Trigeminal Neuralgia: Channels, Pathophysiology, and Therapeutic Challenges
- 484 Downloads
Abstract
Trigeminal neuralgia (TN) is a condition characterized by paroxysmal excruciating and usually unilateral pain attacks within the territory of one or more divisions of the trigeminal nerve. The underlying pathophysiological mechanisms remain poorly understood. The abrupt onset and termination of electric shock-like severe pain, the triggering role of non-noxious light sensory stimuli, the spreading of pain beyond the stimulated area, and the post-attack refractoriness represent some of the intriguing and challenging aspects of TN pathophysiology. This chapter reviews the updated pathophysiological hypotheses for TN, the emerging role of ion channels potentially representing novel therapeutic targets for the treatment of the disorder, and the current therapeutic approach based on a diagnostic work-up and treatment algorithm.
Keywords
Trigeminal neuralgia Neuropathic pain Ion channels Voltage-gated sodium channels (VGSC) Calcium-activated potassium channels (BKCa) Calcium channels Transient receptor potential (TRP) channels Chronic constriction injury of the infraorbital nerve (CION) Carbamazepine Eslicarbazepine OnabotulinumtoxinA Neurovascular compressionReferences
- 1.Zakrzewska JM, Linskey ME. Trigeminal neuralgia. BMJ. 2014;348:g474. http://www.ncbi.nlm.nih.gov/pubmed/24534115 PubMedCrossRefGoogle Scholar
- 2.Jannetta PJ. Arterial compression of the trigeminal nerve at the pons in patients with trigeminal neuralgia. J Neurosurg. 1967;26(1part2):159–62. http://www.ncbi.nlm.nih.gov/pubmed/6018932 CrossRefGoogle Scholar
- 3.Jannetta PJ. Microsurgical approach to the trigeminal nerve for tic douloureux. Basel: Karger Publishers; 1976. p. 180–200. https://www.karger.com/Article/FullText/428328 Google Scholar
- 4.Love S, Coakham HB. Trigeminal neuralgia: pathology and pathogenesis. Brain. 2001;124(Pt 12):2347–60. https://www.ncbi.nlm.nih.gov/pubmed/11701590.PubMedCrossRefGoogle Scholar
- 5.Truini A, Prosperini L, Calistri V, Fiorelli M, Pozzilli C, Millefiorini E, et al. A dual concurrent mechanism explains trigeminal neuralgia in patients with multiple sclerosis. Neurology. 2016;86(22):2094–9.PubMedCrossRefGoogle Scholar
- 6.Woolf CJ, Ma Q. Nociceptors-noxious stimulus detectors. Neuron. 2007;55(3):353–64.PubMedCrossRefGoogle Scholar
- 7.Waxman SG, Zamponi GW. Regulating excitability of peripheral afferents: emerging ion channel targets. Nat Neurosci. 2014;17(2):153–63.PubMedCrossRefGoogle Scholar
- 8.Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces. Pain. 1988;33:87–107. https://doi.org/10.1016/0304-3959(88)90209-6.PubMedCrossRefGoogle Scholar
- 9.Ahmad S, Dahllund L, Eriksson AB, Hellgren D, Karlsson U, Lund PE, et al. A stop codon mutation in SCN9A causes lack of pain sensation. Hum Mol Genet. 2007;16(17):2114–21.PubMedCrossRefGoogle Scholar
- 10.Yuan J, Matsuura E, Higuchi Y, Hashiguchi A, Nakamura T, Nozuma S, et al. Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation. Neurology. 2013;80(18):1641–9.PubMedCrossRefGoogle Scholar
- 11.Leipold E, Liebmann L, Korenke GC, Heinrich T, Giesselmann S, Baets J, et al. A de novo gain-of-function mutation in SCN11A causes loss of pain perception. Nat Genet. 2013;45(11):1399–404. http://www.ncbi.nlm.nih.gov/pubmed/24036948 PubMedCrossRefGoogle Scholar
- 12.Bennett DLH, Woods CG. Painful and painless channelopathies. Lancet Neurol. 2014;13(6):587–99.CrossRefGoogle Scholar
- 13.Faber CG, Hoeijmakers JGJ, Ahn HS, Cheng X, Han C, Choi JS, et al. Gain of function Na V1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71(1):26–39.PubMedCrossRefGoogle Scholar
- 14.Faber CG, Lauria G, Merkies ISJ, Cheng X, Han C, Ahn H-S, et al. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A. 2012;109(47):19444–9. http://www.pnas.org/content/109/47/19444.long PubMedPubMedCentralCrossRefGoogle Scholar
- 15.Huang J, Han C, Estacion M, Vasylyev D, Hoeijmakers JGJ, Gerrits MM, et al. Gain-of-function mutations in sodium channel NaV1.9 in painful neuropathy. Brain. 2014;137(6):1627–42.PubMedCrossRefGoogle Scholar
- 16.Waxman SG. Painful Na-channelopathies: an expanding universe. Trends Mol Med. 2013;19(7):406–9. https://doi.org/10.1016/j.molmed.2013.04.003.PubMedCrossRefGoogle Scholar
- 17.Tanaka BS, Zhao P. A gain-of-function mutation in Nav1.6 in a case of trigeminal neuralgia. Mol Med. 2016;22(1):1. http://www.molmed.org/content/pdfstore/16_131_Tanaka.pdf CrossRefGoogle Scholar
- 18.Siqueira SRDT, Alves B, Malpartida HMG, Teixeira MJ, Siqueira JTT. Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia. Neuroscience. 2009;164(2):573–7. https://doi.org/10.1016/j.neuroscience.2009.08.037.PubMedCrossRefGoogle Scholar
- 19.Lulz AP, Kopach O, Santana-Varela S, Wood JN. The role of Nav1.9 channel in the development of neuropathic orofacial pain associated with trigeminal neuralgia. Mol Pain. 2015;11:1–7.CrossRefGoogle Scholar
- 20.Leo S, D’Hooge R, Meert T. Exploring the role of nociceptor-specific sodium channels in pain transmission using Nav1.8 and Nav1.9 knockout mice. Behav Brain Res. 2010;208(1):149–57. https://doi.org/10.1016/j.bbr.2009.11.023.PubMedCrossRefGoogle Scholar
- 21.Minett MS, Falk S, Santana-Varela S, Bogdanov YD, Nassar MA, Heegaard AM, et al. Pain without nociceptors? Nav1.7-independent pain mechanisms. Cell Rep. 2014;6(2):301–12. https://doi.org/10.1016/j.celrep.2013.12.033.PubMedPubMedCentralCrossRefGoogle Scholar
- 22.Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature. 1997;389(6653):816–24. http://www.ncbi.nlm.nih.gov/pubmed/9349813 PubMedCrossRefGoogle Scholar
- 23.Urano H, Ara T, Fujinami Y, Yukihiro Hiraoka B. Aberrant TRPV1 expression in heat hyperalgesia associated with trigeminal neuropathic pain. Int J Med Sci. 2012;9(8):690–7.PubMedPubMedCentralCrossRefGoogle Scholar
- 24.Zuo X, Ling JX, Xu GY, Gu JG. Operant behavioral responses to orofacial cold stimuli in rats with chronic constrictive trigeminal nerve injury: effects of menthol and capsazepine. Mol Pain. 2013;9(1):28.PubMedPubMedCentralGoogle Scholar
- 25.Trevisan G, Benemei S, Materazzi S, De Logu F, De Siena G, Fusi C, et al. TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress. Brain. 2016;139(5):1361–77.PubMedCrossRefGoogle Scholar
- 26.Liu C-Y, Lu Z-Y, Li N, Yu L-H, Zhao Y-F, Ma B. The role of large-conductance, calcium-activated potassium channels in a rat model of trigeminal neuropathic pain. Cephalalgia. 2015;35(1):16–35. http://journals.sagepub.com/doi/10.1177/0333102414534083 PubMedCrossRefGoogle Scholar
- 27.Li KW, Yu YP, Zhou C, Kim DS, Lin B, Sharp K, et al. Calcium channel α2δ1 proteins mediate trigeminal neuropathic pain states associated with aberrant excitatory synaptogenesis. J Biol Chem. 2014;289(10):7025–37.PubMedPubMedCentralCrossRefGoogle Scholar
- 28.Choi S, Yu E, Hwang E, Llinás RR. Pathophysiological implication of Ca V 3.1 T-type Ca 2+ channels in trigeminal neuropathic pain. Proc Natl Acad Sci U S A. 2016;113(8):2270–5. http://www.pnas.org/lookup/doi/10.1073/pnas.1600418113 PubMedPubMedCentralCrossRefGoogle Scholar
- 29.Cruccu G, Gronseth G, Alksne J, Argoff C, Brainin M, Burchiel K, et al. AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol. 2008;15(10):1013–28.PubMedCrossRefGoogle Scholar
- 30.Wiffen PJ, Derry S, Moore RA, McQuay HJ. Carbamazepine for acute and chronic pain in adults. Cochrane Database Syst Rev. 2011;(1):CD005451.Google Scholar
- 31.Di Stefano G, La Cesa S, Truini A, Cruccu G. Natural history and outcome of 200 outpatients with classical trigeminal neuralgia treated with carbamazepine or oxcarbazepine in a tertiary centre for neuropathic pain. J Headache Pain. 2014;15(1):1–5.CrossRefGoogle Scholar
- 32.Tangamornsuksan W, Chaiyakunapruk N, Somkrua R, Lohitnavy M, Tassaneeyakul W. Relationship between the HLA-B*1502 allele and carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2013;149(9):1025–32. http://www.ncbi.nlm.nih.gov/pubmed/23884208 PubMedCrossRefGoogle Scholar
- 33.Beydoun A. Safety and efficacy of oxcarbazepine: results of randomized, double-blind trials. Pharmacotherapy. 2000;20(8):152S–8S. http://www.ncbi.nlm.nih.gov/pubmed/10937814 PubMedCrossRefGoogle Scholar
- 34.Vincent M, Wang S. Headache classification committee of the International Headache Society (IHS) the international classification of headache disorders, 3rd edition. Cephalalgia. 2018;38(1):1–211. http://journals.sagepub.com/doi/10.1177/0333102417738202 CrossRefGoogle Scholar
- 35.Maarbjerg S, Wolfram F, Gozalov A, Olesen J, Bendtsen L. Significance of neurovascular contact in classical trigeminal neuralgia. Brain. 2015;138(2):311–9.PubMedCrossRefGoogle Scholar
- 36.Sanchez-Larsen A, Sopelana D, Diaz-Maroto I, Perona-Moratalla AB, Gracia-Gil J, García-Muñozguren S, et al. Assessment of efficacy and safety of eslicarbazepine acetate for the treatment of trigeminal neuralgia. Eur J Pain. 2018;22(6):1080–7. http://www.ncbi.nlm.nih.gov/pubmed/29369456 PubMedCrossRefGoogle Scholar
- 37.Morra ME, Elgebaly A, Elmaraezy A, Khalil AM, Altibi AMA, TL-H V, et al. Therapeutic efficacy and safety of Botulinum Toxin A Therapy in Trigeminal Neuralgia: a systematic review and meta-analysis of randomized controlled trials. J Headache Pain. 2016;17(1):63. http://thejournalofheadacheandpain.springeropen.com/articles/10.1186/s10194-016-0651-8 PubMedPubMedCentralCrossRefGoogle Scholar
- 38.Zakrzewska JM, Palmer J, Morisset V, Giblin GM, Obermann M, Ettlin DA, et al. Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. Lancet Neurol. 2017;16(4):291–300. https://doi.org/10.1016/S1474-4422(17)30005-4.PubMedCrossRefGoogle Scholar
- 39.Katusic S, Beard CM, Bergstralth E, Kurland LT. Incidence and clinical features of trigeminal neuralgia, Rochester, Minnesota, 1945-1984. Ann Neurol. 1990;27(1):89–95. http://www.ncbi.nlm.nih.gov/pubmed/2301931 PubMedCrossRefGoogle Scholar
- 40.Heinskou TB, Rochat P, Maarbjerg S, et al. Prognostic factors for outcome of microvascular decompression in trigeminal neuralgia. Cephalalgia. 2018;. in pressGoogle Scholar
- 41.Barker FG, Jannetta PJ, Bissonette DJ, Larkins MV, Jho HD. The long-term outcome of microvascular decompression for trigeminal neuralgia. N Engl J Med. 1996;334(17):1077–83. http://www.nejm.org/doi/abs/10.1056/NEJM199604253341701 CrossRefGoogle Scholar