| Neuropathic pain | |
|---|---|
| Specialty | Neurology andpsychiatry |
| Duration | Variable |
| Causes | Damage to the nervous system resulting fromdiabetes mellitus,multiple sclerosis,COVID-19, infection, injury, and stroke, among others |
| Risk factors | Diabetes mellitus; multiple sclerosis; exposure toneurotoxicants;alcoholism; history of chemo- and/or radiotherapy; & nutritional deficiencies, among others |
| Diagnostic method | Clinical interview;quantitative sensory testing;electroneuromyography;nerve stimulation; biopsy; imaging, & patient self-rating of symptoms |
| Differential diagnosis | Diabetic and metabolic neuropathy;demyelinating disease (e.g., multiple sclerosis); malignancy; spinal cord injury; primaryneuralgia;mononeuritis multiplex;sciatica;pruritic processes;fibromyalgia; andfunctional pain syndrome, among others |
| Treatment | Physical therapy; exercise;psychotherapy;antidepressants;gabapentinoids;anticonvulsants;Tramadol;neuromodulation, and topical agents, among others |
| Frequency | 4.1%-12.4% (12-month prevalence, US adults)[1] |
Neuropathic pain ispain caused by a lesion or disease of thesomatosensory nervous system.[2][3] Neuropathic pain may be associated with abnormal sensations calleddysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous and/or episodic (paroxysmal) components. The latter resemble stabbings or electric shocks. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching.[3]
Up to 7–8% of the European population is affected by neuropathic pain,[4] and in 5% of persons it may be severe.[5][6] The pain may result from disorders of theperipheral nervous system or thecentral nervous system (brain and spinal cord). 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 ofperipheral neuropathy, the pain may progress to insensitivity.
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 defineddermatomes 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 ormultiple sclerosis.Quantitative sensory testing (QST), 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.[7]
Thegold standard for diagnosingsmall fiber neuropathy as the etiology of neuropathic pain isskin biopsy.Sudomotor assessment, throughelectrochemical skin conductance, an accurate objective technique, could be considered as a good screening tool to limitskin biopsy in patients in whom it is not suitable.[8][9]
Neuropathic pain may be divided into peripheral, central or mixed (peripheral and central) types. Central neuropathic pain is found inspinal cord injury[10] andmultiple sclerosis.[11] Peripheral neuropathies are commonly caused bydiabetes,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.[12][13] Neuropathic pain is common incancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect ofchemotherapy (chemotherapy-induced peripheral neuropathy),[14][15] radiation injury or surgery.[3]
Neuropathic pain has profound physiological effects on the brain, which can manifest as psychological disorders. Rodent models in which the social effects of chronic pain can be isolated from other factors suggest that induction of chronic pain can cause anxiety-depressive symptoms and that particular circuits in the brain have a direct connection.[16][17] 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. People with neuropathic pain may have difficulty working exhibiting higher levels of presenteeism, absenteeism and unemployment,[18] exhibit higher levels of substance misuse (which may be related to attempted self-medication),[19][20] and present difficulties with social interactions.[21] Moreover, uncontrolled neuropathic pain is a significant risk factor for suicide.[22] Certain classes of neuropathic pain may cause serious adverse effects necessitating hospital admission. For instance,trigeminal neuralgia can present as a severe crisis wherein the patient may have difficulty talking, eating, and drinking.[23] As neuropathic pain may be comorbid with cancer, it can have important dose limiting effects on certain classes of chemotherapeutic.[24]
Neuropathic pain can be very difficult to treat, with only some 40–60% of people achieving partial relief.[25]
First-line treatments include certain antidepressants (tricyclic antidepressants andserotonin–norepinephrine reuptake inhibitors) andanticonvulsants (pregabalin andgabapentin).[26][27]Opioid analgesics are recognized as useful in some cases but not recommended as first-line treatments.[27] A broader range of treatments is used in specialist care. There is limited data and guidance for the long-term treatment of pain. Notably, strong evidence fromrandomized controlled trials is not universal for all interventions.[citation needed]
Pregabalin and gabapentin may reduce pain associated withdiabetic neuropathy.[28][26][29][30] The anticonvulsantscarbamazepine andoxcarbazepine are especially effective intrigeminal neuralgia. Carbamazepine is a voltage-gated sodium channel inhibitor and reduces neuronal excitability by preventing depolarization.[31] 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 orfibromyalgia in some people.[26] There is no test to predict the effectiveness ofgabapentin for individuals, so a short trial is suggested to assess its effectiveness. While 62% of users may experience at least one adverse event, serious adverse events are rare.[26]
Ameta-analysis of randomized clinical trials suggests thatlamotrigine is not useful for most patients, although it may have been used in the treatment of refractory cases.[32]
Dualserotonin-norepinephrine reuptake inhibitors in particularduloxetine, as well astricyclic antidepressants in particularamitriptyline, andnortriptyline are considered first-line medications for this condition.[27]
Opioids, while commonly used in chronic neuropathic pain, are not recommended as first- or second-line treatment.[33] In the short and long term, they are of unclear benefit. However, clinical experience suggests that opioids liketramadol may be useful for treating sudden-onset severe pain.[34] In the intermediate term, low-quality evidence supports utility.[34]
Several opioids, particularlylevorphanol,methadone, andketobemidone, possessNMDA receptor antagonism in addition to their μ-opioid agonist properties. Methadone does so because it is aracemic 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 an analgesic in experimental models of chronic pain.[35]
There is little evidence to indicate that one potent 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.[36] It is unclear iffentanyl gives pain relief to people with neuropathic pain.[37] The potential pain relief benefits of strong opioids must be weighed against their significantaddiction potential under normal clinical use, and some authorities suggest that they should be reserved forcancer pain.[38] Importantly, recent observational studies suggest a pain-relief benefit in non-cancer-related chronic pain of reducing or terminating long-term opioid therapy.[39][40]
Non-pharmaceutical treatments such as exercise, physical therapy, andpsychotherapy may be useful adjuncts to treatment.[41]
Local intradermal injection ofbotulinum toxin type A may be helpful in chronic focal painful neuropathies. However, it causes muscle paralysis, which may impact quality of life.[42]
Evidence for the use ofcannabis based medicines is limited. Any potential utility might be offset byadverse effects.[43]
Neuromodulation is a field of science, medicine, and bioengineering that encompasses both implantable and non-implantable technologies (electrical and chemical) for treatment purposes.[44] Implanted devices are expensive and carry the risk of complications. Available studies[citation needed] have focused on conditions with different prevalences than those of neuropathic pain patients in general. More research is needed to define the range of conditions for which they might benefit.
The best long-term results withdeep brain stimulation have been reported with targets in the periventricular/periaqueductalgrey matter (79%) or the periventricular/periaqueductal grey matter plusthalamus and/or internal capsule (87%).[45] There is a significant complication rate, which increases over time.[46]
Stimulating the primary motor cortex using electrodes placed within the skull but outside the thick protective layer known as the dura mater has been employed as a treatment for pain. The stimulation level used in this approach is lower than that required for motor activation. Unlike spinal stimulation, which often causes noticeable tingling sensations (known as paresthesia) at treatment levels, the primary effect observed with this method is simply pain relief.[47][48]
Spinal cord stimulators 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; however, advancements in the past decade have driven complication rates significantly lower. Lack of pain relief occasionally prompts device removal.[49]
TheN-methyl-D-aspartate (NMDA) receptor seems to play a major role in neuropathic pain and in the development ofopioid tolerance.Dextromethorphan is anNMDA antagonist at high doses. Experiments in both animals and humans have established that NMDAantagonists such asketamine anddextromethorphan can alleviate neuropathic pain and reverse opioid tolerance.[50] Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by a very short half-life (ketamine), weak activity (memantine) or unacceptable side effects (dextromethorpan).
Intrathecal pumps deliver medication to the fluid-filled (subarachnoid) space surrounding the spinal cord. Opioids alone or opioids with adjunctive medication (either a local anesthetic or clonidine). Rarely are complications such as serious infection (meningitis), urinary retention, hormonal disturbance, and intrathecal granuloma formation noted with intrathecal infusion associated with the delivery method.
Photoswitchable analogs of the anticonvulsant drugcarbamazepine have been developed to control its pharmacological activity locally and on demand using light, with the purpose of reducing adverse systemic effects.[51] One of these compounds (carbadiazocine, based on a bridgedazobenzene) has been shown to produce analgesia with noninvasive illumination in a rat model of neuropathic pain.
Ziconotide is a voltage-gated calcium channel blocker which may be used in severe cases of ongoing neuropathic pain[52] it is delivered intrathecally.
Ambroxol is a medication that reduces mucus production. Preclinical research suggests it may produce analgesic effects by blockingsodium channels in sensory neurons.[53]
The use ofgene therapy is a potential treatment for chronic neuropathic pain.[54] In animals, a gene therapy for localtransgenes encoding forGABA synthesizing-releasing inhibitory machinery was effective for months at a time. It increases synaptically GABA-mediated neuronal inhibition in the spinal cord (or brain) via the induced expression of genes GAD65 and VGAT without any detected systemic or segmental side effects.[54]
In some forms of neuropathy, the topical application of local anesthetics such aslidocaine 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.[55] 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[56] and topical capsaicin can itself induce pain.[55]
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.[citation needed]
Suppose neuropathic pain arises asnerve compression syndrome. In that case, it may be treatable with anerve decompression.[57][58][59][60][61] When nerves are subject to chronic pressure, they exhibit apathological progression resulting in reversible and partially reversiblenerve injuries that causepain,paresthesias, and potentiallymuscle weakness.[62] In a nerve decompression, a surgeon explores the entrapment site and removes tissue around the nerve to relieve pressure.[57] In many cases the potential for nerve recovery (full or partial) after decompression is excellent, as chronic nerve compression is associated with low-grade nerve injury (Sunderland classification I-III) rather than high-grade nerve injury (Sunderland classification IV-V).[63] Nerve decompressions are associated with a significant reduction in pain, in some cases the complete elimination of pain.[64][58][59]
For patients withdiabetic neuropathy, which affects 30% of diabetes patients,[65] and superimposed nerve compression, nerve decompression may be useful.[66][67] The theory behind the procedure is that diabetic peripheral neuropathy (DPN) predisposes peripheral nerves to compression at anatomic sites of narrowing, and that the majority of peripheral DPN symptoms may actually be attributable to nerve compression rather than DPN itself.[68][69][70] The surgery is associated with lowerpain scores, highertwo-point discrimination (a measure of sensory improvement), lower rate ofulcerations, fewer falls (in the case of lower extremity decompression), and feweramputations.[69][71][66][67]
There is no good evidence that herbal products (nutmeg orSt John's wort) are helpful in treating neuropathic pain.[72]
A 2007 review of studies found that injected (parenteral) administration ofalpha lipoic acid (ALA) was found to reduce the various symptoms of peripheral diabetic neuropathy.[73] While some studies on orally administered ALA had suggested a reduction in both the positive symptoms of diabetic neuropathy (dysesthesia including stabbing and burning pain) as well as neuropathic deficits (paresthesia),[74] the meta-analysis showed "more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone".[73] There is some limited evidence that ALA is also helpful in some other non-diabetic neuropathies.[75]
Benfotiamine is an oralprodrug ofVitamin B1 that has several placebo-controlled double-blind trials proving efficacy in treating neuropathy and various other diabetic comorbidities.[76][77]
The history of pain management dates back to ancient times.Galen also suggested nerve tissue as the transferring route of pain to the brain through the invisible, psychicpneuma.[78] The idea of origination of pain from the nerve itself, without any exciting pathology in other organs, is presented by medieval medical scholars such asRhazes,Haly Abbas andAvicenna. They named this type of pain specifically as "vaja al asab" (nerve originated pain), described itsnumbness,tingling andneedling qualities, and discussed its etiology and differentiating characteristics.[79]The first formal description ofneuralgia was made byJohn Fothergill (1712–1780). In a medical article entitled "Clinical Lecture on Lead Neuropathy" (published in 1924), the word "neuropathy" was used for the first time by Gordon.[80]
The underlying pathophysiology of neuropathic pain remains a contested topic. The etiology and mechanism of pain are related to the cause of the pain. Some forms of neuropathic pain are associated withlesions to the central nervous system, such asthalamic pain associated with lesions (resulting from, for instance,cerebrovascular events) to thethalamus,[81] whereas other forms of pain have a peripheral inciting injury, such as those precipitating traumatic neuropathies.[10] The cause of neuropathy affects its mechanisms, involving different tissues and cells. The exact pathways of neuropathic pain and the relative contributions of each pathway remain matters of controversy. Notably, current understanding relies mainly on rodent models because studying pain-originating tissues in living humans is difficult.[citation needed]
With peripheral nervous system lesions, several processes may occur. Intactneurons may become unusually sensitive, developing spontaneous pathological activity and abnormalexcitability.
During neuropathic pain, ectopic activity arises in peripheralnociceptors, which appears to be partly due to changes inion channel expression at the peripheral level. There may be an increase in the expression or activity ofvoltage-gated sodium andcalcium channels, which will support the generation of action potentials. There may also be a decrease inpotassium channels, which generally oppose the generation of action potentials. These changes appear to support increased excitability, which may allow endogenous stimuli to cause spontaneous pain.[82]
The central mechanisms of neuropathic pain involve several major pathways. Nociception is ordinarilytransduced by a polysynaptic path through the spinal cord, up thespinothalamic tract to the thalamus, and then to thecerebral cortex. Broadly speaking, in neuropathic pain, neurons are hypersensitized,glia become activated, and inhibitory tone is lost.
Thegate control theory of pain, initially proposed byPatrick David Wall andRonald Melzack in 1965, is a major theory of pain perception. The theory posits that the activation of central pain-inhibitory neurons by non-pain-sensing neurons prevents the transmission of non-harmful stimuli to pain centers in the brain. A loss of inhibitory neurons, accompanied by reducedGAD65/67 expression (the enzymes responsible for synthesizingGABA, the predominant inhibitory neurotransmitter in the adult brain), has been observed in certain systems following peripheral neuropathy, such as in rats and mice.[83] However, these observations remain controversial, with some investigators unable to detect a change. The loss of inhibitory inputs may allow fibers to transmit messages via thespinothalamic tract, thus causing pain in normally painless stimuli. This loss of inhibition may not be limited to the spinal cord; a loss of GABA has also been observed in the thalamus ofchronic pain patients.[84]
During neuropathic pain, the glia become "activated," leading to the release of proteins that modulate neural activity. The activation of glia remains an area of intense interest for researchers.Microglia, theimmune cells that reside in the brain and spinal cord, respond to external signals. The source of these cues may include neurons secretingchemokines such asCCL21 and surface-immobilized chemokines such asCX3CL1. Other glia, such asastrocytes andoligodendrocytes, may also release these extrinsic cues for microglia, and microglia themselves may produce proteins that amplify the response.[85] The effect of microglia on neurons that leads to the neurons being sensitized is controversial. Brain-derived neurotrophic factors, prostaglandins, TNF, and IL-1β may be produced by microglia, leading to changes in neurons that result in hyperexcitability.[86][87]
Central sensitization is a potential component of neuropathic pain. It refers to a change insynaptic plasticity, efficacy, and intrinsic disinhibition, resulting in the uncoupling of noxious inputs. In the sensitized neuron, outputs are no longer coupled to the intensity or duration, and many inputs may be combined.[88]
During high-frequency stimulation, synapses conveying nociceptive information may become hyper-efficient in a process similar but not identical tolong-term potentiation.[89] Molecules such assubstance P may be involved in potentiation vianeurokinin receptors.NMDA activation also triggers a change in the post-synapse; it activates receptor kinases that increase receptor trafficking and post-translationally modify receptors, causing changes in their excitability.[88]
The phenomena described above are dependent on changes at the cellular and molecular levels. Altered expression of ion channels, changes in neurotransmitters and their receptors, and altered gene expression in response to neural input are at play.[90] Neuropathic pain is associated with changes in sodium and calcium channel subunit expression resulting in functional changes. In chronic nerve injury, there is redistribution and alteration of subunit compositions of sodium and calcium channels, resulting in spontaneous firing at ectopic sites along the sensory pathway.[13]
Several guidelines agree that first- and second-line drugs for neuropathic pain include anticonvulsants (gabapentin or pregabalin), tricyclic antidepressants, and SNRIs
ALA appears to improve neuropathic symptoms and deficits when administered via parenteral supplementation over a 3-week period. Oral treatment with ALA appears to have more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone.
