THE USE OF BOTULINUM TOXIN A IN THEMANAGEMENT OF TRIGEMINAL NEURALGIA:A SYSTEMATIC LITERATURE REVIEW

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Anton Rubis

5th year, OF group 14

THE USE OF BOTULINUM TOXIN A IN THE

MANAGEMENT OF TRIGEMINAL NEURALGIA:

A SYSTEMATIC LITERATURE REVIEW

Master’s Thesis

Supervisor Professor, DMD, PhD Gintaras Juodžbalys

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY FACULTY OF ODONTOLOGY

CLINIC OF MAXILLOFACIAL AND ORAL SURGERY

THE USE OF BOTULINUM TOXIN A IN THE MANAGEMENT OF TRIGEMINAL NEURALGIA:

A SYSTEMATIC LITERATURE REVIEW Master’s Thesis

Kaunas, 2020

DDS, PhD, Prof. Gintaras Juodžbalys

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FINAL MASTER‘S THESIS IS CONDUCTED

AT THE DEPARTMENT OF MAXILLOFACIAL AND ORAL SURGERY

STATEMENT OF THESIS ORIGINALITY

I confirm that the submitted Final Master‘s Thesis (tittle) THE USE OF BOTULINUM TOXIN A IN THE MANAGEMENT OF TRIGEMINAL NEURALGIA: A SYSTEMATIC LITERATURE REVIEW.

1. Is done by myself.

2. Has not been used at another university in Lithuania or abroad.

3. I did not used any additional sources that are not listed in the Thesis, and I provide a complete list of references.

I confirm by e-mail, and the work will be signed after the end of the quarantine and emergency situation due to

the COVID-19 pandemic in the republic of Lithuania.

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CONCLUSION OF FINAL MASTER‘S THESIS ACADEMIC SUPERVISOR

ON THE DEFENSE OF THE THESIS

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FINAL MASTER‘S THESIS IS APPROVED AT THE DEPARTMENT

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Evaluation of Final Master‘s Thesis Defense Board:

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I, Anton Rubis, confirm by e-mail, that the original Bioethical approval will be added at the end of quarantine and emergency situation due to the COVID-19 pandemic in the republic of Lithuania. Bioethical approval's registration No. is BEC-OF-149.

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EVALUATION TABLE OF THE MASTER’S THESIS OF THE TYPE OF

SYSTEMIC REVIEW OF SCIENTIFIC LITERATURE

Evaluation:...

Reviewer:...

(scientific degree. Name and surname)

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*Remark: the amount of collected points may exceed 10 points.

Reviewer’s comments:

____________________________________________________________________

Reviewer’s name and surname Reviewer’s signature

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ABSTRACT...9

INTRODUCTION...10-12

1. MATERIAL AND METHODS...13-17

1.1 Protocol...13

1.2 Focus questions...13

1.3 Types of publications...13

1.4 Types of studies...13

1.5 Information sources...14

1.6 Type of population...14

1.7 Disease definition...14

1.8 Literature search strategy...14

1.9 Inclusion criteria...14

1.10 Exclusion criteria...15

1.11 Sequential search strategy...15

1.12 Data extraction...15

1.13 Data items...15

1.14 Risk of bias assessment...16

1.15 Statistical analysis...17

2. RESULTS...18-26

2.1 Study selection and exclusion...18

2.2 Exclusion of studies...19

2.3 Quality assessment of the included studies...19

2.4 Study characteristics...20-26

3. DISCUSSION...27-29

4. CONCLUSION...30

5. ACKNOWLEDGEMENT AND CONFLICT OF INTERESTS...30

6. PRACTICAL RECOMMENDATIONS...31

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The Use of Botulinum Toxin in the management of Trigeminal Neuralgia: A

Systematic Literature Review

ABSTRACT

Objectives: The purpose of this article is to systematically review the use, efficacy, differences

between Botulinum toxin type A (BTX-A) doses and side effects of BTX-A therapy in patients with Trigeminal neuralgia.

Material and methods: The search of all chosen publications for the performed reviews was

done in databases including PubMed, Springer link, Science Direct, Cochrane library and in The Journal of Headache and Pain in English language from January 2010 up to February 2020.

Inclusion criteria: full-text studies on humans in English language, in which visual assessment scale (VAS) was present, in which patients with Trigeminal neuralgia (TN) were participated and

comparison between BTX-A and Saline was done.

Results: A total of 86 articles were screened and 4 of the most relevant articles that are suitable to

the citeria were selected. Articles were analyzed regarding VAS, dosages of botox in therapy, side effects. No significant differences between all articles results were found, except time of maximum efficacy of botox therapy. Maximum efficacy was noticed between 6 weeks and 3 months after the procedure with insignificant side effects. Side effects were mostly facial asymmetry after injection, headaches, hematoma, itching in the place of treatment, which disappeared in one week. No

difference between dosages of BTX-A were found.

Conclusion: Based on the results and current findings proved that BTX-A injection therapy

is a safe and effective method in management of TN. However Botulinum toxin A can not be used alone, but can relief symptoms of TN. Further studies has to be done in order to develop optimal treatment protocol.

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INTRODUCTION

Trigeminal neuralgia (TN) is one of the most painful disorders, which presents as recurrent, unilateral, brief but severe, electric-shock-like pains of rapid onset and short duration (up to 2 minutes) in the distribution of the Trigeminal nerve. It may develop without apparent cause or be a result of another diagnosed disorder. In some patients, pain may radiate to another division, but it remains within the Trigeminal dermatomes. The ICHD-3 classify Trigeminal neuralgia as classical, secondary and idiopathic (Annex 2) [1] .

Trigeminal neuralgia is twice more common in women and usually in older individuals ( above 50 years old). May also feature a constant aching pain between attacks, in the affected area, of

moderate intensity. Mostly associated with neurovascular compression of the Trigeminal nerve. It is possible to experience no-pain period for several months or even years, but with time periods become shorter with time [2,3].

Pain in the head and neck is mediated by afferent fibers in the Trigeminal nerve, nervus

intermedius, glossopharyngeal and vagus nerves and the upper cervical roots via the occipital

nerves. Stimulation of these nerves by compression, distortion, exposure to cold or other forms of irritation or by a lesion in central pathways may give rise to stabbing or constant pain felt in the area innervated [4].

The most frequent trigger actions showed were touching face (79%), talking (54%), chewing (44%) and brushing teeth (31%), this showed that for 97% of TN patients paroxysms were associated with triggers [5].

There are no special test to prove TN nowadays, thats why it is a long process and it is really important to diagnose individual with a correct diagnosis, because treatment differs. A diagnosis of TN is made by collecting and going through person’s medical history and description. For a definite diagnosis, for proper diagnostics patient requires objective signs or tests that can show an

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Other disorders that increase facial pain should be ruled out before a diagnosis of TN is made. There is postherpetic neuralgia (nerve pain that occurs after shingles), cluster headaches, and a disorder of the Temporomandibular joint (TMJ), which causes pain in the jaw joint and muscles that control jaw movement. Which is hard to due to the coincidence of the symptoms and the huge number of conditions that can cause facial pain, that is all lead to a long way in order to obtain correct diagnosis [8].

Stefano et al. [9] in key issues of Pharmacological treatment of TN accented one more time, that Carbamazepine and Oxcarbazepine, sodium channel blockers are the first line of treatment. Due to multiple side effects, when its not able reach the higher dosage of medications.

Pharmacological treatment should be one of the first steps in management of TN, surgical options are available as well and may be used together with pharmaceuticals and as well additional therapies possible, some individuals reported, that yoga helps a lot [8].

The main approach to patients with TN is to start with medications and than after careful followups if the patient does not respond to drug treatment - surgery is possible. Results of Leketas et al. [10] research states that surgical treatment results in a 27.53 months remission, less efficient are

pharmacotherapy, resulting in a 15.51 months remission. Surgical management significantly improve lifestyle of TN patients . As well it is possible to mix treatment options like

pharmacological after the surgery or to use together with complementary approaches.

Botulinum neurotoxin ( Botox) has been the № 1 aesthetic procedure performed by plastic surgeons since 1999. In 2018 more than 1.801.033 procedures were performed in the USA. Botulinum neurotoxin type A was approved for facial aesthetics in 2002 as the first botulinum toxin type A (BoNTA) [11].

Botox is a neurotoxic protein and a powerful tool in therapeutics, which is seen in the growing numbers of use. Botulinum toxin is produced by the Clostridium bacterium family [12]. Botulinum drugs are complex mixtures of compounds shows that they consist of botulinum

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Neurotoxin relaxes striated muscle by inhibiting acetylcholine’s release from presynaptic nerve terminals, blocking the neuromuscular junction. Although it is widely accepted that its therapeutic effects are restricted to the peripheral nervous system, as well actions at distant and central sites are presumed. These central effects may be the consequence of hematogenic spread, a retrograde neural transport of Botulinum neurotoxin to the central nervous system (CNS).

When Botulinum neurotoxin (BoNT) blocks the cholinergic synapse the neuron forms new synapses by replacing it is original ones ( sprouting process by Duchen L. W. 1971). However inhibition is only temporarily [14].

In dentistry, controlled clinical trials have demonstrated it is great efficiency in pathologies such as bruxism, TMJ disorders, neuropathic pain and more [12].

The hypothesis of this systematic review is that Botulinum neurotoxin A has no impact on TN patients.

The purpose of this article is to systematically review the use, efficacy, differences between Botulinum toxin type A (BTX-A) doses and side effects of BTX-A therapy in patients with Trigeminal Neuralgia. The objectives of this present study are:

• To evaluate the efficacy and side effects of BTX-A in the patients with TN. • To find differences between BTX-A doses in the patients with TN.

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1. MATERIAL AND METHODS

1.1 Protocol and registration

Analysis and inclusion criteria methods were specified in advance and documented in the protocol for systematic review according to PRISMA-P ( Annex 1).

1.2 Focus questions

The following focus question was framed according to the problem, intervention, comparison and outcome (PICO) process (table 1):

What is the efficacy and differences between BTX-A doses and side effects of BTX-A therapy in patients with Trigeminal Neuralgia?

Table 1. PICO framework of the framed clinical question.

Patient, population, problem Individuals with Trigeminal neuralgia

Intervention Botulinum toxin A

Comparison Saline (NaCl) as a placebo

Outcome Presence or absence or reduction of pain

Study design Randomized, double-blind, placebo

controlled trials

Focus questions What is the efficacy and differences

between BTX-A doses and side effects of BTX-A therapy in

patients with Trigeminal Neuralgia?

1.3 Types of publication

The review included studies on human published in English language.

1.4 Types of studies

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1.5 Information sources

The information source was the MEDLINE (PubMed), Springer link, Science Direct, Cochrane library and The Journal of Headache and Pain.

1.6 Type of population

Patients of all sex and ages, who were diagnosed with Trigeminal Neuralgia, without having any structural pathologies ( underwent MRI or CT). Women, who were not or planing to get pregnant.

1.7 Disease definition

Trigeminal neuralgia, also known as tic douloureux, is a long-term pain condition that affects the Trigeminal nerve, which is usually described as a sharp shooting pain or like “an electric shock” pain.

1.8 Literature search strategy

Wide search of online literature was done by using 4 data bases: PubMed, Springer link, Science Direct, Cochrane library and The Journal of Headache and Pain to find studies that included placebo versus Botulinm toxin A in the treatment or management of the Trigeminal neuralgia.

The Keywords used for the search included: (“trigeminal neuralgia”) OR

(“trigeminal nerve”) AND (“botulinum A toxin”) OR (“botulinum neurtoxin A”). The search was limited to English language. Articles published from January, 1st 2010 up to up to February 20th, 2020 were searched.

Flow diagram of studies selection according PRISMA guidelines (Figure 1).

1.9 Inclusion criteria

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-Studies with the amount of more than 20 individuals -Studies published between Jan 2010- Feb 2020 -Studies in English language

-Studies in which VAS was present -Studies on humans

-Full-text article studies

1.10 Exclusion criteria

-Studies on animals, not on humans

-Prospective study, abstracts, discussions, literature review and systematic reviews -studies which include postherpetic Trigeminal neuralgia

-studies which include neuropathic pains, with not mentioned TN

1.11 Sequential search strategy

The selected articles were subjected to clear inclusion and exclusion

criteria. Following the initial literature search, all article titles were chosen according title relevancy, considering the exclusion criteria. Following, studies were excluded based on irrelevant data obtained from the abstracts. The final stage of screening involved reading the full texts and confirming each study’s eligibility based on the inclusion criteria and exclusion criteria.

1.12 Data extraction

The data were independently extracted from studies in the form of variables, according to the aims and themes of the present review, as listed onwards.

1.13 Data items

Data were collected from the included articles and arranged in the following fields: • “Author ” - revealed the author of publication.

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• “Type of study” - indicated the type of the study.

• “Groups” - indicated the type of therapy (BTX-A or Placebo). • “Sample size” - described the number of patients examined.

• “Methods” - revealed the groups type (BTX-A or 0.9% Saline) and sample sizes( amount of participants in each group).

• “Dosage of BTX-A” - indicated the dose of BTX-A used in the study.

• “Mean age”- described the average age of participants in the study or in each group.

• “Female:male ratio” - indicated the amount of males or females in the study or in each group • “Mean time since TN onset”-described the average time of ongoing TN since it was diagnosed • “Carbamazepine” - described the amount of participants who was on the most common

medication used in treatment of TN before and during the studies.

• “Gabapentin” - described the amount of participants who was on the most common medication used in treatment of TN before and during the studies.

• “Other medications” - described the amount of participants who was on the medications, which are used in treatment of TN before and during the studies and name of medications.

• “Injection protocol” - revealed the dosages and sites of injections in patients. • “Administration of injections” - revealed the type of injection.

• “VAS before the therapy” - described the “visual assessment scale” results before the study(before the injections).

• “Frequency of TN attacks per day” - described the amount of pain attacks due to TN per day before the studies.

• “VAS at the endpoint” - described the “visual assessment scale” results after the injection course. • “Follow-up” - indicated the amount of time during which patients were followed up.

• “Frequency of TN attacks per day at the endpoint” - described the amount of pain attacks due to TN per day after the injection course.

• “Facial asymmetry and disappearance time” - described the amount of people, who had any side effect as a “facial asymmetry” after injections and when it disappeared.

• “Other side effects” - described other possible side effects and amount of people who had it.

1.14 Risk of bias assessment

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the outcome of each selected study. The Cochrane Handbook for Systematic Reviews of Interventions was used to assess bias present in chosen studies [15].

The Cochrane Handbook for Systematic Reviews of Interventions was used to assess bias present in chosen studies.

Risk of bias assessment parameters:

• Random sequence generation (-/+/?) • Allocation concealment (-/+/?)

• Blinding of participants and personnel (-/+/?) • Blinding of outcomes assessment (-/+/?) • Incomplete outcome data (-/+/?)

• Selective reporting (-/+/?) • Other bias (-/+/?)

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2. RESULTS

2.1 Study Selection

The review of selected publications and data extractions were performed following PRISMA flow chart guidelines. The initial identification result of articles from databases and Journal ( The Journal of Headache and Pain) search was 143. The first exclusion was done according to the relevance: 57 duplicated titles and abstracts were excluded. After 86 records were screened of the remaining articles , 71 were excluded due to insufficient required details, articles without access, articles not presenting full-text, due to language (not in English), discussion articles. 15 full-text articles were assessed as eligible. Lastly, four articles met the predefined criteria and were included in the systematic review (Figure 1).

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2.2 Exclusion of studies

The reasons for excluding of 11 full-text articles [16-26] after full-text assessment were as follows: article [16] is preliminary report, articles [17,18, 20, 23, 24] are case reports with no placebo group, articles [19, 22, 26] are literature reviews, article [21] is a study on rats, not on human and article [25] is a systematic review.

2.3 Quality assessment of the included studies

Some aspects were not presented or not presented clearly in all of chosen articles, lack of information and due to the fact that evaluation was done by a student. Risk of bias is unclear for WU et al. [27] in about 71.4% of assessing points. In the study of Shehata et al. [28] unclear risk of bias in approximately 28.57% and one of the lowest risk of bias among all articles, in the study of Zuniga et al. [29] its 57.14% and one point has potentially high risk of bias, in the study of Zhang et al. [30] unclear points were in 28.57% and one of the lowest risk of bias among all articles

( Table 2).

Fig. 2. Cochrane Risk of Bias table.

Wu et al. [27] Shehata et al. [28] Zúñiga et al. [29] Zhang et al. [30]

Random sequence generation ? - ?

-Allocation concealment ? - +

-Binding of participants and

personnel ? - -

-Blinding of outcome assessments ? ? ? ?

Incomplete outcome data ? - ?

-Selective reporting _- _- _-

-Other bias - ? ? ?

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2.4 Study characteristics

All 4 studies were randomized, double-blind, placebo-controlled trials, 2012-2014 years. [27-30] . Characteristics were summarized (Table 3). Number of patients ranged from 20 [28] to 84 [30] (178 individuals in 4 studies) and from 10 patients [27] to 28 patients [30] in the groups. Groups were graded as a control Placebo ( 0.9% NaCL, isotonic or 0.9% saline ) and a BTX-A group ( 1 in each of 3 studies [27-29] and 2 groups with different dosages [30]).

Table 3. Characteristics of studies included in systematic review, methods and dosage.

Author Year Study type Sample _{size (n)} Methods Dosage of _BTX-A

Wu et al. [27] 2012 Shehata et al. [28] 2013 Zúñiga et al. [29] 2013 Zhang et al. [30] 2014 Randomized, double-blind, placebo-controlled study 42 Gr. 1 BTX-A(n=22) Gr. 2 isotonic saline(n=20) 75 U Randomized, double-blind, placebo-controlled study 20 Gr. 1 BTX-A(n=10) Gr. 2 0.9% NaCl (n=10) 100 U Randomized, double-blind, placebo-controlled study 36 Gr. 1 BTX-A (n=20) Gr. 2 0.9% NaCl (n=16) 50 U Randomized, double-blind, placebo-controlled study 80 Gr. 1 BTX-A 25U (n=25) Gr. 1 BTX-A 75U (n=28) Gr. 2 0.9% NaCl (n=27) 25 U and 75 U

n-number; Gr- Group; U-Units per ml of solution; BTX-A - Botulinum toxin type A

Placebo group has 73 individuals and BTX-A has 105 individuals. Dosages of BTX-A started from 25U [30] and up to 100U [28].

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males, except in the placebo group of Wu et al. [27] where half of the group were females, in Placebo group of Zuniga et al. [29] female to male ratio was 6:10 and in placebo group of Zhang et al. [30] males predominated by 1.85%. Mean time since the TN onset is reflected below ( Table 4).

Table 4. Characteristics of studies included in systematic review mean age, female:male ratio and onset time.

Author Year Mean age (years) Female/male ratio Mean time since TN onset Wu et al. [27] 2012 Wu et al. [27] 2012 Shehata et al. [28] 2013 Zúñiga et al. [29] 2013 Zúñiga et al. [29] 2013 Zhang et al. [30] 2014 Zhang et al. [30] 2014 Zhang et al. [30] 2014 BTX-A 59.14 Female:BTX-A 13 (59.09%) BTX-A 72.05 months Placebo 58.00 Female:Placebo 10 (50.00%) Placebo 70.00 months 45.95 ± 10.02 for all participants Female:male=11:9 5.33 ± 1.52 years(range from 3 years to 9 years)

BTX-A 64.5 BTX-A 11:9 BTX-A 6.2 years

Placebo 66.06 Placebo 6:10 Placebo 5.2 years BTX-A (25U) 58.16 Male: BTX-A (25U)

40%

BTX-A (25U)

91.96 months

BTX-A (75U) 62.64 Male: BTX-A (75U) _42.86% BTX-A (75U) _{72.64 months} Placebo 58.41 Male: Placebo 51.85% Placebo 50.96 months BTX-A - Botulinum toxin type A

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Carbamazepine, Gabapentin and opioids. Gabapentin was the second most popular medication among TN patients, Shehata et al. [28] reported that in his study some patients were prescribed to drink it in a combination with CBZ or even with Baclofen as a triple therapy. In others studies [27,29,30] in Placebo group were reported 12 individuals and in the BTX-A 8 patients. As well in the study of Wu et al. [27] 3 participants were on Opioids and Zhang et al. [30] mentioned Opiods as a part of TN management of patients, but did not specify, which were prescribed by specialist earlier before his study. All details on medications are provided (Table 5).

Table 5. Medication, which are used by patients.

Author Groups Carbamazepine (n) Gabapentin (n) Other

medications (n) Wu et al. [27] BTX-A Wu et al. [27] BTX-A Wu et al. [27] Placebo Shehata et al. [28] BTX-A Shehata et al. [28] Placebo Zúñiga et al. [29] BTX-A Zúñiga et al. [29] BTX-A Zúñiga et al. [29] Placebo Zhang et al. [30] BTX-A (25U) Zhang et al. [30] BTX-A (75U) Zhang et al. [30] Placebo 19 7 Opioids 19 7 1 17 9 2

All patients had been treated with drugs known to improve Trigeminal neuralgia, 11 patients were on carbamazepine (600 to 1400 mg) either alone (n = 2), in combination with gabapentine (400 to 1200 mg) (n = 5) or on triple therapy with baclofen (30 to 75 mg) (n = 4). Nine patients were on oxcarbazepine (900 to 1800 mg) either alone (n = 2) or in combination with gabapentine (n = 5).

19 1 Amitriptyline

19 1

0

12 3 2

At baseline, patients usually received medications (e.g.

carbamazepine, gabapentin, or opioids) to alleviate their pain. These medications remained unchanged during the course of the study. There were no new analgesic therapies at any time during the baseline or placebo run-in period.

n-number; mg - milligram; BTX-A - Botulinum toxin type A

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patient’s history. In the study by Shehata [28] BTX-A was administrated in the trigger zones and each point had received 5 units of BTX-A / or 0.1 ml placebo subcutaneously. In the study by Zuniga et al. [29] injections were always administered in a subcutaneous injection in various sites, 1 cm apart from one another in the path of the branch/branches involved ( Annex 4). In the study by Zhang et al. [30] BTX-A were administered intradermally and/or submucosally using a 1 mL syringe with a 0.45 × 16 mm needle. The BTX-A or the same volume of isotonic saline were applied at 20 points, (0.05 ml) per point, between the epidermis and dermis of the skin where pain was experienced according to the patient’s description. In all studies [27-30] Saline was

administrated in the same way as Botulinum.

Table 6. Injection protocol and administration.

Author Year Injection protocol Administration of

injections Wu et al. [27] Shehata et al. [28] Zúñiga et al. [29] Zhang et al. [30] 2012

75 U (1.5 mL) of BTX-A were applied at 15 points, 5 U (0.1 mL) per point in

trigger points

Intradermally and/or submucosally

2013

Every patient received either BTX- A (100 U Botox in 2 mL preservative-free normal saline, resulting in a concentration of 5 units/0.1 mL) or placebo (2 mL 0.9%

NaCl). Overall injected doses ranged from 40 units (8 injection points) to 60

units (12 points)

Subcutaneously

2013

A 1-mL syringe: 0.9% saline plus 50 U of BTX or only 1 mL of 0.9% saline were administered in various sites, 1 cm apart

from one another in the path of the branch/branches involved.

Subcutaneously

2014

The BTX-A or the same volume of isotonic saline were applied at 20 points,

(0.05 ml) per point, between the epidermis and dermis of the skin where pain was experienced according to the

patient’s description.

Intradermally and/or submucosally

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Wu et al. [27] avoided injection in deeper structures such as the muscles to prevent unwanted effects on the underlying muscles. Shehata et al. [28] injected posteriorly a larger dose of the toxin in the masseter to avoid undesired cosmetic effects in patients with mandibular root involvement. Patients of Zuniga et al. [29] with involvement of the third branch of the trigeminal nerve also received intramuscularly either 10 U of BTX or matching placebo, according to randomization, in the masseter muscle, ipsilateral to the pain location. Zhang et al. [30] avoided injection in deeper structures such as the muscles during the procedure to prevent unwanted effects.

Table 7. VAS and frequency of TN attacks before the therapy.

Author Year VAS before the therapy Frequency of TN attacks at the endpoint Wu et al. [27] 2012 Wu et al. [27] 2012 Shehata et al. [28] 2013 Shehata et al. [28] 2013 Zúñiga et al. [29] 2013 Zúñiga et al. [29] 2013 Zhang et al. [30] 2014 Zhang et al. [30] 2014 Zhang et al. [30] 2014 BTX-A 7.05 BTX-A 21.71 Placebo 6.88 Placebo 20.53 BTX-A 8.3 BTX-A 36.7 Placebo 8.5 Placebo 39.2 BTX-A 8.85 BTX-A 29.1 Placebo 8.19 Placebo 31.06

BTX-A (25U) 6.24 BTXA (25U)

-BTX-A (75U) 7.18 BTXA (75U)

-Placebo 6.96 Placebo

-BTX-A - Botulinum toxin type A; VAS- visual assessment scale

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group from 6.88 decreased to 5.0 during the first week and than slowly went up. Mean attack frequency per day in the BTX-A group dropped from 21.71 to 2.0.

In the study of Shehata et al. [28] VAS of the BTX-A group was 8.3 and than decreased to 1.8 during 12 weeks, placebo group showed that VAS of 8.5 dropped to 8.2 . Mean paroxysms frequency in the BTX-A group per day dropped from 36.7 to 4.0 and from 39.2 went to 36.10 in Placebo group. In the study by Zuniga et al. [29] 8.85 to 4.59, which shows good results and mean attacks per day decreased from 29.1 to 7.1 and in Placebo group VAS decreased insignificantly from 8.19 to 6.94 and mean attacks per day decreased from 31.06 to 21.25.

In the study of Zhang et al. [30] after graph evaluation VAS of 75U BTX-A decreased from 7.18 to approximately. 1.8 on the 8th week , VAS of 25U BTX-A group decreased from 6.24 to

approximately 2.05 on the 8th week and VAS of placebo group decreased from 6.96 to

approximately 4.2. No significant difference were observed among patient on the 25U BTX-A and on the 75U BTX-A. Frequency of TN attacks were not reported. Around 66.7-75.9% of the patients reported that their symptoms were “much improved” or “very much improved” according to PGIC. All data might have small mistakes due to the fact, that all articles had charts and graphs.

Table 8. VAS and frequency of TN attacks at the endpoint and follow-up data.

Author Year VAS at the end point Followup Frequency of TN attacks at the _{endpoint (n)}

Wu et al. [27] 2012 Wu et al. [27] 2012 Wu et al. [27] 2012 Shehata et al. [28] 2013 Shehata et al. [28] 2013 Zúñiga et al. [29] 2013 Zúñiga et al. [29] 2013 Zhang et al. [30] 2014 Zhang et al. [30] 2014 Zhang et al. [30] 2014 Zhang et al. [30] 2014 Zhang et al. [30] 2014 BTX-A 1.8 12 weeks BTX-A 2.0 BTX-A 1.8 12 weeks Placebo 19 Placebo 5.0 12 weeks Placebo 19 BTX-A 1.8 12 weeks BTX-A 4.0 Placebo 8.2 12 weeks Placebo 36.10 BTX-A 4.59 111 days BTX-A 7.1 Placebo 6.94 111 days Placebo 21.25 BTX-A (25U) 2.0 8 weeks BTXA (25U) -BTX-A (75U) 1.8 8 weeks BTXA (25U) -BTX-A (75U) 1.8

8 weeks _{BTXA (75U)}

-Placebo 3.8

8 weeks _{BTXA (75U)}

-Placebo 3.8

8 weeks

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Main side eﬀects were facial asymmetry and oedema, hematoma, itching and pain (Table 9). In all studies facial asymmetry were reported by 14 patients in BTX-A groups, which disappeared in 6-7 weeks and 0 cases in placebo group [27-30]. Transient oedema which disappeared in 5-7 days were reported by 4 individuals in BTX-A group and by one

person from placebo group [27,30].

Hematoma was reported by 3 patients from BTX-A group and 2 by placebo patients. Itching and pain was reported by one person ( 2 cases) in BTX-A group and by one (2 cases) in Placebo group [28,29]. All reported side eﬀects are summarized (Table 9).

Table 9. Table of side effects.

Author

Author Year

Facial asymmetry and disappearance time Facial asymmetry and

disappearance time _{Other side effects (n)} Year

BTX-A (n) Placebo (n)

Other side effects (n)

Wu et al. [27] Shehata et al. [28] Shehata et al. [28] Shehata et al. [28] Zúñiga et al. [29] Zhang et al. [30]

2012 5 patients and in 7 _weeks 0

Transient oedema in the area of injection was observed in 3 patients (2 in the BTX-A group and 1 patients from the Placebo group), facial oedema developed in 2 days and disappeared within 7 days.

2013 4 patients

- 0

Hematoma BTX-A 1 and Placebo 2

2013 4 patients

- 0 Itching BTX-A 1 and Placebo 1

2013 4 patients

- 0

Pain BTX-A and Placebo 1

2013 2 patients _- 0

Hematoma at the site of administration (2 patients in BTX-A

group).

2014 3 patients and in 6

weeks 0

Transient oedema in the injection are was observed in 2 patients (both from BTX-A 25U group) and disappeared within 5 days.

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3. DISCUSSION

This systematic review of the literature reported success in the use of botulinum toxin type-A (BTX-A) in the management of Trigeminal neuralgia. All articles were informative and showed, that Botulinum toxin type-A can have a place in the list of modern treatments and managements of Trigeminal neuralgia while having less side effects than other therapies.

Higher doses were found to be safe and effective and, in many cases, more effective than 20 U for those patients with strong glabellar features. Many clinicians today start with dosages of 15 to 20 U and then administer higher dosages depending on the muscle mass and/or sex of the patient [31]. However in the study by Zhang et al. [30] no difference between dosages of BTX-A (25U and 75U) were noticed. In the study by Wu et al. [27] BTX-A dose was 75U and the results showed

significantly decreased of VAS as in the study of Shehata et al. [28] where the dose was 100U. So no significant differences in the doses were found out, that it is why possible to answer the question: Does the BTX-A therapy works in TN patients and it works, but if we will compare all the results, however an administration of higher dosages may provide better and longer results.

In the study of Li et al. [18] 88 TN patients were evaluated receiving BTX-A injections with 14 months follow up. Where within 1 month in 81 patients and at 2 months in all patients (100%) treatment was marked as “effective”. 3 months was the shortest period to be considered as

effective , and in a maximum of 46 patients was noticed. full control over TN pain. The therapeutic effect decreased gradually after 3 months, and the prevalence of effective treatment at 14 months was 38.6%, with complete control of pain seen in 22 patients (25%).

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mandibular divisions of the Trigeminal nerve; it is also stated that some injections were intraoral. No details are provided of the location of trigger areas and numbers injected on each patient” [32]. According to evaluation of Risk of bias of the study by Wu et al. [27] showed an unclear risk of bias by Cochrane ( Table 2 ).

Doctors must consider the possibility of immunogenicity if low clinical responses are observed, especially if treatment was performed not for the first time. Because the neurotoxin in the different formulations is very similar, that is why it is not recommended to change types or brands during therapies. Non-neurotoxin components can act as adjuvants that promote antibody formation and cause immune reactions that lead to treatment nonresponse and compromise outcomes. ”Once antibodies have formed, increasing injection doses may be ineffective and may increase antibody titers” [33].

Botox injections are not the first line for treatment and will not take place of antileptics, but it is possible to recommend this treatment as an addition to pharmaceutical or surgical treatment. One proposed theory for BTX-A relieving pain is by resolving muscle trigger points (TrPs) and it has been reported that around 72% of patients have points (TrPs). From this we can conclude that botox might be useful in 70% of patients with Trigeminal neuralgia, but more studies needed to understand how Botulinum neurotoxin really works [34].

From this we can conclude that botox might be useful in 70% of patients with Trigeminal neuralgia, but more studies needed to understand how botulinum toxin really works.

Some systemic side effects such as dry mouth, fatigue, and flu-like symptoms can occur unrelated to the spreading of the toxin from the injection site. In addition to that, facial asymmetry, bleeding, ecchymosis, or hematoma formation at the injection site is pretty common and can be minimized by cooling down the site of injection before and after procedure [35]. In 2013 Guardiani et al. [19] quoth “If the facial asymmetry is of cosmetic concern, patients can be given contralateral toxin to achieve facial symmetry.”

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If medications are not bringing any effects to patients, they can consider going through surgery, but TN will often return later. Some patients are choosing additional techniques like yoga therapy, psychiatrist courses, creative therapy, sport and other ways of managing TN pains [36].

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4. CONCLUSION

1. BTX-A injection therapy is a safe and effective method in management of TN. Maximum efficacy was noticed between 6 weeks and 3 months after the procedure.

2. Side effects were mostly facial asymmetry after injection, which disappeared within 6 weeks, as well headaches, hematoma, itching in the place of treatment, which disappeared in one week. 3. No significant differences between doses were noticed.

5. ACKNOWLEDGEMENT

I would like to thank Professor Gintaras Juodžbalys for his expert advices, guidance and encouragement throughout this review.

5. CONFLICT OF INTERESTS

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6. PRACTICAL RECOMMENDATIONS

Some scientists proved, that some individuals might be allergic or might develop resistance to Botox, this could play a role in data difference, because some TN patients could have been on Botulinum for a long period of time.

That is why history of botox injections has to be collected in such experiments before the treatment due to that fact that neurotoxin is widely used in cosmetic industry.

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Monotherapy in Symptomatic Trigeminal Neuralgia. Headache: The Journal of Head and Face Pain, 56(6), 1035–1039. DOI:10.1111/head.12791

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27. Wu, C.-J., Lian, Y.-J., Zheng, Y.-K., Zhang, H.-F., Chen, Y., Xie, N.-C., & Wang, L.-J. (2012). Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial. Cephalalgia, 32(6), 443–450. DOI:10.1177/0333102412441721

28. Shehata, H. S., El-Tamawy, M. S., Shalaby, N. M., & Ramzy, G. (2013). Botulinum toxin-type A: could it be an effective treatment option in intractable trigeminal neuralgia? The Journal of Headache and Pain, 14(1). DOI:10.1186/1129-2377-14-92 [URL: https:// thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/1129-2377-14-92] 29. Zúñiga, C., Piedimonte, F., Díaz, S., & Micheli, F. (2013). Acute Treatment of Trigeminal

Neuralgia With Onabotulinum Toxin A. Clinical Neuropharmacology, 36(5), 146–150. DOI:10.1097/wnf.0b013e31829cb60e

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8. ABBREVIATIONS

TMJ- temporomandibular joint

CNS - Centra nervous system

TN - Trigeminal neuralgia CTN - Classical trigeminal neuralgia BTX-A -Botulinum toxin A type BoTN- Botulinum neurotoxin

VAS - Visual assessment scale MRI- Magnetic resonance imaging

CT- Computed tomography n-Number ,

Gr- Group, Ml-Milliliter,

U-Units per ml of solution,

9. ANNEXES

Annex 1. Protocol for systematic review according to PRISMA-P

TITLE

THE USE OF BOTULINUM TOXIN A IN THE

MANAGEMENT OF TRIGEMINAL NEURALGIA: A SYSTEMATIC LITERATURE REVIEW

INTRODUCTION

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Tasks • To evaluate the efficacy and side effects of BTX-A in the patients with TN.

• To find differences between BTX-A doses in the patients with TN. • To discover the length of effect of BTX-A therapy in the patients with

TN.

METHODS

Eligibility criteria PICOS:

• P- Patients: individuals with Trigeminal neuralgia; • I- Intervention: Botulinum toxin A;

• C- Comparison: Saline (NaCL) as a placebo;

• O- Outcome: presence or absence or reduction of pain;

• S- Study design: randomized, double-blind, placebo controlled trials

Inclusion criteria

-Studies of patients with Trigeminal neuralgia -Studies of comparison between BTX-A and Saline -Randomized, double-blind, placebo controlled trials -Studies between Jan 2010- Feb 2020

-Studies with the amount of more than 20 individuals -Studies in English language

-Studies in which VAS was present -Studies on humans

-Full-text article studies Exclusion criteria

-Studies on animals, not on humans

-Prospective studies, abstracts, discussions, literature reviews and systematic reviews

-studies which include postherpetic trigeminal neuralgia

-studies which include neuropathic pains, with not mentioned TN

Information sources

• Electronic databases: PubMed, Springer link, Science Direct, Cochrane library and The Journal of Headache and Pain. • Key words: trigeminal neuralgia, trigeminal nerve, botulinum A

toxin, botulinum neurtoxin A

• Time period: January 2010- February 2020

Study selection • Searching by entering the keywords in a few combination and according to chosen inclusion criteria

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Outcomes and prioritization

Assessing success of Botulinum toxin type A ( BTX-A )therapy in patients with Trigeminal neuralgia, difference in dosages and side effects.

Annex2. Classification of TN by ICHD-3

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THE USE OF BOTULINUM TOXIN A IN THEMANAGEMENT OF TRIGEMINAL NEURALGIA:A SYSTEMATIC LITERATURE REVIEW

Anton Rubis