Disparities in Opioid Overdose Death Trends by Race/Ethnicity, 2018-2019, From the HEALing Communities Study.

Objectives. To examine trends in opioid overdose deaths by race/ethnicity from 2018 to 2019 across 67 HEALing Communities Study (HCS) communities in Kentucky, New York, Massachusetts, and Ohio. Methods. We used state death certificate records to calculate opioid overdose death rates per 100 000 adult residents of the 67 HCS communities for 2018 and 2019. We used Poisson regression to calculate the ratio of 2019 to 2018 rates. We compared changes by race/ethnicity by calculating a ratio of rate ratios (RRR) for each racial/ethnic group compared with non-Hispanic White individuals. Results. Opioid overdose death rates were 38.3 and 39.5 per 100 000 for 2018 and 2019, respectively, without a significant change from 2018 to 2019 (rate ratio = 1.03; 95% confidence interval [CI] = 0.98, 1.08). We estimated a 40% increase in opioid overdose death rate for non-Hispanic Black individuals (RRR = 1.40; 95% CI = 1.22, 1.62) relative to non-Hispanic White individuals but no change among other race/ethnicities. Conclusions. Overall opioid overdose death rates have leveled off but have increased among non-Hispanic Black individuals. Public Health Implications. An antiracist public health approach is needed to address the crisis of opioid-related harms. (Am J Public Health. 2021;111(10):1851-1854. https://doi.org/10.2105/AJPH.2021.306431).

Impact of the Communities That HEAL Intervention on Buprenorphine-Waivered Practitioners and Buprenorphine Prescribing: A Prespecified Secondary Analysis of the HCS Randomized Clinical Trial.

Importance: Buprenorphine significantly reduces opioid-related overdose mortality. From 2002 to 2022, the Drug Addiction Treatment Act of 2000 (DATA 2000) required qualified practitioners to receive a waiver from the Drug Enforcement Agency to prescribe buprenorphine for treatment of opioid use disorder. During this period, waiver uptake among practitioners was modest; subsequent changes need to be examined. Objective: To determine whether the Communities That HEAL (CTH) intervention increased the rate of practitioners with DATA 2000 waivers and buprenorphine prescribing. Design, Setting, and Participants: This prespecified secondary analysis of the HEALing Communities Study, a multisite, 2-arm, parallel, community-level, cluster randomized, open, wait-list-controlled comparison clinical trial was designed to assess the effectiveness of the CTH intervention and was conducted between January 1, 2020, to December 31, 2023, in 67 communities in Kentucky, Massachusetts, New York, and Ohio, accounting for approximately 8.2 million adults. The participants in this trial were communities consisting of counties (n = 48) and municipalities (n = 19). Trial arm randomization was conducted using a covariate constrained randomization procedure stratified by state. Each state was balanced by community characteristics including urban/rural classification, fatal opioid overdose rate, and community population. Thirty-four communities were randomized to the intervention and 33 to wait-list control arms. Data analysis was conducted between March 20 and September 29, 2023, with a focus on the comparison period from July 1, 2021, to June 30, 2022. Intervention: Waiver trainings and other educational trainings were offered or supported by the HEALing Communities Study research sites in each state to help build practitioner capacity. Main Outcomes and Measures: The rate of practitioners with a DATA 2000 waiver (overall, and stratified by 30-, 100-, and 275-patient limits) per 100 000 adult residents aged 18 years or older during July 1, 2021, to June 30, 2022, were compared between the intervention and wait-list control communities. The rate of buprenorphine prescribing among those waivered practitioners was also compared between the intervention and wait-list control communities. Intention-to-treat and per-protocol analyses were performed. Results: A total of 8 166 963 individuals aged 18 years or older were residents of the 67 communities studied. There was no evidence of an effect of the CTH intervention on the adjusted rate of practitioners with a DATA 2000 waiver (adjusted relative rate [ARR], 1.04; 95% CI, 0.94-1.14) or the adjusted rate of practitioners with a DATA 2000 waiver who actively prescribed buprenorphine (ARR, 0.97; 95% CI, 0.86-1.10). Conclusions and Relevance: In this randomized clinical trial, the CTH intervention was not associated with increases in the rate of practitioners with a DATA 2000 waiver or buprenorphine prescribing among those waivered practitioners. Supporting practitioners to prescribe buprenorphine remains a critical yet challenging step in the continuum of care to treat opioid use disorder. Trial Registration: ClinicalTrials.gov Identifier: NCT04111939.

Mortality in the agricultural health study, 1993-2007.

Comparing agricultural cohorts with the general population is challenging because the general healthiness of farmers may mask potential adverse health effects of farming. Using data from the Agricultural Health Study, a cohort of 89,656 pesticide applicators and their spouses (N = 89, 656) in North Carolina and Iowa, the authors computed standardized mortality ratios (SMRs) comparing deaths from time of the enrollment (1993-1997) through 2007 to state-specific rates. To compensate for the cohort's overall healthiness, relative SMRs were estimated by calculating the SMR for each cause relative to the SMR for all other causes. In 1,198,129 person-years of follow-up, 6,419 deaths were observed. The all-cause mortality rate was less than expected (SMR(applicators) = 0.54, 95% confidence interval (CI): 0.52, 0.55; SMR(spouses) = 0.52, 95% CI: 0.50, 0.55). SMRs for all cancers, heart disease, and diabetes were significantly below 1.0. In contrast, applicators experienced elevated numbers of machine-related deaths (SMR = 4.15, 95% CI: 3.18, 5.31), motor vehicle nontraffic accidents (SMR = 2.80, 95% CI: 1.81, 4.14), and collisions with objects (SMR = 2.12, 95% CI: 1.25, 3.34). In the relative SMR analysis for applicators, the relative mortality ratio was elevated for lymphohematopoietic cancers, melanoma, and digestive system, prostate, kidney, and brain cancers. Among spouses, relative SMRs exceeded 1.0 for lymphohematopoietic cancers and malignancies of the digestive system, brain, breast, and ovary. Unintentional fatal injuries remain an important risk for farmers; mortality ratios from several cancers were elevated relative to other causes.

Impact of pesticide exposure misclassification on estimates of relative risks in the Agricultural Health Study.

BACKGROUND: The Agricultural Health Study (AHS) is a prospective study of licensed pesticide applicators and their spouses in Iowa and North Carolina. We evaluate the impact of occupational pesticide exposure misclassification on relative risks using data from the cohort and the AHS Pesticide Exposure Study (AHS/PES). METHODS: We assessed the impact of exposure misclassification on relative risks using the range of correlation coefficients observed between measured post-application urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D) and a chlorpyrifos metabolite and exposure estimates based on an algorithm from 83 AHS pesticide applications. RESULTS: Correlations between urinary levels of 2,4-D and a chlorpyrifos metabolite and algorithm estimated intensity scores were about 0.4 for 2,4-D (n=64), 0.8 for liquid chlorpyrifos (n=4) and 0.6 for granular chlorpyrifos (n=12). Correlations of urinary levels with kilograms of active ingredient used, duration of application, or number of acres treated were lower and ranged from -0.36 to 0.19. These findings indicate that a priori expert-derived algorithm scores were more closely related to measured urinary levels than individual exposure determinants evaluated here. Estimates of potential bias in relative risks based on the correlations from the AHS/PES indicate that non-differential misclassification of exposure using the algorithm would bias estimates towards the null, but less than that from individual exposure determinants. CONCLUSIONS: Although correlations between algorithm scores and urinary levels were quite good (ie, correlations between 0.4 and 0.8), exposure misclassification would still bias relative risk estimates in the AHS towards the null and diminish study power.

Connecting and linking neurocognitive, digital phenotyping, physiologic, psychophysical, neuroimaging, genomic, & sensor data with survey data.

Combining survey data with alternative data sources (e.g., wearable technology, apps, physiological, ecological monitoring, genomic, neurocognitive assessments, brain imaging, and psychophysical data) to paint a complete biobehavioral picture of trauma patients comes with many complex system challenges and solutions. Starting in emergency departments and incorporating these diverse, broad, and separate data streams presents technical, operational, and logistical challenges but allows for a greater scientific understanding of the long-term effects of trauma. Our manuscript describes incorporating and prospectively linking these multi-dimensional big data elements into a clinical, observational study at US emergency departments with the goal to understand, prevent, and predict adverse posttraumatic neuropsychiatric sequelae (APNS) that affects over 40 million Americans annually. We outline key data-driven system challenges and solutions and investigate eligibility considerations, compliance, and response rate outcomes incorporating these diverse "big data" measures using integrated data-driven cross-discipline system architecture.

Operationalizing and selecting outcome measures for the HEALing Communities Study.

BACKGROUND: The Helping to End Addiction Long-termSM (HEALing) Communities Study (HCS) is a multisite, parallel-group, cluster randomized wait-list controlled trial evaluating the impact of the Communities That HEAL intervention to reduce opioid overdose deaths and associated adverse outcomes. This paper presents the approach used to define and align administrative data across the four research sites to measure key study outcomes. METHODS: Priority was given to using administrative data and established data collection infrastructure to ensure reliable, timely, and sustainable measures and to harmonize study outcomes across the HCS sites. RESULTS: The research teams established multiple data use agreements and developed technical specifications for more than 80 study measures. The primary outcome, number of opioid overdose deaths, will be measured from death certificate data. Three secondary outcome measures will support hypothesis testing for specific evidence-based practices known to decrease opioid overdose deaths: (1) number of naloxone units distributed in HCS communities; (2) number of unique HCS residents receiving Food and Drug Administration-approved buprenorphine products for treatment of opioid use disorder; and (3) number of HCS residents with new incidents of high-risk opioid prescribing. CONCLUSIONS: The HCS has already made an impact on existing data capacity in the four states. In addition to providing data needed to measure study outcomes, the HCS will provide methodology and tools to facilitate data-driven responses to the opioid epidemic, and establish a central repository for community-level longitudinal data to help researchers and public health practitioners study and understand different aspects of the Communities That HEAL framework.

Cancer incidence among paraquat exposed applicators in the agricultural health study: prospective cohort study.

Paraquat (1,1'-dimethyl-4, 4'-bipyridinium dichloride) is a nonselective herbicide that is extremely toxic after acute exposure. It was once widely used in North America and is still used in some countries, including the United States. Although there is little firm evidence that paraquat is a carcinogen, previous studies have suggested a potential relationship with some cancers. This prospective cohort study was performed to evaluate the association between lifetime paraquat exposure and cancer incidence among licensed pesticide applicators with 9.1 years of median follow-up. The lifetime ever-use of paraquat was evaluated in 56,224 subjects at baseline and exposure-response relationship was evaluated in 24,667 subjects (44%) who provided detailed information on total life-time paraquat exposure in a second questionnaire. Among the total subjects, the risk for non-Hodgkin's lymphoma (NHL) in the exposed group was marginally elevated (Relative risk [RR], 1.47; 95% confidence interval [CI], 0.97-2.23) compared to the non-exposed group. However, among the 24,667 applicators who supplied total life-time exposure days, the highest tertile of lifetime exposure-days (LE) and intensity-weighted lifetime exposure-days (IWLE) was not significantly associated with NHL risk (RR, 1.57; 95%CI, 0.57-4.23 for LE; RR, 1.42; 95%CI, 0.40-4.71 for IWLE, respectively) and there was no significant exposure-response trend (p-trend > 0.1). There was some suggestion of a possible link between paraquat exposure and NHL risk in humans, but the inconsistency in exposure level trend suggests that this could be a chance finding.

Cancer incidence among pesticide applicators exposed to trifluralin in the Agricultural Health Study.

Trifluralin, 2,6-dinitro-N,N-dipropyl-4-trifluoromethylaniline, is a 2,6-dinitro herbicide widely used to control annual grasses and broadleaf weeds in agricultural settings. The association between trifluralin use and common cancer incidence was evaluated among 50,127 private and commercial pesticide applicators in the Agricultural Health Study (AHS), a prospective cohort study of licensed pesticide applicators and their spouses in Iowa and North Carolina. Poisson regression was used to examine internal dose-response relationships, while controlling for important lifestyle factors and other agricultural exposures. Two metrics of exposure (lifetime days and intensity-weighted lifetime days) were used in exposure-response analyses with non-exposed applicators, as well as applicators in the lowest tertile of exposure, as reference groups. Incident cancers were identified through state tumor registries from enrollment in 1993 through 2002. Trifluralin exposure was not associated with cancer incidence overall among 51% of private and commercial applicators (n=25,712) who had used trifluralin. However, there was an excess of colon cancer in the exposure category of higher half of highest tertile (rate ratios (RR) of 1.76 (95% CI=1.05-2.95) using the non-exposed as a referent and 1.93 (95% CI=1.08-3.45) using those with the lowest tertile of exposure as the referent). There was also a non-significantly elevated risk for kidney cancer and bladder cancer in the highest exposure group, although only the kidney cancer finding was consistent across exposure metrics. Although there was a possible link between trifluralin exposure and colon cancer, small numbers and inconsistencies in dose-response and subgroup analyses indicate that this may be a chance finding.

Epiregulin and EGFR interactions are involved in pain processing.

The EGFR belongs to the well-studied ErbB family of receptor tyrosine kinases. EGFR is activated by numerous endogenous ligands that promote cellular growth, proliferation, and tissue regeneration. In the present study, we have demonstrated a role for EGFR and its natural ligand, epiregulin (EREG), in pain processing. We show that inhibition of EGFR with clinically available compounds strongly reduced nocifensive behavior in mouse models of inflammatory and chronic pain. EREG-mediated activation of EGFR enhanced nociception through a mechanism involving the PI3K/AKT/mTOR pathway and matrix metalloproteinase-9. Moreover, EREG application potentiated capsaicin-induced calcium influx in a subset of sensory neurons. Both the EGFR and EREG genes displayed a genetic association with the development of chronic pain in several clinical cohorts of temporomandibular disorder. Thus, EGFR and EREG may be suitable therapeutic targets for persistent pain conditions.

Mortality among participants in the agricultural health study.

PURPOSE: This analysis of the Agricultural Health Study cohort assesses the mortality experience of licensed pesticide applicators and their spouses. METHODS: This report is based on 52,393 private applicators (who are mostly farmers) and 32,345 spouses of farmers in Iowa and North Carolina. At enrollment, each pesticide applicator completed a 21-page enrollment questionnaire. Mortality assessment from enrollment (1994-1997) through 2000 provided an average follow-up of about 5.3 years, 447,154 person-years, and 2055 deaths. RESULTS: Compared with the general population in the two states, the cohort experienced a very low mortality rate. Standardized mortality ratios (SMRs) for total mortality, cardiovascular disease, diabetes, COPD, total cancer, and cancers of the esophagus, stomach, and lung were 0.6 or lower for both farmers and spouses. These deficits varied little by farm size, type of crops or livestock on the farm, years of handling pesticides, holding a non-farm job, or length of follow up. SMRs among ever smokers were not as low as among never smokers, but were still less than 1.0 for all smoking-related causes of death. No statistically significant excesses occurred, but slightly elevated SMRs, or those near 1.0, were noted for diseases that have been associated with farming in previous studies. CONCLUSIONS: Several factors may contribute to the low mortality observed in this population, including the healthy worker effect typically seen in cohorts of working populations (which may decline in future years), a short follow-up interval, and a healthier lifestyle manifested through lower cigarette use and an occupation that has traditionally required high levels of physical activity.

Cancer incidence in the agricultural health study.

OBJECTIVES: This large, prospective cohort study of private applicators, commercial applicators, and spouses of farmer applicators was undertaken to ascertain the etiology of cancers elevated in agriculture. METHODS: The participants were matched to cancer registry files in Iowa and North Carolina. Incident cases were identified from enrollment through 31 December 2002. Standardized incidence ratios (SIR) were used to compare the cancer incidence of the participants with that of the total population in the two states. RESULTS: The overall cancer incidence among farmers [SIR 0.88, 95% confidence interval (95% CI) 0.84-0.91] and their spouses (SIR 0.84, 95% CI 0.80-0.90) were significantly lower than expected, particularly for respiratory and urinary cancers. Commercial pesticide applicators had an overall cancer incidence comparable with the expected (SIR 1.01, 95% CI 0.84-1.20). Smoking prevalence was significantly lower than the national average. Prostate cancer was elevated among private applicators (SIR 1.24, 95% CI 1.18-1.33) and commercial applicators (SIR 1.37, 0.98-1.86). Excess ovarian cancer was observed for female applicators (SIR 2.97, 95% CI 1.28-5.85), but not for female spouses (SIR 0.55, 95% CI 0.38-0.78). Female spouses had a significant excess of melanoma (SIR 1.64, 95% CI 1.24-2.09), which was not observed among pesticide applicators. CONCLUSIONS: Low overall cancer incidence rates seem to be a result of low overall smoking prevalence and other lifestyle factors, while excess cancer of the prostate and ovaries among applicators may be occupationally related. The excess risk of melanoma observed among spouses was unexpected.

COMT gene locus: new functional variants.

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.

Factors associated with refusal to provide a buccal cell sample in the Agricultural Health Study.

Epidemiological studies are increasingly collecting buccal cells and other sources of DNA for genetic analysis. However, high refusal rates raise concerns about possible selection bias. This study examines the subject characteristics associated with refusal or failure to provide a buccal cell sample. Subjects were male farmers in the Agricultural Health Study, which is being conducted in Iowa and North Carolina. As part of a 5-year follow-up, cohort members were contacted by telephone and asked to participate in a telephone interview and to consent to providing a buccal cell sample using a kit that was mailed to them. Demographic, lifestyle, disease, and occupational characteristics were compared between consenters who returned a sample ("compliers"), nonconsenters ("refusers"), and consenters who failed to return a sample ("noncompliers"). Compliers (n = 8794), refusers (n = 3178), and noncompliers (n = 3008) were quite similar, although compliers tended to be slightly older. Although some significant differences between these groups were observed, the magnitude of these differences was generally small, usually no more than a few percentage points. In conclusion, this study found little difference between male farmers who agreed to provide buccal cell samples versus those who either refused to provide a sample or who agreed but failed to return the sample. Observed differences were typically small and would be unlikely to compromise etiologic associations identified in such a prospective study. In short, there appears to be little selection bias in the Agricultural Health Study buccal cell collection process, further supporting the use of such mailed collection kits in epidemiological research.

Cancer risk and parental pesticide application in children of Agricultural Health Study participants.

Parental exposure to pesticides may contribute to childhood cancer risk. Through the Agricultural Health Study, a prospective study of pesticide applicators in Iowa and North Carolina, we examined childhood cancer risk and associations with parental pesticide application. Identifying information for 17,357 children of Iowa pesticide applicators was provided by parents via questionnaires (1993-1997) and matched against the Iowa Cancer Registry. Fifty incident childhood cancers were identified (1975-1998). Risk of all childhood cancers combined was increased [standardized incidence ratio (SIR) = 1.36; 95% confidence interval (CI), 1.03-1.79]. Risk of all lymphomas combined was also increased (SIR = 2.18; 95% CI, 1.13-4.19), as was risk of Hodgkin's lymphoma (SIR = 2.56; 95% CI, 1.06-6.14). We used logistic regression to explore associations between self-reported parental pesticide application practices and childhood cancer risk. No association was detected between frequency of parental pesticide application and childhood cancer risk. An increased risk of cancer was detected among children whose fathers did not use chemically resistant gloves [odds ratio (OR) = 1.98; 95% CI, 1.05-3.76] compared with children whose fathers used gloves. Of 16 specific pesticides used by fathers prenatally, ORs were increased for aldrin (OR = 2.66), dichlorvos (OR = 2.06), and ethyl dipropylthiocarbamate (OR = 1.91). However, these results were based on small numbers and not supported by prior biologic evidence. Identification of excess lymphoma risk suggests that farm exposures including pesticides may play a role in the etiology of childhood lymphoma.

Multivariable modeling of phenotypic risk factors for first-onset TMD: the OPPERA prospective cohort study.

UNLABELLED: Incidence of temporomandibular disorder (TMD) was predicted with multivariable models that used putative risk factors collected from initially TMD-free individuals in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study. The 202 baseline risk factors included sociodemographic and clinical characteristics, measures of general health status, experimental pain sensitivity, autonomic function, and psychological distress. Study participants (n = 2,737) were then followed prospectively for a median of 2.8 years to ascertain cases of first-onset TMD. Lasso regression and random forest models were used to predict incidence of first-onset TMD using all of the aforementioned measures. Variable importance scores identified the most important risk factors, and their relationship with TMD incidence was illustrated graphically using partial dependence plots. Two of the most important risk factors for elevated TMD incidence were greater numbers of comorbid pain conditions and greater extent of nonspecific orofacial symptoms. Other important baseline risk factors were preexisting bodily pain, heightened somatic awareness, and greater extent of pain in response to examiners' palpation of the head, neck, and body. Several demographic variables persisted as risk factors even after adjusting for other OPPERA variables, suggesting that environmental variables not measured in OPPERA may also contribute to first-onset TMD. PERSPECTIVE: Multivariable methods were used to identify the most important predictors of first-onset TMD in the OPPERA study. Important variables included comorbid pain conditions, preexisting pain, and somatic awareness. Demographic characteristics, which probably reflect environmental variables not measured in OPPERA, also appear to play an important role in the etiology of TMD.

Signs and symptoms of first-onset TMD and sociodemographic predictors of its development: the OPPERA prospective cohort study.

UNLABELLED: Although cross-sectional studies of temporomandibular disorder (TMD) often report elevated prevalence in young women, they do not address the risk of its development. Here we evaluate sociodemographic predictors of TMD incidence in a community-based prospective cohort study of U.S. adults. Symptoms and pain-related disability in TMD cases are also described. People aged 18 to 44 years with no history of TMD were enrolled at 4 study sites when they completed questionnaires about sociodemographic characteristics. During the median 2.8-year follow-up period, 2,737 participants completed quarterly screening questionnaires. Those reporting symptoms were examined clinically and 260 had first-onset TMD. Additional questionnaires asked about severity and impact of their symptoms. Univariate and multivariable Cox regression models quantified associations between sociodemographic characteristics and TMD incidence. First-onset TMD developed in 3.9% of participants per annum, typically producing mild to moderate levels of pain and disability in cases. TMD incidence was positively associated with age, whereas females had only slightly greater incidence than males. Compared to whites, Asians had lower TMD incidence whereas African Americans had greater incidence, although the latter was attenuated somewhat after adjusting for satisfaction with socioeconomic circumstances. PERSPECTIVE: In this study of 18- to 44-year-olds, TMD developed at a higher rate than reported previously for similar age groups. TMD incidence was positively associated with age but weakly associated with gender, thereby differing from demographic patterns of prevalence found in some cross-sectional studies. Experiences related to aging merit investigation as etiologic influences on development of TMD.

General health status and incidence of first-onset temporomandibular disorder: the OPPERA prospective cohort study.

UNLABELLED: Temporomandibular disorder (TMD) overlaps with other health conditions, but no study has examined which of these conditions increase the risk of developing first-onset TMD. The authors prospectively evaluated the relationship between health status at enrollment and subsequent incidence of TMD in 2,722 men and women. Participants aged 18 to 44 years had no history of TMD and were clinically free of TMD when enrolled in 2006 to 2008 at 4 U.S. study sites in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study. First-onset examiner-classified TMD developed in 260 people over a median 2.8 years of follow-up. Cox regression estimated the association between health conditions and TMD incidence while accounting for potential confounders. Incidence of first-onset TMD was 50% higher for people with low back pain (adjusted hazard ratio [AHR] = 1.50, 95% confidence limits [CLs]: 1.08, 2.10) and 75% higher for people with genital pain symptoms (AHR = 1.75, 95% CLs = 1.04, 2.93) than people without a history of these pain disorders. Digit ratio, a marker of intrauterine exposure to sex hormones, was significantly associated with TMD incidence. Other independent predictors of first-onset TMD were sleep disturbance and cigarette smoking. These findings reveal multiple influences of health status on incidence of first-onset TMD. PERSPECTIVE: This article examines health conditions that commonly overlap with TMD to determine which ones predict first-onset TMD. A history of low back pain and genital pain conditions at baseline were important predictors. Novel findings were that disrupted sleep and conditions in utero may increase incidence of first-onset TMD.

Pain sensitivity and autonomic factors associated with development of TMD: the OPPERA prospective cohort study.

UNLABELLED: Multiple studies report that individuals with chronic temporomandibular disorder (TMD) have enhanced sensitivity to experimental pain. Additionally, chronic TMD cases show altered autonomic function, including elevated heart rate and reduced heart rate variability. However, causal inferences regarding the association between TMD and pain sensitivity and autonomic function cannot be drawn from these cross-sectional observations. The prospective Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study examines whether measures of pain sensitivity or cardiac autonomic function provide predictive value in TMD incidence. A cohort of 2,737 initially TMD-free participants was followed for up to 5.2 years, during which time 260 developed first-onset TMD. Fourteen of 39 experimental pain measures produced significant hazard ratios, such that greater pain sensitivity was associated with greater TMD incidence. A single autonomic measure-heart rate at rest-was also associated significantly with greater TMD incidence. In contrast, using the same measures of pain sensitivity and cardiac autonomic function, we previously reported a larger group of variables that was significantly associated with chronic TMD in the OPPERA case-control study. Future studies should investigate whether premorbid pain sensitivity or autonomic function more specifically predicts risk of developing chronic TMD than first-onset TMD. PERSPECTIVE: Our previous case-control studies showed that associations with both pain sensitivity and cardiac autonomic function are profound in chronic TMD cases. Here we show that some measures of enhanced pain sensitivity contribute modestly to the risk of developing TMD whereas autonomic dysregulation appears to confer little or no risk for TMD incidence.

Preclinical episodes of orofacial pain symptoms and their association with health care behaviors in the OPPERA prospective cohort study.

The course of preclinical pain symptoms sheds light on the etiology and prognosis of chronic pain. We aimed to quantify rates of developing initial and recurrent symptoms of painful temporomandibular disorder (TMD) and to evaluate associations with health behaviors. In the OPPERA prospective cohort study, 2,719 individuals aged 18 to 44years with lifetime absence of TMD when enrolled completed 25,103 quarterly (3-monthly) questionnaires during a median 2.3-year follow-up period. Questionnaires documented TMD symptom episodes, headache, other body pain, health care attendance, and analgesic use, and. Kaplan-Meier methods for clustered data estimated symptom-free survival time. Multivariable models assessed demographic variation in TMD symptom rates and evaluated associations with health care and analgesic use. One-third of the study subjects developed TMD symptoms and for a quarter of symptomatic episodes, pain intensity was severe. Initial TMD symptoms developed at an annual rate of 18.8 episodes per 100 persons. The annual rate more than doubled for first-recurrence and doubled again for second or subsequent recurrence such that, 1year after first recurrence, 71% of study subjects experienced a second recurrence. The overall rate increased with age and was greater in African Americans and lower in Asians relative to those of white race/ethnicity. The probability of TMD symptoms was strongly associated with concurrent episodes of headache and body pain and with past episodes of TMD symptoms. Episodes of TMD symptoms, headache, and body pain were associated with increases of ∼10% in probability of analgesic use and health care attendance. Yet, even when TMD, headache, and body pain occurred concurrently, 27% of study subjects neither attended health care nor used analgesics.

Summary of findings from the OPPERA prospective cohort study of incidence of first-onset temporomandibular disorder: implications and future directions.

UNLABELLED: Papers in this issue investigate when and how putative risk factors influence development of first-onset, painful temporomandibular disorder (TMD). The results represent first findings from the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) prospective cohort study that monitored 2,737 men and women aged 18 to 44 years recruited at 4 U.S. study sites. During a median 2.8-year follow-up period, 260 participants developed TMD. The average incidence rate of 4% per annum was influenced by a broad range of phenotypic risk factors including sociodemographic characteristics, health status, clinical orofacial factors, psychological functioning, pain sensitivity, and cardiac autonomic responses. A novel method of multivariable analysis used random forest models to simultaneously evaluate contributions of all 202 phenotypic variables. Variables from the health status domain made the greatest contribution to TMD incidence, followed closely by psychological and clinical orofacial domains. However, only a few measures of pain sensitivity and autonomic function contributed to TMD incidence, and their effects were modest. Meanwhile, age and study site were independent predictors of TMD incidence, even after controlling for other phenotypes. Separate analysis of 358 genes that regulate pain found several novel genetic associations with intermediate phenotypes that, themselves, are risk factors for TMD, suggesting new avenues to investigate biological pathways contributing to TMD. PERSPECTIVE: Collectively, the papers in this issue demonstrate that TMD is a complex disorder with multiple causes consistent with a biopsychosocial model of illness. It is a misnomer and no longer appropriate to regard TMD solely as a localized orofacial pain condition.