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Just Accepted by International Journal of Neuroscience

Botulinum Toxin A in the Treatment of Trigeminal


Neuralgia
Jian-Hua Xia, Cai-Hong He, Hai-Feng Zhang, Ya-Jun Lian, Yuan
Chen, Chuan-Jie Wu, Yun-Qing Ma
doi:10.3109/00207454.2015.1019624

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Abstract
Aims: The aims of this study were to investigate the clinical effects and safety of
botulinum toxin A (BTX-A) in treating trigeminal neuralgia and its influences on
accompanied depression, anxiety, sleep disorders, and quality of life.
Methods and Material: Eighty-seven patients with one-branch classical trigeminal
neuralgia were injected with BTX-A in the pain area. The visual analogic scale (VAS)
score, sleep interferance score, Hamilton Anxiety Scale (HAMA) score, Hamilton
Depression Scale (HAMD) score, and side effects were assessed at 1 week prior to
and 8 weeks after treatment, respectively.
Results: The effective rates after 1, 2, 4, and 8 weeks of treatment were 48.28%,
66.67%, 78.16%, and 80.46%, respectively. The effective rates of anxiety and
depression were 90.32% and 96.77%, respectively. When compared to that before
treatment, the quality of life was significantly better in terms of role-physical (RP),
bodily pain (BP), general health (GH), vitality (VT), social functioning (SF),
role-emotional (RE), and mental health (MH) (all P < 0.01), while physical function
(PF) was not significantly improved (P D 0.317).
Conclusion: BTX-A treatment can significantly relieve the pain in trigeminal
neuralgia patients; improve anxiety, depression, and sleep; and increase the quality
of life. BTX-A treatment is a safe and effective method to treat classical trigeminal
neuralgia.

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Botulinum Toxin A in the Treatment of Trigeminal

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Neuralgia

Jian-Hua Xia, Dr. 1,2,# Cai-Hong He, Dr.1,#; Hai-Feng Zhang, Dr.1,#; Ya-Jun

of Neurology, the First Affiliated Hospital of

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1Department

Zhengzhou University, Jianshe Road NO.1, Zhengzhou 450000,


China

of Neurology, the Central Hospital of Zhumadian City,

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Zhumadian, China

2Department

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Running title: BTX-A treatment in patients

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Lian, Dr. prof.1,*, Yuan Chen, Dr.1; Chuan-Jie Wu, Dr.1; Yun-Qing Ma, Dr.1

# These

authors are contribute equally to this work

*Correspondence

author

Dr. Ya-Jun Lian

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Department of Neurology, the First Affiliated Hospital, Zhengzhou


University
Tel: 86-13838367143

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Email: lianyajun369@sina.com

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Abstract
Aims: The aims of this study were to investigate the clinical effects

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and safety of botulinum toxin A (BTX-A) in treating trigeminal


neuralgia and its influences on accompanied depression, anxiety,
sleep disorders, and quality of life.

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classical trigeminal neuralgia were injected with BTX-A in the pain


area. The visual analogic scale (VAS) score, sleep interferance

score, Hamilton Anxiety Scale (HAMA) score, Hamilton Depression

Scale (HAMD) score, and side effects were assessed at 1 week

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prior to and 8 weeks after treatment, respectively.


Results: The effective rates after 1, 2, 4, and 8 weeks of treatment
were 48.28%, 66.67%, 78.16%, and 80.46%, respectively. The

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effective rates of anxiety and depression were 90.32% and 96.77%,


respectively. When compared to that before treatment, the quality
of life was significantly better in terms of role-physical (RP), bodily
pain (BP), general health (GH), vitality (VT), social functioning (SF),

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Methods and Material: Eighty-seven patients with one-branch

role-emotional (RE), and mental health (MH) (all P < 0.01), while
physical function (PF) was not significantly improved (P = 0.317).
Conclusion: BTX-A treatment can significantly relieve the pain in
trigeminal neuralgia patients; improve anxiety, depression, and

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sleep; and increase the quality of life. BTX-A treatment is a safe


and effective method to treat classical trigeminal neuralgia.

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depression, sleep disorder, quality of life

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Keywords: trigeminal neuralgia, botulinum toxin A, anxiety,

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Background
Trigeminal neuralgia (TN) is defined as a sudden, usually

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unilateral, severe, brief, stabbing, recurrent pain in the distribution


of one or more branches of the fifth cranial nerve by the

International Association for the Study of Pain [1]. Botulinum toxin A

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that relaxes the muscles through the release of acetylcholine at the


neuro-muscle junction. Therefore, BTX-A is widely used in
cosmetology and treating dystonia [2]. Recently, the effects of

BTX-A in pain management are receiving considerable attention. In

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1987, Brin, for the first time, reported that pain was obviously
relieved simultaneously with improved muscle tonus in 74% of
patients who received BTX-A for dystonia disorder[3]. In 2002,

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Micheli first reported that BTX-A can relieve trigeminal neuralgia


[4], supported by subsequent positive reports [5]. The author
treated primary trigeminal neuralgia patients with 75 U of BTX-A or
placebo for 8 weeks and found that the visual analogic scale (VAS)

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(BTX-A) is one type of exotoxin produced by Clostridium botulinum

score in the BTX-A group was significantly decreased from week 1


to week 8, when compared to the placebo group, suggesting that
multiple-site intracutaneous injection of BTX-A in the trigeminal
neuralgia area can significantly relieve pain [6, 7]. Pain usually
results in sleeplessness, anxiety, and depression, which will in turn
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aggravate pain frequency and severity. Many studies have


indicated that multiple types of pain, such as migraines, tension

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headaches, cluster headaches, and trigeminal neuralgia, are


susceptible to anxiety, depression, and sleep disorders, which
seriously affects the quality of life [8-11]. And the anxiety,

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relieved, resulting in an improved quality of life. In 1999,

Zakrzewska et al. [12] indicated that, in 25 patients with trigeminal


neuralgia, 12 (48%) and 13 (52%) patients were accompanied with

anxiety and depression, respectively. These patients reported

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improved anxiety and depression at 2 weeks after semilunar


ganglion radiofrequency thermocoagulation.
The aim of this study was to assess the therapeutic effects of

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BTX-A on trigeminal neuralgia, anxiety, depression, sleep


disorders, and quality of life in 87 patients with one-branch classical
trigeminal neuralgia.

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depression, and sleep disorders can be improved when the pain is

Methods
Subjects
One-branch classical trigeminal neuralgia patients treated in the
Neurology Department as outpatients or inpatients of the First
Affiliated Hospital, Zhengzhou University, from Nov. 2011 to Sept.
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2012 were assessed in this study. The detailed information of the


patients was recorded, including age, gender, occupation,

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education, current disease history, past disease history, family


history, physical examination of the nervous system, and auxiliary
examinations. Regular blood tests, kidney and liver function

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coagulation disorders and severe heart, liver, or kidney disease.


Trigeminal neuralgia was confirmed by inquiry, physical
examination, and CT or magnetic resonance imaging.

This study was approved by the Ethics Committee of the First

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Affiliated Hospital, Zhengzhou University. All patients were


informed of the contents, process, and possible side effects of the
study, and signed the informed consent.

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Treatment strategy

Freeze-dried BTX-A (HENGLI, 100 U/bottle, Lanzhou Institute

of Biological Production) was diluted with 2 ml of 0.9% sodium


chloride injection solution and intracutaneously injected in multiple

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analyses, and an electrocardiogram were performed to exclude

sites of the pain area and trigger site, according to the extent of
pain. A total of 1520 injection sites were made at an injection
depth of 0.1 cm and a separation of 15 mm.
The patients were required to record their daily pain extent, sleep

interferance scores, and side effects in detail at 1 week prior to and


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8 weeks after injection. Weekly follow up in person or by telephone

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interview was performed to assess VAS score, sleep interferance

score, Hamilton Anxiety Scale (HAMA) score, Hamilton Depression

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Study 36-item Short Form Health Survey (SF-36) was used for

assessment 1 week before and 8 weeks after treatment.

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Evaluation of therapeutic effect and safety


VAS score and effective rate

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The pain severity was evaluated through the VAS. The effective

rate was calculated by using the reduced VAS scores after

treatment and was defined as the rate of patients with a VAS score

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Scale (HAMD) score, and side effects. The Medical Outcomes

reduction rate 50%, where the VAS score reduction rate =

(prior-treatment score post-treatment score)/prior-treatment score

100%.

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Anxiety and depression score reduction rate


A HAMA score 7 indicated the existence of anxiety and a

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HAMD score 8 indicated the existence of depression. At the end


of the observation period (end of the 8th week), the HAMA and
HAMD score reduction rates were calculated as follows:

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score)/pre-treatment total score 100%. A score reduction rate of


< 25% was considered as no effect, between 25% and 50% as
improvement, between 50% and 75% as significant improvement,

and 75% as cured. The effective rate = (significant improvement

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patients + cured patients)/total patients 100%.

Sleep interference score

The sleep interferance score was assessed with the 11-point

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mehtod, where 0 refers to no sleep interferance while 10 refers to


the most severe sleep interferance. The patients pointed out their
sleep interferance score according to their feeling.

Quality of life

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(pre-treatment total score post-treatment total

The SF-36 included physical function (PF), role-physical (RP),

bodily pain (BP), general health (GH), vitality (VT), social


functioning (SF), role-emotional (RE), and mental health (MH).

Side effects

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If side effects occurred, the detailed information was recorded,


including signs, time, severity, duration, frequency, treatment,

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outcomes, and correlation with treatment.

Statistical analsysis

SPSS 20.0 was used for statisical analysis with the 2-sided test.

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deviation (SD), maximum, median, and minimum. The 2 -test was


used to analyze the correlation of anxiety and depression with the

effective rate. The Wilcoxon rank test was used to analyze the VAS

score, sleep interferance score, anxiety score, depression score,

significance.

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Results

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and before-after SF-36 score. P < 0.05 was set as the level of

General information and homogeneity analysis of basic data


A total of 87 patients, including 38 males (43.68%) and 49 females

(56.32%), aged 3789 years old (mean, 60.80 years old) were assessed in

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All measurement data were expressed with mean standard

this study. The disease history was 6300 months with a mean of 74.93
months, and the onset frequency was 360 times/day with mean of 18.7
times/day. All patients experienced pain in the unilateral one-branch,
including 5 in the left first branch, 2 in the left second branch, 3 in the left
third branch, 13 in the right first branch, 19 in the right second branch,
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and 19 in the right third branch. All patients received carbamazepine or


gabapentin before injection but with poor effects. Thirteen patients

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received surgical treatment, including 1 with a gamma knife, 3 with


partial sensory trigeminal rhizotomy, and 9 with local block therapy. The

demographic and clinical features of the patients are listed in Table 1.

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Of the 87 patients, 27 (31.03%) patients reported both anxiety and

depression, 52(59.77%) patients reported neither anxiety nor depression,


4(4.60%) patients reported only anxiety, and 4(4.60%) patients reported

only depression (Table 2). There was a close correlation between anxiety

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and depression; the rate of depression in patients with anxiety was greater
than in patients without anxiety (P < 0.01), while the rate of anxiety in
patients with depression was greater than in patients without depression

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(P < 0.01; Table 2).

Pain severity change and effective rate


The VAS score after treatment was significantly less compared to

that before treatment (P < 0.01; Table 3). The effective rates after

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Accompanied anxiety and depression in trigeminal neuralgia

different lengths of treatment are shown in Table 4. There was a


significant difference in the effective rate between 2 weeks and 1
week of treatment (P < 0.05), but not between 4 weeks and 2
weeks or 8 weeks and 4 weeks after treatment (P > 0.05).

Improvement of anxiety and depression


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Compared to that before treatment, the anxiety scores and


depression scores at every week after treatment were significantly

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decreased (P < 0.01; Table 5). The anxiety was not effectively
treated in 1 case, improved in 2 cases, significantly improved in 7

cases, and cured in 21 cases at 8 weeks after treatment, resulting

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effectively treated in 1 case, significantly improved in 4 cases, and


cured in 26 cases, resulting in an effective rate of 96.77% (30/31;

Sleep improvement

Table 6).

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Of the 87 patients, 71.26% (62/87) of patients had sleep


disorders. The sleep interference scores were significantly
decreased at every week after treatment, when compared to that

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before treatment (P < 0.01; Table 7).

Improvement of quality of life


The quality of life, including RP, BP, GH, VT, SF, RE and MH,

was obviously improved when compared to that before treatment,

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in an effective rate of 90.32% (28/31). The depression was not

and there was a significant difference (P < 0.01). However, the PF


was not significantly improved by treatment (P = 0.317; Table 8).

Side effects
Nine patients experienced mild local side effects. Local swelling

in the injection sites occurred in 2 patients and disappeared within 7


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days. Muscle relaxation in the injection sites occurred in 7 patients

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and disappeared within 6 weeks. All these side effects were mild

and automatically disappeared without any further treatment. No

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Discussion

Trigeminal neuralgia is a repetitive paroxysmal sharp pain that

occurs in the innervation areas of the trigeminal nerve lasting for a

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long period. There is no therapy for it with definite and long-term


effects, high safety, and few side effects. Currently, the effects of
BTX-A in pain treatment have received much attention. Brin [13],

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Borodic [14], Piovesan [5], Allam [15], Turk [16], Piovesan , Zuniga
[17], Ngeow [18], Bohluli [19] and Wu [6] have reported that
injection of BTX-A in the facial pain areas significantly relieves
trigeminal neuralgia. In the present study, we found that the VAS

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systemic side effects were observed.

score was significantly decreased at 1 week after injection of


BTX-A, which continued until the end of the 8-week study. Zuniga
et al. treated 12 trigeminal neuralgia patients using BTX-A and 10
patients received significant relief of pain within minutes after
injection [17]. In the present study, pain was reduced within 1 week
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in most patients. One male patient with a VAS score of 8 was totally
relieved from pain after 6 h of treatment and had no recurrence

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throughout the 8-week study. The effective rate after 1, 2, 4, and 8


weeks was 48.28%, 66.67%, 78.16%, and 80.46%, respectively.

There was a significant difference in the effective rate between 2

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weeks. These results indicated that the effect of BTX-A treatment in


trigeminal neuralgia patients is definite. The effective duration of
BTX-A in treating trigeminal neuralgia is not consistent among

various studies. It has been reported that the analgesic time of

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BTX-A treatment in trigeminal neuralgia was consistent with the


time of relieving muscle tension [20]. But other studies have
reported that the analgesic effect of BTX-A in trigeminal neuralgia

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was longer than the time of relieving muscle tension [21, 22]. In the
present study, the VAS score after 8 weeks was still significantly
different from that before treatment, suggesting that BTX-A has a
longer effective duration in treating classical trigeminal neuralgia

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weeks and 1 week of treatment, but not between 4 and 2 or 8 and 4

than oral medications. In our previous study, we found that the


effect of BTX-A in two patients with trigeminal neuralgia lasted for 2
years.
The mechanism of BT effect on pain is complicated, and not very
clear. Recent reports suggested that BTX-A was capable of
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blocking the PKC-induced surface expression of the capsaicin


receptor, TRPV1 [23]. Thus, by preventing the increase of the

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heat sensor, the sensitization of the peripheral nociceptive nerve


could be prevented by pretreatment with BTX-A. Other reports [24]
suggested that BTX-A inhibits neurotransmitter release from

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inflammatory pain via a direct inhibition of peripheral sensitization


and an indirect inhibition of central sensitization.

In the present study, 62 of 87 patients had sleep disorders and

the sleep interference score was significantly decreased after

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treatment, suggesting that BTX-A treatment could improve the


sleep in patients with trigeminal neuralgia. In addition, the
accompanied anxiety, depression, and sleep disorders can

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deteriorate the onset frequency and severity of pain and further


strengthen the feeling of pain in patients. Following the disease
progression, the negative emotional effects can produce other
negative effects, such as economic costs, deterioration of other

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peripheral terminals of sensory neurons, thereby reducing

diseases, and decrease of quality of life. The study regarding


anxiety and depression in chronic pain patients by Zhang et al.
indicated that there were 26 and 17 patients out of 45 patients with
trigeminal neuralgia that experienced anxiety and depression,
respectively, and these patients were completely relieved from pain
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at 3 months after radiofrequency thermocoagulation [25].


This study suggested that anxiety and depression disappeared

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following the relief of pain in trigeminal neuralgia patients. In the


present study, we found that trigeminal neuralgia patients had

obvious anxiety and depression, which seriously affected the daily

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positive correlation between anxiety and depression. The anxiety


score and depression score at the end of observation (8 weeks)
were significantly decreased when compared to that before

treatment. The effective rates for anxiety and depression were

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90.32% and 96.77%, respectively, suggesting that BTX-A


treatment can significantly improve anxiety and depression when it
relieves the pain due to trigeminal neuralgia.

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The quality of life is a type of health index with multiple variables


and comprehensive contents. Currently, the globally applied and
well-recognized measurement apparatus of quality of life is SF-36
[26,27]. In our study RP, BP, GH, VT, SF, RE, and MH were

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life and quality of life of patients. Furthermore, there was a high

significantly improved after treatment, while PF was not.


Parameters of the quality of life (Role-Physical, Bodily Pain,
General Health, Vitality, Social Function, Role-Emotional, and
Mental Health) are more sensitive to reflect the decrease in the
quality of life of trigeminal neuralgia patients, when compared to
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Physical Function. While improving pain, anxiety, depression, and


sleep disorders, local injection of BTX-A can significantly increase

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Role-Physical, Bodily Pain, General Health, Vitality, Social


Function, Role-Emotional, and Mental Health, and therefore
improve the daily life and quality of life of patients.

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was found to be safe. Only local mild side effects were observed,

and there were no systemic side effects. There were 9 patients who

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experienced side effects. Local swelling in the injection sites

occurred in two patients and disappeared within 7 days. Muscle

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relaxation in the injection sites occurred in 7 patients and

disappeared within 6 weeks. No other side effects were observed.

The swelling in 2 patients may be due to a local reaction to the

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In this study, BTX-A treatment of classical trigeminal neuralgia

needle injection. The transient muslce relaxation may be due to the

diffusion of BTX-A into a deeper layer of facial muscles and the

induction of transient muscle paralysis.

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Conclusions
The present study indicated that trigeminal neuralgia patients are

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susceptible to anxiety, depression, and sleep disorders, and there


is a high correlation between anxiety and depression. Local

multiple-site injection of BTX-A can significantly relieve the pain in

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and sleep disorder, and increase the quality of life. Only local mild

side effects were observed, and there was no systemic side effect.
Local injection of BTX-A has significant therapeutic effect and high

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safety.

Acknowledgements

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This study was supported by the National Natural Science

Foundation of China (81371438), the Provincial Natural Science

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classical trigeminal neuralgia patients, improve anxiety, depression

Research Foundation of the HeNan Education Department

(2011A320038) and a project of the HeNan Health Department

(201203006).

Conflicts of interest disclosures


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The authors report no conflicts of interest. The authors alone are


responsible for the content and writing of the paper.

1.

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toxin type a for patients with painful tic convulsif. Clin Neuropharmacol.

21.

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2002;25: 260-262.
Turk U, Ilhan S, Alp R and Sur H, Botulinum toxin and intractable
trigeminal neuralgia. Clin Neuropharmacol. 2005;28: 161-162.

Bohluli B, Motamedi MH, Bagheri SC, Bayat M, Lassemi E, Navi F and

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Moharamnejad N, Use of botulinum toxin A for drug-refractory

trigeminal neuralgia: preliminary report. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod. 2011;111: 47-50.

Morenilla-Palao C, Planells-Cases R, Garcia-Sanz N, Ferrer-Montiel A.

23.

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Regulated exocytosis contributes to protein kinase C potentiation of


vanilloid receptor activity. J Biol Chem. 2004. 279(24): 25665-72.
24.

Aoki KR. Review of a proposed mechanism for the antinociceptive

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action of botulinum toxin type A. Neurotoxicology. 2005. 26(5):


785-93.

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McDermott AM, Toelle TR, Rowbotham DJ, Schaefer CP and Dukes

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22.

26.

EM, The burden of neuropathic pain: results from a crosssectional


survey. European Journal of Pain. 2006;10: 127-127.

MA L, WU B and SUN H, Assessing depression and anxiety in patients


with trigeminal neuralgia. Chinese Journal of Rehabilitation Medicine.
2010;3: 014.

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27.

Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey
(SF-36). I. Conceptual framework and item selection. Med Care. 1992.

TE
D

30(6): 473-83.

EP

Table 1 Demographic and clinical features of patients

Median

Minimum/Maximum

60.80 12.00

61

37/89

74.93 70.08

50

6/300

Pain onset frequency (times/day)

18.70 15.33

15

3/60

VAS score

6.59 2.18

4/10

Sleep interference score

4.03 3.59

0/10

HAMA score

4.87 4.75

0/20

HAMD score

5.74 5.63

0/23

Age (years)

ST

AC

Disease length (months)

Mean SD

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Tables

27

TE
D
EP

Total

27

31

Depression (-)

52

56

Total

31

56

87

-test

ST

Anxiety (-)

AC

Depression (+)

Anxiety (+)

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Table 2 Correlation between anxiety and depression

27

TE
D
EP

C
AC

Treatment group

VAS score

P value

Before treatment

6.59 2.18

1 week after treatment

3.66 2.24

P < 0.001

2 weeks after treatment

2.69 2.10

P < 0.001

3 weeks after treatment

2.09 2.01

P < 0.001

4 weeks after treatment

1.93 1.85

P < 0.001

5 weeks after treatment

1.68 1.74

P < 0.001

6 weeks after treatment

1.74 1.80

P < 0.001

7 weeks after treatment

1.74 1.83

P < 0.001

8 weeks after treatment

1.95 1.96

P < 0.001

ST

(n = 87)

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Table 3 Changes of VAS score (mean SD)

* Wilcoxon rank test

27

TE
D
EP
C
AC

ST

Treatment group

Effective Rate

P value

1 week after treatment

48.28% (42/87)

2 weeks after treatment

66.67% (58/87)

0.014

4 weeks after treatment

78.16% (68/87)

0.090

8 weeks after treatment

80.46% (70/87)

0.708

(n = 87)

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Table 4 The effective rates at different times after treatment

2 -test

27

TE
D
EP
C
AC

ST

Treatment group
(n = 87)

Anxiety (n =

Depression

P value

31)

value

(n = 31)

Before treatment

10.16 3.53

12.26 3.84

1 week after treatment

5.55 3.70

P<

6.65 4.81

P < 0.001

3.68 3.43

P < 0.001

3.03 3.38

P < 0.001

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Table 5 Anxiety and depression changes at different times


(mean SD)

2 weeks after

0.001
3.32 2.64

P<
0.001

treatment
3 weeks after

2.90 2.47

P<
0.001

treatment

27

4 weeks after

2.55 2.13

P<

2.42 2.68

P < 0.001

2.10 2.47

P < 0.001

0.001
treatment
5 weeks after

2.52 2.38

P<

6 weeks after

2.16 2.02

P<

1.77 2.33

0.001

7 weeks after

2.03 1.94

P<

1.65 2.29

8 weeks after

2.06 2.00

treatment

P<

1.77 2.36

0.001

ST

AC

* Wilcoxon rank test

27

P < 0.001

P < 0.001

EP

0.001
treatment

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treatment

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0.001
treatment

P < 0.001

Table 6 Effects of treatment on anxiety and depression

Improved

Significantly improved

1 (3.23%)

2 (6.45%)

7 (22.58%)

Cured

Total

TE
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Anxiety

No effect

21

31

(67.74%)

Depression

1 (3.23%)

0 (0.00%)

4 (12.90%)

26

EP
C
AC
ST
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(83.87%)

27

31

Table 7 Weekly sleep interference scores (mean SD)

Score

P value

4.03 3.59

1 week after treatment

1.46 2.30

P < 0.001

2 weeks after treatment

0.99 1.87

P < 0.001

3 weeks after treatment

0.69 1.77

P < 0.001

4 weeks after treatment

0.41 1.26

P < 0.001

5 weeks after treatment

0.47 1.34

P < 0.001

6 weeks after treatment

0.40 1.28

P < 0.001

0.44 1.38

P < 0.001

AC

7 weeks after treatment


8 weeks after treatment

EP

Before treatment

0.32 1.16

ST

* Wilcoxon rank test.

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(n = 87)

Sleep interference

TE
D

Treatment group

27

P < 0.001

TE
D

RP

BP

GH

VT

Before

87.13

41.95

41.67 15.87

56.55

78.74

treatment

18.52

40.26

After

87.24

81.90

treatment

18.44

33.82

P value

P = 0.317

P < 0.001

18.19
83.10 15.11

65.11
14.61

P < 0.001

ST

AC

* Wilcoxon rank test

27

RE

MH

87.10

63.22

78.85

14.25

20.60

44.03

15.99

86.49 6.61

97.83 7.92

97.70 9.90

90.57 7.29

P < 0.001

P < 0.001

P < 0.001

P < 0.001

P < 0.001

SF

EP

PF

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Table 8 SF-36 comparison between before and after treatment


(mean SD)