The Efficacy of Daily Prefrontal Repetitive Transcranial Magnetic Stimulation (rTMS) for Burning Mouth Syndrome (BMS): a Randomized, Controlled Single Blind Study

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DOI: 10.1016/j.brs.2015.10.005
Cite this publication
The Efficacy of Daily Prefrontal Repetitive Transcranial Magnetic
Stimulation (rTMS) for Burning Mouth Syndrome (BMS):
A Randomized Controlled Single-blind Study
Yojiro Umezaki a,*, Bashar W. Badran a,William H. DeVries a, Jkeonye Moss a,
Theresa Gonzales b, Mark S. George a,c
aBrain Stimulation Laboratory, Department of Psychiatry, Medical University of South Carolina, 67 President Street, Charleston, SC 29425, USA
bDivision of Oral Pathology, College of Dental Medicine, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA
cRalph H. Johnson VA Medical Center, 109 Bee Street, Charleston, SC 29401, USA
ARTICLE INFO
Article history:
Received 1 July 2015
Received in revised form 1 October 2015
Accepted 20 October 2015
Available online
Keywords:
Burning mouth syndrome
Repetitive transcranial magnetic
stimulation
Left dorsolateral prefrontal cortex
Chronic pain
ABSTRACT
Background: Burning mouth syndrome (BMS) is a burning oral sensation without any corresponding ab-
normal findings. In some cases, BMS is refractory to pharmacologic treatments. Repetitive transcranial
magnetic stimulation (rTMS) over left prefrontal cortex induces analgesic effect in both acute and chronic
pain. However, its effect for BMS has not been evaluated.
Objective: The aim of this randomized, controlled, single-blind study was to assess the efficacy of pre-
frontal rTMS for BMS.
Method: Twenty patients with BMS were recruited and randomized to receive 30,000 pulses in total at
10 Hz TMS (n =12) or sham TMS (n =8). We assessed the change of BMS pain condition, functional status
and mood until 2 months after the beginning of treatment.
Results: In the real group, the BMS pain intensity decreased 67%, and 75% of the patients reported >50%
pain decrease on final assessment compared to baseline, without heavy side effects. There was signifi-
cant pain reduction in subjects in the real group immediately after 1 week of treatment, whereas there
was none in those in the sham group. Similar tendency was confirmed in change of functional status.
Mood and the affective aspect of pain were not changed in this study.
Conclusion: BMS pain was significantly improved with 2 weeks of treatment of high frequency rTMS over
left DLPFC compared to sham stimulation. Further study is needed to refine and improve TMS as a po-
tential treatment of BMS.
© 2015 Elsevier Inc. All rights reserved.
Introduction
Burning mouth syndrome (BMS) is a persistent burning, tin-
gling or pricking sensation in the mouth without abnormal clinical
findings that might be causing the symptoms [1,2]. The pain is con-
tinuous, being often better in the morning and worse in the evening.
It is most often experienced in the tongue, but may be felt any-
where in the intraoral mucosa including palate, gum and lips. The
pain is usually bilateral, although it may rarely occur unilaterally,
and it does not comply with peripheral nerve distribution. The es-
timated prevalence of BMS is from 0.7% [3] to 1% [4] in the general
adult population, and the incident rate is 11.4 per 100,000 person-
years [5]. BMS is 2.5–7 times more common in women than in men,
and many affected women are perimenopausal. Around 60% of BMS
patients complain of dry mouth or taste disturbance with the burning
sensation [6].
In the literature, BMS has also been called ‘oral dysesthesia’ [7,8]
or ‘persistent idiopathic orofacial pain’ [9]. According to current di-
agnostic criteria [10], BMS is classified under the heading ‘central
causes of facial pain’. The pathophysiology of BMS has not been fully
elucidated. Some researchers have linked BMS to a peripheral neu-
ropathy that is caused by the dysfunction of excitability of the
trigeminal nerve [11], lingual nerve [12] or the chorda tympani
branch of the facial nerve [6]. However, recent evidence indicates
that dysfunction of the central nervous system can cause BMS. Al-
buquerque et al. [13] used functional magnetic resonance imaging
(fMRI) and showed dysfunction of the anterior cingulate cortex (ACC)
* Corresponding author. Tel.: +1 843 792 2335; fax: +1 843 792 5702.
E-mail address: umezaki@yahoo.com (Y. Umezaki).
Institutional URL: http://academicdepartments.musc.edu/psychiatry/research/bsl/.
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http://dx.doi.org/10.1016/j.brs.2015.10.005
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and the precuneus in patients with BMS. And Jääskeläinen et al.
[14,15] showed striatal dopaminergic dysfunction in BMS patients
using positron emission tomography (PET). BMS is commonly treated
with antidepressants, antipsychotic drugs, anticonvulsant drugs, or
benzodiazepines. However, there are some drug-resistant cases
where the medications do not provide clinical relief. So a new treat-
ment for BMS is needed.
Transcranial magnetic stimulation (TMS) is a non-invasive
brain stimulation technology that can focally stimulate an
individual’s brain via a localized pulsed magnetic field [16,17].It
is capable of stimulating the cortex by depolarizing superficial
neurons. TMS has direct and indirect effects. For example, prefron-
tal TMS affects both the neurons underneath the TMS coil and deeper
limbic regions [18–20]. Repetitive TMS (rTMS) over the dorsolat-
eral prefrontal cortex (DLPFC) is used for mainly medication-
resistant depression [21,22]. Recently several studies showed that
rTMS over left DLPFC induced analgesic effects in both acute and
chronic pain conditions [23–25]. Some studies have found benefi-
cial effects of prefrontal rTMS for fibromyalgia [26], neuropathic
pain [27] and other medically unexplained symptoms of pain [28,29].
However, as far as we know, there are no reports about the effect
of rTMS for BMS.
We thus hypothesized that 10 days of daily left prefrontal rTMS,
applied in a manner similar to that which is approved for treating
depression and which has shown anti-pain effects in other pain syn-
dromes, would produce a significant reduction in BMS pain,
compared to those subjects who received 10 days of sham rTMS.
Materials and methods
Subjects
Thirty subjects naïve to TMS were enrolled after being re-
cruited through local newspaper advertisements, referrals from the
division of oral pathology in the Medical University of South Caro-
lina (MUSC) dental clinic and MUSC broadcast email. Twenty-six
subjects were diagnosed as having BMS [1]; they experienced daily
and deep bilateral burning sensation of the oral mucosa, burning
sensation for at least 4–6 months, constant intensity or increasing
intensity during the day, no worsening but possible improvement
on eating or drinking, no interference with sleep and normal ap-
pearing oral mucosa.
Patients were excluded if evidence was found of inflammation
or autoimmune disease. Patients were not included if they had a
current primary psychiatric condition – including major depres-
sion or major personality disorders – or a history of substance abuse
(except caffeine or nicotine). When the patients reported a history
of a primary psychiatric condition, or had some symptoms sugges-
tive of another condition, a psychiatrist examined them to help
confirm diagnoses. Patients with contraindications for TMS – a
history of seizures, brain surgery, or intracranial hypertension, a pace-
maker or other metallic implants – and patients with medication
changes within 4 weeks of starting the trial or during the trial were
also excluded. Any stable medication was permitted.
The MUSC Institutional Review Board approved this study and
written informed consent was provided from all patients before the
session.
Procedure
On the screening day, YU checked the intra and extra oral con-
ditions of all potential subjects. Patients who met all inclusion criteria
were randomly assigned to one of two groups – one given active
and the other sham stimulation – using a web-based randomiza-
tion generator (www.randomization.com). During a 1-week baseline
observation period, patients were asked to report their mean pain
intensity in a diary each day over the last 24 h on a visual analog
scale (VAS: from none to extreme amount of pain). The stimula-
tion protocol consisted of one session per day for five consecutive
days followed by 2 days without treatment, and then another five
consecutive days of treatment. Patients were asked to report daily
their mean pain intensity on VAS during the stimulation periods
(from day 1 to day 14) and follow-up visits which were scheduled
for assessments at days 15, 30, 60 after the start of the treatment.
Normally, since the VAS score is used to evaluate BMS pain inten-
sity, we set the VAS score as the primary outcome.
Since the pain interacts with functional activity, mood and so
on, we used additional questionnaires as secondary outcome. Ques-
tionnaires for assessing BMS pain, functional impairment related
to BMS pain, mood and effect of intervention were completed in 5
phases (baseline, days 8, 15, 30 and 60 after the start of the treat-
ment). The Brief Pain Inventory (BPI) items for pain interference
[30], the Short Form McGill Pain Questionnaire (SFMPQ) [31], the
Patient Health Questionnaire (PHQ-9) [32], the Patients’ Global Im-
pression of Change (PGIC) [33] and Clinical Global Impression for
global improvement scale (CGI-I) [34] were used. The head pain
intensity under the TMS coil during the TMS session (TMS proce-
dural pain) was also asked using a VAS, immediately after each
TMS session was finished. Additionally, the subjects’ belief of which
group they were in (real or sham) was asked after the course of
treatment.
TMS procedure and design
A MagVenture MagPro ×100 Stimulator (MagVenture, Inc.;
Denmark) with a Cool-B65 A/P coil with figure eight coil was used
for all TMS sessions. The resting motor threshold (RMT) was de-
termined for each individual once a week. The TMS machine was
initially set to 50% of its maximal output. The TMS coil with single
pulse stimulation was positioned roughly around the primary motor
cortex, and moved until the area that best produced contraction of
abductor pollicis brevis (APB) was identified. Custom-developed soft-
ware that employs adaptive parameter estimation by sequential
testing (PEST) [35] data was used to determine RMT using visible
movement.
During active and sham stimulation, the coil was positioned over
the left DLPFC, at medial frontal 10–20 system EEG-electrode lo-
cation (F3) as defined by Beam et al. [36]. The same stimulation
frequency was used for all active subjects: 10 sessions of 10 Hz pulse
train duration 5 s, power intensity levels 110% of RMT, intertrain
interval 10 s for 15 minutes (for a total of 30,000 pulses).
TMS sham design
The coil used in the sham group was the same configuration as
that used with the real group but shielded so that actual stimula-
tion does not occur. All subjects had ECT electrodes (Natus neurology;
Middleton, WI) placed under the TMS coil. For those receiving active
TMS, the electrodes were disconnected, such that there was no
current flowing through during stimulation. In contrast, the elec-
trodes were connected during sham, so participants received a small
electrical stimulation through the electrodes, precisely when the TMS
was being triggered. This system helps keep patients and treaters
blind to randomization assignment. For this trial, unfortunately the
treater was unblinded, but patients were not. To avoid distinguish-
ing the group by talking or attitude, the treater did not talk about
treatment during the session and communication between differ-
ent patients enrolled in the trial was banned.
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Statistical analysis
To compare the biographic data between the real and sham
groups, Mann–Whitney U-tests and Chi-squared tests were used.
For evaluation of BMS pain stability in the baseline period, one-
way ANOVA was used. For the change of VAS, BPI functional
impairment, SFMPQ, PHQ-9, PGIC and CGI-I scores in each phase,
two-way ANOVA of 5 ×2 mixed models were used to examine the
interaction of time (baseline, days 8, 15, 30 and 60) and group (real
TMS and sham TMS). To compare the score in each phase with base-
line, Wilcoxon signed ranked test was used. For evaluation of TMS
procedural pain, two-way ANOVA of 10 ×2 mixed models were used
(time; days 1–5, 8–12, group; real and sham TMS). As for the cor-
relations between each dependent variable, Spearman’s rank
correlation coefficient was calculated. All analyses were run using
SPSS (SPSS software, version 21; SPSS, Chicago, IL).
Results
Subjects
All subjects were enrolled between September 2014 and De-
cember 2014. Fig. 1 shows the CONSORT flowchart in this study.
Twenty-six patients meeting the inclusion criteria were included.
Fourteen and 12 patients were allocated in the real and sham
treatment arms respectively. Two patients in the real group and 4
patients in the sham group dropped out after only two sessions and
were not able to receive the minimum allocated scheduled treat-
ments. Thus, 12 patients in the real group and 8 patients in the sham
group completed all 10 TMS sessions. Though 7 patients in the real
treatment group and 5 patients in the sham treatment group com-
plained of headache as a side effect in the beginning of treatment,
it was very mild and disappeared in one or two days. No one ex-
plicitly dropped out because of side effects. The reason for dropout
was due to lack of compliance; it was confirmed by phone.
Table 1 shows the demographic data. All subjects were women
except for one man in both the real and sham groups. Total mean
age was 63.9 years and mean duration of illness was 63.4 months.
All subjects had some symptoms in the tongue and 30–40% of the
patients had their symptoms in the lips, palate and gum as well.
Around 70% of the patients complained of comorbid dry mouth and
40% of the patients complained of taste disturbance (spontaneous
metallic, acid or bitter taste). In almost all cases, the pain started
spontaneously, but the pain was following dental treatment in 2 cases
(dental implant and pulling out left mandibular wisdom tooth) and
a car accident in one case. Selective serotonin reuptake inhibitors
(SSRIs) were prescribed for around 40% of the patients, but these
did not adequately relieve the BMS pain. Though 30% of the pa-
tients had a prior history of depression, none currently met diagnostic
criteria for depression. Specifically, they were not suicidal, did not
CONSORT 2010 Flow Diagram
Assessed for eligibilit y (n= 30 )
Excluded (n= 4 )
Not meeting inclusion criteria (n= 2 )
Declined to participate (n= 2 )
Other reasons (n= 0 )
Analysed (n= 12 )
Excluded from analysis (give reasons) (n= 0)
Lost to follow-up (give reasons) (n= 0)
Discontinued intervention (give reas ons) (n= 0)
Allocated to intervention (n= 14 )
Received allocated intervention (n= 12 )
Did not receive allocated interventi on (n= 2 )*
Lost to follow-up (give reasons) (n= 0)
Discontinued intervention (give reas ons) (n= 0)
Allocated to intervention (n= 12 )
Received allocated intervention (n= 8 )
Did not receive allocated intervention (n = 4 )*
Analysed (n= 8 )
Excluded from analysis (give reasons) (n= 0)
Allocation
Analysis
Follow-Up
Randomized (n= 26 )
Enrollment
Figure 1. CONSORT flow chart in this study. *Since the patients cannot find the suitable time, 2 patients in the real group and 4 patients in the sham group did not receive
the allocated treatment.
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have prominent depression symptoms, and they were living their
normal social life at the time of enrollment. Twenty percent of pa-
tients had a past history of cancer, but no one had a history of oral
cancer. Age and duration of illness were not significantly different
between the real and sham groups. Pain location, comorbid symp-
toms, trigger of BMS, ongoing medication and medical history were
not significantly different between the groups. No clinical vari-
ables were significantly different between the two groups.
Primary outcome
BMS pain intensity
In the one week baseline period, BMS pain intensity was checked
every day for pain stability. The stability in the baseline was con-
firmed (F(3.566, 67.746) =1.786, NS). Then the VAS score at the last
baseline day was used as the baseline pain intensity in order to
exclude any effect during the baseline period.
Fig. 2 shows the mean BMS pain intensity for each phase of the
study between groups. In the real group, BMS pain intensity was
decreased immediately after 1 week of treatment. The BMS pain in-
tensity temporarily increased on day 30, but decreased again on day
60. The subjects in the real group reported a 67% decrease in BMS
pain intensity, and 75% of the subjects in the real group reported
>50% decrease in BMS pain intensity from baseline to day 60.
There was a significant main effect for time (F(2.66,
47.888) =11.415, p<=.000) and interaction of time and treatment
(F(2.66, 47.888) =6.848, p=.001). Post hoc analysis revealed that VAS
scores were significantly decreased in every phase (days 8, 15, 30
and 60) compared to baseline in the real treatment group (day 8,
Z=−2.631, p=.009; day 15, Z =−3.059, p=.002; day 30, Z =−2.747,
p=.006; day60, Z =−3.059, p=.002), whereas those in the sham group
were not significantly decreased (day 8, Z =−1.703, NS; day 15,
Z=−1.260, NS; day 30, Z =−1.690, NS; day 60, Z =−1.859, NS). VAS
scores were significantly different between groups on day 15
(Z =−2.547, p=.011) and day 60 (Z =−2.781, p=.005), though the
scores were not different between both groups on baseline
(Z =1.235, NS).
Secondary outcome (Table 2)
Resting motor threshold
RMT did not differ between groups (first week, Z =−1.275, NS;
second week, Z =−1.008, NS).
Brief Pain Inventory functional impairment
No main effect for time was observed (F(4, 72) =1.733, NS).
However, time by treatment interaction was significant (F(4,
72) =3.703, p=.008). Post hoc analysis evidenced patients in real
treatment had significant improvement on days 8, 15, 30 and 60
from baseline (day 8, Z =−2.12, p=.034; day 15, Z =−2.983, p=.003;
day 30, Z =−2.316, p=.021; day 60, Z =−2.982, p=.003), whereas
those in sham did not (day 8, Z =−.140, NS; day 15, Z =−.338, NS;
day 30, Z =−.911, NS; day 60, Z =−.280, NS).
Short Form McGill Pain Questionnaire sensory score (SFMPQ)
The main effect for time was not significant for this rating scale
(F(4, 72) =2.349, NS). Time by treatment interaction was not sig-
nificant (F(4, 72) =.729, NS), suggesting no treatment effect for TMS
over time on SFMPQ sensory score. However, on days 30 and 60,
patients in real treatment evidenced a significant improvement (day
30, Z =−2.585, p=.010; day 60, Z =−3.065, p=.002), whereas those
in the sham group did not (day 30, Z =−.949, NS; day 60, Z =−.051,
NS).
Short Form McGill Pain Questionnaire affective score
Main effect for time was not observed (F(4, 72) =1.738, NS). The
time by treatment interaction was not significant (F(4, 72) =.736,
NS).
Table 1
Demographic and clinical characteristics of patients.
Characteristic Real treatment Sham treatment Total
Sex, % female 92.86 91.67 92.31
Age, y, mean (SD) 63.36 (10.78) 64.42 (8.35) 63.85 (9.56)
Duration of illness, m, mean (SD) 61.57 (32.10) 65.58 (55.52) 63.42 (65.51)
Location of pain
Tongue, % 100 100 100
Lip, % 42.86 41.67 42.31
Palate, % 28.57 41.67 34.62
Gum, % 28.57 41.67 34.62
Other symptoms
Dry mouth, % 57.14 83.33 69.23
Taste disturbance, % 28.57 50 38.46
Oral cenesthopathy, % 7.14 25 15.38
Cause
Spontaneous, % 85.71 91.67 88.46
Dental treatment, % 7.14 8.33 7.69
Others, % 7.14 0 3.85
Medicationa
Antidepressants, % 28.57 58.33 42.31
Anticonvulsants, % 7.14 25 15.38
Opiates, % 21.43 25 23.08
Benzodiazepines, % 57.14 66.67 61.54
Total no. of medications, mean (SD) 1.50 (1.51) 2.00 (1.54) 1.73 (1.51)
History
Depression, % 28.57 33.33 30.77
Fibromyalgia, % 7.14 33.33 19.23
Cancer, % 28.57 8.33 19.23
High blood pressure, % 35.71 58.33 46.15
High cholesterol, % 42.86 50 46.15
Others, %b50 25 38.46
aPercentage of patients who were taking medication before and during the study.
bOthers include asthma, diabetes and migraine.
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Short Form McGill Pain Questionnaire Present Pain Intensity (PPI)
Significant main effect on time was observed (F(4, 72) =6.382,
p<=.000). Significant effect between groups was also observed (F(1,
18) =7.925, p=.011). However, time and treatment interaction was
not observed (F(4, 72) =2.428, NS). Post hoc analysis evidenced
SFMPQ PPI scores were significantly different between real and sham
groups on days 15 and 60 (day 15, Z =−2.678, p=.007; day 60,
Z=−2.578, p=.010), though there was no significant difference on
baseline (Z =−1.827, NS).
Patient Health Questionnaire
Significant main effect for time on PHQ9 score was observed
(F(2.730, 49.148) =5.164, p=.004), suggesting overall improve-
ment in the subjects. However, time by treatment interaction was
not observed (F(2.730, 49.148) =2.294, NS). It suggests no advan-
tage of real treatment compared to sham treatment for improving
the mood in these subjects. An overall improvement in mood could
have contributed to reducing pain symptoms, but the PHQ9 changes
did not differ between the two groups.
Figure 2. Mean visual analog scale (VAS) score for burning mouth syndrome (BMS) pain on each phase. X axis shows phase. Y axis shows VAS score of BMS pain. A solid
line and dotted line show VAS score for mean BMS pain in real group and sham group. respectively, on each phase. ** Statistically significant differences(p<=.01) were
observed on day 8, day 15, day 30 and day 60 compared to baseline in the real group, but not in the sham group.
Table 2
Response to therapy by treatment and measurement.
Measurement Baseline Treatment Follow-up
Day 8 Day 15 Day 30 Day 60
Resting motor threshold
Real 56.42 (9.07) 55.58 (9.89)
Sham 53.00 (5.93) 53.50 (6.46)
BPI functional impairment
Real 3.28 (1.94) 2.00 (2.18)*1.52 (1.39)** 1.75 (1.93)*1.20 (1.40)**
Sham 3.22 (2.28) 3.26 (3.07) 3.31 (2.56) 3.65 (2.92) 3.74 (3.27)
SFMPQ sensory score
Real 9.42 (5.65) 6.67 (6.83) 6.33 (6.67) 4.42 (3.99)*4.58 (4.91)**
Sham 11.75 (7.96) 8.88 (6.85) 10.88 (6.38) 10.25 (7.21) 9.38 (6.09)
SFMPQ affective score
Real 3.08 (2.50) 1.92 (2.81) 1.75 (1.71) 2.83 (3.86) 1.67 (1.87)
Sham 5.00 (3.51) 4.63 (3.78) 4.63 (4.17) 5.50 (4.21) 4.50 (3.38)
SFMPQ PPI score
Real 2.54 (0.84) 2.17 (0.58) 1.83 (0.83) 2.17 (0.83) 1.33 (0.78)
Sham 3.63 (1.51) 2.63 (0.92) 3.25 (1.04) 3.00 (1.41) 2.88 (1.36)
PHQ9
Real 9.67 (4.98) 5.50 (4.89) 4.67 (3.94) 4.92 (4.76) 4.08 (3.82)
Sham 11.00 (5.07) 8.13 (4.36) 9.50 (6.52) 10.25 (6.80) 10.00 (6.39)
PGIC
Real 1.08 (0.29) 3.67 (1.50) 3.75 (1.66) 2.92 (2.07) 4.42 (1.83)**
Sham 1.00 (0.00) 2.75 (1.58) 2.75 (1.49) 2.75 (2.19) 2.38 (2.26)
CGI-I
Real 4.00 (0.00) 2.58 (0.51)** 2.17 (0.72)** 2.25 (0.97)** 1.67 (0.78)**
Sham 4.00 (0.00) 3.25 (0.89) 3.25 (0.89) 3.25 (1.17) 3.38 (0.92)
*p<0.05.
** p<0.01.
The data represent mean scores and standard deviations.
BPI; Brief Pain Inventory, SFMPQ; Short Form McGill Pain Questionnaire, PHQ9; Patient Health Questionnaire, PGIC; Patients’ Global Impression of Change, CGI-I; Clinical
Global Impression for global improvement scale.
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    Background: Transcranial Direct Current Stimulation (tDCS) and Transcranial Magnetic Stimulation (TMS) have been described as promising alternatives to treat different pain syndromes. This study evaluated the effects of TMS and tDCS in the treatment of chronic orofacial pain, through a systematic review. Methods: An electronic search was performed in major databases: MEDLINE, Scopus, Web of Science, Cochrane, Embase, LILACS, BBO, Open Gray and CINAHL. The eligibility criteria comprised randomized clinical trials (RCTs) that applied TMS or tDCS to treat chronic orofacial pain. The variables analyzed were pain, functional limitation, quality of life, tolerance to treatment, somatosensory changes, and adverse effects. The risk of bias was assessed through the Cochrane Collaboration tool, and the certainty of evidence was evaluated through GRADE. The protocol was registered in the PROSPERO database (CRD42018090774). Results: The electronic search resulted in 636 studies. Thereafter, the eligibility criteria were applied and the duplicates removed, resulting in eight RCTs (four TMS and four tDCS). The findings of these studies suggest that rTMS applied to the Motor cortex (M1), the dorsolateral prefrontal cortex (DLPFC) and the secondary somatosensory cortex (S2) provide adequate orofacial pain relief. Two studies reported significant pain improvement with tDCS applied over M1 while the other two failed to demonstrate significant effects compared to placebo. Conclusions: rTMS, applied to M1, DLPFC or S2, is a promising approach for the treatment of chronic orofacial pain. Moreover, tDCS targeting M1 seems to be also effective in chronic orofacial pain treatment. The included studies used a wide variety of therapeutic protocols. In addition, most of them used small sample sizes, with a high risk of biases in their methodologies, thus producing a low quality of evidence. The results indicate that further research should be carried out with caution and with better-standardized therapeutic protocols.
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    Objectives To determine the frequency of use of the core outcome domains published by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) in burning mouth syndrome (BMS) randomized controlled trials (RCTs). Methods This systematic review, conducted as part of the World Workshop on Oral Medicine VII (WWOM VII), was performed by searching the literature for studies published in PubMed, Web of Science, PsycINFO, Cochrane Database/Cochrane Central, and Google Scholar from January 1994 (when the first BMS definition came out) through October 2017. Results A total of 36 RCTs (n = 2,175 study participants) were included and analyzed. The overall reporting of the IMMPACT core and supplemental outcome domains was low even after the publication of the IMMPACT consensus papers in 2003 and 2005 (mean before IMMPACT consensus publication = 2.6 out of 6; mean after IMMPACT publication = 3.8 out of 6). Use of validated assessment tools recommended by the IMMPACT consensus was scarce (1.9 out of 6). None of the RCTs reviewed cited the IMMPACT consensus papers. Conclusions The underreporting of IMMPACT outcome domains in BMS RCTs is significant. Raising awareness regarding the existence of standardized outcome domains in chronic pain research is essential to ensure more accurate, comparable, and consistent interpretation of RCT findings that can be clinically translatable.
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    Burning Mouth Syndrome (BMS), a chronic intraoral burning sensation or dysesthesia without clinically evident causes, is one of the most common medically unexplained oral symptoms/syndromes. Even though the clinical features of BMS have been astonishingly common and consistent throughout the world for hundreds of years, BMS remains an enigma and has evolved to more intractable condition. In fact, there is a large and growing number of elderly BMS patients for whom the disease is accompanied by systemic diseases, in addition to aging physical change, which makes the diagnosis and treatment of BMS more difficult. Because the biggest barrier preventing us from finding the core pathophysiology and best therapy for BMS seems to be its heterogeneity, this syndrome remains challenging for clinicians. In this review, we discuss currently hopeful management strategies, including central neuromodulators (Tricyclic Antidepressants - TCAs, Serotonin, and Norepinephrine Reuptake Inhibitors - SNRIs, Selective Serotonin Reuptake Inhibitors - SSRIs, Clonazepam) and solutions for applying non-pharmacology approaches. Moreover, we also emphasize the important role of patient education and anxiety management to improve the patients’ quality of life. A combination of optimized medication with a short-term supportive psychotherapeutic approach might be a useful solution.
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    Highlights • Patients with sickle-cell disease (SCD) have greater resting-state functional connectivity between the locus coeruleus (LC) and dorsolateral prefrontal cortex (dlPFC). • Patients with SCD have greater resting state centrality of the LC • SCD patients with chronic pain exhibited even greater functional connectivity between the LC and dlPFC. • This study supports hyper-connectivity between the LC and PFC is a potential chronic pain generator.
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    Purpose of Review Sleep disturbances have been linked to chronic pain disorders and it has been suggested that they affect each other in a circular fashion. However, with the exception of sleep bruxism and temporomandibular disorders, very little is known about the interaction between sleep and specific orofacial pain disorders. We aimed to review and evaluate the existing knowledge about the relationship between orofacial pain and sleep disorders. Furthermore, to elaborate on management options for patients with orofacial pain and sleep disorders. Recent Findings Orofacial pain disorders such as temporomandibular disorders, burning mouth syndrome, and painful post-traumatic trigeminal neuropathy are reciprocally related to disturbances in sleep quality. Furthermore, in the case of temporomandibular disorders, it has been shown that sleep quality disturbances occur before pain onset. Regarding sleep bruxism, the recent literature seems to indicate that when sleep bruxism is assessed objectively (i.e., polysomnography), most sleep bruxism parameters do not seem to be able to explain temporomandibular disorder occurrence. Finally, very few studies have assessed the effect sleep quality improvement has on chronic orofacial pain parameters such as intensity and frequency. Summary In general, there is a lack of studies assessing the relationship between sleep disturbances and orofacial pain disorders, the exception being the relationship between sleep bruxism and TMD. The few studies that exist suggest an association between orofacial pain disorders and decreased sleep quality. As such, it is important that the orofacial pain clinician be aware of comorbid sleep disorders and a multidisciplinary and integrative approach should be used to manage these patients.
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    The authors review the literature and own data concerning therapeutic use of transcranial magnetic stimulation (TMS) in children and adult patients with pain syndromes of different origins. TMS may act as a tool to excite or inhibit neuroplasticity in the central nervous system, which depends of the therapeutic regime used. TMS induces neurogenesis and synaptogenesis, rhythmic TMS may cause long-lasting after-effects, including pain inhibitory effect. A decrease in the threshold and an increase in the amplitude of motor evoked potentials in TMS are the most frequent changes in pain syndromes in the diagnostic modality. The efficacy of different regimes in the treatment of pain syndromes remains understudied. Despite vast knowledge on clinical use of TMS in pain syndromes in adults, in pediatrics its use is limited to migraine treatment. TMS is a valuable diagnostic and therapeutic tool that should be more often implemented in neurorehabilitation and treatment of neurological diseases in adults and children with pain syndromes.
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    Objectives: Neuropsychological associations can be considerable in occlusal dysesthesia (OD) patients who routinely complain of persistent occlusal discomfort, and somatization effects in the superior medial prefrontal cortex and the temporal and parietal regions are also present. However, the relationship between physical activity, i.e., chewing, prefrontal cognitive demand, and psychiatric states in OD patients remains unclear. We investigated this relationship in this study. Materials and methods: OD patients (n = 15) and healthy control (n = 15; HC) subjects were enrolled in this study. Occlusal contact, chewing activities of the masticatory muscles, prefrontal activities, and psychiatric states such as depression and somatization, of the participants were evaluated. Functional near-infrared spectroscopy was used to determine prefrontal hemodynamics and the Symptom Checklist-90-R was used to score the psychiatric states. Results: We observed a significant association between prefrontal deactivation during chewing and somatization subscales in OD patients. Further, there were no significant differences with regard to the occlusal state and chewing physical activities between the OD patients and HC subjects. Conclusions: Chewing-related prefrontal deactivation may be associated with somatization severity in OD patients. Clinical relevance: fNIRS is a functional imaging method that uses the principal of neuro-vascular couplings. It is applicable for evaluation of psychiatric state based on prefrontal cortex blood flow in patients with psychiatric disorders.
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    The prefrontal cortex (PFC) is not only important in executive functions, but also pain processing. The latter is dependent on its connections to other areas of the cerebral neocortex, hippocampus, periaqueductal gray (PAG), thalamus, amygdala, and basal nuclei. Changes in neurotransmitters, gene expression, glial cells, and neuroinflammation occur in the PFC during acute and chronic pain, that result in alterations to its structure, activity, and connectivity. The medial PFC (mPFC) could serve dual, opposing roles in pain: (1) it mediates antinociceptive effects, due to its connections with other cortical areas, and as the main source of cortical afferents to the PAG for modulation of pain. This is a ‘loop’ where, on one side, a sensory stimulus is transformed into a perceptual signal through high brain processing activity, and perceptual activity is then utilized to control the flow of afferent sensory stimuli at their entrance (dorsal horn) to the CNS. (2) It could induce pain chronification via its corticostriatal projection, possibly depending on the level of dopamine receptor activation (or lack of) in the ventral tegmental area-nucleus accumbens reward pathway. The PFC is involved in biopsychosocial pain management. This includes repetitive transcranial magnetic stimulation, transcranial direct current stimulation, antidepressants, acupuncture, cognitive behavioral therapy, mindfulness, music, exercise, partner support, empathy, meditation, and prayer. Studies demonstrate the role of the PFC during placebo analgesia, and in establishing links between pain and depression, anxiety, and loss of cognition. In particular, losses in PFC grey matter are often reversible after successful treatment of chronic pain.
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    Background The concept of cenesthopathy was first introduced by Dupré and Camus in 1907 to describe clinically unexplainable bodily sensations mainly attributed to psychiatric pathology. If it occurs in oral regions, it is termed oral cenesthopathy and it has been of special interest to psychiatrists and dentists. While there is no independently defined criteria for this condition, which is classified as either a delusional or a somatoform disorder, clinical practice and research require a standard scale to measure and rate its symptoms. In this study, we included any types of psychosomatic symptoms in oral regions as oral dysesthesia, and developed an Oral Dysesthesia Rating Scale (Oral DRS) and evaluated its validity and reliability as an assessment tool.Methods The scale was developed based on literature review and extensive clinical experience. Twelve reviewers assessed relevancy of each item to oral dysesthesia symptoms by 1¿4 scoring scale and item content validity index was computed. To evaluate the inter-rater reliability of Oral DRS, pairs of raters administered the scale to 40 randomly selected patients with complaints of oral dysesthesia symptoms and Cohen¿s weighted kappa coefficient was determined for each item.ResultsThe scale assesses the severity of feelings of foreign body [A1], exudation [A2], squeezing-pulling [A3], movement [A4], misalignment [A5], pain [A6], and spontaneous thermal sensation or tastes [A7], and the degree of impairment in eating [B1], articulation [B2], work [B3], and social activities [B4] on a scale of 0¿5. Items A1, A2, A3, A4, B3, and B4 demonstrated acceptable content validity. Inter-rater reliabilities were good or excellent for all items evaluated.Conclusion The Oral DRS can help define the nosography of clinically unexplainable oral dysesthesia through further case evaluation and clinical research and facilitate devising of treatment modalities.
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    Chronic oro-facial pain conditions such as persistent idiopathic facial pain (PIFP), atypical odontalgia (AO) and burning mouth syndrome (BMS), usually grouped together under the concept of idiopathic oro-facial pain, remain a diagnostic and therapeutic challenge. Lack of understanding of the underlying pathophysiological mechanisms of these pain conditions is one of the important reasons behind the problems in diagnostic and management. During the last two decades, neurophysiological, psychophysical, brain imaging and neuropathological methods have been systematically applied to study the trigeminal system in idiopathic oro-facial pain. The findings in these studies have provided evidence for neuropathic involvement in the pathophysiology of PIFP, AO and BMS. The present qualitative review is a joint effort of a group of oro-facial pain specialists and researchers to appraise the literature on idiopathic oro-facial pain with special focus on the currently available studies on their pathophysiological mechanisms. The implications of the findings of these studies for the clinical diagnosis and treatment of idiopathic oro-facial pain conditions are discussed. © 2014 John Wiley & Sons Ltd.
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    Objective: To calculate the incidence of burning mouth syndrome (BMS) in Olmsted County, Minnesota, from 2000 through 2010. Patients and methods: By using the medical record linkage system of the Rochester Epidemiology Project, we identified newly diagnosed cases of BMS from January 1, 2000, through December 31, 2010. Diagnoses were confirmed through the presence of burning pain symptoms of the oral mucosa with normal oral examination findings and no associated clinical signs. Incidence was estimated using decennial census data for Olmsted County. Results: In total, 169 incident cases were identified, representing an annual age- and sex-adjusted incidence of BMS of 11.4 per 100,000 person-years. Age-adjusted incidence was significantly higher in women than in men (18.8 [95% CI, 16.4-22.9] per 100,000 person-years vs 3.7 [95% CI, 2.6-5.7] per 100,000 person-years; P<.001). Postmenopausal women aged 50 to 89 years had the highest incidence of the disease, with the maximal rate observed in women aged 70 to 79 years (70.3 per 100,000 person-years). After the age of 50 years, the incidence of BMS in men and women significantly increased across age groups (P=.02). Study participants residing in Olmsted County, Minnesota, were predominantly white, which is a study limitation. In addition, diagnostic criteria for identifying BMS in the present study may not apply for all situations because no diagnostic criteria are universally recognized for identifying BMS. Conclusion: To our knowledge, this is the first population-based incidence study of BMS reported to date. The data reveal that BMS is an uncommon disease highly associated with female sex and advancing age.
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    A group of European experts was commissioned to establish guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS) from evidence published up until March 2014, regarding pain, movement disorders, stroke, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, consciousness disorders, tinnitus, depression, anxiety disorders, obsessive-compulsive disorder, schizophrenia, craving/addiction, and conversion. Despite unavoidable inhomogeneities, there is a sufficient body of evidence to accept with level A (definite efficacy) the analgesic effect of high-frequency (HF) rTMS of the primary motor cortex (M1) contralateral to the pain and the antidepressant effect of HF-rTMS of the left dorsolateral prefrontal cortex (DLPFC). A Level B recommendation (probable efficacy) is proposed for the antidepressant effect of low-frequency (LF) rTMS of the right DLPFC, HF-rTMS of the left DLPFC for the negative symptoms of schizophrenia, and LF-rTMS of contralesional M1 in chronic motor stroke. The effects of rTMS in a number of indications reach level C (possible efficacy), including LF-rTMS of the left temporoparietal cortex in tinnitus and auditory hallucinations. It remains to determine how to optimize rTMS protocols and techniques to give them relevance in routine clinical practice. In addition, professionals carrying out rTMS protocols should undergo rigorous training to ensure the quality of the technical realization, guarantee the proper care of patients, and maximize the chances of success. Under these conditions, the therapeutic use of rTMS should be able to develop in the coming years.