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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 = 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.

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.

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.

The nociceptive flexion reflex (NFR) is a spinally mediated withdrawal response and is used as an electrophysiological marker of descending modulation of spinal nociception. Chemical and pharmacological modulation of nociceptive neurotransmission at the spinal level has been evidenced by direct effects of neurotransmitters and pharmacological agents on the NFR. Largely unexplored are, however, the effects of nonpharmacological noninvasive conservative interventions on the NFR. Therefore, a systematic review and meta-analysis was performed and reported following the PRISMA guidelines to determine whether and to what extent spinal nociception measured through the assessment of the NFR is modulated by conservative therapy in patients and healthy individuals. Five electronic databases were searched to identify relevant articles. Retrieved articles were screened on eligibility using the predefined inclusion criteria. Risk of bias was investigated according to Version 2 of the Cochrane risk-of-bias assessment tool for randomized trials. The evidence synthesis for this review was conducted in accordance with the Grading of Recommendations Assessment, Development and Evaluation. Thirty-six articles were included. Meta-analyses provided low-quality evidence showing that conservative therapy decreases NFR area and NFR magnitude and moderate-quality evidence for increases in NFR latency. This suggests that conservative interventions can exert immediate central effects by activating descending inhibitory pathways to reduce spinal nociception. Such interventions may help prevent and treat chronic pain characterized by enhanced spinal nociception. Furthermore, given the responsiveness of the NFR to conservative interventions, the NFR assessment seems to be an appropriate tool in empirical evaluations of treatment strategies.PROSPERO registration number: CRD42020164495.

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, P0.05), 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.

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. 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. 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 most widely accepted definition of pain considers it a sensory and emotional experience associated with potential or actual physical harm. However, research tends to generalize findings from predominantly European American samples thereby assuming universality across cultures. Because of the high prevalence of pain within the AI group, it is important to consider whether their conceptualization of pain is similar to the universal definition. To accomplish this aim, a semi-structured interview was conducted with 152 AIs (primarily Southern Plains and eastern Oklahoma tribes) and 150 NHWs. Both groups were asked questions including what words describe hurtful experiences, the purpose of painful experiences, individual and culture-specific meanings of pain, and what constituted the opposite of pain. Many similarities were found between groups as well as differences. For example, NHWs used the word pain more often to describe physically hurtful experiences and were more likely to consider pain to be a signal or warning of an abnormality or pathology. By contrast, only AIs reported culture-specific meanings of pain, such as references to AI rituals or ceremonies. These observed differences are attenuated by small effect sizes. These findings are important to consider when hypothesizing the differences in pain among cultural groups.

Jamie L Rhudy,1 Randolph C Arnau,2 Felicitas A Huber,1 Edward W Lannon,1 Bethany L Kuhn,1 Shreela Palit,1 Michael F Payne,1,3 Cassandra A Sturycz,1 Natalie Hellman,1 Yvette M Guereca,1 Tyler A Toledo,1 Joanna O Shadlow1 1The University of Tulsa, Department of Psychology, Tulsa, OK, USA; 2University of Southern Mississippi, Department of Psychology, Hattiesburg, MS, USA; 3Department of Pediatrics, Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USACorrespondence: Jamie L RhudyThe University of Tulsa, Department of Psychology, Tulsa, OK, USATel +1918 631-2839Fax +1918 631-2833Email jamie-rhudy@utulsa.eduIntroduction: Native Americans (NAs) have a higher prevalence of chronic pain than other US racial/ethnic groups, but the mechanisms contributing to this pain disparity are under-researched. Pain catastrophizing is oneof the most important psychosocial predictors of negative pain outcomes, and the Pain Catastrophizing Scale (PCS) has been established as a reliable and valid measure of the pain catastrophizing construct. However, before the PCS can be used to study pain risk in NAs, it is prudent to first determine whether the established 3-factor structure of the PCS also holds true for NAs.Methods: The current study examined the measurement (configural, metric, and scalar) invariance of the PCS in a healthy, pain-free sample of 138 NA and 144 non-Hispanic white (NHW) participants.Results: Results suggest that the previously established 3-factor solution fits for both groups (configural invariance) and that the factor loadings were equivalent across groups (metric invariance). Scalar invariance was also established, except for 1 minor scalar difference in a single threshold for item 3 (suggesting NHWs were more likely to respond with a 4 on that item than NAs).Discussion: Results provide additional evidence for the psychometric properties of the PCS and suggest it can be used to study pain catastrophizing in healthy, pain-free NA samples.Keywords: confirmatory factor analysis, pain catastrophizing, Native Americans, pain, ethnic differences, pain coping

Adverse life events (ALEs) are major life stressors that can occur throughout the lifespan and pose a significant physical or psychological threat to safety and/or security. Research suggests there is a link between ALE exposure and the development of chronic pain. Mechanistic animal and human studies indicate that stressors can have a long-lasting sensitization on nociceptive systems. This chapter reviews studies on ALE exposure and nociceptive processing in pain-free individuals to identify changes in nociceptive pathways that might confer chronic pain risk. Together, these studies indicate that ALE exposure accumulates, in a dose-dependent manner, to promote spinal sensitization. This spinal sensitization is not consistently accompanied by hyperalgesia, implying that compensatory pain inhibitory mechanisms are concurrently activated to keep amplified spinal nociception from resulting in amplified pain perception (i.e., latent spinal sensitization). Thus, chronic pain may be initiated by ALE-evoked latent spinal sensitization, followed by events that impair compensatory pain inhibition processes (e.g., additional adversity/stress, advanced age). Suggestions are made for future research.

Objectives Native Americans (NAs) have the highest prevalence of chronic pain of any racial/ethnic group. This issue has received little attention from the scientific community. One factor that may contribute to racial pain disparities is pain catastrophizing. Pain catastrophizing is a construct related to negative pain outcomes in persons with/without chronic pain. It has been suggested that the relationship between trait catastrophizing and pain is mediated by situation-specific (state) catastrophizing. The present study has 2 aims: (1) to investigate whether state pain catastrophizing mediates the relationship between trait catastrophizing and experimental pain (e.g., cold, ischemic, heat and electric tolerance), and (2) to investigate whether this relationship is stronger for NAs. Methods 145 non-Hispanic Whites (NHWs) and 137 NAs completed the study. Bootstrapped indirect effects were calculated for 4 unmoderated and 8 moderated mediation models (4 models with path a moderated and 4 with path b). Results Consistent with trait-activation theory, significant indirect effects indicated a tendency for trait catastrophizing to be associated with greater state catastrophizing which in turn is associated with reduced pain tolerance during tonic cold (a × b=−0.158) and ischemia stimuli (a × b=−0.126), but not during phasic electric and heat stimuli. Moderation was only noted for the prediction of cold tolerance (path a). Contrary to expectations, the indirect path was stronger for NHWs (a × b for NHW=−.142). Conclusions Together, these findings suggest that state catastrophizing mediates the relationship between trait catastrophizing and some measures of pain tolerance but this indirect effect was non-significant for NAs.

Native Americans (NAs) have a higher prevalence of chronic pain than other U.S. racial/ethnic groups, but there have been few attempts to understand the mechanisms of this pain disparity. This study used a comprehensive battery of laboratory tasks to assess peripheral fiber function (cool/warm detection thresholds), pain sensitivity (eg, thresholds/tolerances), central sensitization (eg, temporal summation), and pain inhibition (conditioned pain modulation) in healthy, pain-free adults (N = 155 NAs, N = 150 non-Hispanic Whites [NHWs]). Multiple pain stimulus modalities were used (eg, cold, heat, pressure, ischemic, and electric), and subjective (eg, pain ratings and pain tolerance) and physiological (eg, nociceptive flexion reflex) outcomes were measured. There were no group differences on any measure, except that NAs had lower cold-pressor pain thresholds and tolerances, indicating greater pain sensitivity than NHWs. These findings suggest that there are no group differences between healthy NAs and NHWs on peripheral fiber function, central sensitization, or central pain inhibition, but NAs may have greater sensitivity to cold pain. Future studies are needed to examine potential within-group factors that might contribute to NA pain risk.

Sexual assault (SA) is associated with an increased risk of chronic pain, but the mechanisms for this relationship are poorly understood. To explore whether disrupted descending inhibition is involved, this study used a conditioned pain modulation task to study the inhibition of pain and the nociceptive flexion reflex (NFR; a correlate of spinal nociception) in 32 pain-free SA survivors. This group was compared with 32 pain-free, trauma-exposed persons without SA and a group of 40 pain-free persons who reported no trauma exposure. Conditioned pain modulation was assessed from painful electric stimulations (test stimulus) delivered to the ankle before, during, and after participants submerged their hand in painful 10°C water (conditioning stimulus). Pain ratings and NFR were assessed in response to test stimuli. All groups demonstrated significant inhibition of pain during conditioned pain modulation. However, only the no trauma exposure group demonstrated significant inhibition of NFR. The persons without SA group showed no inhibition of NFR, whereas the SA group showed significant facilitation of the NFR. These findings suggest that trauma exposure may impair inhibitory cerebrospinal circuits, but that SA may specifically promote facilitation of spinal nociception. Perspective: This study suggests that trauma exposure disrupts the cerebrospinal inhibition of spinal nociception, but that exposure to SA further promotes chronic pain risk by facilitating spinal nociception. This finding help may help to elucidate the pain risk mechanisms in trauma survivors.

Objective This study investigated whether a brief psychotherapy for post-trauma nightmares (exposure, relaxation, and rescripting therapy [ERRT]), reduced suicidal ideation (SI). We hypothesized that: (a) nightmare frequency and severity, post-traumatic stress disorder (PTSD), depression, and sleep quality would be related to SI at pretreatment; (b) SI would decrease from pre- to post-treatment; and (c) the decrease in SI would remain after controlling for change in PTSD and depression. Method Seventy-five individuals exposed to a traumatic event and who experienced frequent nightmares (minimum one per week) participated in ERRT. Participants were not required to have a psychological diagnosis. Thirty percent endorsed SI at pretreatment. Results Depression and PTSD were related to SI at pretreatment. SI decreased following treatment; however, the third hypothesis was not supported. Conclusion Results suggest brief psychotherapy targeting post-trauma nightmares may decrease SI. More research is necessary to determine what factors contribute to decreases in SI.

Native Americans (NAs) have a higher prevalence of chronic pain than any other U.S. racial/ethnic group; however, little is known about the mechanisms for this pain disparity. This study used quantitative sensory testing to assess pain experience in healthy, pain-free adults (n = 137 NAs (87 female), n = 145 non-Hispanic whites (NHW; 68 female)) after painful electric, heat, cold, ischemic, and pressure stimuli. After each stimulus, ratings of pain intensity, sensory pain, affective pain, pain-related anxiety, and situation-specific pain catastrophizing were assessed. The results suggested that NAs reported greater sensory pain in response to suprathreshold electric and heat stimuli, greater pain-related anxiety to heat and ischemic stimuli, and more catastrophic thoughts in response to electric and heat stimuli. Sex differences were also noted; however, with the exception of catastrophic thoughts to cold, these finding were not moderated by race/ethnicity. Together, findings suggest NAs experience heightened sensory, anxiety, and catastrophizing reactions to painful stimuli. This could place NAs at risk for future chronic pain and could ultimately lead to a vicious cycle that maintains pain (eg, pain → anxiety/catastrophizing → pain). Perspective NAs experienced heightened sensory, anxiety, and catastrophizing reactions in response to multiple pain stimuli. Given the potential for anxiety and catastrophic thoughts to amplify pain, this characteristic may place them at risk for pain disorders and could lead to a vicious cycle that maintains pain.

Background The tendency to inhibit anger (anger-in) is associated with increased pain. This relationship may be explained by the negative affectivity hypothesis (anger-in increases negative affect that increases pain). Alternatively, it may be explained by the cognitive resource hypothesis (inhibiting anger limits attentional resources for pain modulation). Methods A well-validated picture-viewing paradigm was used in 98 healthy, pain-free individuals who were low or high on anger-in to study the effects of anger-in on emotional modulation of pain and attentional modulation of pain. Painful electrocutaneous stimulations were delivered during and in between pictures to evoke pain and the nociceptive flexion reflex (NFR; a physiological correlate of spinal nociception). Subjective and physiological measures of valence (ratings, facial/corrugator electromyogram) and arousal (ratings, skin conductance) were used to assess reactivity to pictures and emotional inhibition in the high anger-in group. Results The high anger-in group reported less unpleasantness, showed less facial displays of negative affect in response to unpleasant pictures, and reported greater arousal to the pleasant pictures. Despite this, both groups experienced similar emotional modulation of pain/NFR. By contrast, the high anger-in group did not show attentional modulation of pain. Conclusions These findings support the cognitive resource hypothesis and suggest that overuse of emotional inhibition in high anger-in individuals could contribute to cognitive resource deficits that in turn contribute to pain risk. Moreover, anger-in likely influenced pain processing predominantly via supraspinal (e.g., cortico-cortical) mechanisms because only pain, but not NFR, was associated with anger-in.

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.

Threat-induced pain modulation can increase survival by amplifying physiological and behavioral reactions toward danger. Threat can also modulate spinal nociception, suggesting engagement of endogenous top-down circuitry. A unique method to assess spinal nociception is via reflex receptive fields (RRF) associated with the nociceptive withdrawal reflex (NWR, a protective spinally-mediated reflex). The size of nociceptive RRFs can be modulated by top-down circuitry with the enlargement of RRFs related to increased spinal nociception. Threat has been previously shown to enhance pain and spinal nociception, but the relationship between threat and RRFs has not been investigated. The present study investigated this issue in 25 healthy individuals. RRFs were determined from NWRs measured by electromyography of the tibialis anterior following electrocutaneous stimulations. RRFs and pain were assessed during periods in which participants were under threat of unpredictable painful abdominal stimulations and when they were not under threat. Results indicated that threat periods led to significantly higher pain, larger nociceptive RRFs and NWR magnitudes. These findings imply that threat produces changes in protective reflexes related to spinal nociceptive sensitivity and increased pain perception. This is likely mediated by top-down circuitry that enhances dorsal horn nociceptive neurons by enlarging RRFs and amplifying ascending pain signals. PERSPECTIVE: This article presents the enlargement of RRF during periods of threat. The results from this study may help clarify the mechanism underlining emotional modulation of spinal nociception.

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.

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.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.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.

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.

Poor sleep quality is often comorbid with chronic pain. Research has also shown that poor and disrupted sleep may increase risk for chronic pain by promoting pronociceptive processes. This could occur through disrupted emotional modulation of pain since poor sleep can impact emotional experience and emotional experience modulates pain and nociception. To assess the pain system, nociceptive flexion reflexes (spinal level), pain-evoked potentials (supraspinal level), and perceived pain were recorded during an emotional picture-viewing task in which 37 healthy individuals received painful electric stimulations. The Pittsburgh Sleep Quality Index assessed sleep quality. Individuals with poor sleep quality were unable to inhibit signals at the spinal level in response to positive pictures, whereas emotional modulation of supraspinal nociception and pain perception remained unaffected by sleep quality. This suggests poor sleep quality may promote pronociception by impairing descending, emotional modulation of spinal nociception.

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.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia (FM) has progressed remarkably in recent years. Despite this, currents accounts of FM fail to capture the complex, dynamic and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to synthesise current knowledge on FM, explore and highlight multi-level links and pathways among different systems and build bridges between existing approaches. An extensive panel of international experts in neurophysiology and psychosocial aspects of FM discussed the collected evidence and progressively refined and conceptualized its interpretation. Fibromyalgia is a complex condition resulting from the dynamic interplay between multiple systems and processes. We provided an updated overview of the most relevant observations in FM to date as well as the potential pathways by which they exert they are related and exert their mutual influence, to produce the manifestations commonly associated with FM. This review constituted the first step towards and supported the development of a much needed model capable of integrating the main factors implicated in FM into a single, unified model that may prove valuable in understanding and managing FM.

Emotion has a strong modulatory effect on pain perception and spinal nociception. Pleasure inhibits pain and nociception, whereas displeasure facilitates pain and nociception. Dysregulation of this system has been implicated in development and maintenance of chronic pain. The current study sought to examine whether emotional modulation of pain could be altered through the use of transcranial direct current stimulation (tDCS) to enhance (via anodal stimulation) or depress (via cathodal stimulation) cortical excitability in the dorsolateral prefrontal cortex. Thirty-two participants (15 female, 17 male) received anodal, cathodal, and sham tDCS on three separate occasions, followed immediately by testing to examine the impact of pleasant and unpleasant images on pain and nociceptive flexion reflex (NFR) responses to electrocutaneous stimulation. Results indicated that tDCS modulated the effect of image content on NFR, F(2, 2175.06) = 3.20, P= .04, with the expected linear slope following anodal stimulation (ie, pleasantneutralunpleasant) but not cathodal stimulation. These findings provide novel evidence that the dorsolateral prefrontal cortex is critical to emotional modulation of spinal nociception. Moreover, the results suggest a physiological basis for a previously identified phenotype associated with risk for chronic pain and thus a potentially new target for chronic pain prevention efforts. PERSPECTIVE: This study demonstrated that reduction of dorsolateral prefrontal cortical excitability by transcranial direct current stimulation attenuates the impact of emotional image viewing on nociceptive reflex activity during painful electrocutaneous stimulation. This result confirms there is cortical involvement in emotional modulation of spinal nociception and opens avenues for future clinical research.

BackgroundConditioned pain modulation (CPM) is a task that involves measuring pain in response to a test stimulus before and during a painful conditioning stimulus (CS). The CS pain typically inhibits pain elicited by the test stimulus; thus, this task is used to assess endogenous pain inhibition. Moreover, less efficient CPM-related inhibition is associated with chronic pain risk. Pain catastrophizing is a cognitive-emotional process associated with negative pain sequelae, and some studies have found that catastrophizing reduces CPM efficiency.PurposeThe current study examined the relationship between catastrophizing (dispositional and situation specific) and CPM-related inhibition of pain and the nociceptive flexion reflex (NFR; a marker of spinal nociception) to determine whether the catastrophizing–CPM relationship might contribute to the higher risk of chronic pain in Native Americans (NAs).MethodsCPM of pain and NFR was assessed in 124 NAs and 129 non-Hispanic Whites. Dispositional catastrophizing was assessed at the beginning of the test day, whereas situation-specific catastrophizing was assessed in response to the CS, as well as painful electric stimuli.ResultsSituation-specific, but not dispositional, catastrophizing led to less NFR inhibition but more pain inhibition. These effects were not moderated by race, but mediation analyses found that: (a) the NA race was associated with greater situation-specific catastrophizing, which led to less NFR inhibition and more pain inhibition, and (b) situation-specific catastrophizing was associated with greater CS pain, which led to more pain inhibition.ConclusionsCatastrophizing may contribute to NA pain risk by disrupting descending inhibition.

Several studies have recently suggested that an abnormal processing of respiratory interoceptive and nociceptive (painful) stimuli may contribute to eating disorder (ED) pathophysiology. Mood and anxiety disorders (MA) are also characterized by abnormal respiratory symptoms, and show substantial comorbidity with ED. However, no studies have examined both respiratory and pain processing simultaneously within ED and MA. The present study systematically evaluated responses to perturbations of respiratory and nociceptive signals across the levels of physiology, behavior, and symptom report in a transdiagnostic ED sample (n = 51) that was individually matched to MA individuals (n = 51) and healthy comparisons (HC; n = 51). Participants underwent an inspiratory breath-holding challenge as a probe of respiratory interoception and a cold pressor challenge as a probe of pain processing. We expected both clinical groups to report greater stress and fear in response to respiratory and nociceptive perturbation than HCs, in the absence of differential physiological and behavioral responses. During breath-holding, both the ED and MA groups reported significantly more stress, feelings of suffocation, and suffocation fear than HC, with the ED group reporting the most severe symptoms. Moreover, anxiety sensitivity was related to suffocation fear only in the ED group. The heightened affective responses in the current study occurred in the absence of group differences in behavioral (breath hold duration, cold pressor duration) and physiological (end-tidal carbon dioxide, end-tidal oxygen, heart rate, skin conductance) responses. Against our expectations, there were no group differences in the response to cold pain stimulation. A matched-subgroup analysis focusing on individuals with anorexia nervosa (n = 30) produced similar results. These findings underscore the presence of abnormal respiratory interoception in MA and suggest that hyperreactivity to respiratory signals may be a potentially overlooked clinical feature of ED.

OBJECTIVE Sexual assault (SA) is associated with an increased risk for chronic pain and affective distress. Given that emotional processes modulate pain (e.g., negative emotions enhance pain, positive emotions inhibit pain), increased pain risk in SA survivors could stem from a disruption of emotional modulation processes. METHODS A well-validated affective picture-viewing paradigm was used to study emotional modulation of pain in 33 healthy, pain-free SA survivors and a control group of 33 healthy, pain-free individuals with no reported history of SA (matched on age, sex, race, and number of non-SA traumas). Unpleasant (mutilation), neutral, and pleasant (erotic) pictures were presented, while painful electrocutaneous stimulations were delivered at the ankle. Pain intensity ratings and nociceptive flexion reflex (NFR) magnitudes (a physiologic measure of spinal nociception) were recorded in response to electric stimuli. Multilevel models were used to analyze the data with group (SA versus non-SA) and content (mutilation, neutral, erotic) as independent variables. RESULTS Both groups demonstrated similar emotional modulation of pain (FGroupbyContent(2,646.52) = 0.44, p = .65), but a main effect of group (FGroup(1,65.42) = 4.24, p = .043) indicated the SA group experienced more overall pain from electric stimuli (hyperalgesia). A significant group by content interaction for NFR (p = .035) indicated that emotional modulation of NFR was present for the non-SA group (FContentSimpleEffect(2,684.55) = 12.43, p < .001), but not the SA group (FContentSimpleEffect(2,683.38) = 1.71, p = .18). CONCLUSIONS These findings suggest that SA survivors have difficulty emotionally engaging brain-to-spinal cord mechanisms to modulate spinal nociception. A disruption of descending inhibition plus hyperalgesia could contribute to comorbidity between sexual trauma and chronic pain.

Negative affect is considered an important factor in the etiology of depression and anxiety, and is highly related to pain. However, negative affect is not a unitary construct. To identify specific targets for treatment development, we aimed to derive latent variables of negative affect and test their unique contributions to affective processing during anticipation of unpredictable, painful shock. Eighty-three subjects (43 with depression and anxiety spectrum disorders and 40 healthy controls) completed self-report measures of negative valence and underwent neuroimaging while exploring computer-simulated contexts with and without the threat of a painful, but tolerable, shock. Principal component analysis (PCA) extracted distinct components of general negative affect (GNA) and pain-related negative affect (PNA). While elevated GNA and PNA were both indicative of depression and anxiety disorders, greater PNA was more strongly related to task-specific anxious reactivity during shock anticipation. GNA was associated with increased precuneus and middle frontal gyrus activity, whereas PNA was related to increased bilateral anterior insula activity. Anterior insula activity mediated the relationship between PNA and task-specific anxious reactivity. In conclusion, GNA and PNA have distinct neural signatures and uniquely contribute to anxious anticipation. PNA, via insula activity, may relate to arousal in ways that could contribute to affective dysregulation, and thus may be an important treatment target.

Biological Psychiatry, 3 (6), ISSN:0006-3223, ISSN:1873-2402

Habituation (ie, decreases in responding) and sensitization (ie, increases in responding) after prolonged or repeated exposures to a fixed stimulus have been identified as important in adaptation to repeated or prolonged noxious stimulation. Determinants of habituation or sensitization are poorly understood, and experimental investigation of habituation of pain ratings have generally relied on pain reports and statistical techniques that average responses across a group of participants. Using a cross-sectional design, the current study used multilevel growth curve analyses to examine changes in the nociceptive flexion reflex (NFR), a spinal nociceptive withdrawal reflex, and pain ratings in response to 12 repeated, constant intensity, noxious electrocutaneous stimuli. Unconditional growth curve models indicated that, on average, participants evidenced habituation of the NFR and sensitization of pain ratings. However, a substantial subgroup of participants exhibited the opposite pattern of change. In conditional models, behavioral inhibition, b = .10, P = .003, and behavioral activation, b = −.07, P = .07, independently interacted with the growth curve to predict changes in NFR, but not pain ratings, across the 12 stimuli. These findings provide preliminary experimental support for Jensen and colleagues' 2-factor model of pain experience and implicate a role for approach and avoidance motivations in descending modulation of NFR. Perspective Using repeated NFR stimulation, this study showed that most participants exhibited NFR habituation and pain sensitization; however, a substantial subgroup showed an opposite pattern of pain habituation (25.0%) and NFR sensitization (31.4%). Further, NFR habituation was moderated by individual differences in behavioral activation and behavioral inhibition.

Introduction: Evidence suggests Native Americans (NAs) experience higher rates of chronic pain than the general US population, but the mechanisms contributing to this disparity are poorly understood. Recently, we conducted a study of healthy, pain-free NAs (n = 155), and non-Hispanic whites (NHWs, n = 150) to address this issue and found little evidence that NAs and NHWs differ in pain processing (assessed from multiple quantitative sensory tests). However, NAs reported higher levels of pain-related anxiety during many of the tasks. Objective: The current study is a secondary analysis of those data to examine whether pain-related anxiety could promote pronociceptive processes in NAs to put them at chronic pain risk. Methods: Bootstrapped indirect effect tests were conducted to examine whether pain-related anxiety mediated the relationships between race (NHW vs NA) and measures of pain tolerance (electric, heat, ischemia, and cold pressor), temporal summation of pain and the nociceptive flexion reflex (NFR), and conditioned pain modulation of pain/NFR. Results: Pain-related anxiety mediated the relationships between NA race and pain tolerance and conditioned pain modulation of NFR. Exploratory analyses failed to show that race moderated relationships between pain-related anxiety and pain outcomes. Conclusion: These findings imply that pain-related anxiety is not a unique mechanism of pain risk for NAs, but that the greater tendency to experience pain-related anxiety by NAs impairs their ability to engage descending inhibition of spinal nociception and decreases their pain tolerance (more so than NHWs). Thus, pain-related anxiety may promote pronociceptive processes in NAs to place them at risk for future chronic pain.

Objective To assess conditioned pain modulation efficiency in persons with and without migraine headaches. Design Cross-sectional assessment of experimental pain. Setting University campus and surrounding community in a large Midwestern US city. Subjects Twenty-three adults with and 32 without a history of migraine headaches participated in the study. Participants were mostly female (N = 40) with an average age of 23 years. Methods Four electrocutaneous stimulations of the supraorbital branch of the left trigeminal nerve were delivered at 150% of an individually determined pain threshold. Conditioned pain modulation was assessed by applying a noxious counterstimulus (forearm ischemia) and delivering four more electrocutaneous stimulations. After each stimulation, pain and the nociceptive blink reflex were assessed. Depression and pain catastrophizing were assessed to control for the potential influence of these variables on pain modulation. Results Participants with and without migraine headaches had similar baseline pain responsivity, without significant differences in pain report or nociceptive blink reflexes. Pain report was inhibited by conditioned pain modulation in both the migraine and control groups. However, unlike nonmigraine controls, participants with migraines did not exhibit an inhibition of nociceptive blink reflexes during the ischemia task. This pattern persisted after controlling for level of pain catastrophizing and depression. Conclusions Migraine sufferers exhibited impaired conditioned pain modulation of the nociceptive blink reflex, suggesting a deficiency in inhibition of trigeminal nociception, which may contribute to the development of migraine headaches.

Objectives: We aimed to investigate the possibility of sample size as a possible source of heterogeneity in trials comparing the nociceptive flexion reflex threshold (NFRthr) in fibromyalgia (FM) patients and healthy controls. Methods: A systematic search strategy was designed and conducted in electronic databases such as Ovid MEDLINE, Cochrane Libraries, Embase, and PsycINFO. In total, nine scholarly records were filtered by the inclusion and exclusion criteria, passed for data extraction (e.g. study designs and settings; methodology; total, male, and female sample sizes in FM and healthy control groups, and effect sizes), and statistical analyses (e.g. metaanalysis and meta-regression). Using random-effects model, the effect size (i.e. mean difference between the NFRthr in FM patients and healthy controls) was meta-analyzed. Investigating the sample size as a possible source of heterogeneity and utilizing a restricted maximum likelihood (REML) technique, the trials’ effect sizes were meta-regressed in multiple meta-regression against the total, male, and female sample sizes. Prior to any investigations, the aims of this research were registered in the International Prospective Register of Systematic Reviews (PROSPERO; registration number: CRD42019140354). Results: Results indicated the deficit in NFRthr (overall mean difference = −3.16; 95% 𝐶𝐼: −6.82 𝑡𝑜 0.50) was heterogenous (𝐼 2 = 0.91, 𝜏 2 = 25.04, 𝜒2= 91.22, df & < 0.00001) and the overall effect was not statistically significant (Z = 1.69; 𝑃 = 0.09). The multiple meta-regression analyses indicated that one of the main sources of bias to the effect size in the trials was found to be the total (𝑆𝑆𝑡𝑜𝑡𝑎𝑙 = −0.0570; 𝑃 = 0.040) and female (𝑆𝑆𝑓𝑒𝑚𝑎𝑙𝑒 = −0.0569; 𝑃 = 0.047) sample sizes that participated in the studies. Conclusion: The findings suggest that the total and female sample sizes might be possible sources of bias to effect sizes determined in NFRthr in FM patient and healthy controls. A possible solution might be to conduct sex-specific trials to determine the NFRthr among FM patients in future research. Funding Statement: Authors received no source of funding for this research. Declaration of Interests: Authors declare no conflict of interest. Ethics Approval Statement: PROSPERO; registration number: CRD42019140354

Adverse life experiences (ALEs) are associated with hyperalgesia and chronic pain, but the underlying mechanisms are poorly understood. One potential mechanism is hyperexcitability of spinal neurons (i.e., central sensitization). Given that Native Americans (NA) are more likely to have ALEs, and have a higher prevalence of chronic pain, the relationship between ALEs and spinal hyperexcitability might contribute to their pain risk. The present study assessed temporal summation of the nociceptive flexion reflex (TS-NFR; correlate of spinal hyperexcitability) and pain (TS-Pain) in 246 healthy, pain-free non-Hispanic whites (NHW) and Native Americans (NA). The Life Events Checklist (LEC-4) assessed the number of ALEs. Multilevel growth models were used to predict TS-NFR and TS-Pain, after controlling for age, perceived stress, psychological problems, negative and positive affect, and painful stimulus intensity. ALEs and negative affect were significantly associated with higher pain, but not enhanced TS-Pain. By contrast, ALEs were associated with enhanced TS-NFR. Race did not moderate these relationships. This implies that ALEs promote hyperalgesia as a result of increased spinal neuron excitability. Although relationships between ALEs and NFR/pain were not stronger in NAs, given prior evidence that NAs experience more ALEs, this might contribute to the higher prevalence of chronic pain in NAs. PERSPECTIVE: This study found a dose-dependent relationship between adverse life experiences (ALE) and spinal neuron excitability. Although the relationship was not stronger in Native Americans (NA) than non-Hispanic whites, given prior evidence that NAs experience more ALEs, this could contribute to the higher prevalence of chronic pain in NAs.

Compared to other racial/ethnic minority groups, Native Americans (NAs) are more likely to report experiences of discrimination and also have the highest prevalence of pain conditions. Thus, there is a need to understand how and why these disproportionately high rates occur. Discrimination has been conceptualized within the biopsychosocial model as a chronic psychosocial stressor that can lead to dysfunction of regulatory processes, such as pain. A recent study found that perceived discrimination increased psychological distress that, in turn, led to increased chronic pain. To date, these relationships have not yet been evaluated in NAs. The present study examined perceived discrimination, stress, and pain tolerance in healthy, pain-free NAs (N=112) and NHWs (N=128). Discrimination was measured with the Everyday Discrimination Scale (EDS), stress was measured with the Perceived Stress Scale (PSS), and pain tolerance was measured in reaction to cold, heat, electrocutaneous, and ischemia pain stimuli. Results indicated NAs experienced more discrimination than NHWs (p

Identification of those at risk for chronic pain development may help prevent its onset. The relationship between blood pressure (BP) and pain processing has been studied extensively, but it is unknown whether BP is related to future pain onset. The current study examined whether resting BP predicts the development of chronic pain in participants from the OK-SNAP study who were healthy and pain-free at the time of enrollment. BP was recorded 3 times and averaged at the time of enrollment. Following the OK-SNAP main study, participants were contacted every 6 months to assess for chronic pain. Of the 139 Native American (NA) and 147 non-Hispanic white (NHW) participants enrolled, 208 (73%) responded to at least 1 follow-up. Participants were deemed to have chronic pain if they experienced pain for >3 months that did not remit at subsequent follow-ups (N=35; 17%). These persons were compared to those that reported no persistent pain at any follow-up (N=133; 64%). First, zero-order correlations were conducted between chronic pain onset, BP, and control variables. Systolic BP, diastolic BP, race, general health perception, and age were significantly related to chronic pain onset (ps

The tendency to inhibit anger (anger-in) is associated with increased pain. This relationship may be explained by the negative affectivity hypothesis such that those with high anger-in experience increased negative affectivity and thus increased pain (because negative affect enhances pain). Alternatively, this relationship may be explained by the cognitive resource hypothesis such that anger-in limits attentional resources normally available for pain modulation. The present study examined these competing hypotheses in healthy, pain-free participants using a well-validated picture viewing paradigm (ie, Emotional Controls of Nociception, ECON). ECON is a paradigm in which painful, electrocutaneous stimulations are delivered during and in between pictures of emotional content (mutilation, neutral, and erotica). Pain ratings were assessed in response to electric stimuli. This allows for the assessment of emotional modulation of pain by comparing pain evoked during mutilation and erotic pictures to pain evoked during neutral pictures. Additionally, ECON allows for the assessment of attentional modulation of pain by comparing pain evoked during neutral pictures (distraction) to pain evoked in the absence of pictures (control). Prior to ECON, participants filled out the Anger Expression Inventory to assess their tendency to inhibit anger and 2 groups were formed (high anger-in, N = 71 and low anger-in, N = 27) from their responses (ie, +/- 1SD from the normative mean of anger-in). Results found that both groups demonstrated similar emotional modulation of pain. By contrast, persons in the low anger-in group displayed attentional modulation of pain, whereas persons in the high anger-in group failed to attentionally modulate pain. These findings suggest that cognitive resource deficits in high anger-in individuals may contribute to increased pain risk.

Pain catastrophizing is associated with enhanced pain; however, the mechanisms by which it modulates pain are poorly understood. Evidence suggests that catastrophizing modulates supraspinal processing of pain but does not modulate spinal nociception (as assessed by nociceptive flexion reflex [NFR]). Unfortunately, most NFR studies have been correlational. To address this, this study experimentally reduced catastrophizing to determine whether it modulates spinal nociception (NFR). Healthy pain-free participants (N = 113) were randomly assigned to a brief 30-minute catastrophizing reduction manipulation or a control group that received pain education. Before and after manipulations, 2 types of painful stimuli were delivered to elicit (1) NFR (single trains of stimuli) and (2) temporal summation of NFR (3 stimulations at 2 Hz). After each set of stimuli, participants were asked to report their pain intensity and unpleasantness, as well as their situation-specific catastrophizing. Manipulation checks verified that catastrophizing was effectively reduced. Furthermore, pain intensity and unpleasantness to both stimulation types were reduced by the catastrophizing manipulation, effects that were mediated by catastrophizing. Although NFRs were not affected by the catastrophizing manipulation, temporal summation of NFR was reduced. However, this effect was not mediated by catastrophizing. These results indicate that reductions in catastrophizing lead to reductions in pain perception but do not modulate spinal nociception and provides further evidence that catastrophizing modulates pain at the supraspinal, not the spinal, level.

OBJECTIVE Premenstrual dysphoric disorder (PMDD) is associated with increased pain, but there has been a lack of well-controlled research assessing pain responsivity, sex hormones, and their relationships in this group. This study was designed to address this gap in the literature. MATERIALS AND METHODS Healthy, regularly cycling participants (14 PMDD, 14 non-PMDD) attended pain testing sessions during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (order counterbalanced) and salivary estradiol, progesterone, and testosterone were assessed at each testing session. Pain sensitivity was measured from electrocutaneous threshold/tolerance, ischemic threshold/tolerance, sensory and affective ratings of electrocutaneous and ischemic stimuli, and the nociceptive flexion reflex threshold (NFR, a measure of spinal nociception). RESULTS Women with PMDD had higher sensory pain ratings of electrocutaneous stimuli and trends for lower ischemic thresholds and higher affective pain ratings of electrocutaneous stimuli. However, there were no group differences observed in NFR threshold. Testosterone levels were also lower during the mid-follicular and ovulatory phases in PMDD. Correlations between pain outcomes and estradiol and testosterone indicated that these hormones are hypoalgesic, with estradiol having a greater hypoalgesic effect within the PMDD group. DISCUSSION Overall, women with PMDD may have a phase-independent hyperalgesia, with pain amplification likely occurring at the supraspinal level rather than the spinal level, given the lack of group differences in NFR threshold. Because testosterone was hypoalgesic and lower in women with PMDD, and there were strong associations between pain and estradiol in PMDD, sex hormones may play a role in PMDD-related hyperalgesia.

Anger management styles (i.e., anger-in and anger-out) characterize a person's typical response to anger. Anger-in, the suppression of anger, and anger-out, the outward expression of anger, have been associated with increased acute and chronic pain. Previous research suggests that anger-in is related to pain because of its shared variance with negative affect; anger-out is believed to be related to pain because of a disruption of endogenous opioid systems. It is currently unknown whether anger management styles promote pain by facilitating central sensitization or spinal nociception. This study assessed the relationship between anger management styles and markers of central sensitization (i.e., temporal summation of pain [TS-pain] and nociception flexion reflex [TS-NFR]), spinal nociception (nociception flexion reflex [NFR] threshold), and measures of pain experience. One hundred nine healthy pain-free individuals completed the study. A bootstrapped mediation analysis was conducted to test whether negative affect mediated relationships with anger-in. Results suggested that anger-in and anger-out were associated with lower NFR thresholds (facilitated spinal nociception), but no other outcome. Negative affect did not mediate either of these relationships. These results suggest that anger management styles may amplify spinal nociceptive processes in healthy humans without altering central sensitization.

In healthy individuals, emotions modulate pain and spinal nociception according to a valence linear trend (ie, pain/nociception is highest during negative emotions and lowest during positive emotions). However, emerging evidence suggests that emotional modulation of pain (but not spinal nociception) is disrupted in fibromyalgia and disorders associated with chronic pain risk (eg, major depression, insomnia). The present study attempted to extend this work and to examine whether women with premenstrual dysphoric disorder (PMDD), a cyclical syndrome associated with debilitating affective symptoms during the late-luteal (premenstrual) phase of the menstrual cycle, is also associated with disrupted emotional modulation of pain. To do so, an affective picture-viewing procedure was used to study emotional modulation of pain and spinal nociception in 14 women with PMDD and 14 control women during mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle (verified by salivary hormone levels and luteinizing hormone tests). At each phase, mutilation, neutral, and erotic pictures were presented to manipulate emotion. During picture viewing, suprathreshold electrocutaneous stimuli were presented to evoke pain and the nociceptive flexion reflex (NFR; a physiological measure of spinal nociception). Statistically powerful linear mixed model analyses confirmed that pictures evoked the intended emotional states in both groups across all menstrual phases. Furthermore, emotion modulated pain and NFR according to a valence linear trend in both groups and across all menstrual phases. Thus, PMDD-related affective disturbance is not associated with a failure to emotionally modulate pain, suggesting that PMDD does not share this pain phenotype with major depression, insomnia, and fibromyalgia.