Association between craniofacial pain complaints, somatoform symptoms and chronic diseases

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Association between craniofacial pain complaints, somatoform symptoms and chronic diseases Article in Press: Accepted Manuscript Silvia R.D.T. de Siqueira , Jose Tadeu T. de Siqueira and Manoel Jacobsen Teixeira Archives of Oral Biology, Article 104892, Copyright © 2020 Highlights Craniofacial pain was associated with chronic diseases and somatoform symptoms. Functional disorders were the most prevalent conditions. Gastrointestinal and oral complaints were the most common somatoform complaints. Abstract Objective This case-control study aimed to investigate associations between craniofacial pain complaints, somatoform symptoms and chronic diseases. Design 306 subjects were included in this study (174 patients and 132 healthy subjects). The evaluation consisted of demographic data, number of functional and nonfunctional chronic diseases, medications, somatoform symptoms (xerostomia, dry mucosa, numbness, gastrointestinal complaints), and pain complaints with associated characteristics (number of pain areas, sensation of tired face, bruxism, sleep disturbances, masticatory musculoskeletal evaluation). Statistical analysis included descriptive data, tested with chi-square, Fisher´s exact, nonparametric Kolmogorov-Smirnoff, Student´s t test, Pearson´s coefficient, two-steps cluster classification, multivariate linear and LASSO regressions. Results Functional disorders were prevalent in 111 (63.8%) patients with facial pain. They were taking more medication (p < 0.001) and had more sleep disturbances (p < 0.001), higher xerostomia scores (p < 0.001) and more gastrointestinal complaints (p < 0.001) than controls. There was a positive correlation between the functional score and the number of cranial areas with headache (R = 0.266, <0.001). The regression models for facial pain (R = 0.632), craniofacial pain (R = 0.623) and headache (R = 0.252) showed significant dependency of functional disorders (p < 0.001). Conclusion craniofacial pain was associated with functional diseases and somatoform symptoms. This association needs further investigation to understand the role of those disorders in craniofacial pain, considering that pain complaints are common somatoform and functional symptoms. 1 Introduction Chronic pain affects between 7% and 40% of the adult population, and the craniofacial region is the second more affected ( ; ). There are several etiological factors underlying craniofacial pain symptoms, but common features are present and associated with trigeminal pain processing and sensitization of chronic pain ( ). Patients with orofacial pain often present psychiatric diseases, fibromyalgia and sleep disorders ( ; ; ; ; ; ; ; ), which are commonly associated with functional chronic conditions and somatoform symptoms ( ). It is known that sleep disturbances can be predictive of somatoform syndrome ( ). Thus, the association between craniofacial complaints with functional disorders and somatoform symptoms needed further investigation. Functional disorders and somatoform symptoms are chronic conditions not explained by organic causes. Their prevalence is 11.0%, ( ) and they are often associated with multimorbidity, like other chronic diseases ( ; ), as well as with pain symptoms in general ( ; ; ; ). They include gastro-intestinal conditions, including at least part of food allergies ( ), irritable bowel syndrome ( ), dyspepsia ( ), and xerostomia ( ). Part of cases is misdiagnosed with illnesses having an organic cause, ( ), and less than half of cases are well treated. One of the possible reasons is lack of knowledge by physicians and patients ( ). Thus, the aim of this study was to investigate associations between craniofacial pain complaints, somatoform symptoms and chronic diseases. We hypothesized that patients with craniofacial pain complaints present more functional diseases and somatoform symptoms than healthy subjects. 2 Material and methods This study was conducted on a database composed of subjects, which included patients from the Interdisciplinary Pain Group of the Neurology Department of the Medical School, University of Sao Paulo, Brazil, as well as healthy subjects (volunteers, mostly patients´ relatives and acquaintances). All the data were obtained from a systematized protocol that included medical records and questionnaires for the anamnesis, medical history and examination of patients, according to the Orofacial Pain Protocol ( ). The data were collected between 2002 and 2012. All patients and controls have signed the informed consent and the ethics committee approved the study. The inclusion criteria for the patients’ group consisted of having any chronic craniofacial pain complaint, with more than 6 months of duration. The inclusion criteria for the control group was the absence of any craniofacial pain complaint. Exclusion criteria were presence of multiple sclerosis, tumors and Sjogren Syndrome. All consecutive patients from the period of this study were included. Trained pain specialists had evaluated the patients and controls in order to identify pain characteristics and perform differential diagnosis, and the diagnosis was based on the International Association for the Study of Pain criteria ( ) and the International Headache Society criteria ( ). The criteria of IHS includes all causes of primary and secondary headaches, which comprehend all potential diagnosis of craniofacial pain. Its revised edition has good specificity and sensitivity for temporomandibular disorders, as well as other craniofacial pain syndromes ( ). Patients having TMD as secondary to other causes were not considered as TMD patients, but masticatory complaints were assessed for all patients and evaluated as associated symptoms. A trained dentist clinically examined the orofacial region and mouth. The diagnoses of facial pain are described in Table 1 . Table 1 Distribution of patients according to their first diagnosis (N = 174) N % Trigeminal neuralgia 42 24.1 Trigeminal post-traumatic neuropathy 12 6.9 Trigeminal post-herpetic neuralgia 7 4.0 Burning mouth syndrome 36 20.7 Atypical odontalgia 10 5.7 Persistent idiopathic facial pain 12 6.9 Temporomandibular disorder 30 17.2 Regional complex pain syndrome 5 2.9 Facial palsy 3 1.7 Polineuropathy 4 2.3 Wallemberg syndrome 3 1.7 Fibromyalgia with craniofacial pain symptoms 10 5.7 For this study, the following features from the dataset were analyzed: 1. Demographic characteristics: sex, color, marital status and occupation. The majority were female (217; 70.9%), white (254; 89%, retired (30.4%), and married (140; 45.8%). Mean age was 52.32 ± 19.254 years old. 2. Chronic diseases and medication in use: pre-existent chronic diseases and medications in use. Physicians from specialized areas have made the diagnoses. The pre-existent diseases were obtained from medical records and the systematized evaluation of the patient. Chronic diseases were classified into two groups: functional and nonfunctional disorders. Psychiatric and gastrointestinal disorders were included in the functional group ( ; ; ) and a functional score was created based on the summation of them, except for pain conditions (the functional score excluded fibromyalgia and local pain complaints). Other chronic diseases were classified as nonfunctional, and added to a nonfunctional score. Medications in use were analyzed in two different variables: one that included all medications, and the other that excluded the medications that were used for pain. Medication was included in this study because of its influence in other symptoms, especially those used for pain. 3. Somatoform symptoms: gastric and intestinal complaints, and sensation of dry mucosa and xerostomia, which was assessed by the Xerostomia Inventory, validated to the Portuguese language. ( ; ). This questionnaire contains 30 questions that investigate several dry mucosa complaints. A dry mucosa score was calculated by the summation of dry mucosa complaints (including vaginal, nasal and conjunctiva dry mucosa complaints), and a xerostomia score was calculated by the summation of xerostomia complaints (oral dry mucosa). Eating / drinking complaints (loss of food or liquids due to numbness), sensation of smell / taste loss, and intensity of numbness (in a numeric scale from 0 to 10, from the absence to the highest possible numbness sensation) were evaluated. These factors are associated with the sensation of sensory loss. 4. Pain complaints and associated characteristics ( ): number of pain areas (except at the craniofacial region) and number of cranial areas with headache (the summation of pain at temporal, parietal, frontal and occipital regions) were evaluated. All complaints were included in the calculation of craniofacial pain areas, even when there was more than one in the same patient. Waking-up pain (number of pain areas when waking-up), sensation of tired face, bruxism (according to the report of bed partner), sleep disturbances (in a Likert scale which five degrees of sleep quality), temporomandibular joint noises at the clinical exam, pain in mandibular movements, maximum mouth opening, number of remaining teeth (as a measure of previous history of dental diseases, which can interfere in mandibular functions, nutrition and general health), and number of masticatory muscles trigger points were also assessed. The evaluation of trigger points was performed by a trained Orofacial pain specialist, and consisted of examining masseter and temporal muscles (extra and intraoral) ( ). Besides the role of trigger points in the diagnosis of temporomandibular disorders and painful myofascial syndrome, they are sings of trigeminal sensitization and may be secondary to other primary causes of pain. 2.1 Statistical analysis Initially, all variables were described in terms of frequencies and percentages (categorical data) or means, standard deviations and range (quantitative data). Normal distribution was considered for quantitative variables after testing with Kolmogorov-Smirnoff and according to the central limit theorem. Descriptive analysis included tables and graphs, and association analysis included chi-square with Bonferroni correction in the posthoc analysis and Fisher´s exact test for categorical variables, non-parametric Kolmogorov-Smirnoff test for categorical ordinal variable (sleep), and Student t-test for quantitative variables. After the initial descriptive analysis, data were normalized with Z score. Pearson´s correlation was tested, and the results of both (associations and correlations) were analyzed according to scientific evidences, in order to select the variables for the cluster analysis and regression models. Unsupervised two-step cluster analysis with chi-square, Bonferroni correction and Student´s t test was repeated to determine, in each cluster composition, the associations between variables. The statistical significance in all descriptive and classification steps helped to determine the potential variables for the regressions, supported by the evidences from the scientific literature. The multivariate linear regression was used to fit three models in this study: the number of facial pain complaints, the number of craniofacial areas with pain and the number of headache areas. The independent variables were selected from the association / correlation analysis, scientific literature and significance. LASSO (least absolute shrinkage and selection operator) regression was also performed to check the ranking of independent variables. The level of significance was 5% and the statistical analysis was performed with SPSS (17.0) and R studio. 3 Results In this sample, 174 (56.9%) were facial pain patients and 132 (43.1%) were controls. One hundred sixty-five (165; 53.9%) of the sample had headache. There were statistical differences in sex, occupation, marital status and age in the demographic analysis ( Table 2 ). Table 2 Demographic characteristics of the sample (N = 306) Patients (N = 174) Controls (N = 132) P Frequency (N) Percentages (%) Frequency (N) Percentages (%) Sex Women 146 83.9 71 53.8 <0.001 1 Men 28 16.1 61 46.2 Color White 148 85.1 106 80.3 0.094 2 Black 13 7.5 17 12.9 Brown 11 6.3 4 3.0 Yellow 2 1.1 5 3.8 Occupation Retired 53 30.5 40 30.3 <0.002 2 Home 34 19.5 17 12.9 Unemployed 5 2.9 8 6.1 Student 6 3.4 12 9.1 Commerce 13 7.5 3 2.3 Health profession 5 2.9 4 3.0 Maid 16 9.2 8 6.1 Teacher 12* 6.9 0 0.0 Office work 15 8.6 2 1.5 General services 14 8.0 31 * 23.5 Missing 1 0.6 7 5.3 Marital status Married 80 46.0 60 45.5 0.334 2 Single 47 27.0 47 35.6 Divorced 17 9.8 10 7.6 Widow 28 16.1 15 11.4 Missing 2 1.1 0 0.0 Mean ± SD (range) Confidence intervals (95%) Mean ± SD (range) Confidence intervals (95%) Age (years) ** 54.87 ± 15.520 (14-88) 52.48 ≤ μ ≤57.26 49.09 ± 22.779 (15-89) 45.14 ≤ μ ≤53.05 <0.001 3 1 Fisher´s Exact. 2 Chi-square with Bonferroni correction and posthoc comparison. 3 Student´s t test. * Statistical differences. ** 2 (1.5%) missing in control group and 10 (5.7%) missing in the study group (quantitative variables) Chronic diseases were prevalent in 219 (71.6%) of the sample, and 135 (61.6%) of them had functional disorders. The most frequent condition was cardiovascular (39.2%), followed by: otorhinolaryngologic (20.9%), gastric (19.0%), psychiatric (14.7%), endocrine (12.1%), rheumatologic (13.1%), nephrologic (3.3%) and neurologic diseases (3.3%). Twenty-seven patients with facial pain (15.5%) had fibromyalgia; in the comparison between patients with headache or not, it was prevalent in 23 (13.9%) of them (p < 0.001; Fisher´s exact test) ( Tables 3 and 4 ). Table 3 Chronic diseases, medication and somatoform symptoms of the sample (N = 306) Patients (N = 174) Controls (N = 132) P Frequency (N) Percentages (%) Frequency (N) Percentages (%) Chronic disease Yes 141 19.0 78 59.1 <0.001 1 Functional disorder Yes 111 63.8 24 18.2 <0.001 1 Fibromyalgia Yes 27 15.5 0 0.0 <0.001 1 Medication Yes 144 82.8 57 43.2 <0.001 1 Medication (except for pain) Yes 81 46.6 57 43.2 0.319 1 Yes Stomach complaint Yes 65 37.4 33 25.0 0.026 1 Intestine complaint Yes 72 41.4 27 20.5 <0.001 1 Xerostomia Yes 109 62.6 45 34.1 <0.001 2 Loss of liquids/food Yes 40 23.0 11 8.3 0.001 1 Numbness Yes 81 46.6 4 3.0 <0.001 1 Smell/taste complaint Yes 48 27.6 20 15.2 0.012 1 Mean ± SD (range) Confidence intervals (95%) Mean ± SD (range) Confidence intervals (95%) Number of chronic diseases 1.80 ± 1.608 (0-8) 1.56 ≤ μ ≤2.05 1.03 ± 1.210 (0-6) 0.82 ≤ μ ≤1.24 <0.001 3 Functional score 0.78 ± 0.866 (0-4) 0.65 ≤ μ ≤0.91 0.21 ± 0.479 (0-2) 0.13 ≤ μ ≤0.29 <0.001 3 Nonfunctional score 0.93 ± 1.197 (0-6) 0.75 ≤ μ ≤1.10 0.81 ± 0.997 (0-6) 0.64 ≤ μ ≤0.98 0.374 3 Number of otorhinolaryngologic diseases 0.37 ± 0.762 (0-4) 0.25 ≤ μ ≤0.48 0.20 ± 0.535 (0-4) 0.11 ≤ μ ≤0.30 0.037 3 Number of psychiatric diseases 0.22 ± 0.428 (0-2) 0.15 ≤ μ ≤0.28 0.06 ± 0.240 (0-1) 0.02 ≤ μ ≤0.10 <0.001 3 Number of medications 1.91 ± 1.491 (0-7) 1.68 ≤ μ ≤2.13 0.64 ± 1.006 (0-6) 0.46 ≤ μ ≤0.81 <0.001 3 Number of medications (except for pain) 0.76 ± 1.068 (0-6) 0.60 ≤ μ ≤0.92 0.64 ± 1.006 (0-6) 0.46 ≤ μ ≤0.81 0.288 3 Dry mucosa score 9.76 ± 4.488 (1-23) 9.09 ≤ μ ≤ 10.44 6.69 ± 3.535 (1-19) 6.08 ≤ μ ≤ 7.31 <0.001 3 Xerostomia score 7.14 ± 3.482 (0-16) 6.61 ≤ μ ≤ 7.67 5.04 ± 2.698 (1-16) 4.57 ≤ μ ≤ 5.51 <0.001 3 *Statistical difference. 1 Fisher´s Exact test. 2 Nonparametric Kolmogorov-Smirnoff. 3 Student´s t test. Table 4 Pain complaints and associated characteristics (N = 306) Patients (N = 174) Controls (N = 132) P Frequency (N) Percentages (%) Frequency (N) Percentages (%) Pain (except at the craniofacial region) Yes 152 87.4 80 60.6 <0.001 1 Pain when waking-up Yes 101 58.0 41 31.1 <0.001 1 Sensation of tired face Yes 81 46.6 20 15.2 <0.001 1 Bruxism Yes 86 49.4 18 13.6 <0.001 1 No 49 28.2 108 81.8 Doesn´t know 39 22.4 6 4.5 Sleep Bad 18 10.3 5 3.8 <0.001 2 Relatively bad 23 13.2 7 5.3 Moderate 26 14.9 18 13.6 Reatively good 36 20.7 13 9.8 Good 71 40.8 89* 67.4* Temporomandibular joint noises Yes 66 37.9 40 30.3 0.183 1 Pain in mandibular movements Yes 64 36.8 5 3.8 <0.001 1 Mean ± SD (range) Confidence intervals (95%) Mean ± SD (range) Confidence intervals (95%) Number of cranial areas with headache 0.90 ± 0.761 (0-2) 0.78 ≤ μ ≤ 1.01 0.50 ± 0.704 (0-2) 0.38 ≤ μ ≤ 0.62 <0.001 3 Number of pain areas (except at the craniofacial region) 1.61 ± 0.995 (0-3) 1.47 ≤ μ ≤ 1.76 0.80 ± 0.766 (0-3) 0.67 ≤ μ ≤ 0.93 <0.001 3 Number of pain areas when waking-up 1.83 ± 2.000 (0-6) 1.53 ≤ μ ≤ 2.13 0.54 ± 1.087 (0-4) 0.35 ≤ μ ≤ 0.73 <0.001 3 Number of areas with ‘tired’ sensation 0.70 ± 0.954 (0-3) 0.56 ≤ μ ≤ 0.84 0.16 ± 0.369 (0-1) 0.10 ≤ μ ≤ 0.23 <0.001 2 Number of painful mandibular movements 0.85 ± 1.404 (0-4) 0.64 ≤ μ ≤ 1,07 0.04 ± 0.193 (0-1) 0.00 ≤ μ ≤ 0.07 <0.001 2 Number of remaining teeth 15.56 ± 10.967 (0-28) 13.90 ≤ μ ≤17.23 18.39 ± 10.725 (0-28) 16.53 ≤ μ ≤ 20.25 0.024 2 Max mouth opening (mm) 44.28 ± 8.275 (21-66) 43.02 ≤ μ ≤ 45.53 48.57 ± 8.490 (7-70) 47.10 ≤ μ ≤ 50.04 <0.001 2 Number trigger points 2.69 ± 2.379 (0-6) 2.33 ≤ μ ≤ 3.05 0.25 ± 0.651 (0-4) 0.14 ≤ μ ≤ 0.37 <0.001 2 1 Fisher´s Exact and chi-square with Bonferroni correction. 2 Student´s t test. Pain when waking-up was prevalent in 142 (46.4%); 102 (33.0%) felt tired face, 67 (21.9%) had bruxism, 106 (35.6%) had temporomandibular joint noises and the mean number of masticatory trigger points was 1.63 ± 2.200 (range: 0-6) with a confidence interval of 1.38 ≤ μ ≤ 1.88. The distribution of the sample according to pain complaints and associated characteristics is outlined in Table 4 . Table 5 shows the correlations between chronic diseases, somatoform symptoms and pain. There was a positive correlation between the functional score and the number of cranial areas with headache (R = 0.266, <0.001), number of pain areas (except craniofacial region) (R = 0.400, <0.001), number of pain areas when waking-up (R = 0.374, <0.001) and dry mucosa score (R = 0.269, <0.001). The nonfunctional score had weaker correlation with pain variables and the number of medications were correlated with dry mucosa score (R = 0.249, <0.001) ( Table 5 ). There was also a positive correlation between the number of medications and the functional score (R = 0.347, <0.001); and between the functional score and sensation of ‘tired’ face (R = 0.377, <0.001), number of painful mandibular movements (R = 0.387, <0.001) and number of trigger points (R = 0.564, <0.001). Table 5 Pearson coefficient correlation (chronic diseases, somatoform complaints and pain complaints): R 2 and significance. 2 3 4 5 6 7 8 9 10 1 -0.003 0.964 0.385 < 0.001 -0.033 0.561 0.022 0.707 0.302 < 0.001 -0.156 0.006 0.243 < 0.001 0.010 0.865 -0.149 0.009 2 1.000 0.088 0.123 0.251 < 0.001 0.659 < 0.001 0.347 < 0.001 0.266 < 0.001 0.400 < 0.001 0.374 < 0.001 0.269 < 0.001 3 1.000 0.609 <0.001 0.110 0.055 0.375 < 0.001 0.095 0.098 0.166 0.004 0.145 0.011 0.113 0.049 4 1.000 0.110 0.055 0.125 0.029 0.210 < 0.001 0.115 0.045 0.197 0.001 0.245 < 0.001 5 1.000 0.299 < 0.001 0.125 0.029 0.257 < 0.001 0.221 < 0.001 0.229 < 0.001 6 1.000 0.197 0.029 0.373 < 0.001 0.385 < 0.001 0.249 < 0.001 7 1.000 0.288 < 0.001 0.315 < 0.001 0.295 < 0.001 8 1.000 0.501 < 0.001 0.282 < 0.001 9 1.000 0.375 < 0.001 10 1.000 1 = Age; 2 = Functional score; 3 = Nonfunctional score; 4 = Number of otorhinolaryngologic diseases; 5 = number of psychiatric diseases; 6 = number of medications; 7 = Number of cranial areas with headache; 8 = Number of pain areas (except at the craniofacial region); 9 = Number of pain areas when waking-up; 10 = Dry mucosa score. After the analysis of descriptive data, the following variables were selected for further investigation with classification and regression models: sex, ages, functional score, nonfunctional score / otorhinolaryngologic diseases, number of pain areas (except craniofacial region), number of cranial areas with headache, sleep, digestive complaints (a score created from the summation of stomach and digestive complaints), number of trigger points (as the most representative orofacial variable in association with the functional score), remaining teeth, xerostomia score, numbness and bruxism. The classification analysis showed that otorhinolaryngologic diseases were more associated with craniofacial pain than nonfunctional score, and age and remaining teeth had a weak association with the cluster that included pain patients. Results are outlined in Table 6 . Table 6 Two-steps cluster analysis with Student´s t and chi-square and Bonferroni correction significance (N = 306). Cluster 1 (134; 43.8%) Cluster 2 (172; 56.2%) P Facial pain Yes 3 1.7% 171 98.3% <0.001 1 No 131 99.2% 1 0.8% Sex Female 70 32.3% 64 71.9% <0.001 1 Male 147 67.7% 25 28.1% Sleep Bad 5 21.7% 18 78.3% <0.001 1 Relatively bad 7 23.3% 23 76.7% Moderate 17 38.6% 27 61.4% Reatively good 13 26.5% 36 73.5% Good 92 * 57.5% * 68 * 42.5% * Bruxism Yes 18 26.9% 49 73.1% <0.001 1 No 110 56.7% 84 43.3% Doesn´t know 6 13.3% 39 86.7% Age (years) mean ± SD 49.13 ± 22.715 55.17 ± 15.728 0.006 2 Confidence interval 45.25 ≤ μ ≤53.02 52.81≤ μ ≤57.54 Functional score mean ± SD 0.21 ± 0.476 0.79 ± 0.867 <0.001 2 Confidence interval 0.13 ≤ μ ≤0.29 0.66≤ μ ≤0.92 Otorhinolaryngologic diseases mean ± SD 0.17 ± 0.416 0.40 ± 0.813 0.004 2 Confidence interval 0.10 ≤ μ ≤0.24 0.27≤ μ ≤0.52 number of pain areas (except craniofacial region) mean ± SD 0.4104 ± 0.53751 0.9709 ± 0.74479 <0.001 2 Confidence interval 0.3186 ≤ μ ≤0.5023 0.8588≤ μ ≤1.0830 Number of cranial areas with headache mean ± SD 0.49 ± 0.702 0.91 ± 0.756 <0.001 2 Confidence interval 0.37 ≤ μ ≤0.60 0.80≤ μ ≤1.03 Digestive complaints mean ± SD 0.45 ± 0.620 0.80 ± 0.733 <0.001 2 Confidence interval 0.34 ≤ μ ≤0.55 0.69≤ μ ≤0.91 Number of trigger points mean ± SD 0.23 ± 0.624 2.73 ± 2.365 <0.001 2 Confidence interval 0.12 ≤ μ ≤0.34 2.37 ≤ μ ≤3.08 Remaining teeth mean ± SD 18.15 ± 10.822 15.38 ± 11.030 0.029 2 Confidence interval 16.30 ≤ μ ≤ 20.00 13.72≤ μ ≤17.04 Numbness (intensity scale) mean ± SD 0.19 ± 1.079 3.16 ± 3.838 <0.001 2 Confidence interval 0.01 ≤ μ ≤0.38 2.58≤ μ ≤3.73 Xerostomia score mean ± SD 4.99 ± 2.728 7.24 ± 3.455 <0.001 2 Confidence interval 4.52 ≤ μ ≤5.45 6.72≤ μ ≤7.76 1 Chi-square with post hoc and Bonferroni correction. 2 Student´s t. * Statistical difference. Multivariate linear regression for the number of facial pain complaints resulted in a fitted model with an adjusted R = 0.6173 and a residual standard error (RSE) of 0.6183. The regression of the number of craniofacial pains resulted in a fitted model with an adjusted R = 0.6084 and RSE = 0.3444, and the regression of number of headache areas resulted in a fitted model with an adjusted R = 0.2219 and RSE = 0.8821. The coefficients, confidence intervals and significance are outlined in Table 7 . Table 7 Multivariate regression for facial pain, craniofacial pain and headache: coefficients, confidence intervals and significance. Coefficients Confidence interval P Facial pain model Intercept (α) 0 -0.070 ≤ α ≤0.070 1.000 Sex (β 1 ) -0.076 -0.173≤ β 1 ≤ -0.021 0.013 Age(β 2 ) 0.059 -0.036 ≤ β 2 ≤0.153 0.223 Functional score (β 3 ) 0.204 0.113≤ β 3 ≤0.295 <0.001 Otorhinolaryngologic diseases (β 4 ) -0.006 -0.080 ≤ β 4 ≤0.068 0.872 Number of pain areas (except for craniofacial region) (β 5 ) 0.0057 -0.079≤ β 5 ≤0.090 0.899 Sleep (β 6 ) -0.000 -0.076≤ β 6 ≤0.075 0.992 Digestive complaints (β 7 ) -0.012 -0.089≤ β 7 ≤0.066 0.770 Number of trigger points (β 8 ) 0.466 0.370≤ β 8 ≤0.562 <0.001 Remaining teeth (β 9 ) -0.090 -0.183≤ β 9 ≤0.002 0.056 Xerostomia score (β 10 ) 0.082 0.0036≤ β 10 ≤0.162 0.043 Numbness intensity (β 11 ) 0.157 0.079≤ β 11 ≤0.235 <0.001 Bruxism (β 12 ) 0.125 0.048≤ β 12 ≤0.202 0.002 Craniofacial pain model Intercept (α) 0 -0.070 ≤ α ≤0.070 1.000 Sex (β 1 ) -0.077 -0.278≤ β 1 ≤ -0.124 <0.001 Age(β 2 ) -0.088 -0.184≤ β 2 ≤0.008 0.074 Functional score (β 3 ) 0.152 0.060134169≤ β 3 ≤0.244 0.001 Otorhinolaryngologic diseases (β 4 ) 0.042 -0.032≤ β 4 ≤0.117 0.266 Number of pain areas (except for craniofacial region) (β 5 ) 0.094 0.009≤ β 5 ≤0.180 0.031 Sleep (β 6 ) -0.049 -0.126≤ β 6 ≤0.027 0.206 Digestive complaints (β 7 ) 0.007 -0.071≤ β 7 ≤0.085 0.866 Number of trigger points (β 8 ) 0.413 0.316≤ β 8 ≤0.510 <0.001 Remaining teeth (β 9 ) -0.089 -0.183≤ β 9 ≤0.005 0.063 Xerostomia score (β 10 ) 0.103 0.015≤ β 10 ≤0.190 0.022 Numbness intensity (β 11 ) 0.094 0.015≤ β 11 ≤0.173 0.020 Bruxism (β 12 ) 0.044 -0.034≤ β 12 ≤0.122 0.270 Taste / smell complaints (β 13 ) 0.014 -0.065≤ β 13 ≤0.093 0.726 Headache model Intercept (α) 0 -0.099 ≤ α ≤0.099 1.000 Sex (β 1 ) -0.225 -0.333≤ β 1 ≤ -0.116 <0.001 Age(β 2 ) -0.175 -0.285 ≤ β 2 ≤-0.066 0.001 Functional score (β 3 ) 0.026 -0.103≤ β 3 ≤0.156 0.002 Otorhinolaryngologic diseases (β 4 ) 0.125 0.0196≤ β 4 ≤0.230 0.689 Number of pain areas (except for craniofacial region) (β 5 ) 0.196 0.076≤ β 5 ≤0.316 0.020 Sleep (β 6 ) -0.074 -0.182≤ β 6 ≤0.034 0.002 Digestive complaints (β 7 ) 0.0187 -0.092≤ β 7 ≤0.129 0.180 Number of trigger points (β 8 ) 0.062 -0.074≤ β 8 ≤0.198 0.739 Xerostomia score (β 9 ) 0.059 -0.063≤ β 9 ≤0.182 0.369 Numbness intensity (β 10 ) 0.0232 -0.088≤ β 10 ≤0.135 0.342 Bruxism (β 11 ) -0.069 -0.176≤ β 11 ≤0.038 0.203 Taste / smell complaints (β 12 ) 0.039 -0.072≤ β 12 ≤0.151 0.488 LASSO regression analysis resulted in the following rankings of independent variables: 1. Facial pain (R = 0.632): number of trigger points > functional score > numbness intensity > bruxism > sex > number of pain areas (except for craniofacial region) > remaining teeth > age > xerostomia score > digestive complaints > otorhinolaryngologic diseases > sleep. 2. Craniofacial pain (R = 0.625): number of trigger points > functional score > sex > number of pain areas (except for craniofacial region) > xerostomia score > numbness intensity > sleep > otorhinolaryngologic diseases > bruxism > remaining teeth > age > taste / smell complaints > digestive complaints. 3. Headache (R = 0.252): sex > number of pain areas (except for craniofacial region) > number of trigger points > functional score > xerostomia score > otorhinolaryngologic diseases > age > sleep > taste / smell complaints > bruxism > digestive complaints > numbness intensity. 4 Discussion Facial pain and headache were associated and correlated with functional diseases, fibromyalgia and somatoform symptoms in this study, and the number of facial-, craniofacial pain and headache areas was associated with somatoform symptoms and common comorbidities. On the other side, among nonfunctional illnesses, only otorhinolaryngologic diseases were more frequent in these patients. The main findings of this research show strong associations in the regression models, which may be potentially related to sensitization of trigeminal pathways (for example, the number of trigger points and other inflammatory conditions of the face, such as otorhinolaryngologic diseases), and pain spread, as in fibromyalgia ( ). Besides, chronic illnesses and symptoms with unexplained organic causes were not only local, but also systemic in these patients, and their role should be better investigated. The prevalence of functional diseases was 63.8%, much higher than what is expected (11.0%) ( ), and fibromyalgia was highly prevalent in this group. Patients with facial pain had more pain in other areas, sleep disturbances, digestive complaints, numbness, xerostomia, psychiatric diseases, as well as more local afflictions: sensation of ‘tired face’, bruxism, pain at mandibular movements, trigger points, masticatory complaints, loss of liquids/food and taste/smell complaints. Functional diseases were highly correlated with craniofacial and systemic functional disturbances, especially the number of pain areas and the number of trigger points. These results are in accordance to the previous scientific literature. They show that functional diseases and somatoform symptoms (including chronic pain and fibromyalgia) were associated among each other ( ; ), as well as with psychiatric diseases ( ; ; ; ), and they support the understanding of craniofacial pain as a functional disorder. Moreover, this results show that patients with more areas of pain and functional complaints are more likely to present facial pain and headache. The identification of patients that might develop chronic pain is desirable to design preventive measures that would reduce costs and impairment of quality of life. Those patients would benefit from preventive analgesic measures and early diagnosis and treatment if they are recognized as having a potential risk of developing chronic facial pain. Sleep disturbances were also associated with pain and had a role in regression models. The persistence of chronic pain can disrupt sleep in a circular relationship ( ). Bruxism can be associated with sleep or not, and it is an important factor of pain maintenance in masticatory myofascial conditions ( ). Sleep is associated with functional diseases and common pain comorbidities, such as depression ( ), which shows the complex relationship that those features might have in these patients. In that context, identifying psychiatric illnesses, sleep disturbances and gastrointestinal conditions is important for the assessment of those patients as a ‘whole’ ( ). It is not possible to evaluate only local factors – dental characteristics and the masticatory system – and ignore the craniofacial and systemic implications that facial pain might have. Other chronic diseases, such as otorhinolaryngologic, psychiatric and gastrointestinal may co-occur in these patients and the treatment must include the assessment of those associated disorders. Besides, the correlations between several functional masticatory functional variables (masticatory complaints, quality of chewing, sensation of ‘tired face’) suggests interactions among them and supports that the patients with more craniofacial pain areas has more somatoform complaints and common comorbidities of functional disorders. Women have more morbidities that are painful and more frequency of pain ( ). This study supports that and shows that it was associated with facial pain and headache as a significant factor in the fitted facial-, craniofacial pain and headache models. It also supports that women are more likely to have more craniofacial pain areas and more symptoms that are somatoform or functional. The correlation between remaining teeth and previous surgical and nonsurgical treatments may be justified by the high number of iatrogenic dental procedures that are common in patients with facial pain, continuing even after the correct diagnosis ( ; ). The association between facial pain and this variable might be due to the previous procedures and not due to pain, but longitudinal studies need to confirm that. Otorhinolaryngologic diseases were quite prevalent in this sample, and associated with craniofacial pains. The trigeminal system has an intense convergence of sensory inputs, which are processed in a complex nuclear structure. Local pain symptoms from any facial or cranial structure are able to sensitize the nuclear complex ( ) and may contribute to pain spreading and myofascial sensitization through a retrograde mechanism. Moreover, trigger points were closely associated with facial pain and headache, and they can play a role in sensitization of the trigeminal system, generating craniofacial pain ( ). Thus, it is not surprising that only this group of local nonfunctional diseases were associated with craniofacial pain. Although xerostomia was higher in the group of patients, and it was associated with the groups in cluster analysis and regression models, its correlation with medications suggests that it might be a collateral effect of those in this study. Functional disorders were correlated with medication for pain, supporting that evidence. Further investigation with patients in the moment of diagnoses (before starting the treatment) should clarify this issue. Taste/ smell complaints were included in the craniofacial model and headache due to their role as symptoms of headaches ( ). They were also more prevalent in patients with facial pain in this study. Although they were not significant in the analysis of features in the models, they were relevant in the best-fitted models. All features that were included in the mathematical models in this study were those that played a role in the best-fitted model, even those that are not relevant in the significance analysis. The limitations of this study are the cross-sectional character of this research, which does not allow cause-effect analysis that would contribute with stronger evidences for the identification of risk factors. However, the database used in this study has been conceived to have detailed information of the subjects, which permitted this elaborate analysis. In conclusion, as hypothesized, patients with craniofacial pain complaints had more functional chronic diseases and somatoform symptoms than controls. The associated chronic conditions were: fibromyalgia, psychiatric, gastrointestinal and otorhinolaryngologic diseases, and the somatoform associated symptoms were: sleep disturbances, digestive complaints and xerostomia. These associations need further investigation to understand the role of those disorders in craniofacial pain, considering that pain complaints are common somatoform and functional symptoms. CRediT authorship contribution statement Silvia R.D.T. de Siqueira: Conceptualization, Formal analysis, Writing - original draft. Jose Tadeu T. de Siqueira: Writing - review & editing. Manoel Jacobsen Teixeira: Supervision. Declaration of Competing Interest The authors report no declarations of interest. References Ayouni I., Chebbi R., Hela Z., Dhidah M.: Comorbidity between fibromyalgia and temporomandibular disorders: a systematic review. 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