International Journal of

Environmental Research
and Public Health

Article
Burning Mouth Syndrome and Hypertension: Prevalence,
Gender Differences and Association with Pain and
Psycho-Social Characteristics—A Case Control Study
Daniela Adamo 1,† , Federica Canfora 1,† , Elena Calabria 2, * , Noemi Coppola 1 , Mattia Sansone 1 ,
Gianrico Spagnuolo 1,3 , Giuseppe Pecoraro 1 , Massimo Aria 4 , Luca D’Aniello 5 ,
Michele Davide Mignogna 1,‡ and Stefania Leuci 1,‡

1 Department of Neuroscience, Reproductive Sciences and Odontostomatology, University of Naples Federico

II, 80138 Naples, Italy
2 Department of Health Sciences, School of Dentistry, University Magna Graecia of Catanzaro,
88100 Catanzaro, Italy
3 Therapeutic Dentistry Department, Institute for Dentistry, Sechenov University, Moscow 119991, Russia
4 Department of Economics and Statistics, University Federico II of Naples, 80138 Naples, Italy
5 Department of Social Sciences, University Federico II of Naples, 80138 Naples, Italy
* Correspondence: [email protected]
† These authors contributed equally to this work and share first authorship.
‡ These authors have equally contributed to the study and must be considered as last authors.

Abstract: Background: To assess the prevalence of hypertension (HTN) in burning mouth syndrome
(BMS) patients and to investigate its relationship with sociodemographic factors, pain and the
psychological profile. Methods: A case-control study was conducted by enrolling 242 BMS patients
and 242 controls matched for age and gender. Sociodemographic and clinical characteristics were
Citation: Adamo, D.; Canfora, F.; recorded, and all participants completed numeric rating scale (NRS), the short-form of the McGill pain
Calabria, E.; Coppola, N.; Sansone, questionnaire (SF-MPQ), the Hamilton rating scale for anxiety and depression (HAM-A, HAM-D),
M.; Spagnuolo, G.; Pecoraro, G.; Aria, the Pittsburgh sleep quality index (PSQI) and the Epworth sleepiness scale (ESS). Results: The BMS
M.; D’Aniello, L.; Mignogna, M.D.; patients presented with a statistically significant higher prevalence of HTN compared to that in
et al. Burning Mouth Syndrome and
the controls (55% versus 33.5%; p-value: <0.001) and higher median scores of the NRS, SF-MPQ,
Hypertension: Prevalence, Gender
HAM-A, HAM-D, PSQI and ESS (p < 0.001). Multivariate regression analysis in the BMS patients
Differences and Association with
indicated positive correlations between HTN and age, systemic diseases, drug consumption and
Pain and Psycho-Social
Characteristics—A Case Control
anxiety (p-value: <0.001) and these predictors were responsible for 11.3% of the HTN variance in
Study. Int. J. Environ. Res. Public the BMS patients, when considered together. Conclusions: The prevalence of HTN was significantly
Health 2023, 20, 2040. https:// higher in the BMS patients, since ageing, the presence of comorbidities, drug consumption and
doi.org/10.3390/ijerph20032040 anxiety were potential predictors. Further studies are needed to better investigate the relationship
between BMS and HTN.
Academic Editor: Paul B.
Tchounwou
Keywords: burning mouth syndrome; hypertension; pain; mood disorder; systemic comorbidities
Received: 20 December 2022
Revised: 14 January 2023
Accepted: 19 January 2023
Published: 22 January 2023 1. Introduction
Hypertension (HTN) is defined as a repeatedly elevated blood pressure (BP) exceeding
140/90 mm Hg and represents the leading cause of cardiovascular disease and premature
Copyright: © 2023 by the authors.
death [1]. It affects approximately one billion people and increases with age, with the
Licensee MDPI, Basel, Switzerland. prevalence in individuals between 20 and 44 being about 26%, reaching up to 78% in the
This article is an open access article geriatric population (over 65) [1,2]. Midlife HTN (45–65) is considered an important con-
distributed under the terms and tributor to late-life dementia and Alzheimer’s disease (at an age greater than 65) [3,4]. The
conditions of the Creative Commons individual’s genetic profile, including insufficient physical activity, obesity, dyslipidemia,
Attribution (CC BY) license (https:// diabetes and a high-fat diet, increases the risk of developing HTN [5,6].
creativecommons.org/licenses/by/ Burning mouth syndrome (BMS) is chronic and debilitating oral pain of the normal
4.0/). oral mucosa. The overall prevalence of BMS in clinical practice is on average 4%, reaching a

Int. J. Environ. Res. Public Health 2023, 20, 2040. https://doi.org/10.3390/ijerph20032040 https://www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2023, 20, 2040 2 of 20

prevalence of 18% in post-menopausal women [7]. Its etiopathogenesis remains unclear and
is probably of a multifactorial origin, with growing evidence that BMS may be a neuropathic
disorder, with an increase in central pain sensitization processes and a reduction in the
functioning of the descending pain inhibitory mechanisms [7,8]. BMS is classified as an
idiopathic orofacial pain with or without somatosensory changes in the International
Classification of Orofacial Pain (ICOP 2020) [9]. The diagnosis of BMS has evolved from
basic intraoral exclusion screening to extensive clinical and laboratory investigations [10,11],
which include the screening of comorbidities and other chronic pain and somatosensory
testing. The most common site for BMS is the tongue (anterior two-thirds or tip), followed
by the hard palate, gingivae, lower lips and pharynx. It usually occurs bilaterally and
symmetrically [12–14]. Additional subjective oral symptoms, such as dysgeusia, itching,
xerostomia and sialorrhea have been reported [15,16].
It is known that there are functional interactions between pain and the cardiovascular
system, which may be different between healthy subjects and patients with chronic pain [17].
Indeed, in healthy subjects, through the activation of the sympathetic nervous system, the
acute painful stimuli can induce a blood pressure increase, which in turn may stimulate the
baroreceptors, activating the descending pain inhibitory pathways [18,19]. This mechanism
suggests an inverse relationship between higher blood pressure and acute pain perception
in healthy subjects [20].
Instead, some studies have found that in patients suffering from chronic pain condi-
tions, such as temporomandibular disorders, low back pain and fibromyalgia, the elevated
resting blood pressure level is associated with an increased sensitivity to pain, suggesting a
dysfunction of the blood pressure/pain regulatory feedback loop [21–23]. These dysfunc-
tions may be due to a reduction in baroreceptor sensitivity, which is not able to activate the
pain inhibitory pathways or leads to direct impairment of the pain inhibitory pathways,
not activated by a normal increase in baroreceptor stimulation [22].
Regarding BMS, the relationships between elevated blood pressure and pain and the
prevalence of HTN in this disease are not completely clear [24,25]. In the study of De Pedro
et al., based on a sample set of 20 BMS patients and 40 controls, the authors reported that
BMS patients presented with a worsened health status, suffering from a higher number of
comorbidities and consumed more medications compared with controls [8]. Instead, in the
case control study of JQ Jin et al. on 352 BMS patients and 391 controls, despite significant
differences between groups being found in terms of gender, age, BMI, education level, job
status, brain imaging abnormalities, total cholesterol, scores of anxiety and depression, no
differences were found in the prevalence of HTN between cases and controls [26].
Recently, in a sample of 100 BMS patients, HTN was found in 58% of the subjects and
it was considered the most important predictor of white matter changes (WMCs) of the
brain, which in turn may potentially amplify pain perception in patients affected by this
disease [27].
Therefore, we wanted to further evaluate the prevalence of HTN in a large sample of
BMS patients, compared with that in a control group of subjects without BMS, in order to
compare our results with previous studies and to better elucidate the relationships between
HTN and BMS, analyzing if this comorbidity may be an aggravating factor that should be
investigated for BMS assessments.
To the best of our knowledge, none of these previous studies have been focused
specifically on the analysis of the prevalence of HTN in a sample of BMS patients.
In this study, despite BMS predominantly affecting women with a female/male ratio
of 3:1 [7], the same number of male and female subjects were enrolled in order to eliminate
sex-related differences in the prevalence of HTN in BMS patients, which remains unclear;
indeed, it is well known that the prevalence of HTN is higher in men than in women
prior to the onset of menopause, while this increases in women after menopause with a
sex-convergence of HTN prevalence later in life [2,28].
The endpoints of the current study were:
 with that in a control group of control subjects matched for age and gender;
- to analyze the differences in HTN prevalence between males and females, exploring
this prevalence at different ages;
- to identify the potential predictors of HTN in BMS patients, taking into account the 3 of 20
Int. J. Environ. Res. Public Health 2023, 20, 2040
sociodemographic profile (age, employment and marital status), the body mass index
(BMI), risk factors (smoking and alcohol use), other systemic comorbidities, drug
consumption, pain - evaluation
to investigateand psychological
the prevalence factors.
of HTN in a large sample of BMS patients, compared
with that in a control group of control subjects matched for age and gender;
-
2. Materials and Methods to analyze the differences in HTN prevalence between males and females, exploring
this prevalence at different ages;
2.1. Study Design - to identify the potential predictors of HTN in BMS patients, taking into account the
sociodemographic
A case-control study was carried out profile
over (age, employment
a period fromand marital
April 2020status), the body2022
to January mass index
(BMI), risk factors (smoking and alcohol use), other systemic comorbidities, drug
at the Oral Medicine Department of the University of Naples “Federico II”, after obtaining
consumption, pain evaluation and psychological factors.
the approval from the Ethical Committee of the University (Approval Number: 251/19—
the date of approval2. being
Materials
20 and Methods
February 2019). The study was conducted in accordance
2.1. Study Design
with the ethical principles of the World Medical Association Declaration of Helsinki, and
the adopted methods A conformed
case-control study was the
with carried out over a period of
Strengthening fromthe
AprilReporting
2020 to January
of2022 at
the Oral Medicine Department of the University of Naples “Federico II”, after obtaining the
Observational Studies in Epidemiology (STROBE) guidelines for observational studies
approval from the Ethical Committee of the University (Approval Number: 251/19—the
[29]. date of approval being 20 February 2019). The study was conducted in accordance with
the ethical principles of the World Medical Association Declaration of Helsinki, and the
2.2. Data Collection adopted methods conformed with the Strengthening of the Reporting of Observational
Studies in Epidemiology (STROBE) guidelines for observational studies [29].
All potentially eligible participants were invited to participate in the study, and
written informed consent was
2.2. Data obtained from all subjects involved in the study. First, 250
Collection
patients with BMS of either gender and
All potentially aged
eligible >18 years
participants were
were screened
invited and enrolled
to participate inand
in the study, thewritten
informed consent was obtained from all subjects involved
study. However, only 242 individuals, 121 males and 121 females, met the inclusion and in the study. First, 250 patients
with BMS of either gender and aged >18 years were screened and enrolled in the study.
exclusion criteria (Figure 1: flow chart). Based on the average age and gender distribution
However, only 242 individuals, 121 males and 121 females, met the inclusion and exclusion
of the BMS patients, control subjects
criteria (Figure were
1: flow thenBased
chart). enrolled
on theusing convenient
average sampling
age and gender in order
distribution of the BMS
to obtain controls matched by gender and age. No payment was provided for participation.
patients, control subjects were then enrolled using convenient sampling in order to obtain
controls matched by gender and age. No payment was provided for participation.

Figure 1. Flow Chart ofFigure

the study;
1. FlowAbbreviations: BMS:
Chart of the study; burning BMS:
Abbreviations: mouth syndrome;
burning BMI: body
mouth syndrome; BMI:mass
body mass
index; HAM-A: Hamiltonindex;rating
HAM-A:scale for anxiety;
Hamilton HAM-D:
rating scale Hamilton
for anxiety; rating
HAM-D: scalerating
Hamilton for depression;
scale for depression;
NRS: numeric rating scale; SF-MPQ: short-form Mc-Gill pain questionnaire; PSQI: Pittsburgh sleep
quality index; ESS: Epworth sleepiness scale.
Int. J. Environ. Res. Public Health 2023, 20, 2040 4 of 20

2.3. Inclusion and Exclusion Criteria

The inclusion criteria for the BMS patients, in accordance with the International
Classification of Orofacial Pain (ICOP 2020) 1st edition [9], were: patients experiencing
an intraoral burning or dysesthetic sensation, recurring daily for more than two hours
per day for more than three months, without any evident causative lesions on clinical
examination and investigation; patients with normal blood test findings (including blood
count, blood glucose levels, glycated hemoglobin, serum iron, ferritin and transferrin). In
addition, patients who had been on the medications for at least 6 months before the onset
of oral burning symptoms were admitted, while patients whose chronic therapies had been
modified within the 6 months prior to the onset of BMS were not recruited. The dechallenge
and rechallenge test was used in all subjects with a suspicion of an adverse drug reaction.
Control subjects presenting at the dental clinic of the same university for routine
dental care were consecutively enrolled according to the following criteria: patients with a
normal oral mucosa; patients with normal blood test findings; and patients who had never
experienced any burning or dysesthetic sensation of the oral mucosa.
From both groups, participants were excluded in the case of [30–32]: ongoing treat-
ment with psychotropic drugs; drug addiction; a history or presence of oncological or
autoimmune disorders; the presence of obstructive sleep apnea syndrome (OSAS); or an
incapacity to understand or complete the questionnaires.

2.4. Procedures
Each subject underwent intraoral and extra-oral screening by an expert clinician in
oral medicine and was progressively enlisted for a routine clinical evaluation, including a
medical analysis. The patients were assessed regarding the oral symptoms, and the sites
involved, age, years of education, family situation, job status, risk factors (smoking status
and alcohol consumption), medical comorbidities and systemic drugs taken. Blood pressure
(BP) was obtained in a standardized fashion according to the scientific statement from the
American Heart Association [33]. The BP was calculated as the mean of two measurements
recorded by a physician. We defined HTN as having a systolic blood pressure 140 mm
Hg or greater, a diastolic blood pressure 90 mm Hg or greater or taking medication for
HTN [1]. Moreover, we used the measured weight and height in order to calculate the
BMI as weight (kilograms) divided by the square of height (meters). In accordance with
the WHO classification, the cut-off points considered were: 18.5–24.9 kg/m2 for a normal
weight, 25.0–29.9 kg/m2 for overweight, and >30 kg/m2 , for obesity, in particular, obesity
class I—BMI 30 to 34.9 kg/m2 , obesity class II—BMI 35 to 39.9 kg/m2 , obesity class III—a
BMI greater than or equal to 40 kg/m2 (also referred to as severe, extreme or massive
obesity) [34,35].

2.5. Pain, Psychological Assessment and Sleep Assessment

The evaluation of pain included the administration of the Numeric Rating Scale
(NRS) [36] and the short-form Mc-Gill pain questionnaire (SF-MPQ) [37]. The NRS is a
unidimensional scale used to evaluate the pain intensity through a range of scores from
0 to 10 [38]. Instead, the SF-MPQ measures the qualitative aspect of pain with a sensory
subscale (11 words) and an affective subscale (4 words) in which the patient has to specify,
with a score from 0 to 3, how suitably each word reflects the pain characteristic [39].
The psychological evaluation included the administration of the Hamilton depression
rating scale (HAM-D) [40] and the Hamilton anxiety rating scale (HAM-A) [41]. The HAM-
D is a scale used to measure the presence and severity of depressive symptoms in clinical
practice and research and is administered by a trained physician (GP). The cut-off scores
considered are: a score between 7 and 17 indicates mild depression, a score between 18 and
24 indicates moderate depression and a score greater than 24 indicates severe depression.
The HAM-A is a scale containing 14 items useful to evaluate both somatic anxiety and
psychic anxiety. A total score less than 17 indicates mild anxiety, between 18 and 24
Int. J. Environ. Res. Public Health 2023, 20, 2040 5 of 20

indicates mild-to-moderate anxiety, and between 25 and 30 indicates moderate-to-severe

anxiety [42].
The sleep evaluation included administration of the Pittsburgh Sleep Quality Index
(PSQI) [43] and the Epworth Sleepiness Scale (ESS) [44]. The PSQI assesses sleep quality
and disturbances over a one-month time interval, evaluating seven components, each
scored from 0 to 3: subjective sleep quality, sleep latency, sleep duration, habitual sleep
efficiency, sleep disturbances, use of sleeping medication and daytime dysfunction. A
global PSQI score greater than 5 indicates poor sleep quality [45]. The ESS evaluates the
sleep propensity in daily life through eight items, each scored from 0 to 3. In this scale, a
higher score corresponds to greater daytime sleepiness [44].

2.6. Statistical Analysis

The sample size, equal to 242 patients for each group (the BMS patients and con-
trols), was calculated to obtain a power test value (1-Beta) at no less than 99%, associated
with a significance of no more than 1%. This sample size was obtained using the effect
size value equal to 0.65, measured in a previously published study regarding age-related
white matter changes and the correlation with BMS [27]. The calculations were com-
puted using GPower software (v3.1.9) Faul, F., Erdfelder, E., Buchner, A. et al. Statistical
power analyses using G*Power 3.1: Tests for correlation and regression analyses. Behav-
ior Research Methods 41, 1149–1160 (2009). https://doi.org/10.3758/BRM.41.4.1149 [46].
Data analyses were performed using R software (v. 4.2.0—R Core Team, 2016). Faul, F.,
Erdfelder, E., Buchner, A. et al. Statistical power analyses using G*Power 3.1: Tests for
correlation and regression analyses. Behavior Research Methods 41, 1149–1160 (2009).
https://doi.org/10.3758/BRM.41.4.1149 Descriptive statistics, including means, standard
deviations (SDs), medians and interquartile ranges (IQRs), were calculated to summa-
rize the socio-demographic and clinical characteristics. Fisher’s exact test was used to
assess any significant differences between the frequencies of systematic diseases, drug con-
sumption, antihypertensive drugs, oral symptoms, sites involved and clinical parameters
(psychological profile, sleep assessment and pain assessment) between the BMS patients
and healthy subjects. Instead, the analysis of multiple comparisons between the median
values was computed with the Mann–Whitney U test. A dependence analysis between the
BMS patients with HTN and the controls and between HTN and the qualitative predictors
was performed.
A series of multivariate logistic regression models was computed in order to estimate
the presence of potential predictors of HTN in the BMS group and in the healthy subjects.
The odds ratio (Bland & Altman, 2000) [47] of each regression model was calculated by
considering the socio-demographic variables, smoking, alcohol use, BMI pain intensity
and quality (NRS and SF-MPQ), the psychological profile (HAM-A and HAM-D) and the
quality of sleep (PSQI and ESS). Next, a full model analysis was computed with all the
variables included simultaneously in the model to determine their relative contributions.
In detail, a sequential logistic regression model analysis including the predictors, inserted
one by one, was performed to obtain unadjusted coefficient estimations. Finally, a full
model analysis considering all the predictors simultaneously was carried out to estimate
the adjusted coefficients.
In all analyses, the level of significance after the Bonferroni correction was set for
multiple tests.

3. Results
In total, 242 participants (121 male and 121 female), matched for sex and age, were
included in each group. Table 1 summarizes the characteristics of the participants. In
particular, there were statistically significant differences considering the education level,
employment status and risk factors. Indeed, the mean years of education, as well as the
percentage of employment, was higher in the control group (p-value: <0.001 **, 0.002 **).
In addition, the majority of the BMS patients were non-smokers (181; 74.8%) but included
Int. J. Environ. Res. Public Health 2023, 20, 2040 6 of 20

a statistically significant higher proportion of heavy smokers (>15 cigarettes, 28 subjects:

11.6%; p-value: 0.007 **). Moreover, there was a statistically significant higher percentage of
non-habitual alcohol consumers among the BMS patients and fewer consumers of 1–2 units
of alcohol (p-value: <0.001 **) compared to numbers in the control group. The frequency
distributions of the participants in relation to the BMI categories revealed that overall, the
BMS group showed a considerably higher BMI than the healthy controls (p-value: 0.001 **)
especially with regard to the overweight and class I-II obesity categories. With respect to
the female participants, 106 BMS patients and 102 healthy women were in the menopause
with no statistical differences between the two groups (p-value: 0.783). The comparisons
between the median scores of the clinical parameters showed that overall, the BMS patients
presented with statistically significantly higher median scores for pain (NRS, SF-MPQ),
anxiety (HAM-A), depression (HAM-D) and sleep (PSQI, ESS) compared to those in the
healthy subjects (p-values: <0.001 **).
Int. J. Environ. Res. Public Health 2023, 20, 2040 7 of 20

Table 1. Socio-demographic profile, risk factors and clinical parameters of 242 BMS patients and
242 controls.

Demographic variables BMS CONTROLS p-value

Gender Frequency (%) Frequency (%)
Male 121 (50) 121 (50) 1.000
Female 121 (50) 121 (50)
Mean ± SD Mean ± SD
Age (in years) 0.231
65.61 ± 12.7 64.34 ± 10.4
Mean ± SD Mean ± SD
Education (in years) <0.001 **
9.31 ± 4.49 11.6 ± 4.92
Family situation Frequency (%) Frequency (%)
Single 14 (5.8) 22 (9.1)
Married 182 (75.2) 184 (76) 0.254
Divorced 14 (5.8) 14 (5.8)
Widowed 32 (13.2) 21 (8.7)
Employment Frequency (%) Frequency (%)
Employed 68 (28.1) 101 (41.7)
0.002 **
Unemployed 73 (30.2) 46 (19)
Retired 101 (41.7) 95 (39.3)
Risk factors Frequency (%) Frequency (%) p-value
Smoking
Never 181 (74.8) 176 (72.7)
<5 cigarettes 8 (3.3) 21 (8.7)
0.007 **
5–10 cigarettes 8 (3.3) 16 (6.6)
10–15 cigarettes 17 (7) 16 (6.6)
>15 cigarettes 28 (11.6) 13 (5.4)
Alcohol use
Never 191 (78.9) 149 (61.6)
Yes (1 unit) 36 (14.9) 64 (26.4) <0.001 **
Yes (2 units) 11 (4.5) 23 (9.5)
Yes (>2) 4 (1.7) 6 (2.5)
Body Mass Index (kg/m2 )
BMI < 18.5 0 (0) 6 (2.5)
BMI: 18.5–24.9 normal 67 (27.7) 122 (50.4)
BMI: 25.0–29.9 overweight 139 (57.4) 94 (38.8)
<0.001 **
BMI: 30–34 class I obesity 30 (12.4) 18 (7.4)
BMI: 35–39.99 class II obesity 4 (1.7) 2 (0.8)
BMI > 40 class III obesity 2 (0.8) 0 (0)
MEAN ± SD MEAN ± SD
BMI
27.1 ± 3.48 24.8 ± 3.48
BMS CONTROLS
Clinical parameters p-value
Median; IQR Median; IQR
NRS 10 [10–10] 0 [0–0] <0.001 **
Int. J. Environ. Res. Public Health 2023, 20, 2040 8 of 20

Table 1. Cont.

SF-MPQ 11 [7–12] 0 [0–0] <0.001 **

HAM-D 16 [14–20] 5 [2–10] <0.001 **
HAM-A 17.5 [15–20] 5 [2–9] <0.001 **
PSQI 8 [8–10] 5 [3–8] <0.001 **
ESS 7 [5–9] 5 [3–8] <0.001 **
The significance difference between means was measured by performing a t-student test. ** Significant p ≤ 0.01.
The significance of differences between percentages was measured by performing the Pearson Chi Square test. **
Significant p ≤ 0.01. IQR is the interquartile range. The significance of differences between medians was measured
by performing the Mann–Whitney test. ** Significant with Bonferroni correction 0.008. Abbreviations: BMI: body
mass index, BMS: burning mouth syndrome, ESS: Epworth Sleepiness Scale; HAM-A: Hamilton rating scale for
anxiety; HAM-D: Hamilton rating scale for depression, NRS: numeric rating scale; PSQI: Pittsburgh sleep quality
index; SF-MPQ: short-form McGill pain questionnaire.

Table 2 shows the comorbidity and drug consumption trends in the two groups. A
strongly statistically significantly higher proportion of BMS patients (133; 55%) suffered
from essential HTN compared to that in the controls (81, 33.5%) (p-value: <0.001 **).
Specifically, 22 BMS patients were not aware that they were suffering from HTN, which was
firstly detected through the above screening and subsequently assessed by the specialist.
Instead, no differences were detected with respect to the other systemic diseases. With
regard to drug intake, a higher prevalence of BMS patients were taking drugs compared
with that of the controls (175, 72.3%; 139, 57.4%). A statistically significantly higher number
of BMS patients was in treatment with antiplatelets (66; 27.3%) compared to that of the
healthy subjects (34;14%) (p-value: <0.001 **). No difference was found in antihypertensive
drug consumption between the patients and controls.

Table 2. Evaluation of the prevalence of systemic diseases, drug consumption and antihypertensive
drugs in 242 BMS patients and 242 controls.

BMS CONTROLS
Systemic diseases p-value
Frequency (%) Frequency (%)
Hypertension 133 (55) 81 (33.5) <0.001 **
Hypercholesterolemia 83 (34.3) 69 (28.5) 0.203
Gastrointestinal
43 (17.8) 32 (13.2) 0.209
diseases
Hypothyroidism 29 (12) 22 (9.1) 0.375
Prostatic hypertrophy 23 (9.5) 11 (4.5) 0.049
Other cardiovascular
23 (9.5) 18 (7.4) 0.514
diseases
Myocardial infarction 16 (6.6) 8 (3.3) 0.141
Neoplastic diseases 13 (5.4) 19 (7.9) 0.361
Respiratory diseases 10 (4.1) 10 (4.1) 1.000
HCV infection 3 (1.2) 7 (2.9) 0.339
HBV infection 2 (0.8) 1 (0.4) 1.000
Neurological
2 (0.8) 6 (2.5) 0.285
disorders
Hyperthyroidism 1 (0.4) 3 (1.2) 0.623
Endocrine diseases 1 (0.4) 3 (1.2) 0.623
Int. J. Environ. Res. Public Health 2023, 20, 2040 9 of 20

Table 2. Cont.

BMS CONTROLS
Drug consumption p-value
Frequency (%) Frequency (%)
Antiplatelets 66 (27.3) 34 (14) <0.001 **
Proton pump
53 (21.9) 39 (16.1) 0.132
inhibitors
Statins 50 (20.7) 51 (21.1) 1.000
Beta blockers 42 (17.4) 36 (14.9) 0.537
ACE-inhibitors 38 (15.7) 35 (14.5) 0.800
Angiotensin II
receptor antagonists 37 (15.3) 18 (7.4) 0.009
(ARBs)
Thiazide diuretics 27 (11.2) 27 (11.2) 1.000
Calcium channel
24 (9.9) 13 (5.4) 0.086
blockers
Levothyroxin sodium 24 (9.9) 17 (7) 0.327
Blood thinners 16 (6.6) 5 (2.1) 0.023
Bisphosphonates 5 (2.1) 4 (1.7) 1.000
Steroids 3 (1.2) 5 (2.1) 0.724
A significant difference between the percentages was measured by performing Fisher’s exact test. ** Significant p
≤ 0.01. Significant with Bonferroni correction 0.003 for the systemic diseases and for the drug consumption.

Table 3 and Figure 2 show the frequency distribution of HTN in the BMS patients and
controls, considering the age ranges and gender. There was a significant difference in the
prevalence of HTN between the patients and controls at different ages; indeed, a higher
prevalence of HTN was found in the BMS males older than 75 and in the male controls aged
between 65 and 75 years, respectively. Instead, in the female patients and controls, a higher
prevalence was found at the same age (65–75). It is worth noting that there was a higher
prevalence of HTN in the BMS patients, both males and females, older than 75 (40% and
30.88% respectively) compared with that in the controls (19.05% and 17.95%, respectively).

Table 3. Frequency distribution of HTN by age range and gender of 133 BMS patients and 81 controls.

Male Patients Female Patients

BMS CONTROLS BMS CONTROLS
Frequency (%) Frequency (%) Age Frequency (%) Frequency (%)
65 (48.87) 42 (51.85) All subjects 68 (51.13) 39 (48.15)
0 (0) 2 (4.76) <45 1 (1.47) 0 (0)
6 (9.23) 2 (4.76) 45–55 4 (5.88) 3 (7.69)
9 (13.85) 9 (21.43) 55–65 15 (22.06) 13 (33.33)
24 (36.92) 21 (50) 65–75 27 (39.71) 16 (41.03)
26 (40) 8 (19.05) >75 21 (30.88) 7 (17.95)
 0 (0) 2 (4.76) <45 1 (1.47) 0 (0)
6 (9.23) 2 (4.76) 45–55 4 (5.88) 3 (7.69)
9 (13.85) 9 (21.43) 55–65 15 (22.06) 13 (33.33)
2420,(36.92)
Int. J. Environ. Res. Public Health 2023, 2040 21 (50) 65–75 27 (39.71) 1016 (41.03)
of 20
26 (40) 8 (19.05) >75 21 (30.88) 7 (17.95)

FigureFigure
2. Frequency distribution
2. Frequency distributionof
ofHTN byage
HTN by ageranges
ranges and
and gender
gender among
among 133patients
133 BMS BMS patients
and and
81
controls.controls.

The prevalence of oral symptoms and oral sites involved is shown in Table 4. By
The prevalence
definition, all BMSof oral symptoms
patients and oral
reported a burning sites involved
sensation (242; 100%).is The
shownotherinoral
Table 4.
definition,
symptoms all most
BMSfrequently
patientsreported
reportedwereaxerostomia
burning (149;
sensation (242; 100%).
61.6%), followed The other o
by dysgeusia
(110; 45.6%), globus pharingeus (78; 32.2%), intraoral foreign body
symptoms most frequently reported were xerostomia (149; 61.6%), followed by dysgeu sensation (53; 21.9%),
(110; sialorrhea (47; 19.4%)
45.6%), globus and a subjective
pharingeus change inintraoral
(78; 32.2%), tongue andforeign
gum morphology (42; 17.4%).
body sensation (53; 21.9%
Moreover, 102 (42.1%) BMS patients complained of generalized symptoms affecting all oral
sialorrhea (47;
sites. In 19.4%)
order, and a(211;
the tongue subjective change
87.2%) was in tongue
the most andfollowed
affected site, gum morphology (42; 17.4%
by the anterior
Moreover, 102 (42.1%) BMS patients complained of generalized symptoms
palate (144; 59.5%), the lips (142; 58.7%), the gums (142; 58.7%) and the checks (139; 55.6%). affecting
oral sites. In order, the tongue (211; 87.2%) was the most affected site, followed by t
4. Prevalence
Tablepalate
anterior (144;of59.5%),
oral symptoms and sites
the lips (142;involved in 242
58.7%), BMS
the patients.
gums (142; 58.7%) and the chec
(139; 55.6%). BMS
Oral symptoms
Frequency (%)
Table 4. Prevalence of Burning
oral symptoms and sites involved in 242 BMS patients.
242 (100)
Xerostomia 149 (61.6)
BMS
OralDysgeusia
Symptoms 110 (45.6)
Frequency (%)
Globus pharingeus 78 (32.2)
Burning
Intraoral foreign body sensation 53 (21.9)
242 (100)
Xerostomia
Sialorrhea 47 (19.4)
149 (61.6)
Dysgeusia
Subjective change in tongue and gum 110 (45.6)
42 (17.4)
Globus pharingeus
morphology 78 (32.2)
Itching
Intraoral foreign body sensation 27 (11.2) 53 (21.9)
Tingling sensation
Sialorrhea 25 (10.3) 47 (19.4)
Oral dyskinesia 18 (7.4)
Subjective change in tongue and gum
Occlusal dysesthesia 16 (6.6) 42 (17.4)
morphology
Halitophobia 14 (5.8)
Itching 27 (11.2)
Tingling sensation 25 (10.3)
Int. J. Environ. Res. Public Health 2023, 20, 2040 11 of 20

Table 4. Cont.

BMS
Oral symptoms
Frequency (%)
Dysosmia 5 (2.1)
BMS
Sites involved
Frequency (%)
Generalized 102 (42.1)
Tongue 211 (87.2)
Anterior palate 144 (59.5)
Lips 142 (58.7)
Gums 142 (58.7)
Cheeks 119 (49.4)
Soft palate 110 (45.5)
Floor of the mouth 107 (44.2)

The results of the dependence analysis between HTN and the qualitative and quanti-
tative predictors in the BMS patients and controls are summarized in Table 5. A positive
correlation was found between HTN and employment status (p-value: <0.001 **), systemic
diseases (p-value: <0.001 **), drug consumption (p-value: 0.002 **) and level of education
(p-value: 0.002 **) in the BMS patients. Instead, in the healthy controls, HTN was correlated
only with systemic diseases and drug consumption (p-value: <0.001 **). Specifically, 130
(97.7%) BMS patients suffered from other systemic diseases, in addition to HTN, with only
three patients affected solely by HTN.

Table 5. Dependence analysis of 242 BMS patients and 242 controls with HTN and qualitative and
quantitative Predictors.

Qualitative BMS/HTN Controls/HTN

p-value p-value
variables Frequency (%) Frequency (%)
Marital status
Married 98 (73.3) 0.554 64 (79) 0.524
not married 35 (26.3) 17 (21)
Employment
Employed 25 (18.8) <0.001 ** 26 (32.1) 0.038
Not employed 108 (81.2) 55 (67.9)
Smoking
Smoker 15 (11.3) 0.347 29 (35.8) 0.185
Non-smoker 118 (88.7) 52 (64.2)
Alcohol use
Yes 29 (21.8) 0.874 23 (28.4) 0.384
No 104 (78.2) 58 (71.6)
Systemic
diseases
130 (97.7) <0.001 ** 77 (95.1) <0.001 **
Yes
3 (2.3) 4 (4.9)
No
Drug
consumption
107 (80.5) 0.002 ** 68 (84) <0.001 **
Yes
26 (19.5) 13 (16)
No
Int. J. Environ. Res. Public Health 2023, 20, 2040 12 of 20

Table 5. Cont.

Control/NO
Quantitative BMS/HTN BMS/NO HTN Control/HTN
p-value HTN p-value
variables Median; IQR Median; IQR Median; IQR
Median; IQR
NRS 10 [10–10] 10 [9–10] 0.545 0 [0–0] 0 [0–0] 0.401
SF-MPQ 11 [7–12] 11 [7–12] 0.792 0 [0–1] 0 [0–0] 0.408
HAM-D 16 [14–20] 16 [13–20] 0.799 5 [3–11] 4 [2–9] 0.049
HAM-A 18 [15–21] 17 [15–20] 0.383 6 [3–12] 4 [2–9] 0.034
PSQI 8 [8–10] 8 [8–10] 0.416 6 [3–10] 4 [3–7] 0.017
ESS 7 [6–9] 7 [5–9] 0.642 6 [4–9] 5 [2–8] 0.074
Education
8 [5–13] 9 [8–13] <0.001 ** 13 [8–16] 13 [8–14] 0.936
(in years)
BMI
27.3 [25.6–28.8] 26.1 [24.7–28.3] 0.026 25.6 [23–27.6] 23.9 [21.9–26.3] 0.010
(kg/m2 )
A significant difference between the percentages was measured by performing Fisher’s exact test. ** Significant
with Bonferroni correction 0.003 for qualitative predictors. IQR is the interquartile range. The significance of
differences between medians was measured by performing the Mann–Whitney test. ** Significant with Bonferroni
correction 0.006 for quantitative predictors. Abbreviations: BMI: body mass index; BMS: burning mouth syndrome,
ESS: Epworth sleepiness scale; HAM-A: Hamilton rating scale for anxiety; HAM-D: Hamilton rating scale for
depression; HTN: hypertension, NRS: numeric rating scale; PSQI: Pittsburgh sleep quality index; SF-MPQ:
short-form McGill pain questionnaire.

The hierarchical multiple regression analyses predicting HTN in the BMS patients
and controls are shown in Table 6. Regarding the BMS patients, in the first model (so-
ciodemographic variables, risk factors and BMI), only age was found to be statistically
significant and resulted in a significant increase in the R2 value (14.2%). The addition of
the clinical parameters of pain (NRS, SF-MPQ), anxiety (HAM-A), depression (HAM-D)
and sleep (PSQI) in the second model resulted in a significant increase in the R2 value
(DR2 = 1.5%; p-value: <0.001 **). Moreover, the addition of systemic diseases (model 3) and
drug consumption (model 4) resulted in a significant increase in the R2 values (DR2 = 8.9%,
p-value: <0.001 **; DR2 = 2.3%, p-value: 0.006 ** respectively). The final full model (model
5), in which all variables were entered simultaneously, could explain 11.3% of the variance
in HTN. Therefore, age, anxiety, systemic diseases and drug consumption were predictors
of HTN in the BMS patients, but age and the presence of other comorbidities may be
considered the most important in accordance with model 5.
With respect to the controls, in the first model (sociodemographic variables, risk factors
and BMI), age, smoking and BMI were found to be statistically significant and resulted in a
significant increase in the R2 value (7.2%). The addition of NRS, SF-MPQ, HAM-A, HAM-D,
PSQI AND ESS (model 2) resulted in a significant increase in the R2 value (DR2 = 3.2%;
p-value: 0.004 **). The addition of systemic diseases (model 3) and drug consumption
(model 4) resulted in a significant increase in the R2 values (DR2 = 16.6%, p-value: <0.001 **;
DR2 = 11.8%, p-value: 0.006 ** respectively). The final full model (model 5), in which all
the variables were entered simultaneously, could explain 20.1% of the variance in HTN
(p-value: <0.001 **). Therefore, age, smoking, BMI, systemic diseases, drug consumption
and years of education were predictors of HTN with the presence of other comorbidities
considered the most important.
Int. J. Environ. Res. Public Health 2023, 20, 2040 13 of 20

Table 6. Multivariate logistic regression analysis predicting HTN in 242 BMS patients and 242
controls.

Predictors of HTN
Model 1 Model 2 Model 3 Model 4 Model 5
in BMS patients
OR p-value OR p-value OR p-value OR p-value OR p-value
Age 1.08 <0.001 ** 1.08 <0.001 ** 1.07 <0.001 ** 1.08 <0.001 ** 1.07 <0.001 **
Gender: Male 0.90 0.740 0.86 0.653 0.84 0.606 1.04 0.899 0.88 0.721
Years of education 0.95 0.165 0.95 0.193 0.95 0.135 0.96 0.290 0.95 0.168
Marital status:
0.83 0.601 0.79 0.513 0.67 0.296 0.75 0.429 0.61 0.217
Married
Job: Employed 1.14 0.740 1.12 0.783 1.11 0.800 1.09 0.826 1.07 0.871
Smoker 0.86 0.748 0.85 0.732 0.98 0.967 0.75 0.555 0.85 0.771
Alcohol use 0.83 0.616 0.83 0.629 0.74 0.439 0.80 0.563 0.73 0.431
BMI 1.06 0.147 1.06 0.177 1.07 0.151 1.06 0.176 1.06 0.228
NRS 1.04 0.767 1.05 0.711
SF-MPQ 0.99 0.837 0.99 0.780
HAM-D 0.92 0.099 0.91 0.094
HAM-A 1.10 0.050 * 1.08 0.118
PSQI 0.94 0.334 0.91 0.200
ESS 1.04 0.497 1.07 0.260
Systemic diseases 16.26 <0.001 ** 14.76 <0.001 **
Drug Consumption 2.51 0.007 ** 1.89 0.101
R2 (%) <0.001 ** <0.001 ** <0.001 ** <0.001 ** <0.001 **
R2 change (%) 0.524 <0.001 ** 0.006 ** <0.001 **
Predictors HTN in
Model 1 Model 2 Model 3 Model 4 Model 5
control subjects
OR p-value OR p-value OR p-value OR p-value OR p-value
Age 1.04 0.034 * 1.04 0.040 * 1.04 0.056 1.04 0.049 * 1.04 0.066
Gender: Male 1.22 0.516 1.34 0.360 1.39 0.346 1.48 0.250 1.63 0.183
Years of education 1.03 0.315 1.03 0.336 1.09 0.024 * 1.07 0.075 1.09 0.028 *
Marital status:
1.34 0.409 1.49 0.286 1.49 0.304 1.28 0.509 1.44 0.361
Married
Job: Employed 0.63 0.223 0.55 0.132 0.87 0.764 0.72 0.448 0.72 0.491
Smoker 2.63 0.007 ** 2.41 0.017 * 2.38 0.029 * 2.79 0.009 ** 2.64 0.022 *
Alcohol use 0.52 0.071 0.62 0.203 0.51 0.106 0.49 0.070 0.58 0.216
BMI 1.09 0.042 * 1.09 0.069 1.11 0.029 * 1.09 0.077 1.09 0.101
NRS 0.99 0.960 0.94 0.653
SF-MPQ 1.12 0.356 1.06 0.639
HAM-D 0.98 0.656 0.98 0.636
HAM-A 1.03 0.535 0.99 0.826
PSQI 1.05 0.280 1.04 0.434
ESS 1.06 0.183 1.08 0.113
Systemic diseases 22.17 <0.001 ** 11.72 <0.001 **
Drug Consumption 7.56 <0.001 ** 2.97 0.014 *
R2 (%) 0.005 ** 0.004 ** <0.001 ** <0.001 ** <0.001 **
R2 change (%) 0.124 <0.001 ** <0.001 ** <0.001 **
SE are the standard errors of the beta estimates. The p-values were obtained from the hypothesis test on the
regression coefficients. * Moderately significant 0.01 < p-value ≤ 0.05. ** Strongly significant p-value ≤ 0.01.
Abbreviations: BMI: body mass index; BMS: burning mouth syndrome, NRS: numeric pain intensity scale; T-PRI:
total pain rating index; HAM-A: Hamilton rating scale for anxiety; HAM-D: Hamilton rating scale for depression;
HTN: hypertension, PSQI: Pittsburgh quality index; ESS: Epworth sleepiness scale.

4. Discussion
BMS is a chronic neuropathic orofacial pain condition in which the proportion of
elderly patients with several comorbidities is consistently rising, making the assessment
Int. J. Environ. Res. Public Health 2023, 20, 2040 14 of 20

and treatment increasingly complex [15,16]. Anxiety, depression and sleep disturbances
are the most frequent comorbidities associated with BMS [13,14,48,49]. However, recently,
Canfora et al. have also found a high prevalence of cognitive decline and WMCs in BMS
patients compared with that in a control group of healthy subjects [50].
Moreover, this high prevalence of WMCs in the brain of patients with BMS has been
further confirmed in a more extensive study suggesting a potential role for cardiovascular
risk factors, especially HTN, in the brain’s aging and subsequently in aggravating the
disease [27].
Until now, the role of comorbidities in BMS has been poorly studied and understood,
but in a recent study, de Pedro et al. reported that BMS patients suffer from a worsened
health status, consuming more medications with a worse general quality of life, requiring
an interdisciplinary therapy approach [8].
Therefore, the primary outcome of this study was to establish if there is any difference
in terms of the prevalence of one of the most common medical comorbidities, such as
HTN, between BMS patients and control subjects in order to confirm these previous studies
findings.
The results of this study have indeed shown a statistically significant difference in
the prevalence of HTN in BMS patients compared with that in healthy controls. HTN was
found in 55% (133) of the BMS patients and in 33.5% (81) of the controls. Specifically, HTN
was found in 65 males (48.8%) and in 68 females (51.3%) with BMS, and considering the
age stratification, the highest prevalence of HTN was found in males older than 75 years of
age (26; 40%) and in females between 65 and 75 years of age (27; 39.71%).
In the different age groups, the prevalence of HTN varied between the cases and
controls, mainly in males, with a higher prevalence of HTN in the controls between 65
and 75 years (21; 50%). A considerable difference in the prevalence of HTN was found
in the elderly patients with BMS (>75) compared with that in the controls (male BMS
patients: 26, 40% versus male controls: 8; 19.05%; female BMS patients: 21, 30.88% versus
female controls: 7, 17.95%). In addition, taking into account the median age of the patients
and controls (65 years), the prevalence of HTN is in line with epidemiological studies for
controls (33.5%) but it is higher in BMS patients, reaching 55%.
The prevalence of HTN in our sample of patients is slightly higher than the rate
reported in a previous study by Bruehl et al. [24] on 300 chronic pain patients (39%) but
is similar to the findings of a large Australian study on patients attending in pain clinics
where the prevalence of HTN among chronic pain patients was 5.6 to 9.8 times higher
compared with that in the general population [51].
This high prevalence of HTN in BMS patients may be explained considering that
chronic pain and HTN often co-occur and share several biological and lifestyle risk fac-
tors, with functional and bidirectional interactions between the cardiovascular system and
pain modulatory pathways. Indeed, blood pressure is modulated by functional circuitry
linking the hypothalamus, nucleus tractus solitarius, nucleus raphe magnus and rostral
ventrolateral medulla, involving the activity of the central adrenergic fibers and alpha-2
receptors, which in turn may modulate the descending activity of the anti-nociceptive path-
ways [52,53]. The prolonged activation of the descending adrenergic inhibitory pathways
in patients suffering from BMS [54], especially in those with a long-lasting disease or in
older patients, where aging naturally affects the intra-cortical connectivity of the brain
resulting in an alteration to the modulatory system in the control of pain, may contribute to
a blood pressure regulation system impairment, increasing the risk of HTN [55,56].
Moreover, it is notable that the pathogenesis of HTN is influenced by environmental
and genetic factors, with these latter characteristics seemingly being responsible for 30%
to 50% of any differences in blood pressure among individuals [6,57]. Therefore, it is
possible to consider that the interaction between pain modulation and blood pressure may
also explain why decreased metabolism of norepinephrine to normetanephrine, due to
specific variants of catechol-O-methyltransferase (COMT) with an increase in the cerebral
catecholamines, which can contribute to a higher blood pressure, may also modify the pain
Int. J. Environ. Res. Public Health 2023, 20, 2040 15 of 20

response [58–61]. Indeed, the gene that encodes this protein activity is highly polymorphic,
and carriers of a variant, such as the homozygous met (A) allele, show a significant decrease
in COMT activity, with a higher blood pressure, resulting in a higher prevalence of HTN
compared with that in Met/Val or Val/Val carriers [59].
From the multivariate regression analysis, it is noteworthy that the predictors were
slightly different with regard to the BMS patients and controls. Indeed, HTN was associated
with advancing age, anxiety symptoms, systemic comorbidities and drug consumption in
the BMS patients, while smoking, BMI, and years of education, in addition to advancing
age, the occurrence of systemic comorbidities and drug consumption, were predictors of
HTN in the controls. In the last models, where all variables were entered simultaneously,
only age and the presence of systemic comorbidities remained as predictors of HTN in
BMS patients, while educational level, smoking, the presence of systemic comorbidities
and drug consumption were predictors in the controls, in line with the epidemiological
studies [1,5,57]. It is surprising to consider that common predictors of HTN, such as obesity,
smoking and a lower education level, were significant in relation to the controls but not in
the BMS patients. This result may support the hypothesis that the onset of HTN in BMS
may depend on other factors related to the effect of a painful disease on the brain [52,62].
In this study, age was a stronger predictor of HTN in the BMS patients than in the
controls, which may explain the higher prevalence of HTN in older patients with BMS.
Although, the effect of age was lost in the final regression model of the controls, it is known
that advancing age is a common and universal predictor of a physiological increase in blood
pressure, as suggested by epidemiological studies that reported a progressive increase in
blood pressure of ≈7 mmHg per decade in subjects over 40 years of age, reaching a pressure
of 140 mmHg during the eighth decade [63]. Nevertheless, the aging effect, as a predictor
of HTN, may be stronger with conditions of chronic pain, such as BMS, which may already
have a negative impact on the brain, above and beyond the fact that age-related effects
cause accelerated brain aging [56,62]. Indeed, a previous study has suggested that chronic
pain is associated with an “older” brain, at least two years older than the chronological
age [64].
These results may confirm the findings of previous studies on the multifactorial origin
of HTN, where brain alterations may have a role in initiating HTN, in addition to common
risk factors, suggesting that the brain is either an early target of the disease or that the
disease may also originate in the brain [4,65,66].
As a result, taken together, HTN and BMS may have an additional effect on cerebral
health causing further morphological and chemical alterations in the brain and a reduction
in the grey matter volume in specific brain areas, such as the prefrontal, medial frontal,
inferior temporal and cerebellar areas, progressing as far as cerebral atrophy [67,68]. Brain
aging, in turn, may further affect blood pressure regulation and worsen pain perception,
aggravating both diseases [69].
It is notable that 16.5% (22) of the BMS patients were not aware that they were suffering
from HTN. Therefore, it may be useful not only to consider the history of the patient but
also to evaluate blood pressure to detect and treat unknown cases of HTN in order to
reduce the long-term effect of HTN with respect to any further impairment of the brain in
BMS patients.
In line with previous studies, the coexistence of other systemic comorbidities repre-
sents a strong predictor of HTN in patients and in controls [70,71]. Specifically, it is known
that HTN rarely presents itself, but rather that it is a manifestation of a metabolic syndrome,
characterized by a combination of elevated blood pressure, hypercholesterolemia, insulin
resistance and abdominal obesity [5,72].
In this study, after covariate adjustment, psychological distress was not significantly
associated with the development of HTN. However, it is important to consider that among
mood disorders, anxiety was a predictor of HTN in a single model of the regression. This
result is in line with previous studies, which have demonstrated a bidirectional association
between anxiety and HTN. Indeed, individuals with HTN are more prone to have anxiety
Int. J. Environ. Res. Public Health 2023, 20, 2040 16 of 20

and those with anxiety are at risk of developing HTN, independently from other risk factors
for HTN [73,74]. Moreover, it is known that in a long-term stressful lifestyle, events may
act on the hypothalamic-pituitary-adrenal (HPA) axis, manifesting as anxiety or a somatic
symptom, such as BMS [75]. The activation of the HPA axis, in turn increasing circulating
catecholamines, may contribute to the development of a cardiovascular disease, such as
HTN [75–77].
In contrast with the research of Giummara et al. [51], no correlation between HTN and
pain was found in the BMS patients in our study, confirming the results of another study in
which the association between pain and HTN may be mediated by shared risk factors, such
as obesity and a lower educational level [78].

Limitations
Firstly, an important limitation of the study is related to the hypertension diagnosis
because it was not possible to verify if hypertension preceded the chronic pain onset or
on the contrary, if the chronic pain came first. This could be important considering the
etiopathogenesis of interpretation. In addition, being an explorative study, we matched the
patients taking into account only age and sex, but in further studies, it will be necessary to
match patients and controls also considering risk factors and BMI. Secondly, the assumption
of the duration of antihypertensive drugs and eventually switching therapy could not be
reported by the patients, and as a consequence, we do not know if there were patients
suffering from resistant hypertension; consequently, although no correlation was found
with HTN and pain scores, it is not possible to address the question of whether controlling
the high pressure may have a role in modulating pain perception. Finally, the recruitment
of the participants was undertaken in tertiary referral Oral Medicine Units, and this may
not represent the real analysis of all patients affected by BMS, which are predominantly
women (female/male ratio 3:1) [7].

5. Conclusions
In our research, the BMS patients showed a higher prevalence of HTN compared with
that in the controls, and common predictors, such as smoking, higher BMI and a lower
educational level, did not contribute to HTN in the BMS patients. The onset of HTN in
BMS patients is not completely clear, but it may have a multifactorial etiopathogenesis
in which genetic, biological and environmental factors could act in a synergic way. The
co-occurrence and the long-term effects of HTN and painful disease on patients may in
turn accelerate brain aging, aggravating both diseases and increasing the risk of premature
mortality. Therefore, routine screening for the early detection and proper treatment of HTN
may be considered appropriate in patients suffering from BMS. Although the role of dental
professionals is essential in the diagnosis of BMS, it seems equally important to request
an interdisciplinary care plan to ensure not only adequate pain management but also the
integrated treatment of any comorbidities in order to improve the prognosis and quality of
life of such patients. Further studies are required to confirm the association between HTN
and BMS and to evaluate the impact of an integrated care plan, focused on the treatment of
pain, on comorbidities and also lifestyle and health risk factors in BMS.
Int. J. Environ. Res. Public Health 2023, 20, 2040 17 of 20

Author Contributions: D.A.: Contributed to conception, design, data acquisition and interpretation,
drafted and critically revised the manuscript; F.C.: Contributed to conception, design, data acquisition
and interpretation, drafted and critically revised the manuscript; E.C.: Contributed to design, data ac-
quisition and interpretation, drafted and critically revised the manuscript; N.C. and M.S.: Contributed
to conception and data acquisition, drafted and critically revised the manuscript; G.S.: Contributed
to design and data interpretation, drafted and critically revised the manuscript; G.P.: Contributed to
conception, data acquisition and interpretation, drafted and critically revised the manuscript; M.A.:
Contributed to design and data, performed all statistical analyses and data interpretation, drafted
and critically revised the manuscript; L.D.: Contributed to design and data, performed all statistical
analyses and data interpretation, drafted and critically revised the manuscript; M.D.M.: Contributed
to conception and data interpretation, drafted and critically revised the manuscript; S.L.: Contributed
to conception and data interpretation, drafted and critically revised the manuscript. All authors have
read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: This study was carried out over a period from April 2020
to January 2022 at the Oral Medicine Department of the University of Naples “Federico II”, after
obtaining the approval from the Ethical Committee of the University (Approval Number: 251/19—
the date of approval being 20 February 2019). The study was conducted in accordance with the
ethical principles of the World Medical Association Declaration of Helsinki, and the adopted methods
conformed with the Strengthening of the Reporting of Observational Studies in Epidemiology
(STROBE) guidelines for observational studies.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Data are available by contacting the corresponding author.
Conflicts of Interest: The authors declare no conflict of interest.

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