Neuropathic pain
Neuropathic pain is pain caused by damage or disease affecting the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli. It may have continuous and/or episodic components. The latter resemble stabbings or electric shocks. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching.
Up to 7%-8% of the European population is affected, and in 5% of persons it may be severe.
Neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system. Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed neuropathic pain. Neuropathic pain may occur in isolation or in combination with other forms of pain. Medical treatments focus on identifying the underlying cause and relieving pain. In cases of neuropathy, the pain may progress to insensitivity.
Diagnosis
Diagnosis of pain conditions relies on the character of the pain with a sharp stabbing character and the presence of particular features such as mechanical allodynia and cold allodynia. Neuropathic pain also tends to affect defined dermatomes and there may be limits to the area of pain. For neuropathic pain, clinicians look for an underlying lesion to the nervous system or an inciting cause consistent with the development of neuropathic pain. The obvious presence of an underlying feature or cause is not always detectable, and response to treatment may be used as a surrogate particularly in cases where diagnosis of the underlying lesion leaves the patient in pain for a prolonged period of time. MRI may be helpful in the identification of underlying lesions, reversible causes or serious underlying conditions such as primary presentation of a tumor or multiple sclerosis. Quantitative sensory testing, a system of detailed analysis of the somatosensory system, is frequently used in research situations to identify neuropathic pain and a more detailed analysis of its components. It has been suggested by some authorities that QST may have a future role in the diagnosis of neuropathic pain and in particular the identification of neuropathic pain subtypes. Neuropathic pain can occur alone or in combination with other types of pain. The identification of neuropathic pain components is important as different classes of analgesic are required. Difficulties in identifying subtypes of patients with chronic neuropathic pain underlie some of the difficulties in treatment including identifying suitable cohorts of patients for randomized clinical trials.Cause
Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Peripheral neuropathies are commonly caused by diabetes, metabolic disorders, herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, immune mediated disorders and physical trauma to a nerve trunk. Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves, or as a side effect of chemotherapy, radiation injury or surgery.Comorbidities
Neuropathic pain has profound physiological effects on the brain which can manifest as psychological disorders. Rodent models where the social effects of chronic pain can be isolated from other factors suggest that induction of chronic pain can cause anxio-depressive symptoms and that particular circuits in the brain have a direct connection. Depression and neuropathic pain may have a bidirectional relationship and relief of co-morbid depression may underlie some of the therapeutic efficacy of antidepressants in neuropathic pain. Neuropathic pain has important effects on social well-being that should not be ignored. Neuropathic pain sufferers may have difficulty working exhibiting higher levels of presenteeism, absenteeism and unemployment, exhibit higher levels of substance misuse, and present difficulties with social interactions. Moreover uncontrolled neuropathic pain is a significant risk factor for suicide. Certain classes of neuropathic pain may cause serious adverse effects necessitating hospital admission, for instance trigeminal neuralgia can present as a severe crisis where the patient may have difficulty talking, eating and drinking. As neuropathic pain may be comorbid with cancer, it can have important dose limiting effects on certain classes of chemotherapeutic.Treatments
Neuropathic pain can be very difficult to treat with only some 40-60% of people achieving partial relief.General approach
First line treatments are certain antidepressants, anticonvulsants. Opioid analgesics are recognized as useful agents but are not recommended as first line treatments. A broader range of treatments are used in specialist care. There are limited data and guidance for the long-term treatment of pain. Notably strong evidence from RCTs is not available for all interventions.Primary interventions
Anticonvulsants
Pregabalin and gabapentin may reduce pain associated with diabetic neuropathy. The anticonvulsants carbamazepine and oxcarbazepine are especially effective in trigeminal neuralgia. Carbamazepine is a voltage-gated sodium channel inhibitor, and reduces neuronal excitability by preventing depolarisation. Carbamazepine is most commonly prescribed to treat trigeminal neuralgia due to clinical experience and early clinical trials showing strong efficacy. Gabapentin may reduce symptoms associated with neuropathic pain or fibromyalgia in some people. There is no predictor test to determine if it will be effective for a particular person. A short trial period of gabapentin therapy is recommended, to determine the effectiveness for that person. 62% of people taking gabapentin may have at least one adverse event, however the incidence of serious adverse events was found to be low. Gabapentin and pregabalin are habit forming and have significant abuse potential.Meta analysis of randomized clinical trials suggests that Lamotrigine is not useful for the majority of patients although it may have use in treatment refractory cases.
Antidepressants
Dual serotonin-norepinephrine reuptake inhibitors in particular duloxetine, as well as tricyclic antidepressants in particular amitriptyline, and nortriptyline are considered first-line medications for this condition.Opioids
s, while commonly used in chronic neuropathic pain, are not a recommended first or second line treatment. In the short and long term they are of unclear benefit, although clinical experience suggests that opioids like tramadol may be useful for treating sudden onset severe pain In the intermediate term evidence of low quality supports utility.Several opioids, particularly levorphanol, methadone and ketobemidone, possess NMDA receptor antagonism in addition to their µ-opioid agonist properties. Methadone does so because it is a racemic mixture; only the l-isomer is a potent µ-opioid agonist. The d-isomer does not have opioid agonist action and acts as an NMDA receptor antagonist; d-methadone is analgesic in experimental models of chronic pain.
There is little evidence to indicate that one strong opioid is more effective than another. Expert opinion leans toward the use of methadone for neuropathic pain, in part because of its NMDA antagonism. It is reasonable to base the choice of opioid on other factors. It is unclear if fentanyl gives pain relief to people with neuropathic pain. The potential pain relief benefits of strong opioids must be weighed against their significant addiction potential under normal clinical use and some authorities suggest that they should be reserved for cancer pain. Importantly, recent observational studies suggest a pain-relief benefit in non-cancer related chronic pain of reducing or terminating long-term opioid therapy.
Non-Pharmaceutical Interventions
Non-pharmaceutical treatments such as exercise, physical therapy and psychotherapy may be useful adjuncts to treatment.Secondary and research interventions
Botulinum toxin type A
Local intradermal injection of botulinum neurotoxin type A may be helpful in chronic focal painful neuropathies. However, it causes muscle paralysis which may impact quality of life.Cannabinoids
Evidence for the use of Cannabis based medicines is limited, low-moderate quality evidence suggests a benefit in pain intensity, sleep quality and psychological distress. The use of Cannabis has to be weighed against the negative psychotomimetic effects that may impact quality of life. Therefore cannabis is not recommended as a mainstream treatment but may have a place for treatment refractory cases.Neuromodulators
is a field of science, medicine and bioengineering that encompasses both implantable and non-implantable technologies for treatment purposes.Implanted devices are expensive and carry the risk of complications. Available studies have focused on conditions having a different prevalence than neuropathic pain patients in general. More research is needed to define the range of conditions that they might benefit.
Deep brain stimulation
The best long-term results with deep brain stimulation have been reported with targets in the periventricular/periaqueductal grey matter, or the periventricular/periaqueductal grey matter plus thalamus and/or internal capsule. There is a significant complication rate, which increases over time.Motor cortex stimulation
Stimulation of the primary motor cortex through electrodes placed within the skull but outside the thick meningeal membrane has been used to treat pain. The level of stimulation is below that for motor stimulation. As compared with spinal stimulation, which is associated with noticeable tingling at treatment levels, the only palpable effect is pain relief.Spinal cord stimulators implanted spinal pumps
s use electrodes placed adjacent to but outside the spinal cord. The overall complication rate is one-third, most commonly due to lead migration or breakage but advancements in the past decade have driven complication rates much lower. Lack of pain relief occasionally prompts device removal.NMDA antagonism
The N-methyl-D-aspartate receptor seems to play a major role in neuropathic pain and in the development of opioid tolerance. Dextromethorphan is an NMDA antagonist at high doses. Experiments in both animals and humans have established that NMDA antagonists such as ketamine and dextromethorphan can alleviate neuropathic pain and reverse opioid tolerance. Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by a very short half life, weak activity or unacceptable side effects.Intrathecal drug delivery
s deliver medication to the fluid filled space surrounding the spinal cord. Opioids alone or opioids with adjunctive medication Rarely there are complications such as serious infection, urinary retention, hormonal disturbance and intrathecal granuloma formation have been noted with intrathecal infusion, associated with the delivery method.Conotoxins
is a voltage-gated calcium channel blocker which may be used in severe cases of ongoing neuropathic pain it is delivered intrathecally.Topical agents
In some forms of neuropathy the topical application of local anesthetics such as lidocaine may provide relief. A transdermal patch containing lidocaine is available commercially in some countries.Repeated topical applications of capsaicin are followed by a prolonged period of reduced skin sensibility referred to as desensitization, or nociceptor inactivation. Capsaicin causes reversible degeneration of epidermal nerve fibers. Notably the capsaicin used for the relief of neuropathic pain is a substantially higher concentration than capsaicin creams available over the counter, there is no evidence that over the counter capsaicin cream can improve neuropathic pain and topical capsaicin can itself induce pain.
Surgical Interventions
Orthopaedic interventions are frequently used to correct underlying pathology which may contribute to neuropathic pain. Many orthopaedic procedures have more limited evidence. Historically, neurosurgeons have attempted lesions of regions of the brain, spinal cord and peripheral nervous system. Whilst they cause some short term analgesia, these are considered to be universally ineffective.Alternative therapies
Herbal products
There is no good evidence that herbal products are useful for treating neuropathic pain.Dietary supplements
A 2007 review of studies found that injected administration of alpha lipoic acid was found to reduce the various symptoms of peripheral diabetic neuropathy. While some studies on orally administered ALA had suggested a reduction in both the positive symptoms of diabetic neuropathy as well as neuropathic deficits, the meta-analysis showed "more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone". There is some limited evidence that ALA is also helpful in some other non-diabetic neuropathies.Benfotiamine is an oral prodrug of Vitamin B1 that has several placebo-controlled double-blind trials proving efficacy in treating neuropathy and various other diabetic comorbidities.
History
The history of pain management can be traced back to ancient times. Galen also suggested nerve tissue as the transferring route of pain to the brain through the invisible psychic pneuma. The idea of origination of pain from the nerve itself, without any exciting pathology in other organs is presented by medieval medical scholars such as Rhazes, Haly Abbas and Avicenna. They named this type of pain specifically as "vaja al asab" , described its numbness, tingling and needling quality, discussed its etiology and the differentiating characteristics.The description of neuralgia was made by John Fothergill. In a medical article entitled “Clinical Lecture on Lead Neuropathy" published in 1924 the word "Neuropathy" was used for the first time by Gordon.
Proposed mechanistic basis for neuropathic pain
The underlying pathophysiology of neuropathic pain remains a contested topic. The etiology and mechanism of pain are related to the cause of the pain. Certain forms of neuropathic pain are associated with lesions to the central nervous system such as thalamic pain associated with certain lesions to the thalamus whereas other forms of pain have a peripheral inciting injury such as traumatic neuropathies. The inciting cause of neuropathy has important consequences for its mechanistic basis as different tissues and cells are involved. The mechanistic basis of neuropathic pain remains controversial as do the relative contributions of each pathway. Notably our understanding of these processes is largely driven by rodent models in part because studying these tissues in living adults is difficult.Peripheral
With peripheral nervous system lesions, a number of processes may occur. Intact neurons may become unusually sensitive and develop spontaneous pathological activity and abnormal excitability.During neuropathic pain, ectopic activity arises in the peripheral nociceptors and this appears to be due in part to changes in the ion channel expression at the level of the periphery. There may be an increase in the expression or activity of voltage gated sodium and calcium channels which will support action potential generation. There may also be a decrease in potassium channels which would normally oppose action potential generation. Each of these changes appears to support an increase in excitability, which may allow endogenous stimuli to cause spontaneous pain.