neuropathic pain#Peripheral

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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.{{cite journal |last1=Freynhagen |first1=R |last2=Bennett |first2=M I |title=Diagnosis and management of neuropathic pain |journal=BMJ |date=12 August 2009 |volume=339 |issue=aug12 1 |pages=b3002 |doi=10.1136/bmj.b3002 |pmid=19675082 |pmc=6130809 }}

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.{{cite journal |last1=Fabry |first1=Vincent |last2=Gerdelat |first2=Angélique |last3=Acket |first3=Blandine |last4=Cintas |first4=Pascal |last5=Rousseau |first5=Vanessa |last6=Uro-Coste |first6=Emmanuelle |last7=Evrard |first7=Solène M. |last8=Pavy-Le Traon |first8=Anne |title=Which Method for Diagnosing Small Fiber Neuropathy? |journal=Frontiers in Neurology |date=5 May 2020 |volume=11 |page=342 |doi=10.3389/fneur.2020.00342 |pmid=32431663 |pmc=7214721 |doi-access=free }}{{cite journal |last1=Porubcin |first1=Michal G. |last2=Novak |first2=Peter |title=Diagnostic Accuracy of Electrochemical Skin Conductance in the Detection of Sudomotor Fiber Loss |journal=Frontiers in Neurology |date=17 April 2020 |volume=11 |page=273 |doi=10.3389/fneur.2020.00273 |pmid=32425871 |pmc=7212463 |doi-access=free }}

Neuropathic pain may be divided into peripheral, central or mixed (peripheral and central) types. Central neuropathic pain is found in spinal cord injury{{cite journal |last1=Kaur |first1=Jaskirat |last2=Ghosh |first2=Shampa |last3=Sahani |first3=Asish Kumar |last4=Sinha |first4=Jitendra Kumar |title=Mental Imagery as a Rehabilitative Therapy for Neuropathic Pain in People With Spinal Cord Injury: A Randomized Controlled Trial |journal=Neurorehabilitation and Neural Repair |date=November 2020 |volume=34 |issue=11 |pages=1038–1049 |doi=10.1177/1545968320962498 |pmid=33040678 |s2cid=222300017 }} and multiple sclerosis.{{cite journal |last1=Baron |first1=Ralf |last2=Binder |first2=Andreas |last3=Wasner |first3=Gunnar |title=Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment |journal=The Lancet Neurology |date=August 2010 |volume=9 |issue=8 |pages=807–819 |doi=10.1016/S1474-4422(10)70143-5 |pmid=20650402 |s2cid=14267074 }} 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.{{cite journal|author=Portenoy RK|year=1989|title=Painful polyneuropathy|journal=Neurol Clin|volume=7|issue=2|pages=265–88|doi=10.1016/S0733-8619(18)30813-2|pmid=2566901}}{{cite journal|vauthors=Vaillancourt PD, Langevin HM|year=1999|title=Painful peripheral neuropathies|journal=Med. Clin. North Am.|volume=83|issue=3|pages=627–42, vi|doi=10.1016/S0025-7125(05)70127-9|pmid=10386118}} 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),[http://www.cancersupportivecare.com/nervepain.php] Chemotherapy-induced Peripheral Neuropathy Fact Sheet, Retrieved on 29 December 2008[http://www.cancerbackup.org.uk/resourcessupport/symptomssideeffects/othersymptomssideeffects/peripheralneuropathy] {{Webarchive|url=https://web.archive.org/web/20090708053203/http://www.cancerbackup.org.uk/resourcessupport/symptomssideeffects/othersymptomssideeffects/peripheralneuropathy|date=2009-07-08}} Cancerbackup, Macmillan Cancer Support, Peripheral neuropathy, Retrieved on 29 December 2008 radiation injury or surgery.

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.{{cite journal |last1=Hooten |first1=W. Michael |title=Chronic Pain and Mental Health Disorders |journal=Mayo Clinic Proceedings |date=July 2016 |volume=91 |issue=7 |pages=955–970 |doi=10.1016/j.mayocp.2016.04.029 |pmid=27344405 |doi-access=free }}{{cite journal |last1=Bravo |first1=Lidia |last2=Llorca-Torralba |first2=Meritxell |last3=Suárez-Pereira |first3=Irene |last4=Berrocoso |first4=Esther |title=Pain in neuropsychiatry: Insights from animal models |journal=Neuroscience & Biobehavioral Reviews |date=August 2020 |volume=115 |pages=96–115 |doi=10.1016/j.neubiorev.2020.04.029 |pmid=32437745 |s2cid=218580755 }} 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,{{cite journal |last1=Sadosky |first1=Alesia |last2=Schaefer |first2=Caroline |last3=Mann |first3=Rachael |last4=Daniel |first4=Shoshana |last5=Parsons |first5=Bruce |last6=Tuchman |first6=Michael |last7=Anschel |first7=Alan |last8=Stacey |first8=Brett R |last9=Nalamachu |first9=Srinivas |last10=Nieshoff |first10=Edward |title=Pain severity and the economic burden of neuropathic pain in the United States: BEAT Neuropathic Pain Observational Study |journal=ClinicoEconomics and Outcomes Research |date=October 2014 |volume=6 |pages=483–496 |doi=10.2147/CEOR.S63323 |pmid=25378940 |pmc=4218900 |doi-access=free }} exhibit higher levels of substance misuse (which may be related to attempted self-medication),{{cite journal |last1=Egli |first1=Mark |last2=Koob |first2=George F. |last3=Edwards |first3=Scott |title=Alcohol dependence as a chronic pain disorder |journal=Neuroscience & Biobehavioral Reviews |date=November 2012 |volume=36 |issue=10 |pages=2179–2192 |doi=10.1016/j.neubiorev.2012.07.010 |pmid=22975446 |pmc=3612891 }}{{cite journal |last1=Alford |first1=Daniel P. |last2=German |first2=Jacqueline S. |last3=Samet |first3=Jeffrey H. |last4=Cheng |first4=Debbie M. |last5=Lloyd-Travaglini |first5=Christine A. |last6=Saitz |first6=Richard |title=Primary Care Patients with Drug Use Report Chronic Pain and Self-Medicate with Alcohol and Other Drugs |journal=Journal of General Internal Medicine |date=May 2016 |volume=31 |issue=5 |pages=486–491 |doi=10.1007/s11606-016-3586-5 |pmid=26809204 |pmc=4835374 }} and present difficulties with social interactions.{{cite journal |last1=Dueñas |first1=María |last2=Ojeda |first2=Begoña |last3=Salazar |first3=Alejandro |last4=Mico |first4=Juan Antonio |last5=Failde |first5=Inmaculada |title=A review of chronic pain impact on patients, their social environment and the health care system |journal=Journal of Pain Research |date=28 June 2016 |volume=9 |pages=457–467 |doi=10.2147/JPR.S105892 |pmid=27418853 |pmc=4935027 |doi-access=free }} Moreover, uncontrolled neuropathic pain is a significant risk factor for suicide.{{cite journal |last1=Petrosky |first1=Emiko |last2=Harpaz |first2=Rafael |last3=Fowler |first3=Katherine A. |last4=Bohm |first4=Michele K. |last5=Helmick |first5=Charles G. |last6=Yuan |first6=Keming |last7=Betz |first7=Carter J. |title=Chronic Pain Among Suicide Decedents, 2003 to 2014: Findings From the National Violent Death Reporting System |journal=Annals of Internal Medicine |date=2 October 2018 |volume=169 |issue=7 |pages=448–455 |doi=10.7326/M18-0830 |pmid=30208405 |pmc=6913029 }} 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.{{cite journal |last1=Bennetto |first1=Luke |last2=Patel |first2=Nikunj K |last3=Fuller |first3=Geraint |title=Trigeminal neuralgia and its management |journal=BMJ |date=27 January 2007 |volume=334 |issue=7586 |pages=201–205 |doi=10.1136/bmj.39085.614792.BE |pmid=17255614 |pmc=1782012 }} As neuropathic pain may be comorbid with cancer, it can have important dose limiting effects on certain classes of chemotherapeutic.{{cite journal |last1=Staff |first1=Nathan P. |last2=Grisold |first2=Anna |last3=Grisold |first3=Wolfgang |last4=Windebank |first4=Anthony J. |title=Chemotherapy-induced peripheral neuropathy: A current review: CIPN |journal=Annals of Neurology |date=June 2017 |volume=81 |issue=6 |pages=772–781 |doi=10.1002/ana.24951 |pmid=28486769 |pmc=5656281 }}

Neuropathic pain can be very difficult to treat, with only some 40–60% of people achieving partial relief.{{cite journal|vauthors=Dworkin RH, O'Connor AB, Backonja M, etal|year=2007|title=Pharmacologic management of neuropathic pain: evidence-based recommendations|journal=Pain|volume=132|issue=3|pages=237–51|doi=10.1016/j.pain.2007.08.033|pmid=17920770|s2cid=9333155}}

First-line treatments include certain antidepressants (tricyclic antidepressants and serotonin–norepinephrine reuptake inhibitors) and anticonvulsants (pregabalin and gabapentin).{{cite journal|last1=Dworkin|first1=RH|last2=O'Connor|first2=AB|last3=Audette|first3=J|last4=Baron|first4=R|last5=Gourlay|first5=GK|last6=Haanpää|first6=ML|last7=Kent|first7=JL|last8=Krane|first8=EJ|last9=Lebel|first9=AA|last10=Levy|first10=RM|last11=Mackey|first11=SC|date=Mar 2010|title=Recommendations for the pharmacological management of neuropathic pain: an overview and literature update.|journal=Mayo Clinic Proceedings|volume=85|issue=3 Suppl|pages=S3-14|doi=10.4065/mcp.2009.0649|pmc=2844007|pmid=20194146|last16=Schmader|last22=Wells|last12=Mayer|first12=J|last13=Miaskowski|first13=C|first14=SN|last15=Rice|first15=AS|first22=CD|first21=GA|first16=KE|last21=Walco|first20=DC|last20=Turk|first19=RD|last19=Treede|first18=S|last18=Stanos|first17=B|last17=Stacey|last14=Raja}} Opioid analgesics are recognized as useful in some cases but 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 randomized controlled trials is not universal for all interventions.{{citation needed|date= December 2020}}

Pregabalin and gabapentin may reduce pain associated with diabetic neuropathy.{{Cite journal |last1=Derry |first1=Sheena |last2=Bell |first2=Rae Frances |last3=Straube |first3=Sebastian |last4=Wiffen |first4=Philip J. |last5=Aldington |first5=Dominic |last6=Moore |first6=R. Andrew |date=2019-01-23 |title=Pregabalin for neuropathic pain in adults |journal=The Cochrane Database of Systematic Reviews |volume=1 |issue=1 |pages=CD007076 |doi=10.1002/14651858.CD007076.pub3 |issn=1469-493X |pmc=6353204 |pmid=30673120}}{{cite web|title=Pharmacological treatment for all neuropathic pain except trigeminal neuralgia|url=https://pathways.nice.org.uk/pathways/neuropathic-pain#content=view-node%3Anodes-pharmacological-treatment-for-all-neuropathic-pain-except-trigeminal-neuralgia|date=2013|website=NICE Guidance CG173}}{{cite web|title=Neuropathic pain in adults: pharmacological management in non-specialist settings {{!}} Guidance and guidelines {{!}} NICE|url=https://www.nice.org.uk/guidance/cg173|website=www.nice.org.uk|date=20 November 2013 }} 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 depolarization.{{cite journal |last1=Al-Quliti |first1=Khalid W. |title=Update on neuropathic pain treatment for trigeminal neuralgia: The pharmacological and surgical options |journal=Neurosciences |date=April 2015 |volume=20 |issue=2 |pages=107–114 |doi=10.17712/nsj.2015.2.20140501 |pmid=25864062 |pmc=4727618 }} 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.{{cite journal|last1=Wiffen|first1=PJ|last2=Derry|first2=S|last3=Bell|first3=RF|last4=Rice|first4=AS|last5=Tölle|first5=TR|last6=Phillips|first6=T|last7=Moore|first7=RA|date=9 June 2017|title=Gabapentin for chronic neuropathic pain in adults.|journal=The Cochrane Database of Systematic Reviews|volume=6|issue=2|pages=CD007938|doi=10.1002/14651858.CD007938.pub4|pmc=6452908|pmid=28597471}} There is no test to predict the effectiveness of gabapentin 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.

A meta-analysis of randomized clinical trials suggests that lamotrigine is not useful for most patients, although it may have been used in the treatment of refractory cases.{{cite journal |last1=Wiffen |first1=Philip J |last2=Derry |first2=Sheena |last3=Moore |first3=R Andrew |title=Lamotrigine for chronic neuropathic pain and fibromyalgia in adults |journal=Cochrane Database of Systematic Reviews |year=2013 |volume=2019 |issue=5 |pages=CD006044 |doi=10.1002/14651858.CD006044.pub4 |pmid=24297457 |pmc=6485508 }}

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, while commonly used in chronic neuropathic pain, are not recommended as first- or second-line treatment.{{cite journal|last1=Dowell|first1=D|last2=Haegerich|first2=TM|last3=Chou|first3=R|date=18 March 2016|title=CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016.|journal=MMWR. Recommendations and Reports|volume=65|issue=1|pages=1–49|doi=10.15585/mmwr.rr6501e1|pmid=26987082|quote=Several guidelines agree that first- and second-line drugs for neuropathic pain include anticonvulsants (gabapentin or pregabalin), tricyclic antidepressants, and SNRIs|doi-access=free|pmc=6390846}} In the short and long term they are of unclear benefit. However, clinical experience suggests that opioids like tramadol may be useful for treating sudden-onset severe pain.{{cite journal|last1=McNicol|first1=ED|last2=Midbari|first2=A|last3=Eisenberg|first3=E|date=29 August 2013|title=Opioids for neuropathic pain.|journal=The Cochrane Database of Systematic Reviews|volume=2019 |issue=8|pages=CD006146|doi=10.1002/14651858.CD006146.pub2|pmc=6353125|pmid=23986501}} In the intermediate term, low-quality evidence 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 an analgesic in experimental models of chronic pain.{{cite journal|vauthors=Davis AM, Inturrisi CE|year=1999|title=d-Methadone blocks morphine tolerance and N-methyl-D-aspartate-induced hyperalgesia|url=http://jpet.aspetjournals.org/cgi/content/full/289/2/1048|journal=J. Pharmacol. Exp. Ther.|volume=289|issue=2|pages=1048–53|pmid=10215686}}

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.{{cite journal|vauthors=Bruera E, Palmer JL, Bosnjak S, et al. |year=2004|title=Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study|journal=J. Clin. Oncol.|volume=22|issue=1|pages=185–92|doi=10.1200/JCO.2004.03.172|pmid=14701781|doi-access=free}} It is unclear if fentanyl gives pain relief to people with neuropathic pain.{{Cite journal|last1=Derry|first1=Sheena|last2=Stannard|first2=Cathy|last3=Cole|first3=Peter|last4=Wiffen|first4=Philip J.|last5=Knaggs|first5=Roger|last6=Aldington|first6=Dominic|last7=Moore|first7=R. Andrew|date=2016-10-11|title=Fentanyl for neuropathic pain in adults|journal=The Cochrane Database of Systematic Reviews|volume=10|issue=5 |pages=CD011605|doi=10.1002/14651858.CD011605.pub2|pmc=6457928|pmid=27727431}} 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.{{cite journal |last1=Volkow |first1=Nora D. |last2=McLellan |first2=A. Thomas |title=Opioid Abuse in Chronic Pain — Misconceptions and Mitigation Strategies |journal=New England Journal of Medicine |date=31 March 2016 |volume=374 |issue=13 |pages=1253–1263 |doi=10.1056/NEJMra1507771 |pmid=27028915 |doi-access=free }} Importantly, recent observational studies suggest a pain-relief benefit in non-cancer related chronic pain of reducing or terminating long-term opioid therapy.{{cite journal |last1=Nicholas |first1=Michael K. |last2=Asghari |first2=Ali |last3=Sharpe |first3=Louise |last4=Beeston |first4=Lee |last5=Brooker |first5=Charles |last6=Glare |first6=Paul |last7=Martin |first7=Rebecca |last8=Molloy |first8=Allan |last9=Wrigley |first9=Paul J. |title=Reducing the use of opioids by patients with chronic pain: an effectiveness study with long-term follow-up |journal=Pain |date=March 2020 |volume=161 |issue=3 |pages=509–519 |doi=10.1097/j.pain.0000000000001763 |pmid=31764391 |s2cid=208276026 }}{{cite journal |last1=McPherson |first1=Sterling |last2=Lederhos Smith |first2=Crystal |last3=Dobscha |first3=Steven K. |last4=Morasco |first4=Benjamin J. |last5=Demidenko |first5=Michael I. |last6=Meath |first6=Thomas H.A. |last7=Lovejoy |first7=Travis I. |title=Changes in pain intensity after discontinuation of long-term opioid therapy for chronic noncancer pain |journal=Pain |date=October 2018 |volume=159 |issue=10 |pages=2097–2104 |doi=10.1097/j.pain.0000000000001315 |pmid=29905648 |pmc=6993952 }}

Non-pharmaceutical treatments such as exercise, physical therapy, and psychotherapy may be useful adjuncts to treatment.{{cite journal |last1=Colloca |first1=Luana |last2=Ludman |first2=Taylor |last3=Bouhassira |first3=Didier |last4=Baron |first4=Ralf |last5=Dickenson |first5=Anthony H. |last6=Yarnitsky |first6=David |last7=Freeman |first7=Roy |last8=Truini |first8=Andrea |last9=Attal |first9=Nadine |last10=Finnerup |first10=Nanna B. |last11=Eccleston |first11=Christopher |last12=Kalso |first12=Eija |last13=Bennett |first13=David L. |last14=Dworkin |first14=Robert H. |last15=Raja |first15=Srinivasa N. |title=Neuropathic pain |journal=Nature Reviews Disease Primers |date=21 December 2017 |volume=3 |issue=1 |page=17002 |doi=10.1038/nrdp.2017.2 |pmid=28205574 |pmc=5371025 }}

Local intradermal injection of botulinum toxin type A may be helpful in chronic focal painful neuropathies. However, it causes muscle paralysis, which may impact quality of life.{{cite journal|last1=Mittal|first1=SO|last2=Safarpour|first2=D|last3=Jabbari|first3=B|date=February 2016|title=Botulinum Toxin Treatment of Neuropathic Pain|journal=Seminars in Neurology|volume=36|issue=1|pages=73–83|doi=10.1055/s-0036-1571953|pmid=26866499|s2cid=41120474 }}

Evidence for the use of cannabis based medicines is limited. Any potential utility might be offset by adverse effects.{{cite journal|vauthors=Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W|date=March 2018|title=Cannabis-based medicines for chronic neuropathic pain in adults|journal=Cochrane Database Syst Rev|type=Systematic review|volume=3|issue=7|pages=CD012182|doi=10.1002/14651858.CD012182.pub2|pmc=6494210|pmid=29513392}}

Neuromodulation is a field of science, medicine, and bioengineering that encompasses both implantable and non-implantable technologies (electrical and chemical) for treatment purposes.{{cite journal|author=Krames ES|year=2006|title=Neuromodulatory devices are part of our "Tools of the Trade"|journal=Pain Med|volume=7|pages=S3–5|doi=10.1111/j.1526-4637.2006.00116.x|doi-access=free}} Implanted devices are expensive and carry the risk of complications. Available studies{{citation needed|date=April 2025}} have focused on conditions having different prevalences than neuropathic pain patients, in general. More research is needed to define the range of conditions that they might benefit.

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%).{{cite journal |last1=Bittar |first1=Richard G. |last2=Kar-Purkayastha |first2=Ishani |last3=Owen |first3=Sarah L. |last4=Bear |first4=Renee E. |last5=Green |first5=Alex |last6=Wang |first6=ShouYan |last7=Aziz |first7=Tipu Z. |title=Deep brain stimulation for pain relief: A meta-analysis |journal=Journal of Clinical Neuroscience |date=June 2005 |volume=12 |issue=5 |pages=515–519 |doi=10.1016/j.jocn.2004.10.005 |pmid=15993077 |s2cid=24246117 }} There is a significant complication rate, which increases over time.{{cite journal|vauthors=Oh MY, Abosch A, Kim SH, Lang AE, Lozano AM|year=2002|title=Long-term hardware-related complications of deep brain stimulation|journal=Neurosurgery|volume=50|issue=6|pages=1268–74; discussion 1274–6|doi=10.1097/00006123-200206000-00017|pmid=12015845|s2cid=36904630}}

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.Brown JA, Pilitsis JG. Motor Cortex Stimulation

Pain Medicine 2006; 7:S140.

Osenbach, R. Neurostimulation for the Treatment of Intractable Facial Pain

Pain Medicine 2006; 7:S126

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.{{cite journal|vauthors=Turner JA, Loeser JD, Deyo RA, Sanders SB|year=2004|title=Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications|journal=Pain|volume=108|issue=1–2|pages=137–47|doi=10.1016/j.pain.2003.12.016|pmid=15109517|s2cid=16722691}}

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.{{cite journal|vauthors=Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB|year=1997|title=High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia|journal=Neurology|volume=48|issue=5|pages=1212–8|doi=10.1212/WNL.48.5.1212|pmid=9153445|s2cid=25663595}} 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 drug carbamazepine have been developed to control its pharmacological activity locally and on-demand using light, with the purpose of reducing adverse systemic effects.{{Cite journal |last=Camerin |first=Luisa |last2=Maleeva |first2=Galyna |last3=Gomila-Juaneda |first3=Alexandre |last4=Suárez-Pereira |first4=Irene |last5=Matera |first5=Carlo |last6=Prischich |first6=Davia |last7=Opar |first7=Ekin |last8=Riefolo |first8=Fabio |last9=Berrocoso |first9=Esther |last10=Gorostiza |first10=Pau |date=2024-06-18 |title=Photoswitchable carbamazepine analogs for non‐invasive neuroinhibition in vivo |url=https://onlinelibrary.wiley.com/doi/10.1002/anie.202403636 |journal=Angewandte Chemie International Edition |language=en |doi=10.1002/anie.202403636 |issn=1433-7851|doi-access=free |hdl=2445/215169 |hdl-access=free }} One of these compounds (carbadiazocine, based on a bridged azobenzene) 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{{cite journal|vauthors=Lynch SS, Cheng CM, Yee JL|year=2006|title=Intrathecal ziconotide for refractory chronic pain|journal=Ann Pharmacother|volume=40|issue=7–8|pages=1293–300|doi=10.1345/aph.1G584|pmid=16849624|s2cid=1159955}} it is delivered intrathecally.

Ambroxol is a drug that reduces mucus. Preclinical research suggests it may produce analgesic effects by blocking sodium channels in sensory neurons.{{cite journal |last1=Russo |first1=Marc A. |last2=Baron |first2=Ralf |last3=Dickenson |first3=Anthony H. |last4=Kern |first4=Kai-Uwe |last5=Santarelli |first5=Danielle M. |title=Ambroxol for neuropathic pain: hiding in plain sight? |journal=Pain |date=17 May 2022 |volume=164 |issue=1 |pages=3–13 |doi=10.1097/j.pain.0000000000002693 |pmid=35580314 |s2cid=248858603 }}

The use of gene therapy is a potential treatment for chronic neuropathic pain. In animals, a gene therapy for local transgenes encoding for GABA 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.{{cite journal |last1=Tadokoro |first1=Takahiro |last2=Bravo-Hernandez |first2=Mariana |last3=Agashkov |first3=Kirill |last4=Kobayashi |first4=Yoshiomi |display-authors=et al. |title=Precision spinal gene delivery-induced functional switch in nociceptive neurons reverses neuropathic pain |journal=Molecular Therapy |date=May 2022 |volume=30 |issue=8 |pages=2722–2745 |doi=10.1016/j.ymthe.2022.04.023|pmid=35524407 |pmc=9372322 |s2cid=248553626 }}

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.{{cite journal|vauthors=Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR|year=1999|title=Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation|journal=Pain|volume=81|issue=1–2|pages=135–45|doi=10.1016/S0304-3959(99)00007-X|pmid=10353501|s2cid=8952555}} 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{{cite journal |last1=Derry |first1=Sheena |last2=Moore |first2=R Andrew |title=Topical capsaicin (low concentration) for chronic neuropathic pain in adults |journal=Cochrane Database of Systematic Reviews |date=12 September 2012 |volume=2019 |issue=9 |pages=CD010111 |doi=10.1002/14651858.CD010111 |pmid=22972149 |pmc=6540838 }} and topical capsaicin can itself induce pain.

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|reason=What interventions is this even referring to?|date=July 2024}}

{{See also|Nerve decompression}}

If neuropathic pain arises as nerve compression syndrome, it may be treatable with a nerve decompression.{{cite journal |vauthors=Lipinski LJ, Spinner RJ |date=October 2014 |title=Neurolysis, neurectomy, and nerve repair/reconstruction for chronic pain |url= |journal=Neurosurg Clin N Am |volume=25 |issue=4 |pages=777–87 |doi=10.1016/j.nec.2014.07.002 |pmid=25240664}}{{cite journal |vauthors=Kay J, de Sa D, Morrison L, Fejtek E, Simunovic N, Martin HD, Ayeni OR |date=December 2017 |title=Surgical Management of Deep Gluteal Syndrome Causing Sciatic Nerve Entrapment: A Systematic Review |url= |journal=Arthroscopy |volume=33 |issue=12 |pages=2263–2278.e1 |doi=10.1016/j.arthro.2017.06.041 |pmid=28866346}}{{cite journal |vauthors=ElHawary H, Barone N, Baradaran A, Janis JE |date=February 2022 |title=Efficacy and Safety of Migraine Surgery: A Systematic Review and Meta-analysis of Outcomes and Complication Rates |url= |journal=Ann Surg |volume=275 |issue=2 |pages=e315–e323 |doi=10.1097/SLA.0000000000005057 |pmid=35007230}}{{cite journal |vauthors=Giulioni C, Pirola GM, Maggi M, Pitoni L, Fuligni D, Beltrami M, Palantrani V, De Stefano V, Maurizi V, Castellani D, Galosi AB |date=March 2024 |title=Pudendal Nerve Neurolysis in Patients Afflicted With Pudendal Nerve Entrapment: A Systematic Review of Surgical Techniques and Their Efficacy |url= |journal=Int Neurourol J |volume=28 |issue=1 |pages=11–21 |doi=10.5213/inj.2448010.005 |pmc=10990758 |pmid=38569616}}{{cite journal |vauthors=Lu VM, Burks SS, Heath RN, Wolde T, Spinner RJ, Levi AD |date=January 2021 |title=Meralgia paresthetica treated by injection, decompression, and neurectomy: a systematic review and meta-analysis of pain and operative outcomes |url= |journal=J Neurosurg |volume=135 |issue=3 |pages=912–922 |doi=10.3171/2020.7.JNS202191 |pmid=33450741}} When nerves are subject to chronic pressure, they exhibit a pathological progression resulting in reversible and partially reversible nerve injuries that cause pain, paresthesias, and potentially muscle weakness.{{cite journal |vauthors=Lundborg G, Dahlin LB |date=May 1996 |title=Anatomy, function, and pathophysiology of peripheral nerves and nerve compression |url= |journal=Hand Clin |volume=12 |issue=2 |pages=185–93 |doi= |pmid=8724572}} In a nerve decompression, a surgeon explores the entrapment site and removes tissue around the nerve to relieve pressure. 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).{{cite journal |vauthors=Mackinnon SE |date=May 2002 |title=Pathophysiology of nerve compression |url= |journal=Hand Clin |volume=18 |issue=2 |pages=231–41 |doi=10.1016/s0749-0712(01)00012-9 |pmid=12371026}} Nerve decompressions are associated with a significant reduction in pain, in some cases the complete elimination of pain.{{cite journal |vauthors=Louie D, Earp B, Blazar P |date=September 2012 |title=Long-term outcomes of carpal tunnel release: a critical review of the literature |url= |journal=Hand (N Y) |volume=7 |issue=3 |pages=242–6 |doi=10.1007/s11552-012-9429-x |pmc=3418353 |pmid=23997725}}

For patients with diabetic neuropathy, which affects 30% of diabetes patients,{{cite journal |vauthors=Sun J, Wang Y, Zhang X, Zhu S, He H |date=October 2020 |title=Prevalence of peripheral neuropathy in patients with diabetes: A systematic review and meta-analysis |url= |journal=Prim Care Diabetes |volume=14 |issue=5 |pages=435–444 |doi=10.1016/j.pcd.2019.12.005 |pmid=31917119}} and superimposed nerve compression, nerve decompression may be useful.{{cite journal |vauthors=Xu L, Sun Z, Casserly E, Nasr C, Cheng J, Xu J |date=June 2022 |title=Advances in Interventional Therapies for Painful Diabetic Neuropathy: A Systematic Review |url= |journal=Anesth Analg |volume=134 |issue=6 |pages=1215–1228 |doi=10.1213/ANE.0000000000005860 |pmc=9124666 |pmid=35051958}}{{cite journal |vauthors=Tu Y, Lineaweaver WC, Chen Z, Hu J, Mullins F, Zhang F |date=March 2017 |title=Surgical Decompression in the Treatment of Diabetic Peripheral Neuropathy: A Systematic Review and Meta-analysis |url= |journal=J Reconstr Microsurg |volume=33 |issue=3 |pages=151–157 |doi=10.1055/s-0036-1594300 |pmid=27894152}} 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.{{cite journal |vauthors=Dellon AL |date=February 1988 |title=A cause for optimism in diabetic neuropathy |url= |journal=Ann Plast Surg |volume=20 |issue=2 |pages=103–5 |doi=10.1097/00000637-198802000-00001 |pmid=3355053}}{{cite journal |vauthors=Sessions J, Nickerson DS |date=March 2014 |title=Biologic Basis of Nerve Decompression Surgery for Focal Entrapments in Diabetic Peripheral Neuropathy |url= |journal=J Diabetes Sci Technol |volume=8 |issue=2 |pages=412–418 |doi=10.1177/1932296814525030 |pmc=4455405 |pmid=24876595}}{{cite journal |vauthors=Dellon AL |date=October 2014 |title=Susceptibility of nerve in diabetes to compression: implications for pain treatment |url= |journal=Plast Reconstr Surg |volume=134 |issue=4 Suppl 2 |pages=142S–150S |doi=10.1097/PRS.0000000000000668 |pmid=25254997}} The surgery is associated with lower pain scores, higher two-point discrimination (a measure of sensory improvement), lower rate of ulcerations, fewer falls (in the case of lower extremity decompression), and fewer amputations.{{cite journal |vauthors=Fadel ZT, Imran WM, Azhar T |date=August 2022 |title=Lower Extremity Nerve Decompression for Diabetic Peripheral Neuropathy: A Systematic Review and Meta-analysis |url= |journal=Plast Reconstr Surg Glob Open |volume=10 |issue=8 |pages=e4478 |doi=10.1097/GOX.0000000000004478 |pmc=9390809 |pmid=35999882}}

There is no good evidence that herbal products (nutmeg or St John's wort) are helpful in treating neuropathic pain.{{cite journal|vauthors=Boyd A, Bleakley C, Hurley DA, Gill C, Hannon-Fletcher M, Bell P, McDonough S|date=April 2019|title=Herbal medicinal products or preparations for neuropathic pain|journal=Cochrane Database Syst Rev|type=Systematic review|volume=4|issue=5 |pages=CD010528|doi=10.1002/14651858.CD010528.pub4|pmc=6445324|pmid=30938843}}

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.{{cite journal|author=Foster TS|year=2007|title=Efficacy and safety of alpha-lipoic acid supplementation in the treatment of symptomatic diabetic neuropathy|journal=Diabetes Educ|volume=33|issue=1|pages=111–7|doi=10.1177/0145721706297450|pmid=17272797|s2cid=22801230|quote=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.}} 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),{{cite journal|vauthors=Ziegler D, Ametov A, Barinov A, etal|year=2006|title=Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial|journal=Diabetes Care|volume=29|issue=11|pages=2365–70|doi=10.2337/dc06-1216|pmid=17065669|doi-access=free}} 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.{{cite journal|vauthors=Patton LL, Siegel MA, Benoliel R, De Laat A|year=2007|title=Management of burning mouth syndrome: systematic review and management recommendations|journal=Oral Surg Oral Med Oral Pathol Oral Radiol Endod|volume=103 Suppl|pages=S39.e1–13|doi=10.1016/j.tripleo.2006.11.009|pmid=17379153}}

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.{{cite journal|vauthors=Stracke H, Lindemann A, Federlin K|year=1996|title=A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy|journal=Exp. Clin. Endocrinol. Diabetes|volume=104|issue=4|pages=311–6|doi=10.1055/s-0029-1211460|pmid=8886748}}{{cite journal|author=Thornalley PJ|year=2005|title=The potential role of thiamine (vitamin B(1)) in diabetic complications|journal=Curr Diabetes Rev|volume=1|issue=3|pages=287–98|doi=10.2174/157339905774574383|pmid=18220605}}

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.{{cite journal|last1=Freemon|first1=Frank R.|year=1994|title=Galen's ideas on neurological function|journal=J Hist Neurosci|volume=3|issue=4|pages=263–71|doi=10.1080/09647049409525619|pmid=11618827}} 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.{{cite journal |last1=Heydari |first1=Mojtaba |last2=Shams |first2=Mesbah |last3=Hashempur |first3=Mohammad Hashem |last4=Zargaran |first4=Arman |last5=Dalfardi |first5=Behnam |last6=Borhani-Haghighi |first6=Afshin |title=The origin of the concept of neuropathic pain in Early Medieval Persia (9th–12th century CE) |journal=Acta medico-historica Adriatica |date=2015 |volume=13 |issue=Suppl 2 |pages=9–22 |pmid=26966748 |url=https://hrcak.srce.hr/file/225171 |s2cid=30398883 }}

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.{{cite journal|last1=Scadding|first1=JW|date=March 2004|title=Treatment of neuropathic pain: historical aspects.|journal=Pain Medicine|volume=5|issue=Suppl 1 |pages=S3-8|doi=10.1111/j.1526-4637.2004.04018.x|pmid=14996226|doi-access=free}}

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,{{cite journal |last1=Gritsch |first1=Simon |last2=Bali |first2=Kiran Kumar |last3=Kuner |first3=Rohini |last4=Vardeh |first4=Daniel |title=Functional characterization of a mouse model for central post-stroke pain |journal=Molecular Pain |date=January 2016 |volume=12 |page=174480691662904 |doi=10.1177/1744806916629049 |pmid=27030713 |pmc=4956143 }} 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 and the relative contributions of each pathway remain controversial. Notably, our understanding of these processes is driven mainly by rodent models in part because studying these tissues in living adults is difficult.{{citation needed|date=November 2024}}

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, which appears to be partly due to changes in the ion channel expression at the periphery level. 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 generally oppose action potential generation. These changes appear to support increased excitability, which may allow endogenous stimuli to cause spontaneous pain.{{cite journal |last1=Costigan |first1=Michael |last2=Scholz |first2=Joachim |last3=Woolf |first3=Clifford J. |title=Neuropathic Pain: A Maladaptive Response of the Nervous System to Damage |journal=Annual Review of Neuroscience |date=1 June 2009 |volume=32 |issue=1 |pages=1–32 |doi=10.1146/annurev.neuro.051508.135531 |pmid=19400724 |pmc=2768555 }}

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

File:Gate control A firing.svg]]

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 synthesize GABA, the predominant inhibitory transmitter in the adult brain), has been observed in some systems following peripheral neuropathy, such as in rats and mice.{{cite journal |last1=Manion |first1=John |last2=Waller |first2=Matthew A. |last3=Clark |first3=Teleri |last4=Massingham |first4=Joshua N. |last5=Neely |first5=G. Gregory |title=Developing Modern Pain Therapies |journal=Frontiers in Neuroscience |date=20 December 2019 |volume=13 |page=1370 |doi=10.3389/fnins.2019.01370 |pmid=31920521 |pmc=6933609 |doi-access=free }} 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.{{cite journal |last1=Henderson |first1=L. A. |last2=Peck |first2=C. C. |last3=Petersen |first3=E. T. |last4=Rae |first4=C. D. |last5=Youssef |first5=A. M. |last6=Reeves |first6=J. M. |last7=Wilcox |first7=S. L. |last8=Akhter |first8=R. |last9=Murray |first9=G. M. |last10=Gustin |first10=S. M. |title=Chronic Pain: Lost Inhibition? |journal=Journal of Neuroscience |date=24 April 2013 |volume=33 |issue=17 |pages=7574–7582 |doi=10.1523/JNEUROSCI.0174-13.2013 |pmid=23616562 |pmc=6619566 }}

File:Microglia and neurons.jpg

During neuropathic pain, the glia becomes "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.{{cite journal |last1=Ji |first1=Ru-Rong |last2=Donnelly |first2=Christopher R. |last3=Nedergaard |first3=Maiken |title=Astrocytes in chronic pain and itch |journal=Nature Reviews Neuroscience |date=November 2019 |volume=20 |issue=11 |pages=667–685 |doi=10.1038/s41583-019-0218-1 |pmid=31537912 |pmc=6874831 }} 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 and cause changes in neurons that lead to hyperexcitability.{{cite journal |last1=Ji |first1=Ru-Rong |last2=Chamessian |first2=Alexander |last3=Zhang |first3=Yu-Qiu |title=Pain regulation by non-neuronal cells and inflammation |journal=Science |date=4 November 2016 |volume=354 |issue=6312 |pages=572–577 |doi=10.1126/science.aaf8924 |pmid=27811267 |pmc=5488328 |bibcode=2016Sci...354..572J }}{{cite journal |last1=Siniscalco |first1=Dario |last2=Giordano |first2=Catia |last3=Rossi |first3=Francesco |last4=Maione |first4=Sabatino |last5=de Novellis |first5=Vito |title=Role of Neurotrophins in Neuropathic Pain |journal=Current Neuropharmacology |date=1 December 2011 |volume=9 |issue=4 |pages=523–529 |doi=10.2174/157015911798376208 |pmid=22654713 |pmc=3263449 }}

Central sensitization is a potential component of neuropathic pain. It refers to a change in synaptic plasticity, efficacy, and intrinsic disinhibition, leading 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.{{cite journal |last1=Latremoliere |first1=Alban |last2=Woolf |first2=Clifford J. |title=Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity |journal=The Journal of Pain |date=September 2009 |volume=10 |issue=9 |pages=895–926 |doi=10.1016/j.jpain.2009.06.012 |pmid=19712899 |pmc=2750819 }}

During high-frequency stimulation, synapses conveying nociceptive information may become hyper-efficient in a process similar but not identical to long-term potentiation.{{cite journal |last1=Ji |first1=Ru-Rong |last2=Kohno |first2=Tatsuro |last3=Moore |first3=Kimberly A |last4=Woolf |first4=Clifford J |title=Central sensitization and LTP: do pain and memory share similar mechanisms? |journal=Trends in Neurosciences |date=December 2003 |volume=26 |issue=12 |pages=696–705 |doi=10.1016/j.tins.2003.09.017 |pmid=14624855 |s2cid=14214986 }} 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.

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.{{cite journal|vauthors=Truini A, Cruccu G|date=May 2006|title=Pathophysiological mechanisms of neuropathic pain|journal=Neurol. Sci.|volume=27|issue=Suppl 2 |pages=S179–82|doi=10.1007/s10072-006-0597-8|pmid=16688626|s2cid=28736907}} 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.

• Cranial nerves
• Nerve
• Neuralgia
• Neuritis
• Neuropathy

{{Reflist}}

• {{cite journal|journal=NICE Clinical Guidelines|volume=96|title=The Pharmacological Management of Neuropathic Pain in Adults in Non-Specialist Settings|author=Centre for Clinical Practice at NICE (UK)|location=London|publisher=National Institute for Health and Clinical Excellence (UK)|date=March 2010|url=https://www.ncbi.nlm.nih.gov/books/NBK82991/}}

{{Neuropathy}}

{{Medical resources|DiseasesDB=|ICD10={{ICD10|M79.2}}|ICD9={{ICD9|729.2}}|ICDO=|OMIM=|MedlinePlus=|MeSH=|GeneReviewsNBK=|GeneReviewsName=}}

{{Authority control}}

Category:Pain