Neuropathic pain  is a common chronic pain condition seen in clinical practice. Neuropathic pain (NeP) refers to pain that stems from an injury to a single nerve or to several nerves in the body. It is common, often under diagnosed, under treated and associated with suffering, disability, impaired quality of life and increased cost. The aim  of this presentation is to discuss the clinical picture and overall management of  NeP.  An appreciation of this condition may help in reducing the misery and anxiety of the sufferers.

Introduction
            The  classification of chronic pain falls into three broad categories : pain owing to tissue disease or damage (Nociceptive pain, such as osteoarthritis), pain caused by somatosensory system disease or damage (Neuropathic pain), and coexistence of nociceptive and neuropathic pain (Mixed pain). Neuropathic pain is defined by International Association for Study of Pain (IASP) as pain arising as direct consequence of lesion or disease affecting the somatosensory system.(1,2) Neuropathic pain can occur at any age, but affects older people more frequently than younger people. The exact prevalence of neuropathic pain is not known but is estimated to afflict as much as 7-8% of the general population of Europe (3,4) and its prevalence is likely to increase due to an ageing population. Neuropathic pain intensity can be severe, disabling and often does not diminish with healing. Damage to the nerves can changes a person’s sense of touch and can limit arm and leg movement.  It can be unresponsive to conventional analgesics and hence makes the management challenging. NeP is not only devastating for patients but also places a considerable demand on society, including financial burdens relating to health care costs, workplace disruption and disability. Many patients need treatment for long duration  with multi disciplinary strategies to relieve suffering and to restore function.
Common conditions of neuropathic pain-

 
Mechanisms of neuropathic pain-
The pathophysiology of neuropathic pain is complex and very different from nociceptive pain. Major pathophysiological mechanisms include -
Peripheral sensitization
Central sensitization
Sympathetic activation
Disinhibition
Peripheral neuropathic pain as in the case of diabetic neuropathy, and  postherpetic neuralgia (PHN) is due to neuronal hyper excitability. After a nerve injury regeneration results in the formation of neuromas and sprouting of new nerve projections. There can be increased expression of sodium, calcium (voltage-gated) channels leading to ectopic discharges and reduction in threshold for activation of nociceptors (peripheral sensitization). Collateral sprouting can alter sensory properties and manifest as expanded receptive fields. All these phenomena can lead to altered pain transmission. These  stimulus-evoked (positive) pain types are classified as Allodynia or  Hyperalgesia. The term Allodynia means pain due to a stimulus that does not normally activate the nociceptive system like touch, and the term  Hyperalgesia means increased response to a normally painful stimulus like pin prick. The  term  Hypoalgesia means diminished response to a normally painful stimulus.
Neuropathic pain due to  central mechanisms is usually observed after stroke and  spinal cord injury. Sustained painful stimuli results in central sensitization which is mediated by release of neuromodulators like glutamate, gamma amino butyric acid (GABA), serotonin and norepinephrine and  activation of key excitatory amino acid receptors such as the Nmethyl-D-aspartate (NMDA) receptors. This leads to activation of glial cells which further results in increased neuronal excitability. Decreased  inhibitory pathways including down regulation of GABA receptors also contribute to Neuropathic pain.In some patients there is reduced activation of brainstem descending inhibitory pathways (endogenous opioid, serotonin, and norepinephrine pathways) resulting in central neuropathic pain (Disinhibition). Injury of the nerves can also lead to sprouting of sympathetic neurons into dorsal root ganglia of the injured sensory neurons and into the dermis; this explains the sympathetically maintained pain.
Clinical assessment of neuropathic pain patients-(5)
History
Diagnosis of neuropathic pain is based on history and careful clinical examination. The history should include questions about  the location, intensity, character, temporal profile and possible exacerbating factors of the pain. One of the cardinal symptoms of neuropathic pain is a burning sensation. Variety of terms are used to describe neuropathic pain, like stabbing pain, shooting pains, numbness, pain in a numb area, pins and needles, tingling,  lancinating, electric like, raw skin, deep, dull, aching, squeezing, jabbing, broken-glass, cramping, spasms, icy cold,  frostbite etc. Pain drawing is a good tool to document location of pain. The intensity of the pain can be assessed verbally (mild, moderate, severe, excruciating) numerically (zero to ten) or with a visual analogue scale. Character of the pain whether spontaneous (continuous or paroxysmal) or evoked (allodynia, hyperalgesia, hyperpathia) should be noted. Patient may have other symptoms e.g. motor paresis, muscle cramps, autonomic nervous symptoms depending on the site of the lesion. Concomitant symptoms of co morbidities should be asked specifically like disturbed sleep, anxiety, depressed mood, impaired physical activity and changes in role and social relationships. Screening tools, that is, simple questionnaires can be used to alert a clinician to the need for careful examination in search of neuropathic pain. They contain simple questions and some also have sensory examination items. LANSS (Leeds Assessment Of Neuropathic Symptoms And Signs) DN4 (Douleur neuropathique 4) (originally developed in France) and PainDETECT(6) (originally developed in Germany) are the most widely distributed and are translated in several languages. Their ease of use for both clinicians and patients makes these screening tools attractive because they provide immediate information.
Clinical examination -
The aims of a clinical examination in a patient with suspected neuropathic pain is to identify the neurological abnormalities (to aid the diagnosis) and to localize the lesion (whether it is peripheral or central). Full neurological examination including sensory testing, motor assessment, assessment for cranial nerves and peripheral autonomic nervous function (warmth and colour of skin, sudomotor function) is important.
A standardized bedside examination of patients with neuropathic pain should include the following components: touch, pin prick, pressure, cold, heat, vibration, and temporal summation. Touch can be assessed by gently applying cotton wool to the skin, pin-prick sensation by the response to sharp pin-prick stimuli, deep pain by gentle pressure on muscle and joints, and cold and heat sensation by measuring the response to a thermal stimulus (eg. metal objects kept at 200C or 400C) Vibration can be assessed by determining  response to a tuning fork. The motor assessment muscle strength, tonus, coordination and fluency of movements and examination of tendon reflexes and cranial nerves are performed. The responses should be graded as normal, decreased, or increased. Electrophysiological techniques and nerve biopsy sample can be useful to help assess the attenuation of neuronal function and to documents the extent of neuropathy.Important features suggestive of neuropathic pain are Hyperalgesia, Hypoalgesia, Allodynia. No single feature of pain is diagnostic of neuropathic pain. Combining the symptoms with a clinical examination can increase the likelihood of diagnosing neuropathic pain.
Managment of neuropathic pain-
Management of a patient with neuropathic pain is a long-term process. The aim of pain treatment is pain relief, functional rehabilitation, improving associated symptoms such as mood, disturbed sleep, quality of life, daily activities, and performance at work.  Initially, the diagnostic procedures dominate. History and clinical findings should be documented clearly in the medical charts; this helps assessment of treatment effects at follow-up visits. After setting the diagnosis, more attention is paid to the assessment of treatment effects. Patient education about the nature of the condition and the available treatment options helps in formulating realistic expectations and in developing self management strategies. Broadly the management can be divided into pharmacological and non–pharmacological.
Pharmacological treatment – (7)
The pharmacological management of NeP is challenging because the response to most drugs is unpredictable and different neuropathic pain syndromes respond differently to various types of drugs. Fewer than half of patients achieve significant pain relief from a single medication. Combination therapy using additive or synergistic effects to target different pain mechanisms should be the preferred approach (rational  polypharmacy). The starting doses should be kept low and any titration of each drug should be planned, taking into consideration potential side-effects and interactions with other medications. There are four main drug classes used for treatment of NeP. They  are -Antidepressants, Anti-epileptics, Opioids, and Topical treatments.
Antidepressants-
Tricyclic antidepressants (TCA) are one of the most commonly prescribed groups of drugs for NeP and their use is supported by evidence. Some patients who receive antidepressants for neuropathic pain may experience improvement in insomnia, anxiety, and depression.(8) Onset of analgesia with antidepressants generally occurs before the onset of the antidepressant effect. Patients receiving TCAs were significantly more likely to report at least 30% pain reduction and global improvement. This pain relief is independent of any effects on depression. Adverse effects like dry  mouth, blurred vision, constipation, hypotension, weight gain, sedation may be prudent to avoid the use of TCAs in elderly patient especially in view of toxic effects on heart and the anticholinergic side effects. Second-generation agents (nortriptyline, desipramine), which have more favourable adverse effect profiles may be tolerated better in elderly. Duloxetine is recommended as a first line agent for painful diabetic neuropathy.
Anticonvulsants-
Anticonvulsants are well established in treatment of NeP and are used as first or second line agents. Different drugs produce their analgesic effects by different mechanisms e.g. blockade of calcium channels (Gabapentin, Pregabalin), voltage-dependent sodium channels (Carbamazepine, Phenytoin) and actions on glutamate secretion (Lamotrigine). Older anticonvulasnts e.g. carbamazepine and phenytoin have significant adverse effects, making them poor candidates for first-line therapy. However in trigeminal neuralgia carbamazepine  or oxcarbazepine should be offered as first-line treatment.
Gabapentin is one of the most common anticonvulsants used for treatment of NeP. Patients report atleast 50% pain reduction and global improvement. Gabapentin has added beneficial effects on mood and sleep patterns. It tends to have fewer side effects than many of the first generation anticonvulsants, and has no significant drug interactions. The most common side effects include dizziness, somnolence, nausea, peripheral edema and in coordination. It is recommended in treatment of post herpetic neuralgia.
Pregabalin is a GABA analogue and consequently shares  distinct pharmacokinetic advantages over gabapentin. It has a much higher bioavailability (90% versus 33-66%) and is rapidly absorbed (peak: 1 hr). Additionally it has a greater affinity for the receptor site. Pregabalin provides rapid and sustained relief from NeP in patients with DPN and PHN and improves sleep patterns.(9,10) Dose escalation may be achieved more rapidly than with gabapentin.  It   provides equivalent efficacy to gabapentin, however, at much lower doses and so associated with fewer dose-related adverse events. It is highly effective even in refractory patients.
Opioids :
They are used as second or third line agent for neuropathic pain. Opioids may be effective when other therapies fail. Preferably slow release preparations are used at a lower dose and response to the drug is regularly reviewed and titrated against side effects and pain. Tramadol, fentanlyl and morphine have been shown to be effective in treating neuropathic pain disorders. The use of these drugs can be associated with a poor side effect profile thus limiting their use. Common opioid related adverse effects include nausea, vomiting, constipation, sedation, dizziness. These effects generally decrease after long term treatment, with the exception of constipation.
Topical Lidocaine Patch 5%
Lidocaine Patch 5% can be used preferentially for small areas of peripheral neuropathic pain with mechanical Allodynia or for focal neuropathy especially in PHN. The patch can be affixed directly to the affected areas. Multiple patches may be used to treat multiple painful sites or the patch may be trimmed. It may take up to 2-4 weeks until the full pain relief is evident. Topical treatment means the drug stays and acts primarily locally, with minimal systemic absorption  reducing the risk of side effects, even with chronic use.  The most common adverse event reported with the topical lidocaine patch 5% is transient minor local irritation of the skin.
Capsaicin topical ointment may improve symptoms of PHN, nerve injury and mixed NeP conditions. The intense burning sensation during initial treatment may limit its use.
Other pharmacological Interventions-
IV Ketamine : has been successfully used in sub-anaesthetic doses  for neuropathic pain. .(11) It may be administered orally or by intravenous infusion. Side  effects, including psycho mimetic effects, limit its usefulness. It is generally used in chronic pain states that have a limited response to standard treatment.(11)
IV Lidocaine by intravenous infusion may be effective.(12) Patients who respond may derive benefit from oral Mexiletine. Common adverse effects include nausea  vomiting, abdominal pain,  dizziness and perioral numbness.
Non pharmacological treatment-
Non pharmacological options for the treatment of neuropathic pain are as important as pharmacological options. Simple measures such as massage, exercise, physiotherapy, TENS (Trans cutaneous Electrical Nerve Stimulation) can help in producing marked functional improvements and  should be considered initially. However, evidence supporting the efficacy of nonpharmacological treatment is limited.
Psychological interventions-
Chronic pain conditions can be associated with severe psychological distress, which not only affects the mood and sleep but also the perception of pain. Encouraging pain patient to contribute their treatment plan and helping them develop self management strategies gives them a sense of control. Some of the available treatment options delivered by specialized pain management psychologists include relaxation techniques, hypnosis, counseling, cognitive behavioral therapy and a pain management program. It is difficult to predict the response to individual therapies however matching of therapy to patients needs and lifestyle can help in improving outcomes.
Interventional Treatments for Neuropathic Pain-
Interventional treatments for the management of neuropathic pain are well described and available. They should be offered to any patient whose pain is not adequately treated with first and second line drugs or for patients with side –effects from medication. They include Neural blocks, Sympathetic blocks, Neurolytic techniques, Intrathecal pumps and Stimulatory techniques. Interventional treatments should usually be carried out as part of a multidisciplinary treatment plan.
Neural blockadge with epidural blocks is recommended for patients with postherpatic neuralgia, radiculopathy, and failed back surgery syndrome.(13,14)
Sympathetic blocks may provide relief in patients whose neuropathic pain is maintained via this system (sympathetic –maintained pain). The sympathetic chain can be treated in the cervical, thoracic and lumbar region with local anaesthetic, thermal radiofrequency or nerve destruction using chemical destruction. Duration of effect depends on method of treatment. It provides an effective treatment option for PHN, CRPS.(15)
Neurolytic techniques are primarily employed for pain caused by cancer.
Intrathecal pumps or spinal analgesia is widely used for neuropathic pain and  is a less conservative therapy than spinal cord stimulation. By acting directly on the spinal cord, spinal analgesia may provide improved pain control with fewer side effects than do systemic drugs. Opioids, ziconotide, and local anaesthetics can be delivered intrathecaly in patients with post herpetic neuralgia, painful diabetic neuropathy, spinal cord injury, failed back surgery syndrome, and complex regional pain syndrome.
Stimulatory techniques encompass spinal cord and peripheral nerve stimulation. The main advantage of spinal cord stimulation is that it is a nonpharmacologic intervention that spares patients pharmacy visits, bills, and side effects. Spinal cord stimulation is efficacious in patients with complex regional pain syndrome and failed back surgery syndrome.( 16), and motor cortex stimulation is efficacious in patients with central post-stroke pain.( 17)
Summary
Neuropathic pain  is a common chronic pain condition seen in clinical practice.
NeP is often under diagnosed, under treated and associated with suffering disability, impaired quality of life and increased cost.
Most patients can obtain clinically meaningful relief with appropriate treatment.
Polypharmacy may be required for patients who do not respond adequately to treatment with a single agent.
Interventional treatments should be offered to any patient whose pain is not adequately treated with first and second line drugs or for patients with side –effects from medication.

Treatment should balance efficacy, safety, tolerability, and progress from the least to the most invasive treatments.
The goals of treatment should include not only reducing pain as much as possible but also improving the patient’s QOL.
References

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