Botulinum toxin in pain management of trigeminal neuralgia: literature review

Romero, João Gabriel de Azevedo José; Pedras, Roberto Brígido de Nazareth; Almeida-Leite, Camila Megale

doi:10.5935/2595-0118.20200185

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REVIEW ARTICLE • BrJP 3 (4) • Oct-Dec 2020 • https://doi.org/10.5935/2595-0118.20200185 copy

Botulinum toxin in pain management of trigeminal neuralgia: literature review

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

BACKGROUND AND OBJECTIVES:

Botulinum neurotoxin type A has been an interesting therapeutic complement to the conventional treatment of trigeminal neuralgia, especially in patients without satisfactory response to pharmacotherapy and/or surgical procedures. A detailed and comprehensive literature review its important for the description of the available evidence, allowing for a critical view on the topic. Therefore, this study's objective was to describe the scientific evidence on the use of botulinum toxin type A in the trigeminal neuralgia treatment.

Pubmed and Scielo databases were searched using the descriptors: "trigeminal neuralgia and botulinum toxin". Inclusion criteria were human studies (open-label, double-blind, randomized, and placebo-controlled trials) and reviews of the use of botulinum toxin type A in trigeminal neuralgia treatment, published in English, Spanish or Portuguese from January 2008 to March 2020. Twenty-one articles met the inclusion criteria. Overall, studies demonstrated that botulinum toxin type A significantly reduced pain intensity and paroxysmal episodes, as well as improved quality of life.

CONCLUSION:

Use of botulinum toxin type A in treatment of refractory trigeminal neuralgia shows promising results, but further studies are needed to increase the knowledge and consolidation of this therapeutic alternative.

Keywords:
Botulinum toxins; Facial pain; Trigeminal neuralgia

Authors	Number of patients	Site and route of administration	BoNT/A dose (Total)	Evaluation period	Results	Adverse effects
Zuñiga et al.¹⁶16 Zúñiga C, Díaz S, Piedemonte F, Micheli F. Beneficial effects of botulinum toxin type A in trigeminal neuralgia. ArqNeuropsiquiatr. 2008;66(3):500-3.	12	Trigger zones and masseter/subcutaneous route	20 - 50U	Weekly during 8 weeks after application	Reduction of paroxysmal episodes and pain intensity; 10 patients presented immediate relief or in a couple of minutes after the injection of BoNT/A	Facial asymmetry
Bohluli et al.¹⁷17 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.	15	Trigger zones/ does not report administration route	50-100U in each trigger zone	Base period (1 week) and 1 and 6 months after application	All patients presented reduction of paroxysmal episodes and intensity of pain; 3 patients returned responding to the pharmacological therapy with anticonvulsants	Transitory paresthesia of the facial nerve
Li et al. ²¹21 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;15:43.	88 divided in three groups 43 (BoNT/A ≤ 50U) 32 (BoNT/A 50-100U) 13 (BoNT/A ≥ 100U)	15-20 trigger zones/subcutaneous and/or submucous route (4 - 10 zones)	≤50U 50-100U ≥100U	Weekly for 2 months and monthly until 14 months after application	All patients presented effective improvement after 2 months of treatment; reduction of the effect of BoNT/A after 3 months; absence of significant differences between groups treated with different dosages	Edema and muscle relaxation
Xia et al.²³23 Xia JH, He CH, Zhang HF, Lian YJ, Chen Y, Wu CJ, et al. Botulinum toxin A in treatment of trigeminal neuralgia. Int J Neurosci. 2016;126(4):348-53.	87	15-20 trigger zones or pain sites / intradermal route	Does not mention used dosage	Base period (1 week) and weekly during 8 weeks after application	The results were significant for the reduction of pain intensity by the end of 8 weeks; improvement in anxiety (90.32%), depression (96.77%) and sleep disorders was also registered	Edema and muscle relaxation
Zhang et al.²⁴24 Zhang H, Lian Y, Xie N, Chen C, Zheng Y. Single-dose botulinum toxin type a compared with repeated-dose for treatment of trigeminal neuralgia: a pilot study. J Headache Pain. 2017;18(1):81.	100 divided in two groups 50 (single dose) 50 (two doses)	15-20 points of pain / intradermal and/or submucous route	70 - 100 U (single dose) 100 - 140 U (two doses)	Weekly for 1 month and monthly until 6 months after application	The duration of the BoNT/A effect was greater in the single dosage group; both groups presented significant results for the reduction of pain intensity and no differences were identified in the comparison between groups	Not specified
Borü et al.²⁵25 TürkBörü Ü, Duman A, Bölük C, Coskun Duman S, Tasdemir M. Botulinum toxin in the treatment of trigeminal neuralgia 6-month follow-up. Medicine. 2017;96(39):e8133.	27	Maxillary and mandibular root	100 U	Base period (1 day) and 1 week, 1 and 6 months after application	Significant results for the reduction of pain intensity, frequency of paroxysmal attacks and improvement perception; by the end of treatment, 24 patients presented a reduction of ≥50% in pain intensity	Muscle weakness
Caldera et al.²⁶26 Caldera MC, Senanayake SJ, Perera SP, Perera NN, Gamage R, Gooneratne IK. Efficacy of botulinum toxin type A in trigeminal neuralgia in a south Asian cohort. J Neurosci Rural Pract. 2018;9(1):100-5.	22	Trigger zones or pain sites/intradermal route	15 - 50 U	10, 20, 30, 60 e 90 days after the application	The patients who received the BoNT/A presented significant reduction in pain intensity; no significant differences were found in the comparisons of pain intensity reduction according to different dosages and sites of application.	Not reported
Liu et al.²⁷27 Liu J, Xu YY, Zhang QL, Luo WF. Efficacy and safety of botulinum toxin type A in treating patients of advanced age with idiopathic trigeminal neuralgia. Pain Res Manag. 2018;2018:7365148.	43 14 (≥80 years) 29 (<60 years)	Trigger zones and pain sites /intradermal and/or submucous route	45 - 150 U (≥80 years) 30 - 200 U (<60 years)	1 month after application	The results of the two groups were significant for the reduction of pain intensity; the comparison of results between the two groups was not statistically significant.	Facial palsy and eyelid ptosis
Wu et al. ²⁸28 Wu S, Lian Y, Zhang H, Chen Y, Wu C, Li S, et al. Botulinum toxin A for a refractory trigeminal neuralgia in older patients: a better therapeutic effect. J Pain Res. 2019;12:2177-86.	104 25 (<50 years) 79 (≥50 years)	Trigger zones and/or pain sites/intradermal and/or submucous route	5U for each point (intradermal route) 2,5 U for each point (submucous route)	Weekly for 2 months and monthly for 12 months	The results show that 87 patients presented significant improvement in pain; the group assessment showed good pain control in 83.3% (≥50anos) and 57.7% (<50 years).	Facial asymmetry
Zhang et al.²⁹29 Zhang H, Lian Y, Xie N, Cheng X, Chen C, Xu H, et al. Factors affecting the therapeutic effect of botulinum toxin A on trigeminal neuralgia: A follow-up retrospective study of 152 patients. Exp Ther Med. 2019;18(5):3375-82.	152	15-25 Trigger zones and pain sites/intradermal and/or submucous route	1,25 - 5 U for each trigger zone <40 U 40-70 U >70 U	Minimum monitoring of 6 months and maximum of 28 months	Results show a general efficacy rate of 89.4%, maintaining the effects of BoNT/A during the first 6 months of monitoring.	Facial asymmetry

Authors	Number of patients	Site and route of administration	BoNT/A dosage (Total)	Evaluation period	Results	Adverse effects
Wu et al. ¹⁸18 Wu CJ, Lian YJ, Zheng YK, Zhang HF, Chen Y, Chang N, 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.	42 divided in two groups 22 (BoNT/A) 20 (Placebo)	15 trigger zones/ intradermal and/or submucous route	75 U 5 U in each trigger zone	Base period (1 week) and weekly during 12 weeks after application	Reduction of the paroxysmal episodes and pain intensity; 15 patients presented reduction of >50% in the VAS scores; 17 patients reported improvement after therapy with BoNT/A	Edema and facial asymmetry
Zuñiga et al.¹⁹19 Zúñiga C, Piedemonte F, Díaz S, Micheli F. Acute treatment of trigeminal neuralgia with onabotulinum toxin A. Clin Neuropharmacol. 2013;36(5):146-50.	36 divided in two groups 20 (BoNT/A) 16 (Placebo)	Points in the area innervated by the affected branch and masseter/submucous route	50 U	1, 2 and 3 months after application	Reduction of paroxysmal episodes and pain intensity in the group treated with BoNT/A	Hematoma and facial asymmetry
Shehata et al.²⁰20 Shehata HS, 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.	20 divided in two groups 10 (BoNT/A) 10 (Placebo)	Trigger zones and masseter/submucous route	40 - 60 U 5U in each trigger zone	Each two weeks during the period of 12 weeks after application	Reduction of paroxysmal episodes, pain intensity and use of drugs; improvement of quality of life	Hematoma, facial asymmetry, and pain in the application site
Zhang et al.²²22 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;15:65.	84 divided in three groups 25 (BoNT/A -25U) 28 (BoNT/A-75U) 27 (Placebo)	20 trigger zones/intradermal and/or submucous route	25 U e 75 U	Base period (1 week) and weekly during 8 weeks after application	Reduction of pain intensity in groups treated with BoNT/A; absence of significant differences between groups treated with different doses	Edema and facial asymmetry

Authors	Objective	Database	Articles	Conclusions
Verma³⁰30 Verma G. Role of botulinum toxin type-A (BTX-A) in the management of trigeminal neuralgia. Pain Res Treat. 2013;2013:831094.	Evaluate available evidences on the use of BoNT/A for the treatment of TN	Does not mention the used databases	4 open label studies and 1 placebo-controlled, randomized, double-blind clinical trial	Data available in the literature is insufficient to indicate the use of BoNT/A as an alternative treatment, and new studies with larger samples are necessary.
Hu et al.³¹31 Hu Y, Guan X, Fan L, Li M, Liao Y, Nie Z, et al. Therapeutic efficacy and safety of botulinum toxin type A in trigeminal neuralgia: a systematic review. J Headache Pain. 2013;14:72.	Evaluate the efficacy, safety and tolerability of BoNT/A for the treatment of TN	PubMed, EMBASE (OVID), Cochrane and Web of Science	5 open label studies and 1 placebo-controlled, randomized, double-blind clinical trial	Results available in the literature show that BoNT/A is a promising alternative for the treatment of TN, but new studies are necessary in order to evaluate the optimal dosage, time of therapeutic efficacy and registry of adverse effects
Guardiani et al.³²32 Guardiani E, Sadoughi B, Blitzer A, Sirois D. A new treatment paradigm for trigeminal neuralgia using botulinum toxin type A. Laryngoscope. 2014;124(2):413-7.	Evaluate the available evidence on BoNT/A for the treatment of TN and description of the most indicated administration technique	Google Scholar and Medline	5 open label studies and 2 placebo-controlled, randomized, double- blind clinical trials	BoNT represents a new alternative for the treatment of TN. The most appropriate route of administration is intradermal.
Kowacs et al. ³³33 Kowacs PA, Utiumi MA, Nascimento FA, Piovesan EJ, Teive HA. On a botulinum toxin A for trigeminal neuralgia: a review of the available data. ArqNeuropsiquiatr. 2015;73(10):877-84.	Evaluate available evidences on the use of BoNT/A for the treatment of TN	Does not mention the used databases	7 clinical trials, 2 case series, 5 open label studies, 4 placebo-controlled, randomized, double-blind clinical trials and 1 citation	There are no significant evidences for the recommendation of BoNT/A as a successful alternative for the treatment of TN, but it was considered a promising therapy and new randomized and placebo-controlled studies are necessary.
Shackleton et al.³⁴34 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(1):61-71.	Evaluate available evidences on the use of BoNT/A for the treatment of TN and post-herpetic neuralgia	Medline, Web of Science e Cochrane	6 double-blind, randomized, placebo-controlled clinical trials (4 TN and 2 post-herpetic neuralgia)	There are moderate evidences to support the use of BoNT/A as a potential therapeutic alternative, but new randomized, placebo-controlled studies are necessary.
Morra et al.³⁵35 Morra ME, Elgebaly A, Elmaraezy A, Khalil AM, Altibi AM, Vu TL, 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.	Evaluate the efficacy and safety of the use of BoNT/A for the treatment of TN	10 data bases (Pubmed, Web of Science, Scopus, Google Scholar, WHO Global Health Library and others)	4 double-blind, randomized, placebo-controlled clinical trials	BoNT/A is an alternative for the treatment of TN, but in order to expand evidences, new randomized and placebo-controlled studies are necessary.
Castillo-Alvarez, Bárcena e Marzo-Sola³⁶36 Castillo-Alvarez F, Bárcena IG, Marzo-Sola ME. Botulinum toxin in trigeminal neuralgia. Med Cli. 2017;148(1):28-32.	Evaluate available evidences on the use of BoNT/A for the treatment of TN	Does not mention the used databases	8 clinical cases, 7 open label studies and 4 double-blind, randomized, placebo-controlled clinical trials	BoNT/A may be a safe and effective alternative, but to detail the therapeutic protocol new studies are necessary.

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[1] Correspondence to: Camila Megale Almeida-Leite, Avenida Antônio Carlos, 6627, Pampulha 31270-901 Belo Horizonte, MG, Brasil. E-mail: camila@icb.ufmg.br

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Botulinum toxin in pain management of trigeminal neuralgia: literature review

ABSTRACT

BACKGROUND AND OBJECTIVES:

CONTENTS:

CONCLUSION: