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OnabotulinumtoxinA for trigeminal neuralgia: a review of the available data

Toxina Onabotulínica-A para neuralgia do trigêmeo: uma revisão dos dados disponíveis

Abstracts

Trigeminal neuralgia (TN) patients may develop side effects from centrally acting drugs, have contraindications for neurosurgical procedures, or experience relapse during conventional therapies. OnabotulinumtoxinA (BoNT/A) has been reported to be effective for TN, although this finding has been challenged. An overview of the available evidence based on a narrative/qualitative analysis of the literature is presented. About 90% of patients who receive BoNT/A show an improvement, a higher figure than that reported for the placebo effect of BoNT/A for other headaches. Tolerability of BoNT/A is good, and its few side-effects are transient. The articles reviewed were mainly case reports, case series and open-label trials; however, randomized controlled trials have endorsed the efficacy of BoNT/A for TN. This evidence, together with a better understanding of the analgesic mechanisms of BoNT/A and its proven efficacy in treating other pain syndromes, supports the use of this toxin as a therapeutic option for TN.

trigeminal neuralgia; botulinum neurotoxin type A; botulinum-A toxin; onabotulinumtoxin A; neuropathic pain


Pacientes com neuralgia do trigêmeo (NT) podem apresentar efeitos colaterais decorrentes do uso de drogas psicoativas, contra-indicações a procedimentos neurocirúrgicos ou perda da eficácia destas terapias. A neurotoxina botulínica do tipo A (NTB/A) tem demonstrado ser eficaz no alívio da NT, ainda que este achado tenha sido contestado. Uma análise narrativa/qualitativa da literatura disponível é apresentada. Cerca de 90% dos pacientes que receberam NTB/A melhoram, um número superior aos atribuíveis ao efeito placebo da NTB/A em outras cefaléias. Além disso, a NTB/A mostrou uma baixa incidência de efeitos colaterais, transitórios. Embora a maioria dos artigos consistam de relatos de caso, séries de casos e ensaios abertos, ensaios clínicos randomizados controlados recentes reafirmam a eficácia da NTB/A na NT. Estas evidências, associadas ao melhor entendimento dos mecanismos analgésicos da NTB/A e a sua eficácia em outras síndromes dolorosas, ratificam a NTB/A como uma opção terapêutica para a NT.

neuralgia do trigêmeo; neurotoxina botulínica do tipo A; toxina botulínica do tipo A; toxina onabotulinica A; dor neuropática


Trigeminal neuralgia (TN) is a unilateral disorder characterized by brief electric-shock-like attacks of pain, abrupt in onset and termination and limited to the distribution of one or more divisions of the trigeminal nerve1International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(1 suppl):9-160.. It is reported to have a prevalence of 0.1-0.2 per thousand and an incidence ranging from about 2 to 7.1/100 000/year and extending up to 20/100 000/year in individuals over 60 years of age. The condition is more common in women than in men (ratio 3:2)2Manzoni GC, Torelli P. Epidemiology of typical and atypical craniofacial neuralgias. Neurol Sci. 2005;26(2 suppl):s65-7. doi:10.1007/s10072-005-0410-0. Treatment includes pharmacological therapy, usually with membrane stabilizers; invasive or minimally-invasive (mainly percutaneous procedures) surgical therapies; and radiosurgery3Nurmikko TJ, Jensen TS. Trigeminal neuralgia and other facial neuralgias. In: Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA, eds. The Headaches. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2006: p. 1053-62.. In 2005, OnabotulinumtoxinA (BoNT/A) was reported to be effective for cases of TN that failed to respond to other therapies4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74. The therapeutic effect of BoNT/A in TN was first mentioned after a serendipitous finding by Wang and Jankovic5Wang A, Jankovic J. Hemifacial spasm: clinical findings and treatment. Muscle Nerve. 1998;21(12):1740-7. hdoi:10.1002/(SICI)1097-4598(199812)21:12<1740::AID-MUS17>3.0.CO;2-V
https://doi.org/10.1002/(SICI)1097-4598(...
. Reporting a case similar to the one that motivated a previous study by our group4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74, Jankovic described a patient who presented with hemifacial spasm and TN whose TN improved after treatment of the hemifacial spasm with BoNT/A. Since then, case reports and case series have been published in neurology, headache, pharmacology and pain medicine journals6Micheli F, Scorticati MC, Raina G. Beneficial effects of botulinum toxin type a for patients with painful tic convulsif. Clin Neuropharmacol. 2002;25(5):260-2. doi:10.1097/00002826-200209000-00006,7Borodic GE, Acquadro MA. The use of botulinum toxin for the treatment of chronic facial pain. J Pain. 2002;3(1):21-2. doi:10.1054/jpai.2002.27142,8Allam 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(2):182-4. doi:10.1097/00002508-200503000-00010,9Türk U, Ilhan S, Alp R, Sur H. Botulinum toxin and intractable trigeminal neuralgia. Clin Neuropharmacol. 2005;28(4):161-2. doi:10.1097/01.wnf.0000172497.24770.b0,1010 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(3):336-40. doi:10.1111/j.1468-2982.2005.00959.x,1111 Boscá-Blasco ME, Burguera-Hernández JA, Roig-Morata S, Martinez-Torres I. [Painful tic convulsif and Botulinum toxin]. Rev Neurol. 2006;42(12):729-32. Spanhish.,1212 Uluduz D, Karaali-Savrun F, Gunduz A, Kiziltan ME. An unusual case of vascular loop syndrome. J Headache Pain. 2007;8(8):242-4. doi:10.1007/s10194-007-0404-9,1313 Felicio AC, Godeiro Junior C, Borges V, Silva SM, Ferraz HB. Bilateral hemifacial spasm and trigeminal neuralgia: a unique form of painful tic convulsif. Mov Disord. 2007;22(2):285-86. doi:10.1002/mds.21202,1414 Zúñiga C, Díaz S, Piedimonte F, Micheli F. Beneficial effects of botulinum toxin type A in trigeminal neuralgia. Arq Neuropsiquiatr. 2008;66(3A):500-3. doi:10.1590/S0004-282X2008000400012. This literature, although suggesting the therapeutic effects of BoNT/A in TN, has been challenged1515 Zakrzewska JM, Cohen J, Brown J, Alksne J, Gemillion H, Linskey M et al. An open study of botulinum-A toxin treatment of trigeminal neuralgia. Neurology. 2006;66(9):1458-9. doi:10.1212/01.wnl.0000224704.05779.92or even ignored by panels of experts1616 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):1013-8. doi:10.1111/j.1468-1331.2008.02185.x,1717 Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K et al. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology. 2008;71(15):1183-90. doi:10.1212/01.wnl.0000326598.83183.04.

The present review was undertaken to give readers an overview of the available evidence that BoNT/A has a therapeutic effect on TN.

BOTULINUM NEUROTOXIN AS A THERAPEUTIC OPTION FOR TN

TN usually starts after the age of 602Manzoni GC, Torelli P. Epidemiology of typical and atypical craniofacial neuralgias. Neurol Sci. 2005;26(2 suppl):s65-7. doi:10.1007/s10072-005-0410-0,3Nurmikko TJ, Jensen TS. Trigeminal neuralgia and other facial neuralgias. In: Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA, eds. The Headaches. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2006: p. 1053-62.. In this older age group the disease poses therapeutic problems from a pharmacological and surgical standpoint because patients may develop side effects from centrally acting drugs and have contraindications for neurosurgical procedures. Furthermore, relapse may occur after surgery, and some patients may refuse additional invasive procedures. In this scenario, BoNT/A injections can be considered a therapeutic option for TN. The body of data presented below (Table) shows that most patients benefit from BoNT/A injections, as 213 (89.9%) of the 237 patients described in the studies in our review reported improvements.

Side effects reported consisted mainly of mild and transient facial paresis, which occurred after at least one injection session and was reported by Zúñiga et al. (1/12 and 2/20 patients)1414 Zúñiga C, Díaz S, Piedimonte F, Micheli F. Beneficial effects of botulinum toxin type A in trigeminal neuralgia. Arq Neuropsiquiatr. 2008;66(3A):500-3. doi:10.1590/S0004-282X2008000400012,1818 Zúñiga C, Piedimonte F, Díaz S, Micheli F. Acute treatment of trigeminal neuralgia with onabotulinum toxin A. Clin Neuropharmacol 2013;36(5):146-50. doi:10.1097/WNF.0b013e31829cb60e, Allam et al. (1/1)8Allam 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(2):182-4. doi:10.1097/00002508-200503000-00010, Borodic and Acquadro (proportion not reported)7Borodic GE, Acquadro MA. The use of botulinum toxin for the treatment of chronic facial pain. J Pain. 2002;3(1):21-2. doi:10.1054/jpai.2002.27142, Ngeow and Nair (1/1)1919 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(3):e47-50. doi:10.1016/j.tripleo.2009.03.021, Bohluli et al. (3/15)2020 Bohluli B, Motamedi MH, Bagheri SC, Bayat M, Lassemi E, Navi F 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(1):47-50. doi:10.1016/j.tripleo.2010.04.043, Wu et al. (5/22)2121 Wu CJ, Lian YJ, Zheng YK, Zhang HF, Chen Y, Xie NC et al. Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial. Cephalalgia. 2012;32(6):443-50. doi:10.1177/0333102412441721, Li et al. (10/88)2222 Li S, Lian YJ, Chen Y, Zhang HF, Ma YQ, He CH et al. Therapeutic effect of Botulinum toxin-A in 88 patients with trigeminal neuralgia with 14-month follow-up. J Headache Pain. 2014;15(1):43. doi:10.1186/1129-2377-15-43, Shehata et al. (4/10)2323 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(1):92. doi:10.1186/1129-2377-14-92 and Zhang et al. (3/53)2424 Zhang H, Lian Y, Ma Y, Chen Y, He C, Xie N 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(1):65. doi:10.1186/1129-2377-15-65. Temporary dysesthesia (1/8) and difficulties chewing on the side of the injection (1/8) were reported by Turk et al9Türk U, Ilhan S, Alp R, Sur H. Botulinum toxin and intractable trigeminal neuralgia. Clin Neuropharmacol. 2005;28(4):161-2. doi:10.1097/01.wnf.0000172497.24770.b0. Transient local edema was reported by Wu et al. (2/22) 2121 Wu CJ, Lian YJ, Zheng YK, Zhang HF, Chen Y, Xie NC et al. Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial. Cephalalgia. 2012;32(6):443-50. doi:10.1177/0333102412441721, Li et al. (3/88)2222 Li S, Lian YJ, Chen Y, Zhang HF, Ma YQ, He CH et al. Therapeutic effect of Botulinum toxin-A in 88 patients with trigeminal neuralgia with 14-month follow-up. J Headache Pain. 2014;15(1):43. doi:10.1186/1129-2377-15-43 and Zhang et al. (2/53)2424 Zhang H, Lian Y, Ma Y, Chen Y, He C, Xie N 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(1):65. doi:10.1186/1129-2377-15-65. Local hematoma was reported by Zúñiga et al. (2/20)1818 Zúñiga C, Piedimonte F, Díaz S, Micheli F. Acute treatment of trigeminal neuralgia with onabotulinum toxin A. Clin Neuropharmacol 2013;36(5):146-50. doi:10.1097/WNF.0b013e31829cb60e. Of the patients reported by our group, three presented with facial asymmetry (3/13) and one with ptosis (1/13)4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74. It should be noted that two of our patients who did not belong to our original cohort developed infectious complications (a hard palate abscess and a retropharyngeal abscess) from intra-oral BoNT/A injections. Both patients had had injections in their dental arches. The abscesses resolved with no further complications after antimicrobial therapy, but the fact that this complication occurred prompted us to stop injecting BoNT/A in the dental arches and gums. This complication was not reported by Li et al.2222 Li S, Lian YJ, Chen Y, Zhang HF, Ma YQ, He CH et al. Therapeutic effect of Botulinum toxin-A in 88 patients with trigeminal neuralgia with 14-month follow-up. J Headache Pain. 2014;15(1):43. doi:10.1186/1129-2377-15-43 or Zhang et al.2424 Zhang H, Lian Y, Ma Y, Chen Y, He C, Xie N 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(1):65. doi:10.1186/1129-2377-15-65, whose studies included some patients who received BoNT/A submucosally. None of the patients in the studies by Boscá-Blasco et al. (n = 4)1111 Boscá-Blasco ME, Burguera-Hernández JA, Roig-Morata S, Martinez-Torres I. [Painful tic convulsif and Botulinum toxin]. Rev Neurol. 2006;42(12):729-32. Spanhish., Felicio et al. (n = 1)1313 Felicio AC, Godeiro Junior C, Borges V, Silva SM, Ferraz HB. Bilateral hemifacial spasm and trigeminal neuralgia: a unique form of painful tic convulsif. Mov Disord. 2007;22(2):285-86. doi:10.1002/mds.21202, Micheli et al. (n = 1)6Micheli F, Scorticati MC, Raina G. Beneficial effects of botulinum toxin type a for patients with painful tic convulsif. Clin Neuropharmacol. 2002;25(5):260-2. doi:10.1097/00002826-200209000-00006, Uluduz et al. (n = 1)1212 Uluduz D, Karaali-Savrun F, Gunduz A, Kiziltan ME. An unusual case of vascular loop syndrome. J Headache Pain. 2007;8(8):242-4. doi:10.1007/s10194-007-0404-9, Volcy et al. (n = 1)1010 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(3):336-40. doi:10.1111/j.1468-2982.2005.00959.x reported any side effects. Overall, tolerability was good and operator-dependent effects and side effects were probably related more to the “learning curve” associated with the use of BoNT/A. With practice, these problems would, therefore, probably be eliminated.

However, the use of BoNT/A as a therapeutic option for treating TN has several drawbacks: a) there is a shortage of double-blind trials; b) the method is operator-dependent; c) there are no consensus guidelines; and d) “refractory trigeminal neuralgia” is a concept that has yet to be defined.

Nonetheless, none of these drawbacks seem to justify the rejection of BoNT/A as a therapeutic option for TN. Indeed, many of the medications used to treat TN started being used without a double-blind trial. The efficacy of BoNT/A in TN (about 90% of patients reported an improvement) was not achieved in double-blind trials involving BoNT/A for other head pains, as discussed below.

A few recent randomized, double-blind, placebo-controlled trials provide the best evidence for the efficacy of BoNT/A in TN. A study by Wu et al.2121 Wu CJ, Lian YJ, Zheng YK, Zhang HF, Chen Y, Xie NC et al. Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial. Cephalalgia. 2012;32(6):443-50. doi:10.1177/0333102412441721 and Wu and Lian2525 Wu C, Lian Y. Botulinum toxin type A for trigeminal neuralgia - we have the prima facie evidence. Cephalalgia. 2012;32(15):1156-7. doi:10.1177/0333102412459578 included 39 patients with classical TN according to the ICHD-2 criteria1International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(1 suppl):9-160. who failed to respond to conventional treatment (mean Visual Analog Scale or VAS score ≥ 4, mean attack frequency ≥ 4 per day) after neuroimaging findings ruled out any structural pathology. All the patients’ medication was maintained during the study period. Patients were excluded if they had skin problems at injection sites, were pregnant, were nursing mothers, were planning a pregnancy, were unable to use a reliable contraceptive method, had a medical condition or were using drugs that could interact negatively with BoNT/A. They were followed up for 12 weeks post-treatment. A period of 12 weeks was chosen as this is the typical duration of the motor effects of BoNT/A. Intradermal and/or subcutaneous injections of 75 U of BoNT/A (5 U/0.1 mL) were applied at 15 points (0.1 mL per point). The primary endpoints were pain attack frequency and pain severity, which were significantly affected as early as the first and second weeks, respectively (p < 0.05). Shehata et al.2323 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(1):92. doi:10.1186/1129-2377-14-92 studied 20 subjects with intractable idiopathic TN, which they defined as a failure to achieve a 50% relief in pain intensity quantified by VAS and/or the frequency of paroxysms during the previous three months. Subjects who were pregnant, had symptomatic TN (abnormal neurological examination or MRI) and were potentially unreliable during follow-up were excluded. The active treatment arm consisted of 10 patients who received 0.1 mL of BoNT/A (5 U/0.1 mL) applied subcutaneously per point (total dose ranged from 40 to 60 U) using a “follow the pain” method. After 12 weeks significant reductions in VAS scores (a decrease of 6.5 compared with 0.3 for saline) and the frequency of paroxysms were observed (both were recorded in the second week and were sustained over the follow-up period). Zúñiga et al.1818 Zúñiga C, Piedimonte F, Díaz S, Micheli F. Acute treatment of trigeminal neuralgia with onabotulinum toxin A. Clin Neuropharmacol 2013;36(5):146-50. doi:10.1097/WNF.0b013e31829cb60ereported 36 cases of subjects suffering from classical TN, some of whom had not responded satisfactorily to conventional treatments. The BoNT/A group consisted of 20 subjects who received 50 U of the toxin subcutaneously in various sites 1 cm apart. Subjects with involvement of the third branch of the trigeminal nerve received 10 U intramuscularly in the masseter muscle. At 1 month, the active treatment group reported fewer paroxysms of pain (p = 0.036). At 2 months, subjects in this group who were taking carbamazepine also showed reduced VAS scores (p = 0.02). At 3 months, the improvement in mean VAS score and number of paroxysms was sustained in the BoNT/A group (p = 0.01 and p = 0.006). There was no difference in functional impact scores between the BoNT/A and placebo groups. Finally, Zhang et al.2424 Zhang H, Lian Y, Ma Y, Chen Y, He C, Xie N 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(1):65. doi:10.1186/1129-2377-15-65 studied the effects of different dosages of BoNT/A in 84 patients with classical TN who had failed to respond to recent treatment for TN (mean pain intensity score ≥ 4, mean attack frequency ≥ 4/day; course > 4 months) and were randomized to receive saline, 25 U/mL or 75 U/mL of BoNT/A intradermally and/or submucosally (total doses were divided by 20 and applied at 20 points). Subjects were excluded if they had coagulopathy or severe heart, liver, kidney or other organ dysfunctions; were at risk if exposed to BoNT/A (e.g., myasthenia gravis); had skin problems at injection sites; had used drugs that damage neuromuscular junctions in the previous seven days; had a significant unstable medical condition or mental disease; had a history of substance abuse; or were pregnant, nursing, planning a pregnancy or using unreliable contraception methods. The VAS scores of both BoNT/A groups were lower than in the placebo group from the first to the eighth week (p < 0.017), and there was no difference between the 25 U and 75 U groups. Also, the number of responders (individuals with a reduction in mean pain score from baseline to endpoint > 50%) was higher for the active treatment groups (p < 0.017) and there was no difference between the groups that received different doses of BoNT/A. The authors concluded that both doses of BoNT/A were effective in the short term.

The potential of BoNT/A for use in the treatment of TN is attested to not only by the superior design of the randomized placebo-controlled studies, but also by the body of evidence-animal models, case reports, open trials and randomized controlled trials-available to date.

SOME INSIGHTS BEYOND TN: THE THERAPEUTIC EFFECT OF BONT/A IN MIGRAINE, TENSION-TYPE HEADACHE AND “CHRONIC DAILY HEADACHE”

In a large double-blind, placebo-controlled trial of BoNT/A for migraine, both placebo and BoNT/A proved effective in achieving a 50% or greater reduction in the number of migraine episodes per 30-day period in relation to baseline in at least 50% of all patients. However, further analysis of the data revealed that BoNT/A provided a greater benefit for those patients who had ≥ 12 and ≤ 15 migraine attacks/month2626 Aurora SK, Gawel M, Brandes JL, Pokta S, Vandenburgh AM. Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study. Headache. 2007;47(4):486-99. doi:10.1111/j.1526-4610.2006.00624.x. Conversely, a European placebo-controlled double-blind trial for the treatment of migraine failed to find statistical differences between placebo and BoNT/A groups2727 Relja M, Poole AC, Schoenen J, Pascual J, Lei X, Thompson C. A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches. Cephalalgia. 2007;27(6):492-503. doi:10.1111/j.1468-2982.2007.01315.x. A large double-blind, placebo-controlled, parallel-group study of BoNT/A for chronic tension-type headache revealed a small but significant benefit from BoNT/A at a dose of 150 U, and more patients in three BoNT/A groups than in the placebo groups had a 50% or greater decrease in tension-headache days2828 Silberstein SD, Göbel H, Jensen R, Elkind AH, Degryse R, Walcott JM et al. Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study. Cephalalgia. 2006;26(7):790-800. doi:10.1111/j.1468-2982.2006.01114.x. In placebo-controlled trials of BoNT/A for chronic daily headache, BoNT/A was superior to placebo in decreasing the number of headache days from baseline at some of the time points2929 Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache. 2005;45(4):293-307. doi:10.1111/j.1526-4610.2005.05066.x,3030 Silberstein SD, Stark SR, Lucas SM, Christie SN, Degryse RE, Turkel CC. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc.2005;80(9):1126-37. doi:10.4065/80.9.1126.

SOME INSIGHTS BEYOND TN: THE PLACEBO EFFECT OF BONT/A IN PRIMARY HEADACHES

The placebo effect of BoNT/A has been well described for more benign conditions such as primary headaches. In a large placebo-controlled dose-finding European trial of BoNT/A for migraine, about 25 to 55% of the placebo patients experienced a decrease of at least 50% in migraine frequency2727 Relja M, Poole AC, Schoenen J, Pascual J, Lei X, Thompson C. A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches. Cephalalgia. 2007;27(6):492-503. doi:10.1111/j.1468-2982.2007.01315.x. A slightly higher placebo response was found in a similar study conducted in the USA2626 Aurora SK, Gawel M, Brandes JL, Pokta S, Vandenburgh AM. Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study. Headache. 2007;47(4):486-99. doi:10.1111/j.1526-4610.2006.00624.x. In a large placebo-controlled dose-finding trial of BoNT/A for chronic tension-type headache, placebo responses at multiple time points over 120 days never reached the 25% bracket2828 Silberstein SD, Göbel H, Jensen R, Elkind AH, Degryse R, Walcott JM et al. Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study. Cephalalgia. 2006;26(7):790-800. doi:10.1111/j.1468-2982.2006.01114.x. In the same trial, the placebo also failed to decrease pain severity. In trials of BoNT/A for chronic daily headache, placebo responders rated the improvement from 21 to 23.4%2929 Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache. 2005;45(4):293-307. doi:10.1111/j.1526-4610.2005.05066.x,3030 Silberstein SD, Stark SR, Lucas SM, Christie SN, Degryse RE, Turkel CC. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc.2005;80(9):1126-37. doi:10.4065/80.9.1126. The average reduction in headache days at day 30 in these trials was less than one headache day for the placebo2929 Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache. 2005;45(4):293-307. doi:10.1111/j.1526-4610.2005.05066.x,3030 Silberstein SD, Stark SR, Lucas SM, Christie SN, Degryse RE, Turkel CC. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc.2005;80(9):1126-37. doi:10.4065/80.9.1126.

FURTHER COMMENTS ON PLACEBO AND THERAPEUTIC RESPONSE IN TN

Probably the greatest criticism leveled at studies into the use of BoNT/A to treat TN is the lack of a placebo-controlled methodology. This was highlighted by Zakrzewska et al.1515 Zakrzewska JM, Cohen J, Brown J, Alksne J, Gemillion H, Linskey M et al. An open study of botulinum-A toxin treatment of trigeminal neuralgia. Neurology. 2006;66(9):1458-9. doi:10.1212/01.wnl.0000224704.05779.92 and discussed by Sycha et al.3131 Sycha T, Kranz G, Auff E, Schnider P. Botulinum toxin in the treatment of rare head and neck pain syndromes: a systematic review of the literature. J Neurol. 2004;251(1 Suppl):I19-30. doi:10.1007/s00415-004-1106-8, who claimed that the supposed therapeutic effect could be secondary to an expectancy effect, to the natural course of disease or to spontaneous remission. As reported previously, the placebo effect of BoNT/A for primary headache disorders2626 Aurora SK, Gawel M, Brandes JL, Pokta S, Vandenburgh AM. Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study. Headache. 2007;47(4):486-99. doi:10.1111/j.1526-4610.2006.00624.x

27 Relja M, Poole AC, Schoenen J, Pascual J, Lei X, Thompson C. A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches. Cephalalgia. 2007;27(6):492-503. doi:10.1111/j.1468-2982.2007.01315.x

28 Silberstein SD, Göbel H, Jensen R, Elkind AH, Degryse R, Walcott JM et al. Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study. Cephalalgia. 2006;26(7):790-800. doi:10.1111/j.1468-2982.2006.01114.x

29 Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache. 2005;45(4):293-307. doi:10.1111/j.1526-4610.2005.05066.x
-3030 Silberstein SD, Stark SR, Lucas SM, Christie SN, Degryse RE, Turkel CC. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc.2005;80(9):1126-37. doi:10.4065/80.9.1126 has never reached efficacy rates as high as those described for BoNT/A for TN, even in reports of open-label trials3232 Binder WJ, Brin MF, Blitzer A, Pogoda JM. Botulinum toxin type A (BOTOX) for treatment of migraine. Dis Mon. 2002;48(5):323-35. doi:10.1053/mda.2002.24423, when this effect is expected to be even higher. In a double-blind, placebo-controlled crossover trial of lamotrigine in a group of patients with refractory TN, patients had poor responses to placebo, and only a single patient out of 13 rated the placebo as “much better”3333 Zakrzewska JM, Chaudhry Z, Nurmikko TJ, Patton DW, Mullens EL. Lamotrigine (lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial. Pain. 1997;73(2):223-30. doi:10.1016/S0304-3959(97)00104-8. An analysis of several placebo-controlled studies of carbamazepine for TN showed that only 6 out of 24 placebo patients had a good or excellent response3434 McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A. Anticonvulsant drugs for management of pain: a systematic review. BMJ. 1995;311(7012):1047-52. doi:10.1136/bmj.311.7012.1047. Similarly, the mean reduction in maximal pain intensity at day 14 reached only 26% for the placebo, suggesting that the placebo effect for this condition is limited3434 McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A. Anticonvulsant drugs for management of pain: a systematic review. BMJ. 1995;311(7012):1047-52. doi:10.1136/bmj.311.7012.1047. Furthermore, BoNT/A has been reported to be effective in relieving pain in TN patients treated for hemifacial spasm in whom an analgesic effect was not expected to occur5Wang A, Jankovic J. Hemifacial spasm: clinical findings and treatment. Muscle Nerve. 1998;21(12):1740-7. hdoi:10.1002/(SICI)1097-4598(199812)21:12<1740::AID-MUS17>3.0.CO;2-V
https://doi.org/10.1002/(SICI)1097-4598(...
,6Micheli F, Scorticati MC, Raina G. Beneficial effects of botulinum toxin type a for patients with painful tic convulsif. Clin Neuropharmacol. 2002;25(5):260-2. doi:10.1097/00002826-200209000-00006.

Thus, it seems reasonable to conclude that placebo responses are unlikely to have influenced the high response rate to BoNT/A for TN observed in this review. An exception might have occurred in case number four described by Zúñiga et al.1414 Zúñiga C, Díaz S, Piedimonte F, Micheli F. Beneficial effects of botulinum toxin type A in trigeminal neuralgia. Arq Neuropsiquiatr. 2008;66(3A):500-3. doi:10.1590/S0004-282X2008000400012, in whom a dramatic decrease in pain occurred minutes after the injections, an effect that can explained by DNIC (diffuse noxious inhibitory control)3535 Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M. Long-distance retrograde effects of botulinum neurotoxin A. J Neurosci. 2008;28(14):3689-96. doi:10.1523/JNEUROSCI.0375-08.2008,3636 Aoki KR. Future aspects of botulinum neurotoxins. J Neural Transm. 2008;115(4):567-73. doi:10.1007/s00702-007-0758-9,3737 PichÉ M, Arsenault M, Rainville P. Cerebral and cerebrospinal processes underlying counterirritation analgesia. J Neurosci. 2009;29(45):14236-46. doi:10.1523/JNEUROSCI.2341-09.2009.

CONSIDERATIONS ON THE THERAPEUTIC EFFECT OF BONT/A FOR TN

It may be noteworthy that in the study by Boscá-Blasco et al.1111 Boscá-Blasco ME, Burguera-Hernández JA, Roig-Morata S, Martinez-Torres I. [Painful tic convulsif and Botulinum toxin]. Rev Neurol. 2006;42(12):729-32. Spanhish. patients treated with BoNT/A for TN were not even receiving co-therapy with membrane-stabilizing drugs and that BoNT/A injections were used as the only therapy. The therapeutic effect of BoNT/A was reported to start from 3.2 ± 2 days after the injections, to be significant on day 104Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74,9Türk U, Ilhan S, Alp R, Sur H. Botulinum toxin and intractable trigeminal neuralgia. Clin Neuropharmacol. 2005;28(4):161-2. doi:10.1097/01.wnf.0000172497.24770.b0 and to last from 30 days to 6 months4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74,9Türk U, Ilhan S, Alp R, Sur H. Botulinum toxin and intractable trigeminal neuralgia. Clin Neuropharmacol. 2005;28(4):161-2. doi:10.1097/01.wnf.0000172497.24770.b0,1111 Boscá-Blasco ME, Burguera-Hernández JA, Roig-Morata S, Martinez-Torres I. [Painful tic convulsif and Botulinum toxin]. Rev Neurol. 2006;42(12):729-32. Spanhish.. Follow-up varied from 30 days to 6 months or longer; however, follow-ups longer than 6 months were not described in detail4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74,9Türk U, Ilhan S, Alp R, Sur H. Botulinum toxin and intractable trigeminal neuralgia. Clin Neuropharmacol. 2005;28(4):161-2. doi:10.1097/01.wnf.0000172497.24770.b0,1414 Zúñiga C, Díaz S, Piedimonte F, Micheli F. Beneficial effects of botulinum toxin type A in trigeminal neuralgia. Arq Neuropsiquiatr. 2008;66(3A):500-3. doi:10.1590/S0004-282X2008000400012. Wu et al.2121 Wu CJ, Lian YJ, Zheng YK, Zhang HF, Chen Y, Xie NC et al. Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial. Cephalalgia. 2012;32(6):443-50. doi:10.1177/0333102412441721, in their randomized controlled trial, showed a reduced mean VAS score in the second week and a reduced frequency of attacks at the end of the first week. In an open-label study to evaluate the long term efficacy of BoNT/A, Li et al.2222 Li S, Lian YJ, Chen Y, Zhang HF, Ma YQ, He CH et al. Therapeutic effect of Botulinum toxin-A in 88 patients with trigeminal neuralgia with 14-month follow-up. J Headache Pain. 2014;15(1):43. doi:10.1186/1129-2377-15-43 showed that the prevalence of patients with pain relief ≥ 50% based on VAS score was 63.6 and 38.6% at 6 and 14 months, respectively. The varied duration of the therapeutic effect may have been due to differences between patients, the natural history of the disease, the methodology or different placebo effects, although the response to BoNT/A has been reported to be consistent after regularly administered injections, a result that would not be expected for a placebo. Moreover, the reduction in pain documented in patients in a study by our group4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74 had a centripetal or shrinking pattern, which would not be expected for a placebo effect (Figure 1). In the same study, TN trigger points disappeared after BoNT/A injections for TN, although this was not described in the report4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74. Lastly, in two studies, five previously refractory patients were able to stop concomitant treatment with membrane stabilizers4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74,8Allam 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(2):182-4. doi:10.1097/00002508-200503000-00010. The argument that the remissions could have been drug-induced or due to the natural history of the disease can be refuted by the fact that these patients continued needing BoNT/A injections to remain symptom-free. Recently, Zúñiga et al.1818 Zúñiga C, Piedimonte F, Díaz S, Micheli F. Acute treatment of trigeminal neuralgia with onabotulinum toxin A. Clin Neuropharmacol 2013;36(5):146-50. doi:10.1097/WNF.0b013e31829cb60e showed that only those subjects receiving BoNT/A and carbamazepine reported lower average VAS scores at 2 months after injection. This suggests a synergism between both drugs. It is reasonable to suggest that BoNT/A acts by making neuronal sensitization revert to its baseline state and that carbamazepine sustains this effect. In some patients in whom the therapeutic effect lasted up to six months, BoNT/A-triggered remission rather than a placebo effect might have occurred.

Figure 1
Reduction in pain: the centripetal or shrinking pattern.

BONT/A EFFECT IN SYMPTOMATIC TN

A pertinent question is whether BoNT/A is effective for both classical and symptomatic TN. Most TN patients in whom BoNT/A was tried had classical TN. Six patients had ipsilateral neurological symptoms, such as hemifacial spasm4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74,6Micheli F, Scorticati MC, Raina G. Beneficial effects of botulinum toxin type a for patients with painful tic convulsif. Clin Neuropharmacol. 2002;25(5):260-2. doi:10.1097/00002826-200209000-00006,1111 Boscá-Blasco ME, Burguera-Hernández JA, Roig-Morata S, Martinez-Torres I. [Painful tic convulsif and Botulinum toxin]. Rev Neurol. 2006;42(12):729-32. Spanhish.,1313 Felicio AC, Godeiro Junior C, Borges V, Silva SM, Ferraz HB. Bilateral hemifacial spasm and trigeminal neuralgia: a unique form of painful tic convulsif. Mov Disord. 2007;22(2):285-86. doi:10.1002/mds.21202, and two had contralateral hemifacial spasm but no associated neurological deficit, which in the presence of a vascular loop would differentiate one condition from another. Two of the patients described by Boscá-Blasco et al.1111 Boscá-Blasco ME, Burguera-Hernández JA, Roig-Morata S, Martinez-Torres I. [Painful tic convulsif and Botulinum toxin]. Rev Neurol. 2006;42(12):729-32. Spanhish. had associated Chiari type I malformation, a finding that would render the cases symptomatic. Yoon et al.3838 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(4):630-2. doi:10.1111/j.1526-4637.2010.00801.xdescribed a patient with neuropathic pain after dental procedures3838 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(4):630-2. doi:10.1111/j.1526-4637.2010.00801.x. One of our more recent patients, who was not included in our study, had a severe complication caused by a balloon compression procedure carried out at another center. Her TN persisted, together with hyperesthesia, but she was responsive to BoNT/A procedures. The patient described by Allam et al.8Allam 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(2):182-4. doi:10.1097/00002508-200503000-00010 had post-procedure neuropathic pain, which also improved with BoNT/A injections. Stubblefield et al.3939 Stubblefield MD, Levine A, Custodio CM, Fitzpatrick T. The role of botulinum toxin type A in the radiation fibrosis syndrome: a preliminary report. Arch Phys Med Rehabil. 2008;89(3):417-21. doi:10.1016/j.apmr.2007.11.022 reported on the efficacy of BoNT/A for treating TN and other painful conditions in patients with radiation fibrosis after radiotherapy for cancer. Their report did not give details of the criteria upon which their conclusion was based, and the response of both TN patients and a cervical plexus neuralgia patient were considered together, making it difficult to interpret the results. However, there is new evidence that BoNT/A is effective for other types of neuropathic pain4040 Ranoux D, Attal N, Morain F, Bouhassira D. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol. 2008;64(3):274-83. doi:10.1002/ana.21427. A neuropathic trigeminal pain model in Rattus norvegicus that used saline for comparison also showed the efficacy of BoNT/A4141 Piovesan EJ, Leite LS, Teive HG, Kowacs PA, Mulinari RA, Radunz V et al. Botulinum toxin type-A effect as a preemptive treatment in a model of acute trigeminal pain: a pre-clinical double-blind and placebo-controlled study. Arq Neuropsiquiatr. 2011;69(1):56-63. doi:10.1590/S0004-282X2011000100012.

EXPERIMENTAL BASIS FOR THE IMPROVEMENT OF TN AFTER BONT/A

BoNT/A may cause rapid improvement in neuropathic pain, as in the experimental study by Cui et al.4242 Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain. 2004;107(1-2):125-33. doi:10.1016/j.pain.2003.10.008, in which BoNT/A prevented formalin-induced pain five hours after it was injected in rat hind paws. Thus, the improvement observed by Türk et al.9Türk U, Ilhan S, Alp R, Sur H. Botulinum toxin and intractable trigeminal neuralgia. Clin Neuropharmacol. 2005;28(4):161-2. doi:10.1097/01.wnf.0000172497.24770.b0 several hours after BoNT/A injections were administered cannot be considered necessarily to be secondary to a placebo effect, since an early BoNT/A effect can be supported by this recent evidence. However, in humans the therapeutic effect of BoNT/A for TN seems to peak between days 20 and 30 after the injections4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74. Another finding suggesting BoNT/A is effective for TN is that in some patients the pain paroxysms recurred within 90 days, the time required for neuronal sprouting3535 Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M. Long-distance retrograde effects of botulinum neurotoxin A. J Neurosci. 2008;28(14):3689-96. doi:10.1523/JNEUROSCI.0375-08.2008,3636 Aoki KR. Future aspects of botulinum neurotoxins. J Neural Transm. 2008;115(4):567-73. doi:10.1007/s00702-007-0758-9. These recurrences were reported to occur even in the presence of associated drug therapy4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74,6Micheli F, Scorticati MC, Raina G. Beneficial effects of botulinum toxin type a for patients with painful tic convulsif. Clin Neuropharmacol. 2002;25(5):260-2. doi:10.1097/00002826-200209000-00006,1414 Zúñiga C, Díaz S, Piedimonte F, Micheli F. Beneficial effects of botulinum toxin type A in trigeminal neuralgia. Arq Neuropsiquiatr. 2008;66(3A):500-3. doi:10.1590/S0004-282X2008000400012. In patients who also presented with hemifacial spasm, recurrence of the hemifacial spasm in most cases paralleled that of TN, and both were described as responsive to further injections of BoNT/A6Micheli F, Scorticati MC, Raina G. Beneficial effects of botulinum toxin type a for patients with painful tic convulsif. Clin Neuropharmacol. 2002;25(5):260-2. doi:10.1097/00002826-200209000-00006,1111 Boscá-Blasco ME, Burguera-Hernández JA, Roig-Morata S, Martinez-Torres I. [Painful tic convulsif and Botulinum toxin]. Rev Neurol. 2006;42(12):729-32. Spanhish., suggesting that the drug’s mechanism of action was similar or shared for both conditions. The supposed mechanism of action of BoNT/A for TN is not within the scope of this paper; however, it has been reported that BoNT/A has an analgesic/anti-neuralgic effect by inhibiting the release of selected neuropeptides and glutamate from primary sensory neurons, directly preventing the sensitization of peripheral pain fibers, indirectly preventing central sensitization and, in dorsal root ganglion cells, inhibiting surface expression of TRPV1 (a vanilloid receptor), which is critical for the release of pain mediators3636 Aoki KR. Future aspects of botulinum neurotoxins. J Neural Transm. 2008;115(4):567-73. doi:10.1007/s00702-007-0758-9. More recently, evidence that BoNT/A acts centrally has been reported3535 Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M. Long-distance retrograde effects of botulinum neurotoxin A. J Neurosci. 2008;28(14):3689-96. doi:10.1523/JNEUROSCI.0375-08.2008.

Constriction of Rat Infraorbital Nerve as a Model of Trigeminal Neuropathic Pain and the BoNT/A Effect

Constriction of the infraorbital nerve (a branch of the trigeminal nerve inRattus norvegicus) appears to be a replicable model of trigeminal neuropathy (Figure 2). Unilateral constriction of the infraorbital nerve or injection of formalin in this region produces peripheral and central sensitization. Unilateral application of BoNT/A produces a reduction in plasma extravasation, a major component of inflammation, and eliminates mechanical allodynia from this region4343 Filipović B, Matak I, Bach-Rojecky L, Lacković 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(1):e29803. doi:10.1371/journal.pone.0029803. In animal models in which constriction of the infraorbital nerve produces tactile allodynia with increased expression of FM4-644444 Kitamura Y, Matsuka Y, Spigelman I, Ishihara Y, Yamamoto Y, Sonoyama W 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(4):1422-9. doi:10.1016/j.neuroscience.2009.01.066 and thermal hyperalgesia4545 Kumada A, Matsuka Y, Spigelman I, Maruhama K, Yamamoto Y, Neubert JK 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(1):63-72. doi:10.1111/j.1365-2842.2011.02236.x, both dysfunctions are easily inhibited with prior use of BoNT/A.

Figure 2
Mechanisms involved in the genesis of neuropathic pain.

Neurobiological mechanisms responsible for the antinociceptive activity of BoNT/A

After being injected in the subcutaneous tissue, BoNT/A is taken up by endocytosis at nerve terminals of C fibers and rises by retrograde axonal transport through the trigeminal ganglion to the spinal trigeminal nucleus4646 Matak I, Bach-Rojecky L, Filipović B, Lacković Z. Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A. Neuroscience. 2011;186:201-7. doi:10.1016/j.neuroscience.2011.04.026. One of the main antinociceptive effects of BoNT/A is probably related to its ability to block the transport of nociceptive input to centers modulating nociception4343 Filipović B, Matak I, Bach-Rojecky L, Lacković 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(1):e29803. doi:10.1371/journal.pone.0029803.

BoNT/A negatively modulates nociceptive neurotransmitters. Its action can be preganglionic, on CGRP4747 Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache. 2004;44(1):35-43. doi:10.1111/j.1526-4610.2004.04007.x,4848 Meng J, Wang J, Lawrence G, Dolly JO. Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential. J Cell Sci. 2007;120(16):2864-74. doi:10.1242/jcs.012211,4949 Meng J, Ovsepian SV, Wang J, Pickering M, Sasse A, Aoki KR et al. Activation of TRPV1 mediates calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by a retargeted botulinum toxin with anti-nociceptive potential. J Neurosci. 2009;29(15):4981-92. doi:10.1523/JNEUROSCI.5490-08.2009, substance P5050 Ishikawa H, Mitsui Y, Yoshitomi T, Mashimo K, Aoki S, Mukuno K 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(2):106-9. doi:10.1016/S0021-5155(99)00197-5 and glutamate5151 Carlton SM, Hargett GL, Coggeshall RE. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett. 1995;197(1):25-8. doi:10.1016/0304-3940(95)11889-5, or postganglionic, on synaptic terminations, blocking the release of norepinephrine (NE) and adenosine triphosphate (ATP)5252 Verma G. Role of botulinum toxin type-A (BTX-A) in the management of trigeminal neuralgia. Pain Res Treat. 2013;2013:831094. doi:10.1155/2013/831094,5353 Mense S. Neurobiological basis for the use of botulinum toxin in pain therapy. J Neurol 2004;251(1 Suppl):I1-7. doi:10.1007/s00415-004-1102-z. A third mechanism may involve internal and external sensory adaptation. In external neural adaptation, BoNT/A reduces secretion of neuroeffector substances from mast cells, blood vessel endothelium and sensory nerve tissue5454 Borodic GE, Acquadro M, Johnson EA. Botulinum toxin therapy for pain and inflammatory disorders: mechanisms and therapeutic effects. Expert Opin Investig Drugs. 2001;10(8):1531-44. doi:10.1517/13543784.10.8.1531.

One of the main mechanisms responsible for the antinociceptive action of BoNT/A in the treatment of trigeminal neuralgia may be its ability to modulate intrinsic sensory adaptation (by controlling vesicular traffic), which it does by acting directly on transient receptor potential (TRP) ion channels. The TRPs act as integrators of several stimuli and signaling pathways. Dysfunction of these channels contributes to thermal hyperalgesia and allodynia under painful pathological conditions such as trigeminal neuropathy. Among these receptors, those that can potentially be used to treat trigeminal neuralgia include TRPV1, TRPV2, TRPV4, TRPM3, TRPM8 and TRPA15555 Ferrandiz-Huertas C, Mathivanan S, Wolf CJ, Devesa I, Ferrer-Montiel A. Trafficking of ThermoTRP Channels. Membranes (Basel) 2014;4(3):525-64. doi:10.3390/membranes4030525. The vanilloid receptor TRPV1 is potentially inhibited after injection of BoNT/A in the region of the first trigeminal branch5656 Shimizu T, Shibata M, Toriumi H, Iwashita T, Funakubo M, Sato H et al. Reduction of TRPV1 expression in the trigeminal system by botulinum neurotoxin type-A. Neurobiol Dis. 2012;48(3):367-8. doi:10.1016/j.nbd.2012.07.010. The effect of BoNT/A on TRPV1 expression in trigeminal neuralgia leads to reduced expression of CGRP and satisfactory control of facial pain4949 Meng J, Ovsepian SV, Wang J, Pickering M, Sasse A, Aoki KR et al. Activation of TRPV1 mediates calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by a retargeted botulinum toxin with anti-nociceptive potential. J Neurosci. 2009;29(15):4981-92. doi:10.1523/JNEUROSCI.5490-08.2009. When blocked, TRPA1 provides a satisfactory reduction in facial mechanical allodynia and cold hyperalgesia5757 Honda K, Shinoda M, Furukawa A, Kita K, Noma N, Iwata K. TRPA1 contributes to capsaicin-induced facial cold hyperalgesia in rats. Eur J Oral Sci.2014;122(6):391-6. doi:10.1111/eos.12157,5858 Gualdani R, Ceruti S, Magni G, Merli D, Di Cesare Mannelli L, Francesconi O et al. Lipoic-based TRPA1/TRPV1 antagonist to treat orofacial pain. ACS Chem Neurosci 2015;6(3):380-5.. doi:10.1021/cn500248u. To date, no studies showing the effect of BoNT/A on TRPA1 have been published.

FINAL REMARKS

There is a lack of sufficiently strong evidence to recommend BoNT/A as a therapeutic option with a guaranteed treatment effect. However, as a promising therapy it deserves to be studied further and investigated in additional randomized clinical trials. Further trials have, in fact, been carried out by other centers since the literature review described here was undertaken. We believe BoNT/A can be considered a treatment option and should be tailor-made for the individual on the basis of pain features, previous therapies, associated clinical conditions, recurrence of pain, side effects, contraindications and patient preferences. It is important to remember that there is no consensus regarding when BoNT/A should be indicated for TN. Furthermore, physicians wishing to treat patients with BoNT/A in an off-label fashion should have experience using this neurotoxin for other conditions involving the face, such as hemifacial spasm, or should read the pertinent literature and guidelines carefully to learn about “prohibited areas”, thus avoiding serious cosmetic and functional side effects. A lack of experience on the part of the physician administering the treatment can be overcome by strictly following the methodology described4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74, always bearing in mind that intra-oral injections should be avoided to eliminate the risk of infectious complications.

Table
Reports on the efficacy of BoNT/A for trigeminal neuralgia.

In our previous study 4Piovesan 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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74, the reduction in pain documented in our patients had a centripetal or shrinking pattern, which would not be expected for a placebo effect. A: before BoNT/A treatment the average pain areas were 2.06 cm2, 2.03 cm2 and 2.85 cm2 for V1, V2 and V3, respectively; B: 10 days after treatment there was a significant reduction in the pain area (1.40 cm2; 1.03 cm2 and 1.54 cm2, respectively); C: patients were almost symptom free 20 to 60 days after treatment (0-0.38 cm2, 0.05-0.38 cm2, 0-0.56 cm2, respectively).

References

  • 1
    International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(1 suppl):9-160.
  • 2
    Manzoni GC, Torelli P. Epidemiology of typical and atypical craniofacial neuralgias. Neurol Sci. 2005;26(2 suppl):s65-7. doi:10.1007/s10072-005-0410-0
  • 3
    Nurmikko TJ, Jensen TS. Trigeminal neuralgia and other facial neuralgias. In: Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen P, Welch KMA, eds. The Headaches. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2006: p. 1053-62.
  • 4
    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(8):1306-8. doi:10.1212/01.wnl.0000180940.98815.74
  • 5
    Wang A, Jankovic J. Hemifacial spasm: clinical findings and treatment. Muscle Nerve. 1998;21(12):1740-7. hdoi:10.1002/(SICI)1097-4598(199812)21:12<1740::AID-MUS17>3.0.CO;2-V
    » https://doi.org/10.1002/(SICI)1097-4598(199812)21:12<1740::AID-MUS17>3.0.CO;2-V
  • 6
    Micheli F, Scorticati MC, Raina G. Beneficial effects of botulinum toxin type a for patients with painful tic convulsif. Clin Neuropharmacol. 2002;25(5):260-2. doi:10.1097/00002826-200209000-00006
  • 7
    Borodic GE, Acquadro MA. The use of botulinum toxin for the treatment of chronic facial pain. J Pain. 2002;3(1):21-2. doi:10.1054/jpai.2002.27142
  • 8
    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(2):182-4. doi:10.1097/00002508-200503000-00010
  • 9
    Türk U, Ilhan S, Alp R, Sur H. Botulinum toxin and intractable trigeminal neuralgia. Clin Neuropharmacol. 2005;28(4):161-2. doi:10.1097/01.wnf.0000172497.24770.b0
  • 10
    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(3):336-40. doi:10.1111/j.1468-2982.2005.00959.x
  • 11
    Boscá-Blasco ME, Burguera-Hernández JA, Roig-Morata S, Martinez-Torres I. [Painful tic convulsif and Botulinum toxin]. Rev Neurol. 2006;42(12):729-32. Spanhish.
  • 12
    Uluduz D, Karaali-Savrun F, Gunduz A, Kiziltan ME. An unusual case of vascular loop syndrome. J Headache Pain. 2007;8(8):242-4. doi:10.1007/s10194-007-0404-9
  • 13
    Felicio AC, Godeiro Junior C, Borges V, Silva SM, Ferraz HB. Bilateral hemifacial spasm and trigeminal neuralgia: a unique form of painful tic convulsif. Mov Disord. 2007;22(2):285-86. doi:10.1002/mds.21202
  • 14
    Zúñiga C, Díaz S, Piedimonte F, Micheli F. Beneficial effects of botulinum toxin type A in trigeminal neuralgia. Arq Neuropsiquiatr. 2008;66(3A):500-3. doi:10.1590/S0004-282X2008000400012
  • 15
    Zakrzewska JM, Cohen J, Brown J, Alksne J, Gemillion H, Linskey M et al. An open study of botulinum-A toxin treatment of trigeminal neuralgia. Neurology. 2006;66(9):1458-9. doi:10.1212/01.wnl.0000224704.05779.92
  • 16
    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):1013-8. doi:10.1111/j.1468-1331.2008.02185.x
  • 17
    Gronseth G, Cruccu G, Alksne J, Argoff C, Brainin M, Burchiel K et al. Practice parameter: the diagnostic evaluation and treatment of trigeminal neuralgia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies. Neurology. 2008;71(15):1183-90. doi:10.1212/01.wnl.0000326598.83183.04
  • 18
    Zúñiga C, Piedimonte F, Díaz S, Micheli F. Acute treatment of trigeminal neuralgia with onabotulinum toxin A. Clin Neuropharmacol 2013;36(5):146-50. doi:10.1097/WNF.0b013e31829cb60e
  • 19
    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(3):e47-50. doi:10.1016/j.tripleo.2009.03.021
  • 20
    Bohluli B, Motamedi MH, Bagheri SC, Bayat M, Lassemi E, Navi F 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(1):47-50. doi:10.1016/j.tripleo.2010.04.043
  • 21
    Wu CJ, Lian YJ, Zheng YK, Zhang HF, Chen Y, Xie NC et al. Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial. Cephalalgia. 2012;32(6):443-50. doi:10.1177/0333102412441721
  • 22
    Li S, Lian YJ, Chen Y, Zhang HF, Ma YQ, He CH et al. Therapeutic effect of Botulinum toxin-A in 88 patients with trigeminal neuralgia with 14-month follow-up. J Headache Pain. 2014;15(1):43. doi:10.1186/1129-2377-15-43
  • 23
    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(1):92. doi:10.1186/1129-2377-14-92
  • 24
    Zhang H, Lian Y, Ma Y, Chen Y, He C, Xie N 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(1):65. doi:10.1186/1129-2377-15-65
  • 25
    Wu C, Lian Y. Botulinum toxin type A for trigeminal neuralgia - we have the prima facie evidence. Cephalalgia. 2012;32(15):1156-7. doi:10.1177/0333102412459578
  • 26
    Aurora SK, Gawel M, Brandes JL, Pokta S, Vandenburgh AM. Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study. Headache. 2007;47(4):486-99. doi:10.1111/j.1526-4610.2006.00624.x
  • 27
    Relja M, Poole AC, Schoenen J, Pascual J, Lei X, Thompson C. A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches. Cephalalgia. 2007;27(6):492-503. doi:10.1111/j.1468-2982.2007.01315.x
  • 28
    Silberstein SD, Göbel H, Jensen R, Elkind AH, Degryse R, Walcott JM et al. Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study. Cephalalgia. 2006;26(7):790-800. doi:10.1111/j.1468-2982.2006.01114.x
  • 29
    Mathew NT, Frishberg BM, Gawel M, Dimitrova R, Gibson J, Turkel C. Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Headache. 2005;45(4):293-307. doi:10.1111/j.1526-4610.2005.05066.x
  • 30
    Silberstein SD, Stark SR, Lucas SM, Christie SN, Degryse RE, Turkel CC. Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc.2005;80(9):1126-37. doi:10.4065/80.9.1126
  • 31
    Sycha T, Kranz G, Auff E, Schnider P. Botulinum toxin in the treatment of rare head and neck pain syndromes: a systematic review of the literature. J Neurol. 2004;251(1 Suppl):I19-30. doi:10.1007/s00415-004-1106-8
  • 32
    Binder WJ, Brin MF, Blitzer A, Pogoda JM. Botulinum toxin type A (BOTOX) for treatment of migraine. Dis Mon. 2002;48(5):323-35. doi:10.1053/mda.2002.24423
  • 33
    Zakrzewska JM, Chaudhry Z, Nurmikko TJ, Patton DW, Mullens EL. Lamotrigine (lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial. Pain. 1997;73(2):223-30. doi:10.1016/S0304-3959(97)00104-8
  • 34
    McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A. Anticonvulsant drugs for management of pain: a systematic review. BMJ. 1995;311(7012):1047-52. doi:10.1136/bmj.311.7012.1047
  • 35
    Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M. Long-distance retrograde effects of botulinum neurotoxin A. J Neurosci. 2008;28(14):3689-96. doi:10.1523/JNEUROSCI.0375-08.2008
  • 36
    Aoki KR. Future aspects of botulinum neurotoxins. J Neural Transm. 2008;115(4):567-73. doi:10.1007/s00702-007-0758-9
  • 37
    PichÉ M, Arsenault M, Rainville P. Cerebral and cerebrospinal processes underlying counterirritation analgesia. J Neurosci. 2009;29(45):14236-46. doi:10.1523/JNEUROSCI.2341-09.2009
  • 38
    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(4):630-2. doi:10.1111/j.1526-4637.2010.00801.x
  • 39
    Stubblefield MD, Levine A, Custodio CM, Fitzpatrick T. The role of botulinum toxin type A in the radiation fibrosis syndrome: a preliminary report. Arch Phys Med Rehabil. 2008;89(3):417-21. doi:10.1016/j.apmr.2007.11.022
  • 40
    Ranoux D, Attal N, Morain F, Bouhassira D. Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann Neurol. 2008;64(3):274-83. doi:10.1002/ana.21427
  • 41
    Piovesan EJ, Leite LS, Teive HG, Kowacs PA, Mulinari RA, Radunz V et al. Botulinum toxin type-A effect as a preemptive treatment in a model of acute trigeminal pain: a pre-clinical double-blind and placebo-controlled study. Arq Neuropsiquiatr. 2011;69(1):56-63. doi:10.1590/S0004-282X2011000100012
  • 42
    Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain. 2004;107(1-2):125-33. doi:10.1016/j.pain.2003.10.008
  • 43
    Filipović B, Matak I, Bach-Rojecky L, Lacković 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(1):e29803. doi:10.1371/journal.pone.0029803
  • 44
    Kitamura Y, Matsuka Y, Spigelman I, Ishihara Y, Yamamoto Y, Sonoyama W 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(4):1422-9. doi:10.1016/j.neuroscience.2009.01.066
  • 45
    Kumada A, Matsuka Y, Spigelman I, Maruhama K, Yamamoto Y, Neubert JK 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(1):63-72. doi:10.1111/j.1365-2842.2011.02236.x
  • 46
    Matak I, Bach-Rojecky L, Filipović B, Lacković Z. Behavioral and immunohistochemical evidence for central antinociceptive activity of botulinum toxin A. Neuroscience. 2011;186:201-7. doi:10.1016/j.neuroscience.2011.04.026
  • 47
    Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache. 2004;44(1):35-43. doi:10.1111/j.1526-4610.2004.04007.x
  • 48
    Meng J, Wang J, Lawrence G, Dolly JO. Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential. J Cell Sci. 2007;120(16):2864-74. doi:10.1242/jcs.012211
  • 49
    Meng J, Ovsepian SV, Wang J, Pickering M, Sasse A, Aoki KR et al. Activation of TRPV1 mediates calcitonin gene-related peptide release, which excites trigeminal sensory neurons and is attenuated by a retargeted botulinum toxin with anti-nociceptive potential. J Neurosci. 2009;29(15):4981-92. doi:10.1523/JNEUROSCI.5490-08.2009
  • 50
    Ishikawa H, Mitsui Y, Yoshitomi T, Mashimo K, Aoki S, Mukuno K 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(2):106-9. doi:10.1016/S0021-5155(99)00197-5
  • 51
    Carlton SM, Hargett GL, Coggeshall RE. Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett. 1995;197(1):25-8. doi:10.1016/0304-3940(95)11889-5
  • 52
    Verma G. Role of botulinum toxin type-A (BTX-A) in the management of trigeminal neuralgia. Pain Res Treat. 2013;2013:831094. doi:10.1155/2013/831094
  • 53
    Mense S. Neurobiological basis for the use of botulinum toxin in pain therapy. J Neurol 2004;251(1 Suppl):I1-7. doi:10.1007/s00415-004-1102-z
  • 54
    Borodic GE, Acquadro M, Johnson EA. Botulinum toxin therapy for pain and inflammatory disorders: mechanisms and therapeutic effects. Expert Opin Investig Drugs. 2001;10(8):1531-44. doi:10.1517/13543784.10.8.1531
  • 55
    Ferrandiz-Huertas C, Mathivanan S, Wolf CJ, Devesa I, Ferrer-Montiel A. Trafficking of ThermoTRP Channels. Membranes (Basel) 2014;4(3):525-64. doi:10.3390/membranes4030525
  • 56
    Shimizu T, Shibata M, Toriumi H, Iwashita T, Funakubo M, Sato H et al. Reduction of TRPV1 expression in the trigeminal system by botulinum neurotoxin type-A. Neurobiol Dis. 2012;48(3):367-8. doi:10.1016/j.nbd.2012.07.010
  • 57
    Honda K, Shinoda M, Furukawa A, Kita K, Noma N, Iwata K. TRPA1 contributes to capsaicin-induced facial cold hyperalgesia in rats. Eur J Oral Sci.2014;122(6):391-6. doi:10.1111/eos.12157
  • 58
    Gualdani R, Ceruti S, Magni G, Merli D, Di Cesare Mannelli L, Francesconi O et al. Lipoic-based TRPA1/TRPV1 antagonist to treat orofacial pain. ACS Chem Neurosci 2015;6(3):380-5.. doi:10.1021/cn500248u

Publication Dates

  • Publication in this collection
    11 Aug 2015
  • Date of issue
    Oct 2015

History

  • Received
    20 Mar 2015
  • Reviewed
    23 Apr 2015
  • Accepted
    12 May 2015
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