ORIGINAL RESEARCH ARTICLE

CNS Drugs 2011; 25 (10): 847-857

1172-7047/11/0010-0847/$49.95/0

2011 Adis Data Information BV. All rights reserved.

Topiramate versus Carbamazepine

for the Treatment of Classical
Trigeminal Neuralgia
A Meta-Analysis
Qiang-ping Wang and Min Bai
Department of Neurosurgery, Dujiangyan Peoples Hospital, Dujiangyan Medical Center, Dujiangyan, China

Abstract

Background: Carbamazepine is currently the drug of first choice in the

treatment of trigeminal neuralgia. However, it is reported as efficacious in
only 7080% of patients, and can be associated with adverse effects such as
drowsiness, confusion, nausea, ataxia, nystagmus and hypersensitivity, which
may necessitate discontinuation of medication. Therefore, alternative drugs
such as oxcarbazepine, baclofen and topiramate are also used to treat the
disease.
Objectives: The aim of this study was to compare the effectiveness and safety
of topiramate with carbamazepine in the treatment of classical trigeminal
neuralgia.
Methods: We searched the Cochrane Central Register of Controlled Trials
(CENTRAL) [Issue 3 of 12, March 2011], MEDLINE, EMBASE, the
Chinese Biomedical Database (CBM), the Chinese National Knowledge Infrastructure (CNKI) and the Chinese Science and Technique Journals
Database (VIP) for the period January 1998 to March 2011, and we also
manually searched all relevant journals. We included all confirmed randomized controlled trials treating trigeminal neuralgia with topiramate and carbamazepine. We evaluated the risk of bias of the included trials according to
the Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.
The Cochrane Collaborations software RevMan 5.1 was used for the metaanalysis.
Results: A total of six randomized controlled trials with poor methodological
quality were included. All trials were conducted in China. Altogether, they
included 354 patients with trigeminal neuralgia. The results of the metaanalysis showed that topiramate was more effective than carbamazepine after
a treatment duration of 2 months (relative risk [RR] = 1.20, 95% CI 1.04, 1.39,
p = 0.01). However, no difference was found in the effectiveness rate after a
treatment duration of 1 month (RR = 1.00, 95% CI 0.87, 1.14, p = 0.94), in the
remission rate after a treatment duration of 1 month (RR = 1.06, 95% CI 0.83,

Wang & Bai

848

1.36, p = 0.63), in the remission rate after a treatment duration of 2 months

(RR = 1.31, 95% CI 0.96, 1.80, p = 0.09) or in adverse events when comparing
topiramate with carbamazepine.
Conclusions: Present trials comparing topiramate with carbamazepine are all
poor in methodological quality. A meta-analysis of these studies showed that
the overall effectiveness and tolerability of topiramate did not seem to differ
from carbamazepine in the treatment of classical trigeminal neuralgia.
However, the meta-analysis yielded a favourable effect of topiramate compared with carbamazepine after a treatment duration of 2 months. Results
were limited due to the poor methodological quality and the geographic localization of the randomized controlled trials identified. Therefore, large,
international, well conducted, randomized controlled trials are needed to
further assess the relative efficacy and tolerability of topiramate and carbamazepine in this indication.

Background
Trigeminal neuralgia is the most common
neuralgia and is often defined as sudden, severe,
brief, stabbing, usually unilateral, recurrent episodes of pain in the distribution of one or more
branches of the trigeminal nerve.[1] The annual
incidence of trigeminal neuralgia is 45/100 000[2]
and it can be classified into classical and symptomatic trigeminal neuralgia.[3] Symptomatic trigeminal neuralgia includes all cases of trigeminal
neuralgia secondary to a tumour, multiple sclerosis,
structural abnormalities of the skull base, etc.
whereas the diagnosis of classical trigeminal
neuralgia can only be made in cases without an
established aetiology, i.e. idiopathic, as well as in
cases with potential vascular compression of the
fifth cranial nerve, according to the latest classification of the International Headache Society.[3]
There is a distinct difference between the
treatment of classical trigeminal neuralgia and
symptomatic trigeminal neuralgia. CT or MRI is
primarily considered to determine whether there
are structural causes in patients with trigeminal
neuralgia.[4] The primary disease should be managed first in patients with symptomatic trigeminal neuralgia. There are many methods for the
treatment of classical trigeminal neuralgia, including pharmacotherapy, a block or destruction
of portions of the trigeminal nerve, cryotherapy,
2011 Adis Data Information BV. All rights reserved.

pharmaceutical injection, peripheral acupuncture,

radiofrequency thermocoagulation, g knife surgery
and other surgery options. The efficacies of Gasserian ganglion percutaneous techniques and microvascular decompression for classical trigeminal
neuralgia have been demonstrated;[4] however, they
should be reserved for when there is a decrease in
efficacy or tolerability of medication because they
are destructive processes.[5] Other treatments such
as g knife surgery, cryotherapy, pharmaceutical
injection and peripheral acupuncture show some
degree of therapeutic effectiveness, but they also
present various kinds of adverse effects or limits.[6]
Therefore, drugs still play the most important role
in the treatment of classical trigeminal neuralgia
especially in patients who have been newly diagnosed. Carbamazepine is considered a first-line
treatment for classical trigeminal neuralgia, and
it has been demonstrated to achieve a reduction
in attacks in up to 88% of patients.[4,7-9] However,
the efficacy of carbamazepine is compromised by
poor tolerability of severe adverse effects such
as drowsiness, confusion, nausea and ataxia.[10]
Oxcarbazepine has also been shown to be effective and is considered a second-line treatment for
trigeminal neuralgia,[4,11] but it is expensive. Baclofen, lamotrigine, pimozide and some other
drugs are also used in the treatment of trigeminal
neuralgia; however, the efficacy of these drugs
remains uncertain.[4]
CNS Drugs 2011; 25 (10)

Topiramate vs Carbamazepine for Classical Trigeminal Neuralgia

Topiramate, a sulfamate-substituted monosaccharide, was first identified as an antiepileptic

drug. Compared with other antiepileptics, this
drug acts at different neural transmission levels
such as sodium channels and enhances GABA
levels, and has been termed a neurostabilizer.[12]
It is used to treat CNS conditions such as neuropathies, eating disorders, alcohol and drug
dependence, migraine, nerve injury, restless leg
syndrome, essential tremor and psychiatric diseases.[13-15] Topiramate is generally well tolerated
at low doses[16] but at high doses it may cause
various kinds of adverse effects including paraesthesia, dysphasia, fatigue, confusion and insomnia.[17] Topiramate is also used for the treatment
of classical trigeminal neuralgia, but its efficacy
remains controversial. Great disparities in results
have been obtained among research into the efficacy of topiramate for classical trigeminal neuralgia.[18-26] In order to determine the effectiveness
and safety of topiramate for classical trigeminal
neuralgia, we conducted a systematic review to
critically evaluate all of the currently available,
randomized controlled trials that compared topiramate with carbamazepine in the treatment of
classical trigeminal neuralgia.
Methods
Data Sources

The following electronic databases were searched

from January 1998 to March 2011: Cochrane Central Register of Controlled Trials (CENTRAL)
[Issue 3 of 12, March 2011], MEDLINE, EMBASE,
the Chinese Biomedical Database (CBM), the
Chinese National Knowledge Infrastructure
(CNKI) and the Chinese Science and Technique
Journals Database (VIP). The first search term
was tic douloureux, trigeminal neuralgia, trigeminal neuropathy or facial pain, the second
search term was carbamazepine or tegretol,
and the third search term was topiramate or
topamax. We combined these three terms for the
electronic search. Corresponding Chinese terms
were also searched. There were no language restrictions. In addition, we also manually searched
all relevant journals. References were addressed
2011 Adis Data Information BV. All rights reserved.

849

in original articles, and reviews were further

searched for relevant studies. Dissertations and
abstracts were also included.
Study Selection

All randomized controlled trials comparing

topiramate with carbamazepine in the treatment
of classical trigeminal neuralgia were considered.
Trigeminal neuralgia had to have been diagnosed
according to a standardized criterion such as the
classification of the International Headache
Society,[3] and classical trigeminal neuralgia had
to have been confirmed by CT or MRI. To be
included in our analysis, trials were required to
have similar baseline characteristics in both study
groups. Trials that involved patients with other
diseases such as organic pain, psychiatric diseases
or other kinds of facial pain were excluded. Trials
using any other medications were also excluded.
Outcome Measures

The main outcomes were the number of participants who responded to treatment, the number of participants who achieved remission and
the number of adverse events reported. We extracted and classified the outcomes of the selected
trials according to the authors original definitions only when they met explicit criteria such as
the system proposed by Spacek et al.[27] If appropriate, we classified the outcomes according
to an explicit criterion when the authors original
definitions did not.
Data Extraction and Quality Assessment

The two authors of this article (Qiang-ping

Wang and Min Bai) independently identified every
potential article and assessed its methodological
quality. Data from all articles were validated and
extracted according to predefined criteria (table I).
Risk of bias was assessed according to the latest
Cochrane classification.[29] Disagreements were
resolved by discussion between the two authors.
Data Synthesis

To compare the effectiveness and safety

of topiramate with carbamazepine we used the
CNS Drugs 2011; 25 (10)

Wang & Bai

2011 Adis Data Information BV. All rights reserved.

a Structural causes were observed by CT or MRI.

b Patients presented with organic pain, mental disease or other facial pain.
c The diagnosis standard proposed by Zheng and Deng.[28]
d Patients presented with impaired sensory or motor function, or with focal neurological signs.
bid = twice daily; ICHD = International Classification of Headache Disorders, 2nd edition;[3] ID = initial dosage; MD = maximal dosage; NR = not reported; tid = three times daily;
VAS = Visual Analogue Scale.

NR
ID: 0.2 g tid
MD: 0.6 g/day
22/21
Structurala
Neurologicald
Zhengc
Xia,[26] 2010

4871

15

NR

ID: 25 mg bid
MD: 200 mg/day

NR
ID: 0.1 g tid
MD: 0.8 g/day
33/33
Structural
Neurologicald
Zheng

Li et al.,[25] 2010

4073; mean: 49.2

30

942;
median: 12

ID: 25 mg bid
MD: 400 mg/day

NR
ID: 0.1 g tid
MD: 0.6 g/day
33/33

Structurala
NR
Gong,[24] 2010

4078; mean: 49.7

45

842;
median: 12

ID: 25 mg bid
MD: 600 mg/day

NR
ID: 0.1 g tid
MD: 1.1 g/day
34/31
Structurala
Neurologicald
Zhengc
Zeng and
Chen,[23] 2009

5073
TPM: mean: 57.4 15.6
CBZ: mean: 58.2 14.9

30 (16/14)

NR

ID: 25 mg bid
MD: 400 mg/day

VAS
ID: 0.2 g tid
MD: 0.6 g/day
Pain
ICHD
Dong et al.,[22]
2008

23/23

4078
TPM: mean: 56 10
CBZ: mean: 54 7

22 (11/11)

NR

ID: 25 mg bid
MD: 200 mg/day

NR
ID: 0.1 g tid
MD: 1.0 g/day
38/30

NR
Chen,[21] 2008

Structurala

5082

35

NR

ID: 25 mg bid
MD: 400 mg/day

Method for outcome

assessment
Treatment
duration (mo)
Dosage
regimen (CBZ)
Dosage regimen
(TPM)
Disease
duration (mo)
Male patients
(TPM/CBZ)
Age (y)
No. in group
(TPM/CBZ)
Exclusion
criteria
Inclusion
criteria
Study, year

Table I. General information from randomized controlled trials comparing topiramate (TPM) with carbamazepine (CBZ) in the treatment of classical trigeminal neuralgia

850

Cochrane Collaborations software RevMan 5.1

(The Nordic Cochrane Centre, The Cochrane
Collaboration, 2011, Copenhagen, Denmark) to
abstract the risk estimates (relative risk: RR) and
the 95% confidence intervals (CI). For studies
without sufficient information, we contacted the
primary authors in order to acquire and verify
data when necessary. In order to ensure clinical
homogeneity, we divided trials into two subgroups
according to the duration of the intervention. The
chi-square (w2) test and the Higgins I2 test were used
to assess heterogeneity. We then pooled the data
across studies using fixed effects models if statistical
heterogeneity did not exist. If appropriate, a metaanalysis was conducted using random effects models when statistical heterogeneity did exist.
Results
Study Description and Quality

The literature search revealed 93 articles, of

which 87 studies were excluded (figure 1). Six
trials met our inclusion criteria, and their general
information is listed in table I. All trials originated from China, and all articles were published
in Chinese. No article published in another language was found. Only one trial[22] included
patients with the diagnosis of classical trigeminal
neuralgia according to the International Classification of Headache Disorders (ICHD) that was
formulated by the Headache Classification Subcommittee of the International Headache Society.[3]
Three trials[23,25,26] included patients diagnosed according to a Chinese criterion that was published
by Zheng and Deng.[28] The following main points
were proposed by Zheng and Deng[28] to aid in the
diagnosis of trigeminal neuralgia:
! The pain is always located in the distribution
of the trigeminal nerve.
! The pain is always unilateral.
! The pain is provoked by touching a relevant
trigger point but attacks of pain can also be
spontaneous.
! The pain is recurrent; each single burst of pain
lasts under 2 minutes on average.
! There is no pain between bursts of pain, and
most patients will have complete remission of
pain for weeks or months, at least initially.
CNS Drugs 2011; 25 (10)

Topiramate vs Carbamazepine for Classical Trigeminal Neuralgia

Potentially relevant articles

identified (n = 93)

Articles excluded by screening the

title and abstract (n = 76):
not relevant to this study (n = 55)
duplicated studies (n = 2)
case report (n = 7)
not a clinical trial (n = 12)

Further evaluation
(n = 17)

Articles excluded after reading the

full text (n = 11):
non-randomized controlled trials
(n = 2)
uncontrolled trials (n = 3)
mixing CTN with other neuralgia (n = 1)
no usable information for meta-analysis
and authors uncontactable (n = 3)
comparing TPM with placebo (n = 2)

851

tensity by more than 50%, and remission was

defined as the disappearance of the symptoms of
trigeminal neuralgia. A reduction of <50% or no
change was considered ineffective therapy.
The quality assessment of the trials is shown in
table II. All trials had a high risk of bias. Details
of how patients were randomized were only given
in two trials,[23,25] and detailed information on
randomization and allocation concealment was not
provided in other studies. The method of blinding
of patients and assessors was not reported in any
of the trials. The baseline characteristics were
similar between groups in all trials (p > 0.05), as
mentioned, but detailed information with respect
to sex, age or severity of clinical status was not
presented in most trials. Details of follow-up and
the number of dropouts or withdrawals were not
clearly reported in any of the trials.
Outcomes
Effectiveness Rate

Trials met the inclusion

criteria (n = 6)
Fig. 1. Flowchart of trial selection process. CTN = classical trigeminal neuralgia; TPM = topiramate.

! Other unilateral facial pains such as toothache, temporomandibular disorders, postherpetic neuralgia and traumatic neuropathic
trigeminal pain have been excluded.
Altogether, a total of 354 patients were included
in the six trials. All patients were adults, and the
duration of disease ranged from 8 to 42 months.
All topiramate groups were given an initial dosage of 25 mg twice per day, and the dosage was
gradually increased according to clinical symptoms. The maximal dosage ranged from 200 to
600 mg/day among trials. Duration of treatment
in three of the trials was 1 month,[21,22,24] and it
was 2 months in the other trials.[23,25,26] There
was only one trial[22] that assessed the results
using the Visual Analog Scale (VAS).[27] Details
of how the outcomes were measured were not
given in other trials. Outcomes in all trials were
classified according to the system proposed by
Spacek et al.[27] Response to treatment was defined as a reduction in both frequency and in 2011 Adis Data Information BV. All rights reserved.

The number of patients who responded to the

therapy was provided in all trials. A small degree
of heterogeneity between the trials was observed
(w2 = 8.33, p = 0.14, I2 = 40%), so we conducted
a meta-analysis using random effects models
(figure 2). We found no significant differences
between the two groups in a pooled analysis
(RR = 1.08, 95% CI 0.96, 1.21, p = 0.20). In subgroup analyses, there were also no significant differences between groups after a treatment duration
of 1 month (RR = 1.00, 95% CI 0.87, 1.14, p = 0.94,
heterogeneity: w2 = 3.04, p = 0.22, I2 = 34%). However, the meta-analysis showed statistically significantly superior effectiveness of topiramate
compared with carbamazepine after a treatment
duration of 2 months (RR = 1.20, 95% CI 1.04,
1.39, p = 0.01, heterogeneity: w2 = 0.24, p = 0.89,
I2 = 0%). Even though the CI of the summary estimates in the two subgroups overlapped to a
small degree, substantial differences were observed between the two subgroups with different
therapy durations (w2 = 3.41, p = 0.06, I2 = 70.7%).
Remission Rate

The number of patients who gained remission

after treatment was provided in all trials. No
heterogeneity between the trials was observed
CNS Drugs 2011; 25 (10)

Wang & Bai

852

Table II. Methodological quality of randomized controlled trials comparing topiramate with carbamazepine in the treatment of classical
trigeminal neuralgia, using Cochrane criteria for assessment of bias[29]
Study, year

Allocation
concealment

Random
sequence
generation

Blinding of
participants
and personnel

Incomplete
outcome data

Blinding of
outcome
assessment

Selective
reporting

Other bias
(outcome
assessment)

Chen,[21] 2008

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Dong et al.,[22] 2008

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

Low
High

Zeng and Chen,[23] 2009

Lowa

Unclear

Unclear

Unclear

Unclear

Unclear

Gong,[24] 2010

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Li et al.,[25] 2010

Lowb

Unclear

Unclear

Unclear

Unclear

Unclear

High

Xia,[26] 2010

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

High

Coin tossing.

Drawing of lots.

High = high risk of bias; Low = low risk of bias; Unclear = unclear risk of bias.

(w2 = 2.14, p = 0.83, I2 = 0%, figure 3). We conducted

a meta-analysis using fixed effects models. The
meta-analysis showed no significant differences
between the two groups in a pooled analysis
(RR = 1.17, 95% CI 0.96, 1.42, p = 0.12). No significant differences were yielded between the two
Topiramate
Study or subgroup, year events total

groups after a treatment duration of 1 month

(RR = 1.06; 95% CI 0.83, 1.36, p = 0.63, heterogeneity: w2 = 0.60, p = 0.74, I2 = 0%) or after a
treatment duration of 2 months (RR = 1.31, 95% CI
0.96, 1.80, p = 0.09, heterogeneity: w2 = 0.21, p = 0.90,
I2 = 0%) via subgroup analyses. There were no

Carbamazepine
Risk ratio
total Weight M-H, random, 95% CI
events

Risk ratio
M-H, random, 95% CI

Effectiveness rate (1 month)

Chen,[21] 2008
Dong et al.,[22] 2008
Gong,[24] 2010
Subtotal (95% CI)

33
20
29

38
23
33
94

22
21
31

30
23
33
86

14.4%
18.6%
24.4%
57.5%

1.18 [0.92, 1.52]

0.95 [0.78, 1.17]
0.94 [0.80, 1.09]
1.00 [0.87, 1.14]

33
21
31
85

17.7%
11.6%
13.3%
42.5%

1.24 [1.00, 1.53]

1.13 [0.85, 1.52]
1.20 [0.92, 1.57]
1.20 [1.04, 1.39]

74
82
Total events
Heterogeneity: 2 = 3.04, df = 2 (p = 0.22); I 2 = 34%
Test for overall effect: Z = 0.07 (p = 0.94)
Effectiveness rate (2 months)
33
25
31
Li et al.,[25] 2010
22
16
19
Xia,[26] 2010
34
22
29
Zeng and Chen,[23] 2009
89
Subtotal (95% CI)
63
79
Total events
Heterogeneity: 2 = 0.24, df = 2 (p = 0.89); I 2 = 0%
Test for overall effect: Z = 2.51 (p = 0.01)

171 100.0%
183
Total (95% CI)
137
161
Total events
Heterogeneity: 2 = 8.33, df = 5 (p = 0.14); I 2 = 40%
Test for overall effect: Z = 1.28 (p = 0.20)
Test for subgroup differences: 2 = 3.41, df = 1 (p = 0.06); I 2 = 70.7%

1.08 [0.96, 1.21]

0.2

0.5
1
Favours
carbamazepine

2
Favours
topiramate

Fig. 2. Forest plot of the effectiveness rate of topiramate vs carbamazepine for classical trigeminal neuralgia. df = degrees of freedom;
M-H = Mantel-Haenszel test.

2011 Adis Data Information BV. All rights reserved.

CNS Drugs 2011; 25 (10)

Topiramate vs Carbamazepine for Classical Trigeminal Neuralgia

Topiramate
Study or subgroup, year events total

Carbamazepine
events total Weight

853

Risk ratio
M-H, fixed, 95% CI

Risk ratio
M-H, fixed, 95% CI

Remission rate (1 month)

20
38
Chen,[21] 2008
13
14
23
Dong et al.,[22] 2008
15
22
Gong,[24] 2010
33
21
Subtotal (95% CI)
94
56
Total events
49
Heterogeneity: 2 = 0.60, df = 2 (p = 0.74); I 2 = 0%
Test for overall effect: Z = 0.48 (p = 0.63)

30
23
33
86

16.8%
17.4%
24.3%
58.6%

1.21 [0.73, 2.02]

0.93 [0.60, 1.45]
1.05 [0.74, 1.49]
1.06 [0.83, 1.36]

33 17.4%
21 8.3%
31 15.8%
85 41.4%

1.40 [0.89, 2.20]

1.36 [0.64, 2.91]
1.19 [0.70, 2.03]
1.31 [0.96, 1.80]

171 100.0%

1.17 [0.96, 1.42]

Remission rate (2 months)

21
Li et al.,[25] 2010
33
15
Xia,[26] 2010
10
22
7
Zeng and Chen,[23] 2009
17
34
13
Subtotal (95% CI)
89
48
Total events
35
Heterogeneity: 2 = 0.21, df = 2 (p = 0.90); I 2 = 0%
Test for overall effect: Z = 1.69 (p = 0.09)
Total (95% CI)
Total events

183
104

84

Heterogeneity: 2 = 2.14, df = 5 (p = 0.83); I 2 = 0%

Test for overall effect: Z = 1.54 (p = 0.12)
Test for subgroup differences: 2 = 1.08, df = 1 (p = 0.30); I 2 = 7.7%

0.1

0.2
0.5
1
Favours
carbamazepine

2
5
Favours
topiramate

10

Fig. 3. Forest plot of the remission rate of topiramate vs carbamazepine for classical trigeminal neuralgia. df = degrees of freedom;
M-H = Mantel-Haenszel test.

significant differences between the two subgroups

(w2 = 1.08, p = 0.30, I2 = 7.7%).
Safety

Detailed information about adverse events

was provided in all trials. Among participants
allocated to receive topiramate, 29 of 183 (15.8%)
experienced some adverse events, mainly manifested as somnolence (8), dizziness (7), nausea (7),
ataxia (2) and confusion (2). 36 of 171 (21.1%)
participants allocated to receive carbamazepine
presented with adverse events, mainly manifested
as dizziness (12), somnolence (6), nystagmus (5),
ataxia (4), nausea (3) and fatigue (2) [table III].
The meta-analysis on individual adverse events
such as dizziness (figure 4), nausea and somnolence showed no significant differences between
the two groups (table III). However, participants
allocated to carbamazepine groups might be more
likely to experience adverse effects such as nystagmus, fatigue and rash, which were not recorded
in the topiramate groups, although our analysis
2011 Adis Data Information BV. All rights reserved.

did not reveal significant differences between

treatments for these events.
Discussion
We conducted a systematic review and metaanalysis of all available randomized controlled
trials on the comparative efficacy and adverse
events of topiramate compared with carbamazepine.
The results showed equally favourable effectiveness and acceptable tolerability of topiramate compared with carbamazepine in the treatment of
classical trigeminal neuralgia, which differed from
the conclusions of some authors and guidelines.[4-11]
We considered that there were two possible explanations for these findings as follows: topiramate
might indeed be effective, or existing studies might
have been inadequately designed and the effects of
topiramate might have been overestimated.
There were many limitations in our analysis,
precluding a firm conclusion on the effectiveness
of topiramate for classical trigeminal neuralgia.
CNS Drugs 2011; 25 (10)

Wang & Bai

0.49
0.27
0.46
0.33
0.07
0.62
0.32
0.45
0.33
0.18

0.59

0.13, 70.02
0.01, 3.67
0.01, 7.22
0.04, 3.11
0.04, 1.17
0.23, 12.29
0.23, 91.66
0.20, 2.05
0.56, 5.50
0.22, 1.33
95% CI of RR

0.49, 3.42

3.00
0.18
0.30
0.33
0.20
1.67
4.57
0.64
1.30
1.76
0.54
RR

0/0
0/0
0/0
0/0
0/2
0/0
0/0
0/1
3/2
1/0
1/2

2011 Adis Data Information BV. All rights reserved.

p-Value

RR = relative risk.

22/21
Xia,[26] 2010

0/0
0/0
0/0
0/1
0/0
1/1
0/0
1/0
0/2
1/2
1/2
33/33
2010
Li et al.,

0/0
0/0
0/0
0/0
0/0
1/0
0/0
1/0
1/1

1/1

0/1
33/33
Gong,[24] 2010

[25]

0/0
0/2
0/1
0/0
0/1
0/0
2/0
1/1

2/0

1/1
34/31
Zeng and Chen,[23]
2009

0/1

1/0
0/0
0/0
0/1
0/0
0/0
0/0
2/2

0/0

0/0
23/23
Dong et al.,[22] 2008

0/0

0/0
0/0
0/0
0/0
0/2
0/0
0/0
1/4

2/0

4/0
38/30
Chen,[21] 2008

0/2

Rash
Fatigue
Weight loss
(TPM/CBZ) (TPM/CBZ) (TPM/CBZ)
Leukopenia
(TPM/CBZ)
Nystagmus
(TPM/CBZ)
Ataxia
Confusion
Xerostomia
(TPM/CBZ) (TPM/CBZ) (TPM/CBZ)
No. in group Dizziness
Nausea
Somnolence
(TPM/CBZ) (TPM/CBZ) (TPM/CBZ) (TPM/CBZ)
Study, year

Table III. General information and meta-analysis results of adverse events reported in randomized controlled trials comparing topiramate (TPM) with carbamazepine (CBZ) in the
treatment of classical trigeminal neuralgia

854

All of the trials had a high risk of bias. None of

the trials estimated the appropriate sample size,
and smaller samples are more likely to suffer from
selection bias. Detailed information with respect
to sex, age, characteristics of pain and duration
or severity of clinical status was not presented in
most trials. Although randomization was mentioned, details of the randomization methods
were not clearly described in most trials. Blinding
method, allocation concealment, follow-up or
dropouts were not reported in any of the trials.
Details on how outcomes were measured were
not given in most trials. As described in the six
trials, the outcome assessments were conducted
at the end of treatment. However, the outcome
should be measured over a period of time rather
than at one timepoint. Sometimes pain relief can
occur for a short period of time but cannot be
maintained long term, so positive results might
have been obtained by chance in these trials. Moreover, all of the trials included were conducted in
China where most studies performed are reported
as positive.[30] Although all of the studies had positive results, it is likely that the effects were overestimated due to the low quality of these trials.
We found that there were very few studies to
compare topiramate with carbamazepine in the
treatment of classical trigeminal neuralgia. Although great efforts were made to seek out all
relevant studies, we could only find eligible randomized controlled trials published in the Chinese
language. Is topiramate known to be ineffective
or less effective than carbamazepine in the treatment of classical trigeminal neuralgia? We did not
find evidence to support this hypothesis within the
published literature. The Chinese studies might
indeed be inadequately designed and the effects
of topiramate might be exaggerated, but could all
six trials make the same mistake and yield similar
results? Or are there any known differences in response to topiramate or carbamazepine between
Chinese and non-Chinese populations? We performed a literature search in order to clarify this,
but satisfying answers were not found. Zhao et al.[31]
studied the pharmacokinetic characteristics of
topiramate in Chinese volunteers and compared
the results with Western studies. They found that
Chinese volunteers achieved a faster time-to-peak
CNS Drugs 2011; 25 (10)

Topiramate vs Carbamazepine for Classical Trigeminal Neuralgia

Study, year

855

Topiramate Carbamazepine
Risk ratio
events total events total Weight M-H, fixed, 95% CI

Chen,[21] 2008

38

30 35.6%

0.20 [0.02, 1.67]

Dong et al.,[22] 2008

23

23 15.9%

1.00 [0.15, 6.51]

Gong,[24] 2010

33

33

Li et al.,[25] 2010

33

33 15.9%

0.50 [0.05, 5.25]

Xia,[26] 2010

22

21 16.3%

0.48 [0.05, 4.88]

Zeng and Chen,[23] 2009 1

34

31

Total events

8.0% 1.00 [0.07, 15.33]

8.3% 0.91 [0.06, 13.96]

171 100.0%

183

Total (95% CI)

Risk ratio
M-H, fixed, 95% CI

0.54 [0.22, 1.33]

12

Heterogeneity: 2 = 1.62, df = 5 (p = 0.90); I 2 = 0%

Test for overall effect: Z = 1.34 (p = 0.18)

0.01

0.1
1
Favours
carbamazepine

10
Favours
topiramate

100

Fig. 4. Forest plot of the adverse event of dizziness reported for topiramate compared with carbamazepine. df = degrees of freedom;
M-H = Mantel-Haenszel test.

and higher peak serum topiramate concentrations. A longer plasma elimination half-life was
also found in Chinese compared with Western populations. However, this pharmacokinetic study
could not support such an important conclusion
that topiramate was more effective for classical
trigeminal neuralgia in Chinese than in Western
populations. Therefore, any differences in therapeutic response to topiramate or carbamazepine
between Chinese and non-Chinese populations
still need to be examined in high-quality trials.
Due to the adverse effect profile of carbamazepine, more effective and safer alternative drugs need
to be found to treat classical trigeminal neuralgia.
Our study found equally favourable effectiveness
and acceptable tolerability of topiramate compared with carbamazepine in the treatment of
classical trigeminal neuralgia. However, we could
not draw an affirmative conclusion due to the
poor methodological quality and localized population of the trials included. Therefore, this
study aimed at presenting the available results
and providing a reference point for future studies,
with the expectation that future large, international, well conducted, randomized controlled
trials will precisely assess the effectiveness of topiramate for classical trigeminal neuralgia.
There are some suggestions for future studies.
First, patients included in trials should be diagnosed according to strict criteria such as those of
2011 Adis Data Information BV. All rights reserved.

the IHCD. As trigeminal neuralgia is characterized by occasional attacks and remission phases
in its natural history, especially in its initial phases,
adequate selection of the clinical phase and detailed
records of the history are important. Second,
adequate randomization and allocation concealment methods should be used. Third, participants
and outcome assessors should be blinded with adequate methods. Furthermore, rigorous approaches
should be used in outcome measurement to make
sure the results are objective and authentic. As
pain is inherently difficult to measure because of
its subjective nature and the strong influence of
social context, emotion and other nonphysiological
variables,[32] an objective, authentic and standardized instrument for outcome measurement such
as the VAS, the multi-institutional Initiative on
Methods, Measurement, and Pain Assessment in
Clinical Trials (IMMPACT)[33] or the Brief Pain
Inventory-Facial[34] is obligatory. Moreover, an
intent-to-treat analysis should be applied to reduce the impact of dropouts or withdrawals.
Conclusions
Current trials comparing topiramate with carbamazepine are all poor in terms of methodological quality. The meta-analysis of these studies
showed that the overall effectiveness and tolerability of topiramate does not seem to differ from
CNS Drugs 2011; 25 (10)

Wang & Bai

856

carbamazepine in the treatment of classical trigeminal neuralgia. However, the meta-analysis

yielded a favourable effect of topiramate compared
with carbamazepine after a treatment duration of
2 months. Results are limited by the poor methodological quality and localized population of
the trials included. Therefore, large, international,
well conducted, randomized controlled trials are
needed to further assess the relative efficacy and
tolerability of topiramate and carbamazepine in
this indication.
Acknowledgements
We thank Dr Ding Lei for providing valuable advice for
this article. We also thank all staff members of the Cochrane
Collaboration for providing Cochrane methodology and the
Cochrane RevMan 5.1 programme that was used in this article. No sources of funding were used to prepare this study. All
authors agree with the opinions and conclusions expressed in
this manuscript and have no conflicts of interest.

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Correspondence: Dr Qiang-ping Wang, Department of

Neurosurgery, Dujiangyan Peoples Hospital, Dujiangyan
Medical Center, Baolian street no.1, Dujiangyan 611830,
China.
E-mail: 187317846@qq.com

CNS Drugs 2011; 25 (10)

Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.