Opioid Receptor Mu 1 Gene (OPRM1) A118G Polymorphism and Emotional Modulation of Pain.

Purpose: The A118G polymorphism in the opioid receptor mu 1 gene (OPRM1) is associated with decreased opioid receptor availability, altered emotion, and increased pain. Given that emotions modulate pain (positive emotions inhibit pain, negative emotions enhance pain), we predicted that G allele carriers would experience impaired emotional modulation of pain compared to non-G allele carriers. Patients and Methods: Emotional pictures (ie, erotica, neutral, attack) from the International Affective Picture System were used by permission from the authors to experimentally manipulate emotions in 64 adult participants while painful electrocutaneous stimulations were delivered in a cross-sectional study. Ratings of arousal and valence/pleasure were made in response to pictures, and pain ratings and a physiological measure of spinal nociception (ie, nociceptive flexion reflex, NFR) were collected in response to painful stimulations. Secondary analyses were conducted to examine the relationship between the A118G polymorphism and emotional modulation of pain/NFR. Results: Exposure to emotional pictures elicited similar changes in valence, but G-carriers rated erotic pictures as more arousing. In non-carriers, pain was facilitated by attack pictures and pain and NFR were inhibited by erotic pictures relative to neutral pictures. Among G-carriers, pain was facilitated by negative emotional pictures but there was no pain or NFR inhibition by positive emotional pictures. Conclusion: The altered response to pleasant stimuli further supports the role of opioids in appetitive behavior and describes how the A118G polymorphism may prevent carriers from inhibiting pain during pleasure.

Optimizing Temporal Summation of Heat Pain Using a Constant Contact Heat Stimulator.

Purpose: Temporal summation (TS) of pain occurs when pain increases over repeated presentations of identical noxious stimuli. TS paradigms can model central sensitization, a state of hyperexcitability in nociceptive pathways that promotes chronic pain onset and maintenance. Many experimenters use painful heat stimuli to measure TS (TS-heat); yet, TS-heat research faces unresolved challenges, including difficulty evoking summation in up to 30-50% of participants. Moreover, substantial variability exists between laboratories regarding the methods for evoking and calculating TS-heat. Patients and Methods: To address these limitations, this study sought to identify optimal parameters for evoking TS-heat in healthy participants with a commercially available constant contact heat stimulator, the Medoc TSA-II. Working within constraints of the TSA-II, stimulus trains with varying parameters (eg, stimulus frequency, baseline temp, peak temp, peak duration, testing site) were tested in a sample of 32 healthy, chronic pain-free participants to determine which combination best evoked TS-heat. To determine whether TS scoring method altered results, TS-heat was scored using three common methods. Results: Across all methods, only two trains successfully evoked group-level TS-heat. These trains shared the following parameters: site (palmar hand), baseline and peak temperatures (44°C and 50°C, respectively), and peak duration (0.5 s). Both produced summation that peaked at moderate pain (~50 out of 100 rating). Conclusion: Future TS-heat investigations using constant contact thermodes and fixed protocols may benefit from adopting stimulus parameters that include testing on the palmar hand, using 44°C baseline and 50°C peak temperatures, at ≥0.33 Hz stimulus frequency, and peak pulse durations of at least 0.5 seconds.

Sleep Problems Mediate the Relationship Between Psychosocial Stress and Pain Facilitation in Native Americans: A Structural Equation Modeling Analysis from the Oklahoma Study of Native American Pain Risk.

BACKGROUND: Native Americans (NAs) are more likely to experience chronic pain than non-Hispanic Whites (NHWs); however, the proximate causes predisposing NAs to chronic pain remain elusive. Likely due to centuries of adversity, discrimination, and marginalization, NAs report greater psychological stress than NHWs, which may place them at risk for sleep problems, a well-established risk factor for chronic pain onset. PURPOSE: This study examined the effects of psychological stress and sleep problems on subjective and physiological measures of pain processing in NAs and NHWs. METHODS: Structural equation modeling was used to determine whether ethnicity (NA or NHW) was associated with psychological stress or sleep problems and whether these variables were related to conditioned pain modulation of pain perception (CPM-pain) and the nociceptive flexion reflex (CPM-NFR), temporal summation of pain (TS-pain) and NFR (TS-NFR), and pain tolerance in a sample of 302 (153 NAs) pain-free participants. RESULTS: NAs experienced more psychological stress (Estimate = 0.027, p = .009) and sleep problems (Estimate = 1.375, p = .015) than NHWs. When controlling for age, sex, physical activity, BMI, and general health, NA ethnicity was no longer related to greater sleep problems. Psychological stress was also related to sleep problems (Estimate = 30.173, p = <.001) and psychological stress promoted sleep problems in NAs (indirect effect = 0.802, p = .014). In turn, sleep problems were associated with greater TS-pain (Estimate = 0.714, p = .004), but not other pain measures. CONCLUSIONS: Sleep problems may contribute to chronic pain risk by facilitating pain perception without affecting facilitation of spinal neurons or endogenous inhibition of nociceptive processes. Since psychological stress promoted pain facilitation via enhanced sleep problems, efforts to reduce psychological stress and sleep problems among NAs may improve health outcomes.

The Relationship Between Experienced Discrimination and Pronociceptive Processes in Native Americans: Results From the Oklahoma Study of Native American Pain Risk.

Native Americans (NAs) have higher pain rates than the general U.S. population. It has been found that increased central sensitization and reduced pain inhibition are pronociceptive processes that increase pain risk; yet, little attention has focused on the influence of psychosocial factors. Discrimination is a psychosocial factor associated with increased pain in other minoritized groups; however, it is unclear whether it also promotes pain in NAs. This study analyzed data from 269 healthy, pain-free participants (N = 134 non-Hispanic whites [NHWs], N = 135 NAs) from the Oklahoma Study of Native American Pain Risk. Experienced discrimination was measured using the Everyday Discrimination Scale (EDS). Nociceptive processes were measured via static measures of spinal sensitivity (nociceptive flexion reflex [NFR] threshold, 3-stimulation NFR threshold), temporal summation of pain (TS-Pain) and nociceptive flexion reflex (TS-NFR), and conditioned pain modulation of pain (CPM-Pain) and NFR (CPM-NFR). Results demonstrated that greater discrimination was associated with enhanced TS-NFR and impaired CPM-NFR but not static measures of spinal sensitivity or measures of pain modulation (TS-Pain, CPM-Pain). Although the effects of discrimination on outcomes were similar in both groups (not moderated by ethnicity), NAs experienced higher levels of discrimination and therefore discrimination mediated a relationship between ethnicity and impaired CPM-NFR. This indicates experienced discrimination may promote a pain risk phenotype in NAs that involves spinal sensitization resulting from impaired inhibition of spinal nociception without sensitization of pain experience. PERSPECTIVE: This study found that discrimination was associated with spinal sensitization and impaired descending inhibition of spinal nociception. These findings bolster our understanding of how social stressors experienced disproportionately by minoritized groups can contribute to pain outcomes.

The role of self-evaluated pain sensitivity as a mediator of objectively measured pain tolerance in Native Americans: findings from the Oklahoma Study of Native American Pain Risk (OK-SNAP).

Native Americans (NAs) are at increased risk for chronic pain. One mechanism contributing to this pain disparity could be personal pain beliefs, which may influence actual pain sensitivity. Thus, we examined whether self-evaluated pain sensitivity (SEPS) mediates the relationship between ethnicity [NAs vs. non-Hispanic Whites (NHWs)] and objectively-measured pain tolerance, and whether catastrophic thinking and pain-related anxiety influence these pain beliefs. 232 healthy, pain-free NAs and NHWs completed questionnaires measuring SEPS, catastrophizing, and anxiety. Objective pain tolerance was also assessed. Results suggested: (1) NAs reported higher levels of SEPS, catastrophizing, and anxiety, (2) catastrophizing may have enhanced anxiety and both catastrophizing and anxiety were associated with higher SEPS, and (3) anxiety and SEPS were associated with lower pain tolerance. A significant bootstrapped mediation analysis suggested NAs experienced higher pain-related anxiety, which may have promoted higher SEPS, that in turn reduced pain tolerance. Longitudinal research is needed to confirm this.

Psychosocial and cardiometabolic predictors of chronic pain onset in Native Americans: serial mediation analyses of 2-year prospective data from the Oklahoma Study of Native American Pain Risk.

ABSTRACT: Chronic pain results in considerable suffering, as well as significant economic and societal costs. Previous evidence suggests that Native Americans (NAs) have higher rates of chronic pain than other U.S. racial or ethnic groups, but the mechanisms contributing to this pain disparity are poorly understood. The Oklahoma Study of Native American Pain Risk was developed to address this issue and recruited healthy, pain-free NAs and non-Hispanic Whites. Cross-sectional analyses identified several measures of adversity (eg, trauma and discrimination), cognitive-affective factors (perceived stress and pain-related anxiety/catastrophizing), and cardiometabolic factors (eg, body mass index, blood pressure, and heart rate variability) that were associated with pronociceptive processes (eg, central sensitization, descending inhibition, and hyperalgesia). Every 6-months after enrollment, eligible participants (N = 277) were recontacted and assessed for the onset of chronic pain. This study examines predictors of chronic pain onset in the 222 participants (80%) who responded over the first 2 years. The results show that NAs developed chronic pain at a higher rate than non-Hispanic Whites (OR = 2.902, P < 0.05), even after controlling for age, sex, income, and education. Moreover, serial mediation models identified several potential pathways to chronic pain onset within the NA group. These paths included perceived discrimination, psychological stress, pain-related anxiety, a composite measure of cardiometabolic risk, and impaired descending inhibition of spinal nociception (assessed from conditioned pain modulation of the nociceptive flexion reflex). These results provide the first prospective evidence for a pain disparity in NAs that seems to be promoted by psychosocial, cardiometabolic, and pronociceptive mechanisms.

Sleep Buffers the Effect of Discrimination on Cardiometabolic Allostatic Load in Native Americans: Results from the Oklahoma Study of Native American Pain Risk.

OBJECTIVES: Compared to other racial/ethnic groups, Native Americans (NAs) are more likely to develop health conditions associated with allostatic load (stress-related wear-and-tear). Psychosocial factors (i.e., adverse life events, discrimination, psychological distress) often promote stress and may help explain greater allostatic load in NAs. Moreover, previous research suggests sleep may either mediate or moderate the effects of some psychosocial stressors, like discrimination, on allostatic load. The current study investigated the relationship between adverse life events, discrimination, psychological stress, sleep, and cardiometabolic load. METHODS: Using a sample of 302 healthy, chronic pain-free NAs and non-Hispanic White (NHW) participants, bootstrapped mediation analyses were conducted to determine whether the relationship between NA race/ethnicity and cardiometabolic allostatic load (composite score of body mass index, mean arterial pressure, and heart rate variability) was mediated by psychosocial stressors. Models also assessed whether sleep disturbance served as an additional mediator or a moderator to the effects. RESULTS: Consistent with prior research, we found that NAs experienced greater discrimination, adverse life events (potentially traumatic events), and cardiometabolic allostatic load than NHWs. Further, discrimination was associated with increased psychological stress for NAs, but this did not explain why NAs experience higher cardiometabolic allostatic load. A moderating effect of sleep on discrimination was found, such that discrimination partially contributed to the relationship between NA race/ethnicity and cardiometabolic allostatic load, but only for participants reporting greater sleep disturbance. Implications These findings highlight that good sleep can buffer the effect of psychosocial stress on cardiometabolic allostatic load in Native Americans.

The Association Between Adverse Life Events, Psychological Stress, and Pain-Promoting Affect and Cognitions in Native Americans: Results from the Oklahoma Study of Native American Pain Risk.

Native Americans (NAs) experience higher rates of chronic pain. To examine the mechanisms for this pain inequity, we have previously shown that NAs report higher levels of pain-related anxiety and pain catastrophizing, which are in turn related to pronociceptive (pain-promoting) processes. But, it is currently unclear why NAs would report greater pain-related anxiety and catastrophizing. Given that NAs are also more likely to experience adverse life events (ALEs) and associated psychological distress, it was hypothesized that higher anxiety/catastrophizing in NAs would be partially explained by higher rates of ALEs and psychological distress. Structural equation modeling was used to analyze these pathways (NA ethnicity ➔ ALEs ➔ psychological distress ➔ pain anxiety/catastrophizing) in 305 healthy, pain-free adults (N = 155 NAs, N = 150 non-Hispanic Whites [NHWs]). Pain-related anxiety and situational pain catastrophizing were assessed in response to a variety of painful tasks. The Life Events Checklist was used to assess cumulative exposure to ALEs that directly happened to each participant. A latent psychological distress variable was modeled from self-reported perceived stress and psychological symptoms. Results found that NAs experienced more ALEs and greater psychological distress which was associated with higher rates of pain-related anxiety and pain catastrophizing. Notably, NAs did not report greater psychological distress when controlling for ALE exposure. This suggests that a higher risk of chronic pain in NAs may be due, in part, to psychological distress, pain-related anxiety, and pain catastrophizing that are promoted by exposure to ALEs. These results highlight several targets for intervention to decrease NA pain risk.

Are Cardiometabolic Markers of Allostatic Load Associated With Pronociceptive Processes in Native Americans?: A Structural Equation Modeling Analysis From the Oklahoma Study of Native American Pain Risk.

Native Americans (NAs) experience higher rates of chronic pain than the general U.S. population, but the risk factors for this pain disparity are unknown. NAs also experience high rates of stressors and cardiovascular and metabolic health disparities (eg, diabetes, cardiovascular disease) consistent with allostatic load (stress-related wear-and-tear on homeostatic systems). Given that allostatic load is associated with chronic pain, then allostatic load may contribute to their pain disparity. Data from 302 healthy, pain-free men and women (153 NAs, 149 non-Hispanic Whites [NHW]) were analyzed using structural equation modeling to determine whether cardiometabolic allostatic load (body mass index, blood pressure, heart rate variability) mediated the relationship between NA ethnicity and experimental measures of pronociceptive processes: temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR), conditioned pain modulation of pain (CPM-pain) and NFR (CPM-NFR), and pain tolerance. Results indicated that NAs experienced greater cardiometabolic allostatic load that was related to enhanced TS-NFR and impaired CPM-NFR. Cardiometabolic allostatic load was unrelated to measures of pain perception (CPM-pain, TS-pain, pain sensitivity). This suggests cardiometabolic allostatic load may promote spinal sensitization in healthy NAs, that is not concomitant with pain sensitization, perhaps representing a unique pain risk phenotype in NAs. PERSPECTIVE: Healthy, pain-free Native Americans experienced greater cardiometabolic allostatic load that was associated with a pronociceptive pain phenotype indicative of latent spinal sensitization (ie, spinal sensitization not associated with hyperalgesia). This latent spinal sensitization could represent a pain risk phenotype for this population.

The Relationship Between Adverse Life Events and Endogenous Inhibition of Pain and Spinal Nociception: Findings From the Oklahoma Study of Native American Pain Risk (OK-SNAP).

Adverse life events (ALEs) are a risk factor for chronic pain; however, mechanisms underlying this association are not understood. This study examined whether cumulative ALE exposure impairs endogenous inhibition of pain (assessed from pain report) and spinal nociception (assessed from nociceptive flexion reflex; NFR) in healthy, pain-free Native Americans (n = 124) and non-Hispanic Whites (n = 129) during a conditioned pain modulation (CPM) task. Cumulative ALE exposure was assessed prior to testing by summing the number of potentially traumatic events experienced by each participant across their lifespan. Multilevel modeling found that ALEs were associated with NFR modulation during the CPM task even after controlling for general health, body mass index, sex, age, blood pressure, sleep quality, stimulation intensity, stimulus number, perceived stress, and psychological distress. Low exposure to ALEs was associated with NFR inhibition, whereas high exposure to ALEs was associated with NFR facilitation. By contrast, pain perception was inhibited during the CPM task regardless of the level of ALE exposure. Race/ethnicity did not moderate these results. Thus, ALEs may be pronociceptive for both Native Americans and non-Hispanic Whites by impairing descending inhibition of spinal nociception. This could contribute to a chronic pain risk phenotype involving latent spinal sensitization. PERSPECTIVE: This study found that adverse life events were associated with impaired descending inhibition of spinal nociception in a sample of Native Americans and non-Hispanic Whites. These findings expand on previous research linking adversity to chronic pain risk by identifying a proximate physiological mechanism for this association.