Pulp Sensitivity: Influence of Sex, Psychosocial Variables, COMT Gene, and Chronic Facial Pain Irena Mladenovic, DDS, MS, PhD,* Jelena Krunic, DDS, MS, PhD, † Gordana Supic, MS, PhD, ‡§ Ruzica Kozomara, DDS, MD, MS, PhD, §k Dejan Bokonjic, MD, MS, PhD, ¶ Nikola Stojanovic, DDS, MS, PhD, † and Zvonko Magic, MD, MS, PhD ‡§ Abstract Introduction: The purpose of this study was to evaluate the associations of variability in pulp sensitivity with sex, psychosocial variables, the gene that encodes for the enzyme catechol-O-methyltransferase (COMT), and chronic painful conditions (temporomandibular disor- ders [TMDs]). Methods: The study was composed of 97 subjects (68 women and 29 men aged 20–44 years). The electric (electric pulp tester) and cold (refrigerant spray) stimuli were performed on mandibular lateral in- cisors. The results were expressed as pain threshold values for electric pulp stimulation (0–80 units) and as pain intensity scores (visual numeric scale from 0–10) for cold stimulation. The Research Diagnostic Criteria for TMD were used to assess TMD, depression, and so- matization. DNA extracted from peripheral blood was genotyped for 3 COMT polymorphisms (rs4680, rs6269, and rs165774) using the real-time TaqMan method. Multivariate linear regression was used to investigate the joint effect of the predictor variables (clinical and genetic) on pulp sensitivity (dependent vari- ables). Results: Threshold responses to electric stimuli were related to female sex (P < .01) and the homozy- gous GG genotype for the rs165774 polymorphism (P < .05). Pain intensity to cold stimuli was higher in TMD patients (P < .01) and tended to be higher in women. Multivariate linear regression identified sex and the rs165774 COMT polymorphism as the determi- nants of electric pain sensitivity, whereas TMD accounts for the variability in the cold response. Conclusions: Our findings indicate that sex/a COMT gene variant and TMD as a chronic painful condition may contribute to individual variation in electric and cold pulp sensi- tivity, respectively. (J Endod 2018;-:1–5) Key Words Catechol-O-methyltransferase, chronic pain, dental pulp tests, pulp sensitivity, sex P ulp sensitivity testing is an essential part of the diagnostic process in the assessment of pulpal hea- lth. Thermal cold and elec- tric tests are the most commonly used pulp sens- itivity tests to assess pulp status from the sensory response. These tests have been proven to be accurate and reliable methods for the dif- ferentiation of vital and nonvital pulps (1), but uncertainty concerning the determina- tion of pulpal disease/health may occur. Many factors may affect diagnostic accuracy and the use of these tests (2–5). Sex has been proposed to be of relevance to nociception. Women show a higher risk for many pain conditions, including various acute and chronic clinical pain con- ditions, and response to pain treatment (6). There are data elements indicating that sex may contribute to the difference in pulp sensitivity (7, 8), but not all studies support these findings (4, 9). Stimulus perception has also been associated with a number of psychological factors, such as emotional distress, catastrophizing, psychosocial stress, anxiety, depression, and somatic awareness (10). Both depression and somati- zation might contribute to clinical pain measures in chronic pain populations (11); hence, their association with the pulp sensitivity response has not yet been elucidated. In the last decade, genetics has become a well-established factor that contributes to pro- cessing of nociceptive information and pain-related behavior (12, 13). Gene encoding for the catabolic enzyme catechol-O-methyltransferase (COMT), located in the chromo- some 22q11, has been largely investigated in relation to pain sensitivity (14, 15). COMT inactivates dopamine, noradrenaline, and adrenaline, neurotransmitters involved in numerous physiological processes, including pain modulation (15). Single- nucleotide polymorphisms (SNPs) in the COMT gene may induce low COMT enzyme activity, produce an elevated level of catecholamines, and ultimately decrease tolerance to pain (14). It has also been confirmed that COMT genetic variants have modality- and sex-specific effects on pain sensitivity in both animal and human model studies (15). Regarding the potential role of genetic polymorphisms in tooth pain, 1 study has explored cyclooxygenase-2 gene variants associated with pain after endodontic treat- ment (16). However, there are no published data on genetic influence regarding indi- vidual variation in the pulp sensitivity response. From the *Department of Oral Rehabilitation, † Department of Dental Pathology, and ¶ Center for Biomedical Science, Faculty of Medicine, University of East Sarajevo, Foca, Bosnia and Herzegovina; and ‡ Institute for Medical Research, k Clinic for Maxillofacial Surgery, Military Medical Academy, Belgrade, Serbia; and § Faculty of Medicine, University of Defence, Belgrade, Serbia. Address requests for reprints to Dr Irena Mladenovic, Department of Oral Rehabilitation, Faculty of Medicine, Studentska 5, 73 300 Foca, BiH. E-mail address: eirene14a@yahoo.com 0099-2399/$ - see front matter Copyright ª 2018 American Association of Endodontists. https://doi.org/10.1016/j.joen.2018.02.002 Significance When performing pulp sensibility testing, women and GG genotype carriers of the COMT rs165774 variant show a decreased pulp pain threshold to electric stimuli, whereas the presence of chronic facial pain increases pulp pain intensity to cold stimuli. Clinical Research JOE — Volume -, Number -, - 2018 Variability in Pulp Sensitivity 1