Neuropathic pain is pain caused by damage or disease affecting the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (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.
Up to 7%-8% of the European population is affected, and in 5% of persons it may be severe. Neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain.
- 1 Cause
- 2 Mechanisms
- 3 Treatments
- 3.1 Anticonvulsants
- 3.2 Antidepressants
- 3.3 Botulinum toxin type A
- 3.4 Cannabinoids
- 3.5 Herbal products
- 3.6 Dietary supplements
- 3.7 Neuromodulators
- 3.8 NMDA antagonism
- 3.9 Opioids
- 3.10 Topical agents
- 3.11 Surgical Interventions
- 4 Research directions
- 5 History
- 6 See also
- 7 References
- 8 External links
Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Aside from diabetes (see diabetic neuropathy) and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, immune mediated disorders and physical trauma to a nerve trunk. Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy (chemotherapy-induced peripheral neuropathy), radiation injury or surgery.
After a peripheral nerve lesion, aberrant regeneration may occur. Neurons become unusually sensitive and develop spontaneously pathological activity and abnormal excitability. This phenomenon is called "peripheral sensitization".
The (spinal cord) dorsal horn neurons give rise to the spinothalamic tract (STT), which constitutes the major ascending nociceptive pathway. As a consequence of spontaneous activity arising in the periphery, STT neurons develop increased background activity, enlarged receptive fields and increased responses to afferent impulses, including normally innocuous tactile stimuli. This phenomenon is called central sensitization. Central sensitization is an important mechanism of persistent neuropathic pain.
Other mechanisms may take place at the central level after peripheral nerve damage. The loss of afferent signals induces functional changes in dorsal horn neurons. A decrease in the large fiber input decreases the activity of interneurons inhibiting nociceptive neurons i.e. loss of afferent inhibition. Hypoactivity of the descending antinociceptive systems or loss of descending inhibition may be another factor. With the loss of neuronal input (deafferentation) the STT neurons begin to fire spontaneously, a phenomenon designated "deafferentation hypersensitivity."
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. 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.
Neuropathic pain can be very difficult to treat with only some 40-60% of people achieving partial relief.
Favored treatments are certain antidepressants (tricyclic antidepressants and serotonin–norepinephrine reuptake inhibitors), anticonvulsants (pregabalin and gabapentin), and topical lidocaine. Opioid analgesics are recognized as useful agents but are not recommended as first line treatments.
Pregabalin and gabapentin may reduce pain associated with diabetic neuropathy. The anticonvulsants carbamazepine and oxcarbazepine are especially effective in trigeminal neuralgia. Gabapentin may reduce symptoms associated with neuropathic pain or fibromyalgia in some people. There is no predictor test to determine if it will be effective for a particular person. A short trial period of gabapentin therapy is recommended, to determine the effectiveness for that person. 62% of people taking gabapentin may have at least one adverse event, however the incidence of serious adverse events was found to be low.
Dual serotonin-norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, and milnacipran, as well as tricyclic antidepressants such as amitriptyline, nortriptyline, and desipramine are considered first-line medications for this condition. While amitriptyline and desipramine have been used as first-line treatments, the quality of evidence to support their use is poor.
Botulinum toxin type A
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. 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), 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.
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%). There is a significant complication rate, which increases over time.
Motor cortex stimulation
Stimulation of the primary motor cortex through electrodes placed within the skull but outside the thick meningeal membrane (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.
Spinal cord stimulators and implanted 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.
Intrathecal pumps deliver medication directly to the fluid filled (subarachnoid) space surrounding the spinal cord. Opioids alone or opioids with adjunctive medication (either a local anesthetic or clonidine) or more recently ziconotide are infused. Complications such as serious infection (meningitis), urinary retention, hormonal disturbance and intrathecal granuloma formation have been noted with intrathecal infusion.
There are no randomized studies of infusion pumps. For selected patients 50% or greater pain relief is achieved in 38% to 56% at six months but declines with the passage of time. These results must be viewed skeptically since placebo effects cannot be evaluated.
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. 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).
Opioids, while commonly used in chronic neuropathic pain, are not a recommended first or second line treatment. In the short and long term they are of unclear benefit. In the intermediate term evidence of low quality supports utility.
Several opioids, particularly levorphanol, methadone and ketobemidone, possess NMDA 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 antagonist; d-methadone is analgesic in experimental models of chronic pain.
There is little evidence to indicate that one strong opioid is more effective than another. Expert opinion leans toward the use of methadone for neuropathic pain, in part because of its NMDA antagonism. It is reasonable to base the choice of opioid on other factors. It is unclear if fentanyl gives pain relief to people with neuropathic pain.
In some forms of neuropathy, especially post-herpetic neuralgia, the topical application of local anesthetics such as lidocaine is reported to 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 not only depletes substance P but also results in a reversible degeneration of epidermal nerve fibers. Nevertheless, benefits appear modest with standard (low) strength preparations, and topical capsaicin can itself induce pain.
In some cases a nerve block can be used to treat.
Carbamazepine acts by inhibiting voltage-gated sodium channels, thereby reducing the excitability of neural membranes. Carbamazepine has also been shown to potentiate gamma aminobutyric acid (GABA) receptors made up of alpha1, beta2, and gamma2 subunits. This may be relevant to its efficacy in neuropathic pain. Carbamazepine is commonly used to help with pain attacks during night.
The history of pain management can be traced back to ancient times. Galen also suggested nerve tissue as the transferring route of pain to the brain through the invisible psychic pneuma. The idea of origination of pain from the nerve itself, without any exciting pathology in other organs is presented by medieval medical scholars such as Rhazes, Haly Abbas and Avicenna. They named this type of pain specifically as "vaja al asab" [nerve originated pain], described its numbness, tingling and needling quality, discussed its etiology and the differentiating characteristics. 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.
- Cranial nerves
- Neuralgia-inducing cavitational osteonecrosis
- Somatosensory Rehabilitation of Pain
- "Taxonomy". International Association for the Study of pain. Retrieved 3 May 2015.
- 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.
- Bouhassira D, Lantéri-Minet M, Attal N, Laurent B, Touboul C (June 2008). "Prevalence of chronic pain with neuropathic characteristics in the general population". Pain. 136 (3): 380–7. doi:10.1016/j.pain.2007.08.013. PMID 17888574.
- Foley P, Vesterinen H, Laird B, et al. (2013). "Prevalence and natural history of pain in adults with multiple sclerosis: Systematic review and meta-analysis". Pain. 154 (5): 632–42. doi:10.1016/j.pain.2012.12.002. PMID 23318126.
- Portenoy RK (1989). "Painful polyneuropathy". Neurol Clin. 7 (2): 265–88. doi:10.1016/S0733-8619(18)30813-2. PMID 2566901.
- 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.
-  Chemotherapy-induced Peripheral Neuropathy Fact Sheet, Retrieved on 29 December 2008
-  Cancerbackup, Macmillan Cancer Support, Peripheral neuropathy, Retrieved on 29 December 2008
- Wieseler-Frank J, Maier SF, Watkins LR (2005). "Central proinflammatory cytokines and pain enhancement". Neuro-Signals. 14 (4): 166–74. doi:10.1159/000087655. PMID 16215299.
- 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.
- 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.
- 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: CD007938. doi:10.1002/14651858.CD007938.pub4. PMC 6452908. PMID 28597471.
- 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.
- Moore, R. Andrew; Straube, Sebastian; Wiffen, Philip J.; Derry, Sheena; McQuay, Henry J. (2009-07-08). "Pregabalin for acute and chronic pain in adults". The Cochrane Database of Systematic Reviews (3): CD007076. doi:10.1002/14651858.CD007076.pub2. ISSN 1469-493X. PMC 4167351. PMID 19588419.
- "Pharmacological treatment for all neuropathic pain except trigeminal neuralgia". NICE Guidance CG173. 2013.
- "Neuropathic pain in adults: pharmacological management in non-specialist settings | Guidance and guidelines | NICE". www.nice.org.uk.
- Wiffen, PJ; Derry, S; Moore, RA (Dec 3, 2013). "Lamotrigine for chronic neuropathic pain and fibromyalgia in adults". The Cochrane Database of Systematic Reviews. 12 (12): CD006044. doi:10.1002/14651858.CD006044.pub4. PMC 6485508. PMID 24297457.
- Moore, R. Andrew; Derry, Sheena; Aldington, Dominic; Cole, Peter; Wiffen, Philip J. (2015-07-06). "Amitriptyline for neuropathic pain in adults". The Cochrane Database of Systematic Reviews (7): CD008242. doi:10.1002/14651858.CD008242.pub3. ISSN 1469-493X. PMC 6447238. PMID 26146793.
- Hearn, L; Moore, RA; Derry, S; Wiffen, PJ; Phillips, T (Sep 23, 2014). "Desipramine for neuropathic pain in adults". The Cochrane Database of Systematic Reviews. 9 (9): CD011003. doi:10.1002/14651858.CD011003.pub2. PMID 25246131.
- Semenchuk MR, Davis B (March 2000). "Efficacy of sustained-release bupropion in neuropathic pain: an open-label study". The Clinical Journal of Pain. 16 (1): 6–11. doi:10.1097/00002508-200003000-00002. PMID 10741812.
- Semenchuk MR, Sherman S, Davis B (November 2001). "Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain". Neurology. 57 (9): 1583–8. doi:10.1212/WNL.57.9.1583. PMID 11706096.
- Shah TH, Moradimehr A (February 2010). "Bupropion for the Treatment of Neuropathic Pain". The American Journal of Hospice & Palliative Care. 27 (5): 333–6. doi:10.1177/1049909110361229. PMID 20185402.
- 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.
- 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: CD012182. doi:10.1002/14651858.CD012182.pub2. PMC 6494210. PMID 29513392.
- Mason O1, Morgan CJ, Dhiman SK, Patel A, Parti N, Patel A, Curran HV (19 November 2008). "Acute cannabis use causes increased psychotomimetic experiences in individuals prone to psychosis". Psychological Medicine (journal). 39 (6): 951–956. doi:10.1017/S0033291708004741. PMID 19017430.CS1 maint: Uses authors parameter (link)
- 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: CD010528. doi:10.1002/14651858.CD010528.pub4. PMC 6445324. PMID 30938843.
- 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.
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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Bittar RG, Kar-Purkayastha I, Owen SL, et al. (2005). "Deep brain stimulation for pain relief: a meta-analysis". J Clin Neurosci. 12 (5): 515–9. doi:10.1016/j.jocn.2004.10.005. PMID 15993077.
- 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.
- 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
- 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.
- 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.
- Turner JA, Sears JM, Loeser JD (2007). "Programmable intrathecal opioid delivery systems for chronic noncancer pain: a systematic review of effectiveness and complications". Clin J Pain. 23 (2): 180–95. doi:10.1097/01.ajp.0000210955.93878.44. PMID 17237668.
- 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.
- 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. PMID 26987082.
Several guidelines agree that first- and second-line drugs for neuropathic pain include anticonvulsants (gabapentin or pregabalin), tricyclic antidepressants, and SNRIs
- McNicol, ED; Midbari, A; Eisenberg, E (29 August 2013). "Opioids for neuropathic pain". The Cochrane Database of Systematic Reviews (8): CD006146. doi:10.1002/14651858.CD006146.pub2. PMC 6353125. PMID 23986501.
- 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.
- 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.
- 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: CD011605. doi:10.1002/14651858.CD011605.pub2. PMC 6457928. PMID 27727431.
- 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.
- Finnerup NB, Otto M, Jensen TS, Sindrup SH (2007). "An Evidence-Based Algorithm for the Treatment of Neuropathic Pain". MedGenMed. 9 (2): 36. PMC 1994866. PMID 17955091.
- Al-Quliti, Khalid W. (April 2015). "Update on neuropathic pain treatment for trigeminal neuralgia". Neurosciences. 20 (2): 107–114. doi:10.17712/nsj.2015.2.20140501. ISSN 1319-6138. PMC 4727618. PMID 25864062.
- Swidan, Sahar Z.; Mohamed, Hagar A. (February 2016). "Use of Topical Pain Medications in the Treatment of Various Pain Syndromes". Topics in Pain Management. 31 (7): 1–8. doi:10.1097/01.TPM.0000480460.46614.c1.
- Freemon, Frank R. (1994). "Galen's ideas on neurological function". J Hist Neurosci. 3 (4): 263–71. doi:10.1080/09647049409525619. PMID 11618827.
- Heydari, M.; Shams, M.; Hashempur, M. H.; Zargaran, A.; Dalfardi, B.; Borhani-Haghighi, A. (2015). "The origin of the concept of neuropathic pain in Early Medieval Persia (9th - 12th century CE)". Acta Med Hist Adriat. 13 Suppl 1: 9–22. PMID 26966748.
- 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.
- Centre for Clinical Practice at NICE (UK). The Pharmacological Management of Neuropathic Pain in Adults in Non-Specialist Settings. NICE Clinical Guidelines. March 2010.