Topical Review: Potential Use of Botulinum Toxin in the Management of Painful Posttraumatic Trigeminal Neuropathy

Painful posttraumatic trigeminal neuropathy (PPTTN) is a chronic condition that is difficult to endure and has a poorly understood pathophysiology. Treatment options are limited and often unsatisfactory due to insufficient efficacy and significant adverse effects. Botulinum toxin type A (BTX-A), initially used in the management of pathologically sustained or twisting muscular contractions, has recently been advocated for treatment of neuropathic pain. Its action is not limited to the blockage of acetylcholine release at the neuromuscular junction, but also includes inhibition of exocytosis of other neurotransmitters by interfering with the SNARE complexes of synaptic membranes. When injected into the painful location, the toxin can be taken up by peripheral terminals of nociceptive afferent nerve fibers, and this action suppresses peripheral and central release of algogenic neurotransmitters such as glutamate or substance P, thus promoting analgesia. Several randomized controlled trials in humans have provided emerging evidence for the therapeutic use of BTX-A in neuropathic pain states, including trigeminal neuralgia. This evidence, in addition to its good safety profile and long-lasting effect, suggests that BTX-A could be a potential novel treatment for PPTTN.

botulinum toxin; neuropathic pain; review; treatment; trigeminal

1. O’Connor AB. Neuropathic pain: Quality-of-life impact, costs and cost effectiveness of therapy. Pharmacoeconomics 2009; 27:95–112.

2. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol 2015;14:162–173.

3. Forssell H, Tenovuo O, Silvoniemi P, Jääskeläinen SK. Differences and similarities between atypical facial pain and trigeminal neuropathic pain. Neurology 2007;69:1451–1459.

4. Melis M, Lobo SL, Ceneviz C, et al. Atypical odontalgia: A review of the literature. Headache 2003;43:1060–1074.

5. Marbach JJ, Raphael KG. Phantom tooth pain: A new look at an old dilemma. Pain Med 2000;1:68–77.

6. Baad-Hansen L. Atypical odontalgia - pathophysiology and clinical management. J Oral Rehabil 2008;35:1–11.

7. Pfaffenrath V, Rath M, Pöllmann W, Keeser W. Atypical facial pain--Application of the IHS criteria in a clinical sample. Cephalalgia 1993;13(suppl):84–88.

8. Woda A, Pionchon P. A unified concept of idiopathic orofacial pain: Clinical features. J Orofac Pain 1999;13:172–184.

9. Nixdorf D, Moana-Filho E. Persistent dento-alveolar pain disorder (PDAP): Working towards a better understanding. Rev Pain 2011;5:18–27.

10. Benoliel R, Zadik Y, Eliav E, Sharav Y. Peripheral painful traumatic trigeminal neuropathy: Clinical features in 91 cases and proposal of novel diagnostic criteria. J Orofac Pain 2012; 26:49–58.

11. Benoliel R, Kahn J, Eliav E. Peripheral painful traumatic trigeminal neuropathies. Oral Dis 2012;18:317–332.

12. Haviv Y, Zadik Y, Sharav Y, Benoliel R. Painful traumatic trigeminal neuropathy: An open study on the pharmacotherapeutic response to stepped treatment. J Oral Facial Pain Headache 2014; 28:52–60.

13. Smith JG, Elias LA, Yilmaz Z, et al. The psychosocial and affective burden of posttraumatic neuropathy following injuries to the trigeminal nerve. J Orofac Pain 2013;27:293–303.

14. Cruccu G, Finnerup NB, Jensen TS, et al. Trigeminal neuralgia: New classification and diagnostic grading for practice and research. Neurology 2016;87:220–228.

15. Peñarrocha MA, Peñarrocha D, Bagán JV, Peñarrocha M. Post-traumatic trigeminal neuropathy. A study of 63 cases. Med Oral Patol Oral Cir Bucal 2012;17:e297–e300.

16. Dagsdóttir LK, Skyt I, Vase L, Baad-Hansen L, Castrillon E, Svensson P. Reports of perceptual distortion of the face are common in patients with different types of chronic oro-facial pain. J Oral Rehabil 2016;43:409–416.

17. List T, Leijon G, Svensson P. Somatosensory abnormalities in atypical odontalgia: A case-control study. Pain 2008; 139:333–341.

18. Costigan M, Scholz J, Woolf CJ. Neuropathic pain: A maladaptive response of the nervous system to damage. Annu Rev Neurosci 2009;32:1–32.

19. Bai G, Ren K, Dubner R. Epigenetic regulation of persistent pain. Transl Res 2015;165:177–199.

20. Moreau N, Mauborgne A, Bourgoin S, et al. Early alterations of Hedgehog signaling pathway in vascular endothelial cells after peripheral nerve injury elicit blood-nerve barrier disruption, nerve inflammation, and neuropathic pain development. Pain 2016; 157:827–839.

21. Bouhassira D, Attal N. Translational neuropathic pain research: A clinical perspective. Neuroscience 2016;338:27–35.

22.

Goto T, Oh SB, Takeda M, et al. Recent advances in basic research on the trigeminal ganglion. J Physiol Sci 2016;66: 381–386.

23. Martini R, Willison H. Neuroinflammation in the peripheral nerve: Cause, modulator, or bystander in peripheral neuropathies? Glia 2016;64:475–486.

24. von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 2012;73:638–652.

25. Iwata K, Imamura Y, Honda K, Shinoda M. Physiological mechanisms of neuropathic pain: The orofacial region. Int Rev Neurobiol 2011;97:227–250.

26. Ganzberg S. Pain management part II: Pharmacologic management of chronic orofacial pain. Anesth Prog 2010;57:114–118.

27. Aggarwal VR, Lovell K, Peters S, Javidi H, Joughin A, Goldthorpe

J. Psychosocial interventions for the management of chronic orofacial pain. Cochrane Database Syst Rev 2011;(11): CD008456.

28. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:e1113–e1188.

29. Hargreaves KM. Orofacial pain. Pain 2011;152:S25–S32.

30.

Kim DW, Lee SK, Ahnn J. Botulinum toxin as a pain killer: Players and actions in antinociception. Toxins (Basel) 2015; 7:2435–2453.

31.

Pellett S, Yaksh TL, Ramachandran R. Current status and future directions of botulinum neurotoxins for targeting pain processing. Toxins (Basel) 2015;7:4519–4563.

32. Wheeler A, Smith HS. Botulinum toxins: Mechanisms of action, antinociception and clinical applications. Toxicology 2013;306:124–146.

33. Ishikawa H, Mitsui Y, Yoshitomi T, et al. Presynaptic effects of botulinum toxin type A on the neuronally evoked response of albino and pigmented rabbit iris sphincter and dilator muscles. Jpn J Ophthalmol 2000;44:106–109.

34. Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 2004;107:125–133.

35. Filipovic´ B, Matak I, Bach-Rojecky L, Lackovic´ Z. Central action of peripherally applied botulinum toxin type A on pain and dural protein extravasation in rat model of trigeminal neuropathy. PLoS One 2012;7:e29803.

36. Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M. Long-distance retrograde effects of botulinum neurotoxin A. J Neurosci 2008;28:3689–3896.

37. Matak I, Riederer P, Lackovic´ Z. Botulinum toxin’s axonal transport from periphery to the spinal cord. Neurochem Int 2012;61:236–239.

38. Marinelli S, Nazio F, Tinari A, et al. Schwann cell autophagy counteracts the onset and chronification of neuropathic pain. Pain 2014;155:93–107.

39. Vacca V, Marinelli S, Luvisetto S, Pavone F. Botulinum toxin A increases analgesic effects of morphine, counters development of morphine tolerance and modulates glia activation and μ opioid receptor expression in neuropathic mice. Brain Behav Immun 2013;32:40–50.

40. Caleo M, Antonucci F, Restani L, Mazzocchio R. A reappraisal of the central effects of botulinum neurotoxin type A: By what mechanism? J Neurochem 2009;109:15–24.

41. Lackovic´ Z, Filipoviic´ B, Matak I, Helyes Z. Activity of botulinum toxin type A in cranial dura: Implications for treatment of migraine and other headaches. Br J Pharmacol 2016;173: 279–291.

42. Sikandar S, Gustavsson Y, Marino MJ, et al. Effects of intraplantar botulinum toxin-B on carrageenan-induced changes in nociception and spinal phosphorylation of GluA1 and Akt. Eur J Neurosci 2016;44:1714–1722.

43. Camprubí-Robles M, Planells-Cases R, Ferrer-Montiel A. Differential contribution of SNARE-dependent exocytosis to inflammatory potentiation of TRPV1 in nociceptors. FASEB J 2009; 23:3722–3733.

44.

Shimizu T, Shibata M, Toriumi H, et al. Reduction of TRPV1 expression in the trigeminal system by botulinum neurotoxin type-A. Neurobiol Dis 2012;48:367–378.

45. Apostolidis A, Popat R, Yiangou Y, et al. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol 2005;174:977–982.

46. Xiao L, Cheng J, Zhuang Y, et al. Botulinum toxin type A reduces hyperalgesia and TRPV1 expression in rats with neuropathic pain. Pain Med 2013;14:276–286.

47. Xiao L, Cheng J, Dai J, Zhang D. Botulinum toxin decreases hyperalgesia and inhibits P2X3 receptor over-expression in sensory neurons induced by ventral root transection in rats. Pain Med 2011;12:1385–1394.

48. Luvisetto S, Marinelli S, Cobianchi S, Pavone F. Anti-allodynic efficacy of botulinum neurotoxin A in a model of neuropathic pain. Neuroscience 2007;145:1–4.

49. Bach-Rojecky L, Relja M, Lackovic´ Z. Botulinum toxin type A in experimental neuropathic pain. J Neural Transm (Vienna) 2005;112:215–219.

50. Bach-Rojecky L, Salkovic´ -Petrisic´ M, Lackovic´ Z. Botulinum toxin type A reduces pain supersensitivity in experimental diabetic neuropathy: Bilateral effect after unilateral injection. Eur J Pharmacol 2010;633:10–14.

51.

Marinelli S, Vacca V, Ricordy R, et al. The analgesic effect on neuropathic pain of retrogradely transported botulinum neurotoxin A involves Schwann cells and astrocytes. PLoS One 2012; 7:e47977.

52. Kitamura Y, Matsuka Y, Spigelman I, et al. Botulinum toxin type a (150 kDa) decreases exaggerated neurotransmitter release from trigeminal ganglion neurons and relieves neuropathy behaviors induced by infraorbital nerve constriction. Neuroscience 2009;159:1422–1499.

53. Kumada A, Matsuka Y, Spigelman I, et al. Intradermal injection of Botulinum toxin type A alleviates infraorbital nerve constriction-induced thermal hyperalgesia in an operant assay. J Oral Rehabil 2012;39:63–72.

54. Matsuka Y, Yokoyama T, Yamamoto Y, et al. Application of purified botulinum type a neurotoxin to treat experimental trigeminal neuropathy in rats and patients with urinary incontinence and prostatic hyperplasia. J Toxicol 2012;2012:648384.

55. Wu C, Xie N, Lian Y, et al. Central antinociceptive activity of peripherally applied botulinum toxin type A in lab rat model of trigeminal neuralgia. SpringerPlus 2016;5:431.

56. Paterson K, Lolignier S, Wood JN, McMahon SB, Bennett DL. Botulinum toxin-A treatment reduces human mechanical pain sensitivity and mechanotransduction. Ann Neurol 2014; 75:591–596.

57. Layeeque R, Hochberg J, Siegel E, et al. Botulinum toxin infiltration for pain control after mastectomy and expander reconstruction. Ann Surg 2004;240:608–613.

58. Tsai CP, Liu CY, Lin KP, Wang KC. Efficacy of botulinum toxin type a in the relief of Carpal tunnel syndrome: A preliminary experience. Clin Drug Investig 2006;26:511–515.

59. Relja M, Militec Z. Botulinum toxin type-A in the treatment of painful diabetic neuropathy: A prospective study [Proceedings of the 58th Annual Meeting of the American Academy of Neurology, 1–8 April 2006, San Diego]. San Diego: AAN, 2006.

60. Wittekindt C, Liu WC, Preuss SF, Guntinas-Lichius O. Botulinum toxin A for neuropathic pain after neck dissection: A dose-finding study. Laryngoscope 2006;116:1168–1171.

61.

Ranoux D, Attal N, Morain F, Bouhassira D. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol 2008;64:274–283.

62. Yuan RY, Sheu JJ, Yu JM, et al. Botulinum toxin for diabetic neuropathic pain: A randomized double-blind crossover trial. Neurology 2009;72:1473–1478.

63. Apalla Z, Sotiriou E, Lallas A, Lazaridou E, Ioannides D. Botulinum toxin A in postherpetic neuralgia: A parallel, randomized, double-blind, single-dose, placebo-controlled trial. Clin J Pain 2013;29:857–864.

64. Xiao L, Mackey S, Hui H, Xong D, Zhang Q, Zhang D. Subcutaneous injection of botulinum toxin a is beneficial in postherpetic neuralgia. Pain Med 2010;11:1827–1833.

65. Han ZA, Song DH, Oh HM, Chung ME. Botulinum toxin type A for neuropathic pain in patients with spinal cord injury. Ann Neurol 2016;79:569–578.

66. Attal N, de Andrade DC, Adam F, et al. Safety and efficacy of repeated injections of botulinum toxin A in peripheral neuropathic pain (BOTNEP): A randomised, double-blind, placebo-controlled trial. Lancet Neurol 2016;15:555–565.

67. Ngeow WC, Nair R. Injection of botulinum toxin type A (BOTOX) into trigger zone of trigeminal neuralgia as a means to control pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010;109:e47–e50.

68. Allam N, Brasil-Neto JP, Brown G, Tomaz C. Injections of botulinum toxin type a produce pain alleviation in intractable trigeminal neuralgia. Clin J Pain 2005;21:182–184.

69. Türk U, Ilhan S, Alp R, Sur H. Botulinum toxin and intractable trigeminal neuralgia. Clin Neuropharmacol 2005;28:161–162.

70. Borodic GE, Acquadro MA. The use of botulinum toxin for the treatment of chronic facial pain. J Pain 2002;3:21–27.

71. Piovesan EJ, Teive HG, Kowacs PA, Della Coletta MV, Werneck LC, Silberstein SD. An open study of botulinum-A toxin treatment of trigeminal neuralgia. Neurology 2005;65:1306–1308.

72. Zúñiga C, Díaz S, Piedimonte F, Micheli F. Beneficial effects of botulinum toxin type A in trigeminal neuralgia. Arq Neuropsiquiatr 2008;66(3A):500–503.

73. Bohluli B, Motamedi MH, Bagheri SC, et al. Use of botulinum toxin A for drug-refractory trigeminal neuralgia: Preliminary report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111:47–50.

74. Wu CJ, Lian YJ, Zheng YK, et al. Botulinum toxin type A for the treatment of trigeminal neuralgia: Results from a randomized, double-blind, placebo-controlled trial. Cephalalgia 2012;32:443–450.

75. Shehata HS, El-Tamawy MS, Shalaby NM, Ramzy G. Botulinum toxin-type A: Could it be an effective treatment option in intractable trigeminal neuralgia? J Headache Pain 2013;14:92.

76. Zúñiga C, Piedimonte F, Díaz S, Micheli F. Acute treatment of trigeminal neuralgia with onabotulinum toxin A. Clin Neuropharmacol 2013;36:146–150.

77. Li S, Lian YJ, Chen Y, et al. Therapeutic effect of Botulinum toxin-A in 88 patients with trigeminal neuralgia with 14-month follow-up. J Headache Pain 2014;15:43.

78. Zhang H, Lian Y, Ma Y, et al. Two doses of botulinum toxin type A for the treatment of trigeminal neuralgia: Observation of therapeutic effect from a randomized, double-blind, placebo-controlled trial. J Headache Pain 2014;15:65.

79.

Xia JH, He CH, Zhang HF, et al. Botulinum toxin A in the treatment of trigeminal neuralgia. Int J Neurosci 2016;126:348–353.

80. Shackleton T, Ram S, Black M, Ryder J, Clark GT, Enciso R. The efficacy of botulinum toxin for the treatment of trigeminal and postherpetic neuralgia: A systematic review with meta-analyses. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:61–71.

81. Yoon SH, Merrill RL, Choi JH, Kim ST. Use of botulinum toxin type A injection for neuropathic pain after trigeminal nerve injury. Pain Med 2010;11:630–632.

82. Cuadrado ML, García-Moreno H, Arias JA, Pareja JA. Botulinum neurotoxin type-A for the treatment of atypical odontalgia. Pain Med 2016;17:1717–1721.

83. Herrero Babiloni A, Kapos FP, Nixdorf DR. Intraoral administration of botulinum toxin for trigeminal neuropathic pain. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;121:e148–e153.

84.

Xia JH, He CH, Zhang HF, et al. Botulinum toxin A in the treatment of trigeminal neuralgia. Int J Neurosci 2016;126:348–353.

85. Turkel CC, Bowen B, Liu J, Brin MF. Pooled analysis of the safety of botulinum toxin type A in the treatment of poststroke spasticity. Arch Phys Med Rehabil 2006;87:786–792.

86. Intiso D. Therapeutic use of botulinum toxin in neurorehabilitation. J Toxicol 2012;2012:802893.

87. Verma G. Role of botulinum toxin type-A (BTX-A) in the management of trigeminal neuralgia. Pain Res Treat 2013:e831094.

88. Naumann M, Albanese A, Heinen F, Molenaers G, Relja M. Safety and efficacy of botulinum toxin type A following longterm use. Eur J Neurol 2006;13(suppl 4):35–40.

89. Aurora SK, Dodick DW, Diener HC, et al. Onabotulinumtoxin A for chronic migraine: Efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program. Acta Neurol Scand 2014;129:61–70.

90. Fabbri M, Leodori G, Fernandes RM, et al. Neutralizing antibody and botulinum toxin therapy: A systematic review and meta-analysis. Neurotox Res 2016;29:105–117.

91. Oh HM, Chung ME. Botulinum toxin for neuropathic pain: A review of the literature. Toxins (Basel) 2015;7:3127–3154.

92. Micheli F, Scorticati MC, Raina G. Beneficial effects of botulinum toxin type a for patients with painful tic convulsif. Clin Neuropharmacol 2002;25:260–262.

93. Volcy M, Tepper SJ, Rapoport AM, Sheftell FD, Bigal ME. Botulinum toxin A for the treatment of greater occipital neuralgia and trigeminal neuralgia: A case report with pathophysiological considerations. Cephalalgia 2006;26:336–340.

94. Boscá-Blasco ME, Burguera-Hernández JA, Roig-Morata S, Martínez-Torres I. Painful tic convulsif and Botulinum toxin [in Spanish]. Rev Neurol 2006;42:729–732.

95. Uluduz D, Karaali-Savrun F, Gunduz A, Kiziltan ME. An unusual case of vascular loop syndrome. J Headache Pain 2007; 8:242–244.

96. Felicio AC, Godeiro Cde O Jr, Borges V, Silva SM, Ferraz HB. Bilateral hemifacial spasm and trigeminal neuralgia: A unique form of painful tic convulsif. Mov Disord 2007;22:285–286.

97. Batifol D, Finiels PJ. Botulinum toxin in trigeminal neuralgia: Which is the best way of delivery? J Spine Neurosurg 2016;5:4.