ORIGINAL ARTICLE

Immune and Endocrine Function in Patients With

Burning Mouth Syndrome
Kazuyoshi Koike, DDS, PhD,*w Takahiro Shinozaki, DDS,*w Kazuhiko Hara, DDS,*
Noboru Noma, DDS, PhD,*w Akiko Okada-Ogawa, DDS, PhD,*w Masatake Asano, DDS, PhD,wz
Masamichi Shinoda, DDS, PhD,wy Eli Eliav, DMD, DDS, PhD,8 Richard H. Gracely, PhD,z
Koichi Iwata, DDS, PhD,wy and Yoshiki Imamura, DDS, PhD*w

Key Words: burning mouth syndrome, depression, anxiety,

Objectives: Research suggests that varied etiologic factors are immune, endocrine, pain
responsible for burning mouth syndrome (BMS). We examined the
role of immune and endocrine function in the pathology of BMS. (Clin J Pain 2014;30:168–173)
Methods: We conducted a case-control study to evaluate immune
(lymphocyte subpopulations) and endocrine (hypothalamus-pitui-
tary-adrenal axis and sympathetic-adrenomedullary system) func-
tion in 47 female BMS patients and 47 age-matched female controls
presenting at an university clinic. Psychological state was assessed
B urning mouth syndrome (BMS) is one of the most fre-
quently observed oral disorders. Its prevalence in the
general population has been reported to be as low as 0.7%1
with the Zung Self-Rating Depression Scale and Taylor Manifest
and as high as 13%,2 depending on the diagnostic criteria
Anxiety Scale.
used. The main symptoms of BMS are pain/discomfort in
Results: BMS patients were significantly more anxious than con- the tongue, palate, and gums and taste disturbance.
trols (P = 0.011). Plasma adrenaline level was significantly lower Although the cause of BMS is not clear, some of its clinical
(P = 0.020) in BMS patients than in controls, and linear regression features are well known. It predominantly affects women
analysis of all patients combined revealed that depression level was after menopause3,4 and is believed to be associated with
significantly positively associated with plasma noradrenaline and
hormone withdrawal in some patients.5 BMS is diagnosed
cortisol levels (P = 0.002 and 0.001, respectively). However, as
compared with controls, BMS patients had a significantly lower after exclusion of organic pathologies (eg, xerostomia, lichen
CD8(+) cell count (P < 0.001) and a significantly higher CD4/CD8 planus, and allergy to dental materials) that manifest similar
ratio (P = 0.002). Discriminant analysis revealed that CD8(+) cell signs and symptoms.4 In recent years, considerable attention
count and CD4/CD8 ratio were independent variables that dis- has focused on the influence of physical and psychological
tinguished BMS patients from controls. stresses on immune and endocrine function, and the role of
the immune system in conditions of psychological stress has
Discussion: The immunoendocrine system is substantially involved,
and may have a key role, in the mechanism of chronic pain in BMS been repeatedly shown.6–12 BMS is associated with psycho-
patients. Immune function was significantly and specifically sup- logical conditions such as depression, hypochondria, and
pressed in BMS, although the hypothalamic-pituitary-adrenal axis cancer phobia.13–16 Indeed, a systematic review suggested
and sympathetic nervous system were predominantly activated by that psychological interventions that help patients cope with
psychological stress that was not specific to BMS. symptoms might help in alleviating the symptoms of BMS.17
These findings suggest that BMS may be closely associated
with immune and endocrine function. However, no studies
have investigated overall innate and acquired immune
Received for publication February 7, 2012; revised February 5, 2013; function in BMS, although changes in the levels of some
accepted February 7, 2013. cytokines have been observed in people with BMS.6,7,18–23
From the Departments of *Oral Diagnostic Sciences; zPathology;
yPhysiology, Nihon University School of Dentistry; wDivision of The essential immunoendocrine profile of BMS, for
Clinical Research, Dental Research Center, Nihon University example, activation of innate and acquired immune system
School of Dentistry, Tokyo, Japan; 8Department of Diagnostic and cellular and humoral immunity, we attempted to
Sciences, Division of Orofacial Pain, University of Medicine and identify factors associated with BMS by comparing BMS
Dentistry, New Jersey Dental School, Newark, NJ; and zCenter for
Neurosensory Disorders, University of North Carolina School of patients and controls. If BMS has a profile similar to that of
Dentistry, Chapel Hill, NC. other chronic psychological conditions, the immune and
The authors declare no conflict of interest. Supported in part by endocrine system would respond in association with psy-
Grants-in-Aid for Scientific Research to Y.I.; Nihon University chological stresses. We further assessed psychological sta-
Multidisciplinary Research Grants for 2010, 2011, and 2012 to Y.I,
K.I., and M.S.; a Sato Fund Research Grant to Y.I.; and Grants tus, using inventories to elucidate the relationship between
from the Dental Research Center, Nihon University School of psychological stresses and immune and endocrine function.
Dentistry to Y.I. R.G. formerly received honoraria from Eli Lilly We examined plasma levels of CD4(+) cells (T-help-
Pharm. (Indianapolis, IN), Jazz Pharm. (Philadelphia, PA), Abbot ers), CD8(+) cells (T-cytotoxic cells), and CD4/CD8 ratio
Pharm. (Abbott Park, IL), Wyeth Pharm. (Overland Park, KS),
and D C Rheumatological Society and currently owns stock in (an index of immune regulation), as measures of the
Algynomics Inc (Chapel Hill, NC). acquired immune system, and natural killer (NK) cell
Reprints: Yoshiki Imamura, DDS, PhD, Department of Oral Diag- activity, as a measure of the innate immune system. In
nostic Sciences, Nihon University School of Dentistry, Kandasur- addition, plasma adrenocorticotropic hormone (ACTH)
ugadai 1-8-13, Chiyoda-ku, Tokyo 101-8310, Japan (e-mail:
imamura@dent.nihon-u.ac.jp). and cortisol levels were measured to assess the function of
Copyright r 2013 by Lippincott Williams & Wilkins the hypothalamus-pituitary-adrenal (HPA) axis, and

168 | www.clinicalpain.com Clin J Pain  Volume 30, Number 2, February 2014

Clin J Pain  Volume 30, Number 2, February 2014 Immune and Endocrine Function in BMS

adrenaline and noradrenaline levels were measured to chairside, in Japanese, and the patients were requested to
assess the function of the sympathetic-adrenomedullary complete them after the initial interview.
system.
Immune and Endocrine Investigations
PATIENTS AND METHODS Because levels of stress hormones fluctuate in a circa-
dian rhythm, all blood samples were obtained during a
Patients designated daytime period, namely, between 1:00 and
This case-control study enrolled 47 Japanese women 3:00 PM. Plasma was prepared by immediate centrifugation
aged 38 to 70 years, who satisfied the inclusion and exclu- at 3000 rpm for 10 minutes followed by freezing at 201C.
sion criteria for BMS (BMS patients) and 47 Japanese Lymphocyte subpopulations were identified and quantified
female controls aged 34 to 76 years with no systemic or by laser flow cytometry (Cytoron Absolute; Ortho Clinical
local problems associated with BMS (controls). Although Diagnostics, Rochester, NY). Two-color flow cytometry
56 BMS patients and 53 controls were recruited for this (FITC-labeled monoclonal antibody plus PE-labeled mon-
study, 9 patients and 6 controls subsequently declined to oclonal antibody) was used to measure CD4/CD8 ratio.30,31
participate. The inclusion and exclusion criteria for BMS Decoupling diluted lysing solution was added to hemolyze
have been described in previous reports and are shown red cells. NK cell activity was evaluated with the 51C-release
in Table 1.15,24,25 Patients with conditions that might induce assay by observing the cytotoxicity of NK cells against
changes in immune and endocrine function were excluded. K-562 target cells.32,33 ACTH and cortisol were measured
These conditions included endocrine gland dysfunction, by radioimmunoassay with a gamma counter (ARC-1000;
hormone replacement therapy, steroid hormone therapy, Aloka, Tokyo, Japan),34,35 and adrenaline and noradrena-
autoimmune diseases, congenital or acquired immunodefi- line were measured by high-performance liquid chroma-
ciency, and uncontrolled diabetes mellitus. All BMS tography with a fluorescence detector (FP920; Jasco,
patients had a duration of burning pain of Z3 months. In Tokyo, Japan).36,37 The measurements were performed at
the current study, all patients were recruited from patients a cooperating extramural laboratory (SRS; Tokyo, Japan),
seeking dental care at an university clinic. They were and reagents were obtained commercially.
informed of the purpose and protocol of the study and gave
their informed consent. This study was conducted accord- Statistical Analyses
ing to the Helsinki Declaration and was approved by the
Endocrine behavior in BMS was investigated by
Ethical Review Board of Nihon University School of
comparing data on immune and endocrine variables
Dentistry.
between BMS patients and controls. The t test was used for
comparison of values between the 2 groups. In linear
Psychological Testing
regression analysis, Pearson correlation coefficients were
All patients underwent psychological testing using the used to evaluate correlations between the identified varia-
Zung Self-Rating Depression Scale26,27 and the Taylor bles and levels of depression and anxiety. In addition,
Manifest Anxiety Scale.28,29 All tests were provided discriminant analysis was used to identify independent
variables that were useful in distinguishing BMS. SPSS
TABLE 1. Inclusion and Exclusion Criteria for Burning Mouth Statistics 20.0 for Windows (IBM, Tokyo, Japan) was used
Syndrome (BMS) for these analyses, and a P value of <0.05 was considered
Inclusion criteria to indicate statistical significance.
Complaint of superficial pain on tongue
No organic lesion that corresponds to patient complaint
No sign of anemia on laboratory testing
RESULTS
No tongue pain while eating Table 2 shows the characteristics of the participants.
No complaint of pain on palpation of tongue There was no statistical difference in the mean age of BMS
Exclusion criteria patients and controls (52.7 ± 1.9 vs. 53.6 ± 1.5 y, respec-
Systemic conditions (conditions that may induce changes in tively; P = 0.722). The average score on the Self-Rating
immune and endocrine function) Depression Scale in the BMS group was 42.1 ± 1.5, as
Nutritional deficiency compared with 38.7 ± 1.3 in the control group, and the
Dysfunction of endocrine glands data did not significantly differ between groups (P = 0.143).
Under hormone replacement therapy and steroid hormone
therapy
However, the average score on the Manifest Anxiety Scale
Uncontrolled diabetes mellitus
Certain pathologies involving the central nervous system, ie, TABLE 2. Characteristics of Participants
multiple sclerosis or Parkinson Disease
Auto immune diseases including Sjögren Syndrome Controls BMS Patients
Congenital and acquired immunodeficiency Participants (n) 47 47
Local conditions Age (age range), y 53.6 ± 1.5 (34-76) 52.7 ± 1.9 (38-70)
Allergy to metals or dental materials Duration of disorder N/A Z3 mo
Oral candidiasis SDS score 38.7 ± 1.3 42.1 ± 1.5
Lichen planus MAS score 15.2 ± 1.4 20.3 ± 1.4
Occult viral infection, eg, herpes simplex, zoster sine herpete
Postherpetic neuralgia Data are mean ± SEM, unless otherwise indicated.
All participants were Japanese women. The controls were patients who
All patients underwent laboratory testing to exclude the conditions listed sought dental treatment at the university clinic for conditions related to
in the exclusion criteria above. Patients who satisfied the inclusion and neither BMS nor membrane diseases.
exclusion criteria were diagnosed as having BMS and were included in this BMS indicates burning mouth syndrome, MAS, Manifest Anxiety Scale;
study. N/A, not applicable; SDS, Self-Rating Depression Scale.

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Koike et al Clin J Pain  Volume 30, Number 2, February 2014

50.0
p = 0.020
Plasma Concentration (pg/ml)*

45.0
40.0
35.0
30.0
25.0
20.0
15.0
10.0
5.0
0.0
na S

TH MS

tis S
na M S

e
re M

or M
lin
e

ad t B

AC t B

C nt B
re t B
lin

ol
or n

on
Ad on

N o

o
C

C
C

FIGURE 2. Lymphocyte subpopulations and NK cell activity

(mean ± SEM). CD8 (+)CD8(+) cell count was significantly lower
FIGURE 1. Plasma concentrations of stress hormones (mean ± (P < 0.001), and CD4/CD8 ratio was significantly higher
SEM). There were patients and controls that significantly differed (P = 0.002), in patients than in controls. CD4(+) cell count and
in plasma concentration of adrenaline (P = 0.020). ACTH indi- CD4/CD8 ratio were significant variables in distinguishing burn-
cates adrenocorticotropic hormone; BMS, burning mouth syn- ing mouth syndrome (BMS) (P = 0.041 and 0.029; odds ratio =
drome. *10  pg/mL in noradrenaline. 0.837 and 0.964; and 95% confidence interval for odds ratio:
0.706-0.993 and 0.983-0.966, respectively), although no sig-
nificant correlation was observed between any of these param-
in the BMS group was 20.3 ± 1.4, which was significantly eters and scores on psychological tests. These findings indicate
higher than the average score of 15.2 ± 1.4 in the control that the significant differences between groups were likely due to
group (P = 0.011). a difference in pathology rather than a disparity in psychological
Figure 1 shows selected results of endocrine testing in background factors. NK indicates natural killer cell. *10  % in
the 2 groups. The only significant difference was a sig- CD4/CD8 ratio.
nificantly lower level of plasma adrenaline in the BMS
group (27.3 ± 2.2 vs. 36.2 ± 3.0 pg/mL in controls; DISCUSSION
P = 0.020); levels of noradrenaline, ACTH, and cortisol did The main finding of this study was that cellular
not significantly differ between groups (P = 0.465, 0.914, immune function was significantly and specifically sup-
and 0.208, respectively). pressed in patients with BMS, although the HPA axis and
Figure 2 summarizes lymphocyte subpopulations and sympathetic-adrenomedullary system were activated in
NK cell activity in controls and BMS patients. CD4(+) cell association with psychological stress that was not specific to
count did not differ (46.8 ± 1.2% in controls vs. 46.2 ± BMS.
1.2% in BMS patients; P = 0.772). However, CD8(+) cell BMS is an idiopathic disorder that is diagnosed only
count was significantly lower in the BMS group after exclusion of organic diseases. Although there is con-
(24.1 ± 1.1%) than in controls (29.4 ± 0.9%; P < 0.001). siderable evidence for the involvement of psychosocial
The CD4/CD8 ratio was significantly higher in BMS patients factors in BMS,13,14,16 recent studies have revealed other
(2.18 ± 0.14) than in controls (1.66 ± 0.07; P = 0.002). NK possible causes.4,38–44 Altered trigeminal and chorda tym-
cell activity did not significantly differ between groups pani nerve sensation and reflexes,38–40,42,43,45,46 saliva
(30.9 ± 2.4% in BMS patients vs. 31.0 ± 1.9% in controls; composition,41 and morphologic changes in tissues44 have
P = 0.043). Discriminant analysis showed that the canonical been observed in patients with BMS. Damage to taste buds
correlation of this function was 0.614 and Wilks l was 0.423 induces decreased afferent inputs and may modulate central
(P < 0.001). Tests of equality of group means showed that inhibition of inputs from the trigeminal system.4 Oral
CD8(+) cell count (F = 17.6, P < 0.001) and CD4/CD8 dryness probably affects gustatory function,47–49 although
ratio (F = 11.8, P < 0.001) were eligible variants in dis- it should be excluded from possible comorbid conditions.4
criminating BMS patients from controls. The structure Limited understanding of the pathology of BMS compli-
matrix coefficients for CD8(+) cell count and CD4/CD8 cates its diagnosis. Immune and endocrine behaviors in
ratio were 0.563 and 0.460, respectively. When the patients patients with BMS are poorly understood. However, the
were analyzed together, linear regression analysis showed results of the current study provide insight regarding the
that depression level was significantly associated with plasma pathogenesis of BMS.
noradrenaline, ACTH, and cortisol levels (P = 0.002, We examined the activity of the HPA axis—which is
P = 0.046, and P = 0.001, respectively), and Pearson corre- often used as a biochemical index of stress reactions—by
lation analysis revealed a strong correlation between measuring ACTH, cortisol, adrenaline, and noradrenaline
depression level and plasma levels of noradrenaline and levels. The t test revealed a significantly higher level of
cortisol (r = 0.380, P < 0.001; and r = 0.344, P = 0.001, anxiety (P = 0.011) and a significantly lower plasma adre-
respectively; Fig. 3). In contrast, linear regression analysis naline level (P = 0.020) in the BMS group than in the
showed no significant associations between psychological control group. Although BMS patients were more anxious
factors and immunologic profile, which suggests that the than controls, no significant differences in plasma levels of
significant differences in CD8(+) cell count and CD4/CD8 ACTH, cortisol, or noradrenaline were observed. This
ratio between BMS patients and controls (Fig. 2) were not behavior of the endocrine system in BMS, including the
because of psychological factors. decrease in adrenaline level, probably reflects dysregulation

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Clin J Pain  Volume 30, Number 2, February 2014 Immune and Endocrine Function in BMS

A B

FIGURE 3. Scatter plots showing the correlation of SDS score (depression) with plasma concentrations of noradrenaline and cortisol. A,
Plasma noradrenaline by SDS score; (B), plasma cortisol by SDS score. SDS score was strongly correlated with plasma concentrations of
noradrenaline and cortisol. Elevation of plasma levels of these hormones in the H-burning mouth syndrome group was assumed to be
due to depression. SDS indicates Self-Depression Scale.

of the HPA axis50 and a subsequent reduction in adreno- suggest a neuropathic etiology,4,38–44 based on clinical
medullary response to stresses.51,52 Linear regression observations of altered trigeminal and chorda tympani
showed that psychological stress was significantly positively nerve sensation and reflexes.38–40,42,43,45,46 We did not
associated with cortisol and noradrenaline levels, which investigate the neuropathic components of BMS in the
suggests that these endocrine parameters behave in concert current study and cannot account for the observed immu-
with psychological stress and might not specifically reflect nologic changes in relation to neuropathic etiology. We
the pathology of BMS. hypothesize that immunologic changes, including CD8(+)
Many studies have evaluated the association between cell count and CD4/CD8 ratio, are key independent vari-
psychological stress and the immune system.53 However, ables in distinguishing BMS patients from controls. Further
the mechanisms that mediate immune reactions associated research is expected to clarify the precise etiology and
with BMS are unclear.6,7,18–23 The CD4/CD8 ratio was pathology of BMS.
significantly higher in BMS patients than in controls
(because of the low CD8 [+] cell count in the former).
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Clin J Pain  Volume 30, Number 2, February 2014 Immune and Endocrine Function in BMS

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