Carolina Beraldo Meloto

Painful Temporomandibular Disorder Decade of Discovery from OPPERA Studies

In 2006, the OPPERA project (Orofacial Pain: Prospective Evaluation and Risk Assessment) set out to identify risk factors for development of painful temporomandibular disorder (TMD). A decade later, this review summarizes its key findings. At 4 US study sites, OPPERA recruited and examined 3,258 community-based TMD-free adults assessing genetic and phenotypic measures of biological, psychosocial, clinical, and health status characteristics. During follow-up, 4% of participants per annum developed clinically verified TMD, although that was a “symptom iceberg” when compared with the 19% annual rate of facial pain symptoms. The most influential predictors of clinical TMD were simple checklists of comorbid health conditions and nonpainful orofacial symptoms. Self-reports of jaw parafunction were markedly stronger predictors than corresponding examiner assessments. The strongest psychosocial predictor was frequency of somatic symptoms, although not somatic reactivity. Pressure pain thresholds measured at cranial sites only weakly predicted incident TMD yet were strongly associated with chronic TMD, cross-sectionally, in OPPERA’s separate case-control study. The puzzle was resolved in OPPERA’s nested case-control study where repeated measures of pressure pain thresholds revealed fluctuation that coincided with TMD’s onset, persistence, and recovery but did not predict its incidence. The nested case-control study likewise furnished novel evidence that deteriorating sleep quality predicted TMD incidence. Three hundred genes were investigated, implicating 6 single-nucleotide polymorphisms (SNPs) as risk factors for chronic TMD, while another 6 SNPs were associated with intermediate phenotypes for TMD. One study identified a serotonergic pathway in which multiple SNPs influenced risk of chronic TMD. Two other studies investigating gene-environment interactions found that effects of stress on pain were modified by variation in the gene encoding catechol O-methyltransferase. Lessons learned from OPPERA have verified some implicated risk factors for TMD and refuted others, redirecting our thinking. Now it is time to apply those lessons to studies investigating treatment and prevention of TMD.

Association of matrix metalloproteinase gene polymorphism with temporomandibular joint degeneration.

Temporomandibular joint (TMJ) degeneration is a frequent cause of orofacial pain. Matrix metalloproteinases (MMPs) degrade extracellular matrix components and play an important role in TMJ degeneration. We investigated the frequency of the MMP1 1G/2G polymorphism (rs1799750), the MMP3 5A/6A polymorphism (rs3025058), and the MMP9 C/T polymorphism (rs3918242) in individuals with TMJ degeneration, in order to analyze the association of polymorphisms in these genes with TMJ degeneration. The population studied comprised 117 healthy controls and 115 individuals diagnosed with TMJ degeneration upon examination of magnetic resonance imaging (MRI) and computed tomography (CT) images. Genotypes were determined using PCR restriction fragment length polymorphism (RFLP). Logistic regression analyses revealed an association between the MMP1 2G/2G genotype and degeneration; in contrast, there was no association between either the MMP3 or the MMP9 genotype and degeneration. Our results may indicate a role for the MMP1 polymorphism in TMJ degeneration.

Genetic predictors of human chronic pain conditions.

Chronic pain conditions are multifactorial disorders with a high frequency in the population. Their pathophysiology is often unclear, and treatment is inefficient. During the last 20years, genetic linkage analysis and association studies have made considerable strides toward identifying key molecular contributors to the onset and maintenance of chronic pain. Here, we review the genetic variants that have been implicated in chronic pain conditions, divided into the following etiologically-grouped categories: migraine, musculoskeletal pain disorders, neuropathic pain disorders, and visceral pain disorders. In rare familial monogenic pain conditions several strong-effect mutations have been identified. In contrast, the genetic landscape of common chronic pain conditions suggests minor contributions from a large number of single nucleotide polymorphisms representing different functional pathways. A comprehensive survey of up-to-date genetic association results reveals migraine and musculoskeletal pain to be the most investigated chronic pain disorders, in which nearly half of identified genetic variability alters neurotransmission pathways.

Subgrouping of Low Back Pain Patients for Targeting Treatments Evidence from Genetic, Psychological, and Activity-related Behavioral Approaches

Introduction:Many patients with low back pain (LBP) are treated in a similar manner as if they were a homogenous group. However, scientific evidence is available that pain is a complex perceptual experience influenced by a wide range of genetic, psychological, and activity-related factors. The leading question for clinical practice should be what works for whom. Objectives:The main aim of the present review is to discuss the current state of evidence of subgrouping based on genetic, psychosocial, and activity-related factors in order to understand their contribution to individual differences. Results:Based on these perspectives, it is important to identify patients based on their specific characteristics. For genetics, very promising results are available from other chronic musculoskeletal pain conditions. However, more research is warranted in LBP. With regard to subgroups based on psychosocial factors, the results underpin the importance of matching patients’ characteristics to treatment. Combining this psychosocial profile with the activity-related behavioral style may be of added value in tailoring the patient’s treatment to his/her specific needs. Conclusions:For future research and treatment it might be challenging to develop theoretical frameworks combining different subgrouping classifications. On the basis of this framework, tailoring treatments more specifically to the patient needs may result in improvements in treatment programs for patients with LBP.

Water Sorption of heat-polymerized acrylic resins processed in mono and bimaxillary flasks

This study evaluated water sorption in heat-polymerized acrylic resins processed in monomaxillary flasks by water bath and in bimaxillary flasks by microwave energy and water bath. Fifty heat-polymerized acrylic resin specimens were fabricated according to the 12th specification of the American Dental Association and assigned to 3 groups: group 1 was processed by water bath in monomaxillary metallic flask; group 2 was processed by microwave energy in bimaxillary PVC flask; and group 3 was processed by water bath in bimaxillary metallic flask. Specimens were submitted to water sorption test, means were calculated and analyzed statistically by Students t-test. Means (in g/cm3) were: group 1--0.024085, group 2--0.025312 and group 3--0.022098. Microwave energy processing and the amount of stone and resin used in the bimaxillary PVC flask did not influence water sorption; specimens processed in bimaxillary metallic flask by water bath presented lower water sorption means, suggesting an inadequate polymerization of the acrylic resin mass.

COMT gene locus: new functional variants

Abstract Catechol-O-methyltransferase (COMT) metabolizes catecholaminergic neurotransmitters. Numerous studies have linked COMT to pivotal brain functions such as mood, cognition, response to stress, and pain. Both nociception and risk of clinical pain have been associated with COMT genetic variants, and this association was shown to be mediated through adrenergic pathways. Here, we show that association studies between COMT polymorphic markers and pain phenotypes in 2 independent cohorts identified a functional marker, rs165774, situated in the 3′ untranslated region of a newfound splice variant, (a)-COMT. Sequence comparisons showed that the (a)-COMT transcript is highly conserved in primates, and deep sequencing data demonstrated that (a)-COMT is expressed across several human tissues, including the brain. In silico analyses showed that the (a)-COMT enzyme features a distinct C-terminus structure, capable of stabilizing substrates in its active site. In vitro experiments demonstrated not only that (a)-COMT is catalytically active but also that it displays unique substrate specificity, exhibiting enzymatic activity with dopamine but not epinephrine. They also established that the pain-protective A allele of rs165774 coincides with lower COMT activity, suggesting contribution to decreased pain sensitivity through increased dopaminergic rather than decreased adrenergic tone, characteristic of reference isoforms. Our results provide evidence for an essential role of the (a)-COMT isoform in nociceptive signaling and suggest that genetic variations in (a)-COMT isoforms may contribute to individual variability in pain phenotypes.

Modification of COMT-dependent pain sensitivity by psychological stress and sex

Abstract Catecholamine-O-methyltransferase (COMT) is a polymorphic gene whose variants affect enzymatic activity and pain sensitivity via adrenergic pathways. Although COMT represents one of the most studied genes in human pain genetics, findings regarding its association with pain phenotypes are not always replicated. Here, we investigated if interactions among functional COMT haplotypes, stress, and sex can modify the effect of COMT genetic variants on pain sensitivity. We tested these interactions in a cross-sectional study, including 2 cohorts, one of 2972 subjects tested for thermal pain sensitivity (Orofacial Pain: Prospective Evaluation and Risk Assessment) and one of 948 subjects with clinical acute pain after motor vehicle collision (post–motor vehicle collision). In both cohorts, the COMT high–pain sensitivity (HPS) haplotype showed robust interaction with stress and number of copies of the HPS haplotype was positively associated with pain sensitivity in nonstressed individuals, but not in stressed individuals. In the post–motor vehicle collision cohort, there was additional modification by sex: the HPS–stress interaction was apparent in males, but not in females. In summary, our findings indicate that stress and sex should be evaluated in association studies aiming to investigate the effect of COMT genetic variants on pain sensitivity.

Prevalence of temporomandibular disorders in postmenopausal women and relationship with pain and HRT

The prevalence of temporomandibular disorders (TMD) is higher in females, reaching their high peak during reproductive years, probably because of the action of some female hormones, which alter pain threshold. This study aimed to investigate the prevalence of TMD in postmenopausal women and its relationship with pain and hormone replacement therapy (HRT). In total, 284 patients were evaluated and classified using the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Pain was measured using the Visual Analogue Scale (VAS), and patients were also asked about the use of HRT. All data was analyzed using analysis of variance (ANOVA) and chi-square test. In total, 155 subjects did not have TMD and 129 had TMD; TMD group patients were classified according to RDC/TMD axis I classification as follows: muscle disorder group (1.6%), disk displacement group (72.87%), and arthralgia, osteoarthritis, and osteoarthrosis group (37.98%). Pain was registered in 35 patients who belonged to the TMD group, while 48 patients reported the use of HRT. There was a similar percentage of TMD and non TMD patients; moreover, the use of exogenous hormones was no associated with TMD, suggesting that there is no influence on the pain threshold.

Effect of double flasking and investing methods on artificial teeth movement in complete dentures processing.

PURPOSE The aim of this study was to evaluate linear dimensional alterations of artificial teeth for complete dentures when using different investment and flasking techniques. BACKGROUND Dimensional changes in the vertical dimension may occur owing to changes in artificial teeth positioning caused by different investing and flasking techniques. MATERIALS AND METHODS Thirty pairs of the complete dentures were manufactured and randomly divided into three groups (n = 10): (1) invested with type III stone in monomaxillary PVC flask; (2) invested with type III stone in bimaxillary PVC flask; and (3) invested with laboratory silicone in bimaxillary PVC flask. Dentures were polymerised by microwave, and 12 linear distances were measured before and after denture processing. Data were analysed by one-way anova, considering manufacturing technique as the study factor. Tukeys HSD was used as post hoc ANOVA (p = 0.05). RESULTS Most of the linear distances were comparable for all groups. All transversal maxillary and mandibular distances were higher for group 1 compared with groups 2 and 3 (p < 0.05), except the distance 3-6 for mandibular arch, in which no difference was found between groups (p < 0.05). Both maxillary diagonal distances were higher in group 1 (p < 0.05), and no differences were found among all groups for mandibular measurements. CONCLUSIONS Double flasking technique independent on the investment material is shown to be the most effective method to reduce changes in artificial teeth positioning.

The Human Pain Genetics Database (HPGDB): a resource dedicated to human pain genetics research

Abstract The Human Pain Genetics Database (HPGDB) is a comprehensive variant-focused inventory of genetic contributors to human pain. After curation, the HPGDB currently includes 294 studies reporting associations between 434 distinct genetic variants and various pain phenotypes. Variants were then submitted to a comprehensive analysis. First, they were validated in an independent high-powered replication cohort by testing the association of each variant with 10 different pain phenotypes (n = 1320-26,973). One hundred fifty-five variants replicated successfully (false discovery rate 20%) in at least one pain phenotype, and the association P values of the HPGDB variants were significantly lower compared with those of random controls. Among the 155 replicated variants, 21 had been included in the HPGDB because of their association with analgesia-related and 13 with nociception-related phenotypes, confirming analgesia and nociception as pathways of vulnerability for pain phenotypes. Furthermore, many genetic variants were associated with multiple pain phenotypes, and the strength of their association correlated between many pairs of phenotypes. These genetic variants explained a considerable amount of the variance between different pairs of pain phenotypes, indicating a shared genetic basis among pain phenotypes. In addition, we found that HPGDB variants show many pleiotropic associations, indicating that genetic pathophysiological mechanisms are also shared among painful and nonpainful conditions. Finally, we demonstrated that the HPGDB data set is significantly enriched for functional variants that modify gene expression, are deleterious, and colocalize with open chromatin regions. As such, the HPGDB provides a validated data set that represents a valuable resource for researchers in the human pain field.