Neuropathic pain

Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system.^[2][3] Neuropathic pain may be associated with abnormal sensations called dysesthesia 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]

Neuropathic pain
Specialty	Neurology and psychiatry
Duration	Variable
Causes	Damage to the nervous system resulting from diabetes mellitus, multiple sclerosis, infection, injury, and stroke, among others
Risk factors	Diabetes mellitus; multiple sclerosis; exposure to neurotoxicants; 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; primary neuralgia; mononeuritis multiplex; sciatica; pruritic processes; fibromyalgia; and functional 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]

Up to 7-8% of the European population is affected,^[4] and in 5% of persons it may be severe.^[5][6] Neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) 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

Quantitative sensory testing may assist with diagnosis of specific deficits

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 (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]

The gold standard for diagnosing small fiber neuropathy as the etiology of neuropathic pain is skin biopsy. Sudomotor assessment, through electrochemical skin conductance, an accurate objective technique, could be considered as a good screening tool to limit skin biopsy in patients in whom it is not suitable.^[8][9]

Cause

Central neuropathic pain is found in spinal cord injury,^[10] multiple sclerosis,^[11] 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.^[12][13] Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy (chemotherapy-induced peripheral neuropathy),^[14][15] radiation injury or surgery.^[3]

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.^[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 where 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]

Treatments

Neuropathic pain can be very difficult to treat with only some 40-60% of people achieving partial relief.^[25]

General approach

First line treatments are certain antidepressants (tricyclic antidepressants and serotonin–norepinephrine reuptake inhibitors), anticonvulsants (pregabalin and gabapentin).^[26][27] Opioid analgesics are recognized as useful agents but are not recommended as first line treatments.^[27] 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 randomized controlled trials is not available for all interventions.^{[citation needed]}

Primary interventions

Anticonvulsants

Pregabalin and gabapentin may reduce pain associated with diabetic neuropathy.^{[28][26][29][30]} 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.^[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 or fibromyalgia in some people.^[26] 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.^[26]

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.^[32]

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.^[27]

Opioids

Opioids, while commonly used in chronic neuropathic pain, are not a recommended first or second line treatment.^[33] 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^[34] In the intermediate term evidence of low quality supports utility.^[34]

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.^[35]

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.^[36] It is unclear if fentanyl gives pain relief to people with neuropathic pain.^[37] 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.^[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 Interventions

Non-pharmaceutical treatments such as exercise, physical therapy and psychotherapy may be useful adjuncts to treatment.^[41]

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.^[42]

Cannabinoids

Evidence for the use of Cannabis based medicines is limited. Any potential utility might be offset by adverse effects.^[43]

Neuromodulators

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 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 (79%), or the periventricular/periaqueductal grey matter plus thalamus and/or internal capsule (87%).^[45] There is a significant complication rate, which increases over time.^[46]

Motor cortex stimulations

Stimulation of the primary motor cortex through electrodes placed within the skull but outside the thick meningeal membrane (dura) 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 (paresthesia) at treatment levels, the only palpable effect is pain relief.^[47][48]

Spinal cord stimulators implated spinal pumps

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 but advancements in the past decade have driven complication rates much lower. Lack of pain relief occasionally prompts device removal.^[49]

NMDA antagonism

The N-methyl-D-aspartate (NMDA) 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.^[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 drug delivery

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 there are complications such as serious infection (meningitis), urinary retention, hormonal disturbance and intrathecal granuloma formation have been noted with intrathecal infusion, associated with the delivery method.

Conotoxins

Ziconotide is a voltage-gated calcium channel blocker which may be used in severe cases of ongoing neuropathic pain^[51] it is delivered intrathecally.

Ambroxol

Ambroxol is a drug that reduces mucus. Preclinical research suggests it may produce analgesic effects by blocking sodium channels in sensory neurons.^[52]

Gene therapy

The use of gene therapy is a potential treatment for chronic neuropathic pain.^[53] In animals a gene therapy for local transgenes encoding for GABA synthesizing-releasing inhibitory machinery has been demonstrated and was effective for months at a time. It increases synaptically GABA-mediated neuronal inhibition in the spinal cord (or in the brain) via the induced expression of genes GAD65 and VGAT without any detected systemic or segmental side effects.^[53]

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.^[54] 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^[55] and topical capsaicin can itself induce pain.^[54]

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 (nutmeg or St John's wort) are useful for treating neuropathic pain.^[56]

Dietary supplements

A 2007 review of studies found that injected (parenteral) administration of alpha lipoic acid (ALA) was found to reduce the various symptoms of peripheral diabetic neuropathy.^[57] 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),^[58] the meta-analysis showed "more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone".^[57] There is some limited evidence that ALA is also helpful in some other non-diabetic neuropathies.^[59]

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.^[60][61]

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.^[62] 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" [nerve originated pain], described its numbness, tingling and needling quality, discussed its etiology and the differentiating characteristics.^[63] The description of neuralgia was made by John 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.^[64]

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 (for instance strokes) to the thalamus^[65] whereas other forms of pain have a peripheral inciting injury such as traumatic neuropathies.^[10] 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.^[66]

Central

Central mechanisms of neuropathic pain involve a number of major pathways. Nociception is ordinarily transduced by a polysynaptic pathway through the spinal cord, and up the spinothalamic tract to the thalamus and then the cortex. Broadly speaking in neuropathic pain, neurons are hypersensitized, glia become activated and there is a loss of inhibitory tone.

Pain gates

 

Gate control theory of pain

A major hypothesis in the theory of pain perception is the gate control theory of pain, proposed by Wall and Melzack in 1965. The theory predicts 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, GAD65/67 expression (the enzymes that synthesise GABA; the predominant inhibitory transmitter in the adult brain), has been observed in some systems following peripheral neuropathy such as in rats, and mice.^[67] 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 the spinothalamic tract thus causing pain in normally painless stimuli. This loss of inhibition may not be limited to the spinal cord and a loss of GABA has also been observed in chronic pain patients in the thalamus.^[68]

Glia

 

Microglia (identified by alpha-coronin1a), and neurons in culture. Microglia are proposed to release molecules that alter the excitability of neurons.

During neuropathic pain, 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, the brain and spinal cord resident immune cells, respond to extrinsic cues. The source of these cues may include neurons secreting chemokines such as CCL21 and surface immobilized chemokines such as CX3CL1. Other glia such as astrocytes and oligodendrocytes may also release these extrinsic cues for microglia and microglia themselves may produce proteins that amplify the response.^[69] The effect of microglia on neurons that leads to the neurons being sensitized is controversial. Brain derived neurotrophic factor, prostaglandins, TNF and IL-1β may be produced by microglia and cause changes in neurons that lead to hyperexcitability.^[70][71]

Central sensitization

Central sensitization is a potential component of neuropathic pain. It refers to a change in synaptic plasticity, efficacy, and intrinsic disinhibition that leads to an uncoupling of noxious inputs. In the sensitized neuron, outputs are no longer coupled to the intensity or duration and many inputs may be combined.^[72]

Circuit Potentiation

During high frequency stimulation synapses conveying nociceptive information may become hyper efficient in a process that is similar although not identical to long-term potentiation.^[73] Molecules such as substance P may be involved in potentiation via neurokinin 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.^[72]

Cellular

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, as well as altered gene expression in response to neural input, are at play.^[74] 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]

See also

• Cranial nerves
• Nerve
• Neuralgia
• Neuritis
• Neuropathy

References

1. DiBonaventura, Marco D.; Sadosky, Alesia; Concialdi, Kristen; Hopps, Markay; Kudel, Ian; Parsons, Bruce; Cappelleri, Joseph C.; Hlavacek, Patrick; Alexander, Andrea H.; Stacey, Brett R.; Markman, John D.; Farrar, John T. (2017). "The prevalence of probable neuropathic pain in the US: results from a multimodal general-population health survey". Journal of Pain Research. 10: 2525–2538. doi:10.2147/JPR.S127014. PMC 5677393. PMID 29138590.
2. . Archived from the original on 13 January 2015. Retrieved 15 Nov 2023.
3. Kaur, Jaskirat; Ghosh, Shampa; Sahani, Asish Kumar; Sinha, Jitendra Kumar (June 2019). "Mental imagery training for treatment of central neuropathic pain: a narrative review". Acta Neurologica Belgica. 119 (2): 175–186. doi:10.1007/s13760-019-01139-x. PMID 30989503. S2CID 115153320.
4. De Courcy, Jonathan; Liedgens, Hiltrud; Obradovic, Marko; Holbrook, Tim; Jakubanis, Rafal (April 2016). "A burden of illness study for neuropathic pain in Europe". ClinicoEconomics and Outcomes Research. 8: 113–126. doi:10.2147/CEOR.S81396. PMC 4853004. PMID 27217785.
5. Torrance N, Smith BH, Bennett MI, Lee AJ (April 2006). "The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey". J Pain. 7 (4): 281–9. doi:10.1016/j.jpain.2005.11.008. PMID 16618472.
6. Bouhassira, Didier; Lantéri-Minet, Michel; Attal, Nadine; Laurent, Bernard; Touboul, Chantal (June 2008). "Prevalence of chronic pain with neuropathic characteristics in the general population" (PDF). Pain. 136 (3): 380–387. doi:10.1016/j.pain.2007.08.013. PMID 17888574. S2CID 599627.
7. Freynhagen, R; Bennett, M I (12 August 2009). "Diagnosis and management of neuropathic pain". BMJ. 339 (aug12 1): b3002. doi:10.1136/bmj.b3002. PMC 6130809. PMID 19675082.
8. Fabry, Vincent; Gerdelat, Angélique; Acket, Blandine; Cintas, Pascal; Rousseau, Vanessa; Uro-Coste, Emmanuelle; Evrard, Solène M.; Pavy-Le Traon, Anne (5 May 2020). "Which Method for Diagnosing Small Fiber Neuropathy?". Frontiers in Neurology. 11: 342. doi:10.3389/fneur.2020.00342. PMC 7214721. PMID 32431663.
9. Porubcin, Michal G.; Novak, Peter (17 April 2020). "Diagnostic Accuracy of Electrochemical Skin Conductance in the Detection of Sudomotor Fiber Loss". Frontiers in Neurology. 11: 273. doi:10.3389/fneur.2020.00273. PMC 7212463. PMID 32425871.
10. Kaur, Jaskirat; Ghosh, Shampa; Sahani, Asish Kumar; Sinha, Jitendra Kumar (November 2020). "Mental Imagery as a Rehabilitative Therapy for Neuropathic Pain in People With Spinal Cord Injury: A Randomized Controlled Trial". Neurorehabilitation and Neural Repair. 34 (11): 1038–1049. doi:10.1177/1545968320962498. PMID 33040678. S2CID 222300017.
11. Baron, Ralf; Binder, Andreas; Wasner, Gunnar (August 2010). "Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment". The Lancet Neurology. 9 (8): 807–819. doi:10.1016/S1474-4422(10)70143-5. PMID 20650402. S2CID 14267074.
12. Portenoy RK (1989). "Painful polyneuropathy". Neurol Clin. 7 (2): 265–88. doi:10.1016/S0733-8619(18)30813-2. PMID 2566901.
13. Vaillancourt PD, Langevin HM (1999). "Painful peripheral neuropathies". Med. Clin. North Am. 83 (3): 627–42, vi. doi:10.1016/S0025-7125(05)70127-9. PMID 10386118.
14. [1] Chemotherapy-induced Peripheral Neuropathy Fact Sheet, Retrieved on 29 December 2008
15. [2] 2009-07-08 at the Wayback Machine Cancerbackup, Macmillan Cancer Support, Peripheral neuropathy, Retrieved on 29 December 2008
16. Hooten, W. Michael (July 2016). "Chronic Pain and Mental Health Disorders". Mayo Clinic Proceedings. 91 (7): 955–970. doi:10.1016/j.mayocp.2016.04.029. PMID 27344405.
17. Bravo, Lidia; Llorca-Torralba, Meritxell; Suárez-Pereira, Irene; Berrocoso, Esther (August 2020). "Pain in neuropsychiatry: Insights from animal models". Neuroscience & Biobehavioral Reviews. 115: 96–115. doi:10.1016/j.neubiorev.2020.04.029. PMID 32437745. S2CID 218580755.
18. Sadosky, Alesia; Schaefer, Caroline; Mann, Rachael; Daniel, Shoshana; Parsons, Bruce; Tuchman, Michael; Anschel, Alan; Stacey, Brett R; Nalamachu, Srinivas; Nieshoff, Edward (October 2014). "Pain severity and the economic burden of neuropathic pain in the United States: BEAT Neuropathic Pain Observational Study". ClinicoEconomics and Outcomes Research. 6: 483–496. doi:10.2147/CEOR.S63323. PMC 4218900. PMID 25378940.
19. Egli, Mark; Koob, George F.; Edwards, Scott (November 2012). "Alcohol dependence as a chronic pain disorder". Neuroscience & Biobehavioral Reviews. 36 (10): 2179–2192. doi:10.1016/j.neubiorev.2012.07.010. PMC 3612891. PMID 22975446.
20. Alford, Daniel P.; German, Jacqueline S.; Samet, Jeffrey H.; Cheng, Debbie M.; Lloyd-Travaglini, Christine A.; Saitz, Richard (May 2016). "Primary Care Patients with Drug Use Report Chronic Pain and Self-Medicate with Alcohol and Other Drugs". Journal of General Internal Medicine. 31 (5): 486–491. doi:10.1007/s11606-016-3586-5. PMC 4835374. PMID 26809204.
21. Dueñas, María; Ojeda, Begoña; Salazar, Alejandro; Mico, Juan Antonio; Failde, Inmaculada (28 June 2016). "A review of chronic pain impact on patients, their social environment and the health care system". Journal of Pain Research. 9: 457–467. doi:10.2147/JPR.S105892. PMC 4935027. PMID 27418853.
22. Petrosky, Emiko; Harpaz, Rafael; Fowler, Katherine A.; Bohm, Michele K.; Helmick, Charles G.; Yuan, Keming; Betz, Carter J. (2 October 2018). "Chronic Pain Among Suicide Decedents, 2003 to 2014: Findings From the National Violent Death Reporting System". Annals of Internal Medicine. 169 (7): 448–455. doi:10.7326/M18-0830. PMC 6913029. PMID 30208405.
23. Bennetto, Luke; Patel, Nikunj K; Fuller, Geraint (27 January 2007). "Trigeminal neuralgia and its management". BMJ. 334 (7586): 201–205. doi:10.1136/bmj.39085.614792.BE. PMC 1782012. PMID 17255614.
24. Staff, Nathan P.; Grisold, Anna; Grisold, Wolfgang; Windebank, Anthony J. (June 2017). "Chemotherapy-induced peripheral neuropathy: A current review: CIPN". Annals of Neurology. 81 (6): 772–781. doi:10.1002/ana.24951. PMC 5656281. PMID 28486769.
25. Dworkin RH, O'Connor AB, Backonja M, et al. (2007). "Pharmacologic management of neuropathic pain: evidence-based recommendations". Pain. 132 (3): 237–51. doi:10.1016/j.pain.2007.08.033. PMID 17920770. S2CID 9333155.
26. Wiffen, PJ; Derry, S; Bell, RF; Rice, AS; Tölle, TR; Phillips, T; Moore, RA (9 June 2017). "Gabapentin for chronic neuropathic pain in adults". The Cochrane Database of Systematic Reviews. 6 (2): CD007938. doi:10.1002/14651858.CD007938.pub4. PMC 6452908. PMID 28597471.
27. Dworkin, RH; O'Connor, AB; Audette, J; Baron, R; Gourlay, GK; Haanpää, ML; Kent, JL; Krane, EJ; Lebel, AA; Levy, RM; Mackey, SC; Mayer, J; Miaskowski, C; Raja, SN; Rice, AS; Schmader, KE; Stacey, B; Stanos, S; Treede, RD; Turk, DC; Walco, GA; Wells, CD (Mar 2010). "Recommendations for the pharmacological management of neuropathic pain: an overview and literature update". Mayo Clinic Proceedings. 85 (3 Suppl): S3-14. doi:10.4065/mcp.2009.0649. PMC 2844007. PMID 20194146.
28. Derry, Sheena; Bell, Rae Frances; Straube, Sebastian; Wiffen, Philip J.; Aldington, Dominic; Moore, R. Andrew (2019-01-23). "Pregabalin for neuropathic pain in adults". The Cochrane Database of Systematic Reviews. 1 (1): CD007076. doi:10.1002/14651858.CD007076.pub3. ISSN 1469-493X. PMC 6353204. PMID 30673120.
29. "Pharmacological treatment for all neuropathic pain except trigeminal neuralgia". NICE Guidance CG173. 2013.
30. "Neuropathic pain in adults: pharmacological management in non-specialist settings | Guidance and guidelines | NICE". www.nice.org.uk. 20 November 2013.
31. Al-Quliti, Khalid W. (April 2015). "Update on neuropathic pain treatment for trigeminal neuralgia: The pharmacological and surgical options". Neurosciences. 20 (2): 107–114. doi:10.17712/nsj.2015.2.20140501. PMC 4727618. PMID 25864062.
32. Wiffen, Philip J; Derry, Sheena; Moore, R Andrew (2013). "Lamotrigine for chronic neuropathic pain and fibromyalgia in adults". Cochrane Database of Systematic Reviews. 2019 (5): CD006044. doi:10.1002/14651858.CD006044.pub4. PMC 6485508. PMID 24297457.
33. Dowell, D; Haegerich, TM; Chou, R (18 March 2016). "CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016". MMWR. Recommendations and Reports. 65 (1): 1–49. doi:10.15585/mmwr.rr6501e1. PMC 6390846. PMID 26987082. Several guidelines agree that first- and second-line drugs for neuropathic pain include anticonvulsants (gabapentin or pregabalin), tricyclic antidepressants, and SNRIs
34. McNicol, ED; Midbari, A; Eisenberg, E (29 August 2013). "Opioids for neuropathic pain". The Cochrane Database of Systematic Reviews. 2019 (8): CD006146. doi:10.1002/14651858.CD006146.pub2. PMC 6353125. PMID 23986501.
35. Davis AM, Inturrisi CE (1999). "d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia". J. Pharmacol. Exp. Ther. 289 (2): 1048–53. PMID 10215686.
36. Bruera E, Palmer JL, Bosnjak S, et al. (2004). "Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study". J. Clin. Oncol. 22 (1): 185–92. doi:10.1200/JCO.2004.03.172. PMID 14701781.
37. Derry, Sheena; Stannard, Cathy; Cole, Peter; Wiffen, Philip J.; Knaggs, Roger; Aldington, Dominic; Moore, R. Andrew (2016-10-11). "Fentanyl for neuropathic pain in adults". The Cochrane Database of Systematic Reviews. 10 (5): CD011605. doi:10.1002/14651858.CD011605.pub2. PMC 6457928. PMID 27727431.
38. Volkow, Nora D.; McLellan, A. Thomas (31 March 2016). "Opioid Abuse in Chronic Pain — Misconceptions and Mitigation Strategies". New England Journal of Medicine. 374 (13): 1253–1263. doi:10.1056/NEJMra1507771. PMID 27028915.
39. Nicholas, Michael K.; Asghari, Ali; Sharpe, Louise; Beeston, Lee; Brooker, Charles; Glare, Paul; Martin, Rebecca; Molloy, Allan; Wrigley, Paul J. (March 2020). "Reducing the use of opioids by patients with chronic pain: an effectiveness study with long-term follow-up". Pain. 161 (3): 509–519. doi:10.1097/j.pain.0000000000001763. PMID 31764391. S2CID 208276026.
40. McPherson, Sterling; Lederhos Smith, Crystal; Dobscha, Steven K.; Morasco, Benjamin J.; Demidenko, Michael I.; Meath, Thomas H.A.; Lovejoy, Travis I. (October 2018). "Changes in pain intensity after discontinuation of long-term opioid therapy for chronic noncancer pain". Pain. 159 (10): 2097–2104. doi:10.1097/j.pain.0000000000001315. PMC 6993952. PMID 29905648.
41. Colloca, Luana; Ludman, Taylor; Bouhassira, Didier; Baron, Ralf; Dickenson, Anthony H.; Yarnitsky, David; Freeman, Roy; Truini, Andrea; Attal, Nadine; Finnerup, Nanna B.; Eccleston, Christopher; Kalso, Eija; Bennett, David L.; Dworkin, Robert H.; Raja, Srinivasa N. (21 December 2017). "Neuropathic pain". Nature Reviews Disease Primers. 3 (1): 17002. doi:10.1038/nrdp.2017.2. PMC 5371025. PMID 28205574.
42. Mittal, SO; Safarpour, D; Jabbari, B (February 2016). "Botulinum Toxin Treatment of Neuropathic Pain". Seminars in Neurology. 36 (1): 73–83. doi:10.1055/s-0036-1571953. PMID 26866499. S2CID 41120474.
43. Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W (March 2018). "Cannabis-based medicines for chronic neuropathic pain in adults". Cochrane Database Syst Rev (Systematic review). 3 (7): CD012182. doi:10.1002/14651858.CD012182.pub2. PMC 6494210. PMID 29513392.
44. Krames ES (2006). "Neuromodulatory devices are part of our "Tools of the Trade"". Pain Med. 7: S3–5. doi:10.1111/j.1526-4637.2006.00116.x.
45. Bittar, Richard G.; Kar-Purkayastha, Ishani; Owen, Sarah L.; Bear, Renee E.; Green, Alex; Wang, ShouYan; Aziz, Tipu Z. (June 2005). "Deep brain stimulation for pain relief: A meta-analysis". Journal of Clinical Neuroscience. 12 (5): 515–519. doi:10.1016/j.jocn.2004.10.005. PMID 15993077. S2CID 24246117.
46. Oh MY, Abosch A, Kim SH, Lang AE, Lozano AM (2002). "Long-term hardware-related complications of deep brain stimulation". Neurosurgery. 50 (6): 1268–74, discussion 1274–6. doi:10.1097/00006123-200206000-00017. PMID 12015845. S2CID 36904630.
47. Brown JA, Pilitsis JG. Motor Cortex Stimulation Pain Medicine 2006; 7:S140.
48. Osenbach, R. Neurostimulation for the Treatment of Intractable Facial Pain Pain Medicine 2006; 7:S126
49. Turner JA, Loeser JD, Deyo RA, Sanders SB (2004). "Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications". Pain. 108 (1–2): 137–47. doi:10.1016/j.pain.2003.12.016. PMID 15109517. S2CID 16722691.
50. Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB (1997). "High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia". Neurology. 48 (5): 1212–8. doi:10.1212/WNL.48.5.1212. PMID 9153445. S2CID 25663595.
51. Lynch SS, Cheng CM, Yee JL (2006). "Intrathecal ziconotide for refractory chronic pain". Ann Pharmacother. 40 (7–8): 1293–300. doi:10.1345/aph.1G584. PMID 16849624. S2CID 1159955.
52. Russo, Marc A.; Baron, Ralf; Dickenson, Anthony H.; Kern, Kai-Uwe; Santarelli, Danielle M. (17 May 2022). "Ambroxol for neuropathic pain: hiding in plain sight?". Pain. 164 (1): 3–13. doi:10.1097/j.pain.0000000000002693. PMID 35580314. S2CID 248858603.
53. Tadokoro, Takahiro; Bravo-Hernandez, Mariana; Agashkov, Kirill; Kobayashi, Yoshiomi; et al. (May 2022). "Precision spinal gene delivery-induced functional switch in nociceptive neurons reverses neuropathic pain". Molecular Therapy. 30 (8): 2722–2745. doi:10.1016/j.ymthe.2022.04.023. PMC 9372322. PMID 35524407. S2CID 248553626.
54. Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR (1999). "Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation". Pain. 81 (1–2): 135–45. doi:10.1016/S0304-3959(99)00007-X. PMID 10353501. S2CID 8952555.
55. Derry, Sheena; Moore, R Andrew (12 September 2012). "Topical capsaicin (low concentration) for chronic neuropathic pain in adults". Cochrane Database of Systematic Reviews. 2019 (9): CD010111. doi:10.1002/14651858.CD010111. PMC 6540838. PMID 22972149.
56. Boyd A, Bleakley C, Hurley DA, Gill C, Hannon-Fletcher M, Bell P, McDonough S (April 2019). "Herbal medicinal products or preparations for neuropathic pain". Cochrane Database Syst Rev (Systematic review). 4 (5): CD010528. doi:10.1002/14651858.CD010528.pub4. PMC 6445324. PMID 30938843.
57. Foster TS (2007). "Efficacy and safety of alpha-lipoic acid supplementation in the treatment of symptomatic diabetic neuropathy". Diabetes Educ. 33 (1): 111–7. doi:10.1177/0145721706297450. PMID 17272797. S2CID 22801230. 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.
58. Ziegler D, Ametov A, Barinov A, et al. (2006). "Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial". Diabetes Care. 29 (11): 2365–70. doi:10.2337/dc06-1216. PMID 17065669.
59. Patton LL, Siegel MA, Benoliel R, De Laat A (2007). "Management of burning mouth syndrome: systematic review and management recommendations". Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 103 Suppl: S39.e1–13. doi:10.1016/j.tripleo.2006.11.009. PMID 17379153.
60. Stracke H, Lindemann A, Federlin K (1996). "A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy". Exp. Clin. Endocrinol. Diabetes. 104 (4): 311–6. doi:10.1055/s-0029-1211460. PMID 8886748.
61. Thornalley PJ (2005). "The potential role of thiamine (vitamin B(1)) in diabetic complications". Curr Diabetes Rev. 1 (3): 287–98. doi:10.2174/157339905774574383. PMID 18220605.
62. Freemon, Frank R. (1994). "Galen's ideas on neurological function". J Hist Neurosci. 3 (4): 263–71. doi:10.1080/09647049409525619. PMID 11618827.
63. Heydari, Mojtaba; Shams, Mesbah; Hashempur, Mohammad Hashem; Zargaran, Arman; Dalfardi, Behnam; Borhani-Haghighi, Afshin (2015). "The origin of the concept of neuropathic pain in Early Medieval Persia (9th–12th century CE)". Acta medico-historica Adriatica. 13 (Suppl 2): 9–22. PMID 26966748. S2CID 30398883.
64. Scadding, JW (March 2004). "Treatment of neuropathic pain: historical aspects". Pain Medicine. 5 (Suppl 1): S3-8. doi:10.1111/j.1526-4637.2004.04018.x. PMID 14996226.
65. Gritsch, Simon; Bali, Kiran Kumar; Kuner, Rohini; Vardeh, Daniel (January 2016). "Functional characterization of a mouse model for central post-stroke pain". Molecular Pain. 12: 174480691662904. doi:10.1177/1744806916629049. PMC 4956143. PMID 27030713.
66. Costigan, Michael; Scholz, Joachim; Woolf, Clifford J. (1 June 2009). "Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage". Annual Review of Neuroscience. 32 (1): 1–32. doi:10.1146/annurev.neuro.051508.135531. PMC 2768555. PMID 19400724.
67. Manion, John; Waller, Matthew A.; Clark, Teleri; Massingham, Joshua N.; Neely, G. Gregory (20 December 2019). "Developing Modern Pain Therapies". Frontiers in Neuroscience. 13: 1370. doi:10.3389/fnins.2019.01370. PMC 6933609. PMID 31920521.
68. Henderson, L. A.; Peck, C. C.; Petersen, E. T.; Rae, C. D.; Youssef, A. M.; Reeves, J. M.; Wilcox, S. L.; Akhter, R.; Murray, G. M.; Gustin, S. M. (24 April 2013). "Chronic Pain: Lost Inhibition?". Journal of Neuroscience. 33 (17): 7574–7582. doi:10.1523/JNEUROSCI.0174-13.2013. PMC 6619566. PMID 23616562.
69. Ji, Ru-Rong; Donnelly, Christopher R.; Nedergaard, Maiken (November 2019). "Astrocytes in chronic pain and itch". Nature Reviews Neuroscience. 20 (11): 667–685. doi:10.1038/s41583-019-0218-1. PMC 6874831. PMID 31537912.
70. Ji, Ru-Rong; Chamessian, Alexander; Zhang, Yu-Qiu (4 November 2016). "Pain regulation by non-neuronal cells and inflammation". Science. 354 (6312): 572–577. Bibcode:2016Sci...354..572J. doi:10.1126/science.aaf8924. PMC 5488328. PMID 27811267.
71. Siniscalco, Dario; Giordano, Catia; Rossi, Francesco; Maione, Sabatino; de Novellis, Vito (1 December 2011). "Role of Neurotrophins in Neuropathic Pain". Current Neuropharmacology. 9 (4): 523–529. doi:10.2174/157015911798376208. PMC 3263449. PMID 22654713.
72. Latremoliere, Alban; Woolf, Clifford J. (September 2009). "Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity". The Journal of Pain. 10 (9): 895–926. doi:10.1016/j.jpain.2009.06.012. PMC 2750819. PMID 19712899.
73. Ji, Ru-Rong; Kohno, Tatsuro; Moore, Kimberly A; Woolf, Clifford J (December 2003). "Central sensitization and LTP: do pain and memory share similar mechanisms?". Trends in Neurosciences. 26 (12): 696–705. doi:10.1016/j.tins.2003.09.017. PMID 14624855. S2CID 14214986.
74. Truini A, Cruccu G (May 2006). "Pathophysiological mechanisms of neuropathic pain". Neurol. Sci. 27 (Suppl 2): S179–82. doi:10.1007/s10072-006-0597-8. PMID 16688626. S2CID 28736907.

External links

• Centre for Clinical Practice at NICE (UK) (March 2010). "The Pharmacological Management of Neuropathic Pain in Adults in Non-Specialist Settings". NICE Clinical Guidelines. 96. London: National Institute for Health and Clinical Excellence (UK).