Overlapping Chronic Pain Conditions: Implications for Diagnosis and Classification

AbstractThere is increasing recognition that many if not most common chronic pain conditions are heterogeneous with a high degree of overlap or coprevalence of other common pain conditions along with influences from biopsychosocial factors. At present, very little attention is given to the high degree of overlap of many common pain conditions when recruiting for clinical trials. As such, many if not most patients enrolled into clinical studies are not representative of most chronic pain patients. The failure to account for the heterogeneous and overlapping nature of most common pain conditions may result in treatment responses of small effect size when these treatments are administered to patients with chronic overlapping pain conditions (COPCs) represented in the general population. In this brief review we describe the concept of COPCs and the putative mechanisms underlying COPCs. Finally, we present a series of recommendations that will advance our understanding of COPCs.PerspectiveThis brief review describes the concept of COPCs. A mechanism-based heuristic model is presented and current knowledge and evidence for COPCs are presented. Finally, a set of recommendations is provided to advance our understanding of COPCs

Subjective Sleep Quality Deteriorates Before Development of Painful Temporomandibular Disorder

There is good evidence that poor sleep quality increases risk of painful temporomandibular disorder (TMD). However little is known about the course of sleep quality in the months preceding TMD onset, and whether the relationship is mediated by heightened sensitivity to pain. The Pittsburgh Sleep Quality Index was administered at enrollment into the OPPERA prospective cohort study. Thereafter the Sleep Quality Numeric Rating Scale was administered every three months to 2,453 participants. Sensitivity to experimental pressure pain and pinprick pain stimuli was measured at baseline and repeated during follow-up of incident TMD cases (n=220) and matched TMD-free controls (n=193). Subjective sleep quality deteriorated progressively, but only in those who subsequently developed TMD. A Cox proportional hazards model showed that risk of TMD was greater among participants whose sleep quality worsened during follow-up (adjusted hazard ratio=1.73, 95% confidence limits: 1.29, 2.32). This association was independent of baseline measures of sleep quality, psychological stress, somatic awareness, comorbid conditions, non-pain facial symptoms and demographics. Poor baseline sleep quality was not significantly associated with baseline pain sensitivity or with subsequent change in pain sensitivity. Furthermore the relationship between sleep quality and TMD incidence was not mediated via baseline pain sensitivity nor change in pain sensitivity

Identification of clusters of individuals relevant to temporomandibular disorders and other chronic pain conditions: the OPPERA study

The classification of most chronic pain disorders gives emphasis to anatomical location of the pain to distinguish one disorder from the other (eg, back pain vs temporomandibular disorder [TMD]) or to define subtypes (eg, TMD myalgia vs arthralgia). However, anatomical criteria overlook etiology, potentially hampering treatment decisions. This study identified clusters of individuals using a comprehensive array of biopsychosocial measures. Data were collected from a case–control study of 1031 chronic TMD cases and 3247 TMD-free controls. Three subgroups were identified using supervised cluster analysis (referred to as the adaptive, pain-sensitive, and global symptoms clusters). Compared with the adaptive cluster, participants in the pain-sensitive cluster showed heightened sensitivity to experimental pain, and participants in the global symptoms cluster showed both greater pain sensitivity and greater psychological distress. Cluster membership was strongly associated with chronic TMD: 91.5% of TMD cases belonged to the pain-sensitive and global symptoms clusters, whereas 41.2% of controls belonged to the adaptive cluster. Temporomandibular disorder cases in the pain-sensitive and global symptoms clusters also showed greater pain intensity, jaw functional limitation, and more comorbid pain conditions. Similar results were obtained when the same methodology was applied to a smaller case–control study consisting of 199 chronic TMD cases and 201 TMD-free controls. During a median 3-year follow-up period of TMD-free individuals, participants in the global symptoms cluster had greater risk of developing first-onset TMD (hazard ratio = 2.8) compared with participants in the other 2 clusters. Cross-cohort predictive modeling was used to demonstrate the reliability of the clusters

On wind-driven electrojets at magnetic cusps in the nightside ionosphere of Mars

Mars has a complex magnetic topology where crustal magnetic fields can interact with the solar wind magnetic field to form magnetic cusps. On the nightside, solar wind electron precipitation can produce enhanced ionization at cusps while closed field regions adjacent to cusps can be devoid of significant ionization. Using an electron transport model, we calculate the spatial structure of the nightside ionosphere of Mars using Mars Global Surveyor electron measurements as input. We find that localized regions of enhanced ionospheric density can occur at magnetic cusps adjacent to low density regions. Under this configuration, thermospheric winds can drive ionospheric electrojets. Collisional ions move in the direction of the neutral winds while magnetized electrons move perpendicular to the wind direction. This difference in motion drives currents and can lead to charge accumulation at the edges of regions of enhanced ionization. Polarization fields drive secondary currents which can reinforce the primary currents leading to electrojet formation. We estimate the magnitude of these electrojets and show that their magnetic perturbations can be detectable from both orbiting spacecraft and the surface. The magnitude of the electrojets can vary on diurnal and annual time scales as the strength and direction of the winds vary. These electrojets may lead to localized Joule heating, and closure of these currents may require field-aligned currents which may play a role in high altitude acceleration processes

Temporal change in headache and its contribution to the risk of developing first-onset temporomandibular disorder in the Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA) study

While cross-sectional studies have demonstrated an association between headache and temporomandibular disorder (TMD), whether headache can predict the onset of TMD is unknown. The aims of this study were to evaluate the contribution of headache to the risk of developing TMD and describe patterns of change in headache types over time. An initially TMD-free cohort of 2410 persons with low frequency of headache completed quarterly questionnaires assessing TMD and headache symptoms over a median 3.0-year follow-up period. First-onset TMD was confirmed by clinical examination in 199 participants. Baseline reports of migraine (hazard ratio [HR] = 1.67, 95% confidence interval [CI]: 1.06-2.62) or mixed headache types (HR = 4.11, 95% CI: 1.47-11.46), or headache frequency (HR = 2.13, 95% CI: 1.31-3.48) predicted increased risk of developing TMD. In addition, headache dynamics across the follow-up period before the TMD onset were evaluated in a nested case-control study where 248 incident TMD cases were matched to 191 TMD-free controls. Both headache prevalence and frequency increased across the observation period among those who developed TMD but not among controls. Patients with TMD were more likely to experience worsening in the headache type compared with that by controls, eg, prevalence of definite migraine among TMD cases increased 10-fold. Among all headache types experienced by patients with TMD before the TMD onset, migraine had the highest odds of progression relative to remission (odds ratio = 2.8, 95% CI: 1.6-4.8), whereas for controls this ratio was significant only for the tension-type headache (odds ratio = 2.1, 95% CI: 1.2-3.9). The important clinical implication of these findings is that adequate treatment of migraine may reduce the risk for developing TMD

Gender Differences in Acute and Chronic Pain in the Emergency Department: Results of the 2014 Academic Emergency Medicine Consensus Conference Pain Section

Pain is a leading public health problem in the United States, with an annual economic burden of more than $630 billion, and is one of the most common reasons that individuals seek emergency department (ED) care. There is a paucity of data regarding sex differences in the assessment and treatment of acute and chronic pain conditions in the ED. The Academic Emergency Medicine consensus conference convened in Dallas, Texas, in May 2014 to develop a research agenda to address this issue among others related to sex differences in the ED. Prior to the conference, experts and stakeholders from emergency medicine and the pain research field reviewed the current literature and identified eight candidate priority areas. At the conference, these eight areas were reviewed and all eight were ratified using a nominal group technique to build consensus. These priority areas were: 1) gender differences in the pharmacological and nonpharmacological interventions for pain, including differences in opioid tolerance, side effects, or misuse; 2) gender differences in pain severity perceptions, clinically meaningful differences in acute pain, and pain treatment preferences; 3) gender differences in pain outcomes of ED patients across the life span; 4) gender differences in the relationship between acute pain and acute psychological responses; 5) the influence of physician-patient gender differences and characteristics on the assessment and treatment of pain; 6) gender differences in the influence of acute stress and chronic stress on acute pain responses; 7) gender differences in biological mechanisms and molecular pathways mediating acute pain in ED populations; and 8) gender differences in biological mechanisms and molecular pathways mediating chronic pain development after trauma, stress, or acute illness exposure. These areas represent priority areas for future scientific inquiry, and gaining understanding in these will be essential to improving our understanding of sex and gender differences in the assessment and treatment of pain conditions in emergency care settings

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

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

Enhanced ionization of the Martian nightside ionosphere during solar energetic particle events

Electron densities in the Martian nightside ionosphere are more than 90% of time too low to be detected by the Mars Advanced Radar for Subsurface and Ionosphere Sounding radar sounder on board the Mars Express spacecraft. However, the relative number of ionograms with peak electron density high enough to be detected represents a good statistical proxy of the ionospheric density. We focus on solar energetic particle (SEP) events, and we analyze their effects on ionospheric formation. SEP time intervals were identified in situ using the background counts recorded by the ion sensor of the ASPERA-3 instrument on board Mars Express. We show that peak electron densities during the SEP events are large enough to be detected in more than 30% of measurements, and, moreover, the reflections of the sounding signal from the ground almost entirely disappear. Nightside electron densities during SEP events are thus substantially increased as compared to normal nightside conditions

Effect of comorbid migraine on propranolol efficacy for painful TMD in a randomized controlled trial

Introduction The migraine-preventive drug propranolol is efficacious in reducing pain from temporomandibular disorder, suggesting potential modifying or mediating effects of comorbid migraine. Methods In this randomized controlled trial, myofascial temporomandibular disorder patients were treated with propranolol or placebo for 9 weeks. The primary endpoint was change in a facial pain index derived from daily symptom diaries. Linear and logistic regression models tested for a migraine × treatment-group interaction in reducing facial pain index. Counterfactual models explored changes in headache impact and heart rate as mediators of propranolol's efficacy. Results Propranolol's efficacy in reducing facial pain index was greater among the 104 migraineurs than the 95 non-migraineurs: For example, for the binary ≥ 30% reduction in facial pain index, odds ratios were 3.3 (95% confidence limits: 1.4, 8.1) versus 1.3 (0.5, 3.2), respectively, although the interaction was statistically non-significant (p = 0.139). Cumulative response curves confirmed greater efficacy for migraineurs than non-migraineurs (differences in area under the curve 26% and 6%, respectively; p = 0.081). While 9% of the treatment effect was mediated by reduced headache impact, 46% was mediated by reduced heart rate. Conclusions Propranolol was more efficacious in reducing temporomandibular disorder pain among migraineurs than non-migraineurs, with more of the effect mediated by reduced heart rate than by reduced headache impact. Study identification and registration SOPPRANO; NCT02437383; https://clinicaltrials.gov/ct2/show/NCT0243738

Characteristics Associated With High-Impact Pain in People With Temporomandibular Disorder: A Cross-Sectional Study

High-impact (disabling) pain diminishes the quality of life and increases health care costs. The purpose of this study was to identify the variables that distinguish between high- and low-impact pain among individuals with painful temporomandibular disorder (TMD). Community-dwelling adults (N = 846) with chronic TMD completed standardized questionnaires that assessed the following: 1) sociodemographic characteristics, 2) psychological distress, 3) clinical pain, and 4) experimental pain. We used high-impact pain, classified using the Graded Chronic Pain Scale, as the dependent variable in logistic regression modeling to evaluate the contribution of variables from each domain. Cross-validated area under the receiver operating characteristic curve (AUC) quantified model discrimination. One-third of the participants had high-impact pain. Sociodemographic variables discriminated weakly between low- and high-impact pain (AUC =.61, 95% confidence interval [CI] = 0.57, 0.65), with the exception of race. An 18-variable model encompassing all 4 domains had good discrimination (AUC = 0.79, 95% CI = 0.75, 0.82), as did a simplified model (sociodemographic variables plus catastrophizing, jaw limitation, and number of painful body sites) (AUC = 0.79, 95% CI = 0.76, 0.82). Duration of pain, sex, and experimental pain testing results were not associated. The characteristics that discriminated most effectively between people with low- and high-impact TMD pain included clinical pain features and the ability to cope with pain. Perspective: This article presents the results of a multivariable model designed to discriminate between people with high- and low-impact pain in a community-based sample of people with painful chronic TMD. The findings emphasize the importance of catastrophizing, jaw limitation, and painful body sites associated with pain-related impact