afferent fibres with the release of excitatory amino acids and neuropeptides leads to changes in these pain transmitting neurons. This includes an excess of signalling as a result of chemical activation of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. These changes result in hyperexcitability. This can also be caused by a loss of gamma-aminobutyric acid (GABA)-releasing inhibitory interneurons in the spinal horn.
Inhibitory Interneuronal Changes
In addition to changes in pain transmitting neurons, inhibitory interneurons and descending modifying control systems are dysfunctional in individuals with neuropathic pain. There seems to be a shift towards hyperexcitability. Noradrenergic (neurotransmitter) inhibitions, carried out by alpha-two-adrenergic receptors in the the spinal cord, are lessen in neuropathic pain. It appears there is enhanced serotonin signalling through the 5-HT2 and 5-HT3 serotonin receptors that then dominates.
Other causes involved in neuropathic pain contribute to ectopic activity, or out of place impulse generation within the pain pathways, and central sensitization. Spontaneous ectopic activity can be present in both injured and neighbouring uninjured pain afferents. After nerve damage, inflammation induces the recruitment of macrophages. These cells release pro-inflammatory cytokines including tumour necrosis factor alpha, which contribute to pain hypersensitivity. Furthermore, after peripheral and central nerve damage, activated microglia in the CNS release several immune affecting molecules that help to maintain neuropathic pain. These inflammatory processes, in addition to other changes that occur around the peripheral nerve endings, contribute to peripheral sensitization. This is when there is decreased activation thresholds and increased excitability.
How Is it Treated?
Because the cause of the pain can rarely be treated, management of neuropathic pain focuses on treating the symptoms. Patients do not usually respond to pain medication like acetaminophen, NSAIDs or weak opioids (e.g. codeine). The approach to treat neuropathic pain is to first treat with drugs and complementary therapies before other strategies are tried such as interventional therapies including nerve blocks or neuromodulation.
First-line drug treatment for peripheral and central neuropathic pain is with pregabalin (a GABA analogue), gabapentin (a GABA inhibitor), duloxetine (a serotonin-noradrenaline reuptake inhibitor) and various tricyclic antidepressants. These are strongly recommended.
Second-line treatment for peripheral neuropathic pain only is with high-dose capsaicin patches, lidocaine patches and tramadol (an opioid with serotonin and noradrenaline reuptake inhibition effects). They have weak evidence in support of their use.
Third-line treatment and with weak recommendations for use is with strong opioids (oxycodone and morphine) and botulinum toxin A.
Interventional therapy is usually reserved for those who do not respond or only respond partially to the treatment above.
Epidural local anaesthetic and steroid nerve blocks provide transient (1 to 3 months) relief for peripheral neuropathic pain associated with trauma and compression.
Low-intensity spinal cord stimulation, whereby burst or high-frequency (10 kHz with sinusoidal waveforms) stimulation is applied, can provide pain relief.
Stimulation of afferent fibres outside the spinal cord and subcutaneous peripheral nerve field stimulation can provide pain relief in patients with occipital neuralgia and postherpetic neuralgia.
Finally, epidural and transcranial cortical stimulation may reduce pain-associated thalamic hyperactivity or activate descending inhibitory pathways. Repetitive transcranial magnetic stimulation and transcranial direct current stimulation involve stimulation of brain area of interest with magnetic coils or electrodes on the scalp.
Intrathecal therapies involve delivering drugs to targeted nerves via an implanted and refillable pump. Morphine and ziconotide (a calcium channel antagonist) are two drugs approved for use in such devices.
Neuropathic pain is chronic pain that is caused by damage or disease of the somatosensory system. It affects as much as 10% of general population. There are subjective screening tools to help identify patients with neuropathic pain. More stringently, there are objective tests done at the bedside to confirm neuropathic pain. It appears that neuropathic pain is the result of changes in the somatosensory system, including alternation in ion channels, pain transmitting neurons, and inhibitory interneurons. Inflammatory process also appear to contribute to the neuropathic pain. All these contribute to hyperexcitability of the pain transmitting system. Treatment usually consists of drugs to reduce symptoms. For those who are resistant to drugs, interventional therapy may work.
Patients with neuropathic pain have a reduced quality of life. It is often associated with a number of other problems like loss of function, depression, anxiety, disturbed sleep and impaired cognition. Research is still needed so that we can one day be able to treat the underlying causes of neuropathic pain instead of just treating the symptoms.
Baron R, Binder A, Wasner G. 2010. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 9(8):807-19.
Cohen SP, Mao J. 2014. Neuropathic pain: mechanisms and their clinical implications. BMJ. 348:f7656.
Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, Attal N, Finnerup NB, Eccleston C, Kalso E, Bennett DL, Dworkin RH, Raja SN. 2017. Neuropathic pain. Nat Rev Dis Primers. 3:17002.
Questions & Answers
I have peripheral neuropathy. I tried both gabapentin and amitriptyline. I am still experiencing swelling in my legs and feet, numbness, and an electric shooting pain to my legs and feet. Do you have any suggestions?
I think it's best that you talk to your doctor about your concerns. Perhaps you can ask him/her to try second- or third-line treatments or interventional therapies.Helpful 6