Journal Logo


Pain-related anxiety promotes pronociceptive processes in Native Americans: bootstrapped mediation analyses from the Oklahoma Study of Native American Pain Risk

Rhudy, Jamie L.a,*; Huber, Felicitasa; Kuhn, Bethany L.a; Lannon, Edward W.a; Palit, Shreelaa,b; Payne, Michael F.a,c; Hellman, Nataliea; Sturycz, Cassandra A.a; Güereca, Yvette M.a; Toledo, Tyler A.a; Demuth, Mara J.a; Hahn, Burkhart J.a; Shadlow, Joanna O.a

Author Information
doi: 10.1097/PR9.0000000000000808
  • Open


1. Introduction

Chronic pain rates are higher in Native Americans (NAs) than the general US population.3,39,79 These conditions include arthritis,29,46 back pain,3,18 headaches,57 and dental pain,42 among others. Despite this, there have been few attempts to understand the mechanisms contributing to this pain disparity.

Recently, our laboratory conducted the Oklahoma Study of Native American Pain Risk (OK-SNAP) to address this issue. A number of quantitative sensory tests (QST) were used to assess peripheral fiber function, spinal cord pain amplification processes (ie, temporal summation [TS]), endogenous pain inhibition (ie, conditioned pain modulation [CPM]), and pain sensitivity (threshold/tolerance) in healthy, pain-free NAs, and non-Hispanic whites (NHWs). To our surprise, results indicated that NAs and NHWs did not differ on any of these measures of pain processing, with the exception that NAs were more sensitive to cold pain.62 Despite the lack of group differences in QST measures, a robust finding was that NAs reported greater pain-related anxiety in response to painful QST tasks.61 This is consistent with other evidence that minorities tend to report greater pain-related negative affect in response to clinical pain.33,67 Given that negative affect can enhance pain23,52,64,70,72 and promote pain-related suffering,43 greater pain-related anxiety may create a vicious cycle for NAs that enhances and/or initiates chronic pain (eg, pain→anxiety→pain).15,36,72,74

Indeed, pain-related anxiety may serve as a mechanism that promotes pronociceptive processes (ie, increased pain amplification and decreased pain inhibition) to increase chronic pain risk in NAs. Modern statistical methods (ie, bootstrapped indirect tests) provide a statistically powerful way for researchers to test whether mediated (indirect) pathways exist between 2 variables, even when there is not an observed association between those variables.54,55 Specifically, there may be an indirect relationship between NA race and pain processing outcomes that is mediated by pain-related anxiety (NA→pain-related anxiety→pronociception), even when NA race is not directly related to pain outcomes to generate observable group differences in pain processing (ie, even if there is no “total effect”). If there is an indirect effect in the absence of a total effect, this implies that ethnic/racial differences in pronociceptive processes exist only in the presence of pain-related anxiety.

The current study used bootstrapped analyses to examine the indirect relationships between race (NHW vs NA), pain-related anxiety, and QST tasks that assess pain processing. We examined relationships with endogenous inhibition (CPM) of pain and the nociceptive flexion reflex (NFR; a measure of spinal nociception), TS of pain and TS-NFR, and pain tolerance (assessed from electric, heat, ischemic, and cold stimuli) because these pain outcomes have the greatest potential relationship with chronic pain risk.20,21,86,87 Analyses controlled for possible confounding variables, as well as state anxiety unrelated to pain to isolate the effects of pain-related anxiety. We hypothesized that greater pain-related anxiety experienced by NAs would promote pronociceptive processes thus reducing endogenous inhibition, amplifying TS, and lowering pain tolerance.


2.1. Participants

Power analyses for the primary aims of the parent (OK-SNAP) study were conducted with G*Power (version and indicated that 120 per group (N = 240 total) would result in power of 0.80 for most QST outcomes. A sensitivity analysis was conducted using this sample size, power = 0.80, and alpha = 0.05 to determine the effect size that could be detected for analyses in these secondary analyses of OK-SNAP data. According to Fritz and MacKinnon,31 240 participants should provide power to detect a standardized, bootstrapped, indirect effect of α*β ≥ 0.10, which seems acceptable.

Healthy, pain-free participants were recruited in OK-SNAP to help ensure that any observed differences in pain processing were not due to disparities in pain condition/etiology, disease severity, and/or pain treatment.11,47,77 Recruitment efforts included tribal and nontribal newspaper ads, fliers, personal communications with NA groups, email announcements, online platforms (eg, Facebook), and word of mouth. Those who appeared eligible after a phone screen were invited to attend a laboratory testing day, which began with a thorough screening for inclusion/exclusion criteria. Data collection occurred between March 2014 and October 2018.

Participants were excluded for (1) <18 years old, (2) history of self-reported cardiovascular, neuroendocrine, musculoskeletal, neurological disorders, (3) chronic pain or current acute pain, (4) body mass index (BMI) ≥ 35 (due to difficulties recording electromyogram for NFR), (5) current/recent use of antidepressants, anxiolytic, analgesic, stimulant, or antihypertensive medication, (6) current psychotic symptoms (assessed by Psychosis Screening Questionnaire4) or substance use problems, and/or (7) an inability to read and speak English. Native American status was verified from Certificate of Degree of Indian Blood or tribal membership cards. Native American participants represented tribal nations predominately from the southern plains and eastern Oklahoma tribes. All participants were given an overview of procedures and told they could withdraw at any time before they provided verbal and written informed consent. Participants received a $100 honorarium for the completion of each testing day. The study was approved by IRBs of the University of Tulsa, Cherokee Nation, and the Indian Health Service Oklahoma City Area Office.

Of the 329 found eligible, 247 completed both testing days, 41 completed 1 day, and 39 completed part of 1 day. Two participants' data were lost due to a computer malfunction. Twenty-two participants were non-NA minorities and thus were excluded from analyses. Thus, 155 NA (64 men) and 150 NHW (76 men) were included in the current study (Table 1).

Table 1
Table 1:
Participant characteristics by racial/ethnic group.

2.2. Brief overview of procedures

A full description of the parent study is reported elsewhere.62 Testing was conducted over a 2-day period, each lasting 4 to 6 hours. Informed consent and inclusion/exclusion screening were conducted on day 1. On one of the testing days, electric pain tolerance, heat pain tolerance, cold pressor pain tolerance, and ischemia pain tolerance were assessed. Conditioned pain modulation and TS of pain/NFR were assessed on the other testing day. Order of testing day was randomized but blocked by race and sex. Moreover, tests within each day were partly randomized to avoid order effects. Breaks were provided between tasks to minimize carryover.

2.3. Background and control variables

Weight and height were assessed from a medical scale to calculate BMI. Blood pressure (mean arterial blood pressure) was assessed 3 times (3-minute intertest interval) at the beginning of each testing day (Dinamap; GE/Critikon Corporation, Tampa, FL) while participants sat comfortably in a recliner. Other background questionnaires were used to assess dispositional pain catastrophizing (Pain Catastrophizing Scale),75 positive and negative affect before testing (Positive and Negative Affect Schedule),82 state anxiety not specific to pain (State Trait Anxiety Inventory [STAI]),73 perceived sleep quality subscale (Pittsburgh Sleep Quality Index),6 perceived stress (Perceived Stress Scale),12 psychological distress (Global Severity Index of the Symptom Checklist-90-Revised, SCL-90-R),17 general health perception (subscale of the Medical Outcomes Study 36-item Short Form Health Survey [SF-36]),81 and bodily pain (subscale of the SF-36).

2.4. Testing environment and apparatus

Participants were seated in a comfortable reclining chair (Perfect Chair Zero Gravity Recliner, Human Touch, Long Beach, CA) in a sound attenuated and electrically shielded testing room that was adjacent to the room where the experimenter monitored testing. Questionnaires were presented by a computer. Custom-built software (LabVIEW; National Instruments, Austin, TX) was used for experimental control. Electric stimuli were delivered through constant current stimulator (Digitimer DS7A; Hertfordshire, England) and a bipolar electrode (Nicolet; 30-mm interelectrode distance) filled with a conductive gel (EC60; Grass Technologies, West Warwick, RI) attached over the left ankle.

Nociceptive flexion reflex was measured from left biceps femoris electromyography (EMG) using sensors filled with conductive gel (EC60; Grass Technologies). The signal was collected, filtered (10–300 Hz), and amplified (×10,000) using a Grass Technologies (West Warwick, RI) Model 15LT amplifier (with AC Module 15A54). Electromyography was sampled and digitized at 1000 Hz.

Heat stimuli were delivered using a Medoc (Haifa, Israel) Pathway device with a Contact Heat Evoked Potential Stimulator thermode. A circulating water bath (Thermo Fisher Scientific, Pittsburgh, PA) was used to assess cold tolerance and was also used as the painful conditioning stimulus (CS) in the CPM task. The water level was kept constant (6″ deep) across all participants.

2.5. Pain tolerance

Electric pain tolerance was assessed using a single ascending staircase of stimulations that started at 0 mA and increased in 2-mA steps until the participant rated the stimulus as the maximum tolerable pain.59 After each stimulus, the participant rated their pain on a computer-presented visual analog scale (VAS) ranging from “no pain” to “maximum tolerable pain.”

Heat pain tolerance was assessed 5 times (1 practice and 4 averaged trials) by attaching the Contact Heat Evoked Potential Stimulator thermode to the participants' left volar forearm.8 Each trial started from a baseline of 32°C and heated at a rate of 0.5°C/s until the participant terminated the stimulus by pushing a button as soon as the heat became intolerable. The maximum intensity for heat tolerance was set to 51°C.

Cold pressor tolerance was assessed by asking participants to submerge their hand and forearm into 6 ± 0.1°C circulating water.8,48,58 During submersion, participants made continuous ratings on the same VAS used during electric tolerance. The time until a rating of maximum tolerable was defined as pain tolerance (or 5 minutes max was reached).

Ischemia tolerance was assessed using a forearm tourniquet test.30 Participants conducted hand exercises (Lafayette Hand Dynamometer; Lafayette Instrument Company, Lafayette, IN) at 50% grip strength for 2 minutes (1x/s), then raised their arm for 15 seconds to allow for desanguination. A blood pressure cuff was then inflated to 220 mm Hg to occlude blood flow. During occlusion, participants continuously rated their pain on the previously described VAS, and the time taken to achieve a rating of maximum tolerable was defined as pain tolerance (or 25 minutes max was achieved).

2.6. Temporal summation and conditioned pain modulation

2.6.1. Determination of electric stimulus intensity for temporal summation and conditioned pain modulation

To determine the electric stimulus intensity (in mA) to use during these tasks, 3 procedures were conducted, as described elsewhere62: NFR threshold (3 ascending/descending staircases of electric stimuli used to determine the minimum stimulus intensity needed to evoke NFR), Pain30 (if NFR threshold did not evoke a 30 out of 100 VAS rating, an ascending series of electric stimulations was used to determine stimulus needed to evoke Pain30), and 3-stimulation threshold (ascending staircase of trains of 3 stimuli at 2 Hz that was used to determine the stimulus intensity needed to evoke NFR on the third stimulus in the train). Stimuli during TS-NFR assessment were set at 1.2x NFR threshold or 1.2x of 3-stimulation threshold (whichever was higher), whereas stimuli during CPM assessment were set at the highest of 1.2x NFR threshold, 1.2x 3-stimulation threshold, or 1x Pain30.

2.6.2. Temporal summation-nociceptive flexion reflex

Temporal summation-NFR was defined as the degree of reflex summation after a series of 3 suprathreshold stimuli. To assess this, 5 series of 3 suprathreshold stimuli (0.5-second ISI) were used. After each series, participants were instructed to rate the pain intensity for each of the 3 stimulations, using a set of 3 computer-presented VASs ranging from “no pain sensation” to “the most intense pain sensation imaginable.” After the participant completed the ratings, there was an interseries interval of 8 to 12 seconds. The baseline EMG in the 60 ms before the third stimulus in the stimulus series was visually inspected for excessive muscle tension or voluntary movement (ie, EMG > 5 µV). If present, the series was repeated. Nociceptive flexion reflex magnitudes were calculated in d-units by subtracting the 60-ms baseline before the first stimulus in each series from the EMG response 70 to 150 ms after each stimulus in the train. This difference was then divided by the average of the SDs of the rectified EMG from these 2 intervals. Temporal summation-NFR was defined as the difference in the NFR magnitude in response to the third stimulus in the series minus the NFR magnitude in response to the first stimulus.

2.6.3. Temporal summation-Pain

Temporal summation-Pain was defined similar to Farrell and Gibson.28 Five single electric stimuli were delivered using the same suprathreshold intensity as that used during TS-NFR (8- to 12-second interstimulus interval), and participants made pain ratings using the same VAS immediately after each stimulation. Temporal summation-Pain was defined as the difference between average rating of these single stimuli and the average rating of the third stimulus in the 3-stimulus train delivered during TS-NFR.

2.6.4. Conditioned pain modulation

Conditioned pain modulation involved the assessment of pain and NFR in response to electric test stimuli delivered to the ankle before and during a tonic (CS; circulating, 2 minutes, 10 ± 0.1°C water bath). Each CPM phase was 2 minutes and consisted of a 20-second wait period, followed by 5 electric test stimuli (random 8- to 12-second interstimulus interval). There was a 2-minute break between CPM phases. Participants provided electric pain ratings verbally using an NRS that was displayed on a computer screen in front of them (0 “no pain,” 20 “mild pain,” 40 “moderate pain,” 60 “severe pain,” 80 “very severe pain,” and 100 “worst possible pain”). An experimenter recorded the ratings. Nociceptive flexion reflex magnitudes in response to electric test stimuli were used to assess changes in spinal nociception.59 Nociceptive flexion reflex magnitudes were calculated as a d-score (NFR d = [mean rectified EMG of 90- to 150-ms poststimulation interval minus mean of rectified EMG from −60- to 0-ms prestimulation interval] divided by the average SD of the rectified EMG from the 2 intervals). Trials with NFR baselines higher than 3.0 μV were excluded (3% of trials were excluded). Conditioned pain modulation of pain/NFR was defined as the difference in the average electric pain/NFR during the CS minus the average electric pain/NFR during the baseline phase.

2.7. Pain-related anxiety

Pain-related anxiety was measured from a VAS with the anchors “not at all anxious” and “extremely anxious.”63,68 The computer converted the participant's response to scores that ranged from 0 to 100. The VAS was presented following the pain tasks62 with the instructions: “Using this scale, rate how anxious the [insert pain stimulus here] made you feel.” Although different stimuli evoked different mean levels of pain-related anxiety,61 the 10 items loaded onto a single component in a principal component analysis, and Cronbach's alpha was high (α = 0.91). Thus, the items were averaged to create a global pain-related anxiety score. The correlation between pain-related anxiety and state anxiety (from STAI) was r = 0.219; therefore, the degree of overlap with non–pain-related anxiety was minimal.

2.8. Data analysis

Cold pressor tolerance, ischemia tolerance, and psychological distress (Global Severity Index) were transformed to reduce positive skew. Outliers were identified using established procedures and then winsorized to the next nearest nonoutlier value.83 Missing observations on control variables were replaced by the grand mean to avoid listwise deletion. A few participants were excluded from analyses for failing to follow instructions (eg, poor effort, pain tolerance lower than pain threshold)[for a full description see Ref. 62].

Independent-samples t-tests or χ2 analyses were used to examine group differences on background variables. If group differences were found, this was considered as a potential control variable in primary analyses. PROCESS software (v3.3) was used to conduct bootstrapped mediation analyses from 5000 random samples.35 Significant mediation occurs when 0 is not contained in the 95% bootstrapped confidence interval for the indirect effect. Analyses of CPM of pain and TS-Pain controlled for electric stimulus intensity. Moreover, all analyses controlled for STAI state anxiety to control for the effects of non–pain-related anxiety (results same if removed).

3. Results

3.1. Background characteristics

Table 1 presents mean values, SDs, and inferential statistics for background characteristics. Given group differences noted, analyses controlled for BMI, mean arterial blood pressure, sleep quality, perceived stress, and psychological distress. Moreover, given well-established sex differences in pain,1,65 sex was included as a control variable, but its influence (as well as other control variables) will not be discussed to keep the discussion focused.

3.2. Does pain-related anxiety provide an indirect path between race and pain processing?

As noted in Table 2, pain-related anxiety significantly mediated the relationships between NA race and electric tolerance, heat tolerance, ischemia tolerance, cold pressor tolerance, and CPM of NFR (Fig. 1). Thus, pain-related anxiety provides a mechanism linking NA status with lower tolerances and reduced ability to inhibit NFR. Notably, STAI state anxiety was nonsignificant in all models (data not shown). To help visualize these effects, Figure 2 depicts predicted values on dependent variables at group-specific 25th and 75th percentiles for pain-related anxiety (NA: 25th% = 25.50, 75th% = 58.58; NHW: 25th% = 18.70, 75th% = 51.50). As shown, pain-related anxiety generally resulted in lower pain tolerances and reduced NFR inhibition during CPM, but these effects were more pronounced for NAs because they experienced more pain-related anxiety.

Table 2
Table 2:
Results of bootstrapped mediation analyses predicting pain outcomes.
Figure 1.
Figure 1.:
Bootstrapped unstandardized regression coefficients (and 95% bootstrapped confidence intervals) for the mediated relationships between race (NHW = 0 and NA = 1) and electric tolerance (A), heat tolerance (B), ischemia tolerance (C), cold tolerance (D), and conditioned pain modulation (CPM) of the nociceptive flexion reflex (NFR; E). Conditioned pain modulation of NFR was calculated from a change score with negative values indicating inhibition and positive values indicating facilitation. All models controlled for: biological sex, BMI, mean arterial blood pressure, sleep quality, perceived stress, psychological symptoms/distress, and state anxiety. These models suggest that Native Americans (NA) experience greater pain-related anxiety that leads to reduced pain tolerance and less inhibition of NFR. BMI, body mass index.
Figure 2.
Figure 2.:
Predicted group differences on pain-dependent variables. Values on dependent variables were estimated from regression equations, with pain-related anxiety as a predictor. Low (25th percentile) and high (75th percentile) values for pain-related anxiety were entered into the regression equation to make the predictions. Given that Native Americans (NA) reported more pain-related anxiety (25th% = 25.5, 75th% = 58.58) than non-Hispanic whites (NHW; 25th% = 18.70, 75th% = 51.5), this led to lower pain tolerances and reduced NFR inhibition during the conditioned pain modulation (CPM) task for NAs. Because these graphs depict predicted values based on arbitrarily determined low vs high values of pain-related anxiety (essentially points along a regression line), the significance of group differences cannot be tested. Values for ischemia and cold tolerance were inverse transformed to place them back into their original units after being log10 transformed. NFR, nociceptive flexion reflex.

3.3. Exploratory moderation analyses

To examine whether race moderates the relationships between pain-related anxiety and pain outcomes, we conducted bootstrapped hierarchical regression analyses in PROCESS and entered control variables and the main effects of race and pain-related anxiety before the interaction. None of the race × pain-related anxiety interactions were significant (Table 3), indicating that relationships between pain-related anxiety and pain outcomes did not differ between NHWs and NAs.

Table 3
Table 3:
Bootstrapped regression coefficients, 95% confidence intervals (CI), and effect sizes for the interaction of race and pain-related anxiety in predicting pain outcomes.

4. Discussion

We have previously shown that NAs and NHWs are similar in peripheral nociceptive fiber function, spinal amplification, endogenous pain inhibition, and pain sensitivity (except cold pain).62 By contrast, NAs experienced more pain-related anxiety than NHWs.61 Interestingly, NAs do not report more anxiety unrelated to pain (ie, STAI). Given this, the current study tested whether pain-related anxiety might promote pronociceptive processes in NAs. We found that pain-related anxiety mediated the relationship between NA race and pain tolerance measures, as well as CPM-related inhibition of the NFR. It did not mediate relationships with CPM of pain, or TS (TS-Pain and TS-NFR).

4.1. Implications

These findings have several implications. First, they suggest that stronger affective-motivational reactions play a role in pain risk for NAs. There is a large existing literature suggesting that negative affect (especially pain-related anxiety) can facilitate experimental and clinical pain.15,23,36,52,64,70,72,74 Our results support this and underscore the importance of this relationship for NAs because pain-related anxiety served as a mechanism linking NAs to pronociceptive processes. We believe this may also contribute to their increased chronic pain risk (Fig. 3).

Figure 3.
Figure 3.:
Model depicting a hypothetical pathway by which pain-related anxiety could promote chronic pain risk in Native Americans.

Second, pain-related anxiety may promote pain risk in NAs, not because it is a unique mechanism, but because NAs experience greater pain-related anxiety. Exploratory moderation analyses found that race and pain-related anxiety did not interact to predict any pain outcome. This demonstrates that the strength of the relationships between pain-related anxiety and pain outcomes does not vary between NAs and NHWs. Instead, greater pain-related anxiety experienced by NAs pushes them farther along a pain risk continuum because pain-related anxiety is a pronociceptive process.

Third, pain-related anxiety disrupts descending inhibition of spinal nociception (NFR) in NAs without impairing endogenous inhibition of pain and without promoting spinal sensitization (temporary hyperexcitability of dorsal horn neurons due to peripheral input, as assessed by TS-NFR).25,85Figure 2 shows that pain-related anxiety may even tip the modulatory balance toward facilitation (disinhibition). Thus, brain-to-spinal cord (descending) mechanisms may disinhibit spinal neurons when pain-related anxiety is high. This could increase pain risk.

It is worth noting that pain-related anxiety mediated the relationship between NA race and CPM of NFR, but not CPM of pain. This is likely a result of separate neural mechanisms that mediate these processes. An fMRI study53 found that CPM-related changes in pain are likely due to a corticocortical circuit, whereas CPM-related changes in NFR involves a corticospinal circuit. The current study suggests that pain-related anxiety may have an effect on the corticospinal circuit in NAs, without affecting the corticocortical circuit. This implies that pain-related anxiety allows a greater ascending barrage of nociceptive signals through to supraspinal centers. Interestingly, the subjective experience of those signals may still be inhibited, given the lack of mediation for CPM of pain.

It is currently unknown whether a greater ascending nociceptive barrage may still result in negative sequelae, although pain experience is dampened, but recent evidence from our lab suggests this might be the case. Preliminary analyses of OK-SNAP follow-up data suggest that 16% of participants have gone on to develop chronic pain (defined as pain lasting ≥3 months that does not remit at future follow-ups). Analyses show that CPM of NFR, but not CPM of electric pain, predicts this transition.38 However, these preliminary findings should be interpreted with caution until verified after all 5-year follow-up data are collected.

A fourth implication is that the mechanisms that promote NA pain may be different than other minorities. Race/ethnicity is known to contribute to pain and chronic pain prevalence,8,10,19,21,22,32,34,39–41,44,47,49,56,57,67,71,80,84 but most studies have focused on African-American and Hispanic populations. These generally find that these groups have lower pain tolerances and report more pain in response to suprathreshold stimuli than NHWs.7,40,56 This has been hypothesized to stem, in part, from augmented pain amplification processes (enhanced TS-Pain)16,32,49,66 and less effective pain inhibitory processes (eg, CPM).9,16,50 By contrast, we do not find that NAs generally differ from NHWs on these measures.62 Rather, this study suggests that pain-related anxiety is one factor that promotes a racial/ethnic difference for NAs. Notably, these findings are not likely due to an anxiety-related response bias because CPM of NFR was affected.

Given that pain-related anxiety appears to be a promoter of spinal facilitation and hyperalgesia (lower tolerance) in NAs, this implies that targeting pain-related anxiety may reduce pain risk by eliminating or minimizing these downstream pronociceptive effects (Fig. 3). Luckily, a number of cognitive-behavioral treatments (CBTs) exist that reduce pain-related anxiety/fear,2,14,37,51,78 and a few studies have also demonstrated that brief CBT can increase descending inhibition of spinal nociception.26,27,60,76 This study suggests CBTs that target anxiety may be particularly relevant for preventing and/or treating pain in NAs. In addition, evidence suggests that anxiety is associated with the release of cholecystokinin (CCK) that in turn promotes hyperalgesia,13 thus CCK antagonists (eg, proglumide) may help reduce pain-related anxiety's pronociceptive effects in NAs.5

4.2. Potential limitations

We only recruited healthy, pain-free participants, so we cannot generalize our findings to clinical populations, including those with chronic pain. It is possible that pain-related anxiety has different relationships with pronociceptive processes in clinical samples. Moreover, the levels of anxiety may differ in clinical populations, perhaps equalizing groups on this variable and obscuring/eliminating the mediation effects we noted. We also used stringent inclusion criteria that might have excluded persons at the greatest risk for pain and altered the observed relationships. That said, it did not seem to eliminate the higher pain risk in NAs, because our follow-up screens suggest NAs are developing chronic pain at higher rates than NHWs.69

Our NA sample was drawn mostly from tribes in the northeastern Oklahoma region where most NAs are not reservation-dwelling. It is not clear whether our results will generalize to NAs from other geographical regions, particularly those living on reservations where access to health care may be more limited. Moreover, there are likely to be important cultural variables that differ across NAs from different regions that might alter pain processing (eg, diet, beliefs, and acculturation).24 In addition, because our study included multiple pain tasks, we cannot rule out that some carryover effects occurred that could have impacted the results, although the order of tests was altered for each participant.

And finally, our assessment of pain-related anxiety was limited to a single VAS. This choice was made because we wanted to assess anxiety that was happening in the moment during the painful tasks, rather than rely on reports of how participants experience pain-related anxiety in general. Because we assessed it many times, it had to be brief, and we and others have used this approach successfully in previous studies.63,68 Moreover, many of the other measures of pain-related anxiety require respondents to have considerable previous experience with pain and/or chronic pain,45 and our participants were chronic pain-free. To improve the stability of our pain-related anxiety measurement, we averaged the items from multiple tasks. Despite this, other anxiety measures may produce different results.

4.3. Summary

This study examined the impact of pain-related anxiety on measures of pain processing in NAs and NHWs. Mediation analyses indicated that the tendency for NAs to experience greater pain-related anxiety is associated with impaired inhibition of spinal nociception and decreased pain tolerance. Thus, pain-related anxiety may contribute to the pain disparity in NAs.


The authors have no conflicts of interest to declare.


The authors thank Heather B. Coleman, Kathryn A. Thompson, Jessica M. Fisher, Samuel P. Herbig, Ky'Lee B. Barnoski, Garrett Newsom, and Lucinda Chee for their help with data collection. This research was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number R01MD007807. E.W. Lannon, S. Palit, and Y.M. Güereca were supported by a National Science Foundation Graduate Research Fellowship Program. The content is solely the responsibility of the authors and does not necessarily reflect the views of the National Institutes of Health, National Science Foundation, Indian Health Service, or the Cherokee Nation. Aspects of this research have been presented at the International Association for the Study of Pain's 2018 World Congress on Pain and at the 2019 American Pain Society conference.


[1]. Akinci MK, Johnston GAR. Sex differences in acute swim stress-induced changes in the binding of MK-801 to the NMDA subclass of glutamate receptors in mouse forebrain. J Neurochem 1993;61:2290.
[2]. Bailey KM, Carleton RN, Vlaeyen JW, Asmundson GJ. Treatments addressing pain-related fear and anxiety in patients with chronic musculoskeletal pain: a preliminary review. Cogn Behav Ther 2010;39:46–63.
[3]. Barnes PM, Adams PF, Powell-Griner E. Health characteristics of the American Indian or Alaska Native adult population: United States, 2004-2008. In: USDoHaH services editor. Vol. 20. Hyattesville: National Center for Health Statistics, 2010.
[4]. Bebbington P, Nayani T. The psychosis screening questionnaire. Int J Methods Psychatric Res 1995;5:11–19.
[5]. Benedetti F, Amanzio M, Casadio C, Oliaro A, Maggi G. Blockade of nocebo hyperalgesia by the cholecystokinin antagonist proglumide. PAIN 1997;71:135.
[6]. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index (PSQI): a new instrument for psychiatric research and practice. Psychiatry Res 1989;28:193–213.
[7]. Campbell CM, Edwards RR. Ethnic differences in pain and pain management. Pain Manag 2012;2:219–30.
[8]. Campbell CM, Edwards RR, Fillingim RB. Ethnic differences in responses to multiple experimental pain stimuli. PAIN 2005;113:20–6.
[9]. Campbell CM, France CR, Robinson ME, Logan HL, Geffken GR, Fillingim RB. Ethnic differences in diffuse noxious inhibitory controls. J Pain 2008;9:759–66.
[10]. Campbell CM, France CR, Robinson ME, Logan HL, Geffken GR, Fillingim RB. Ethnic differences in the nociceptive flexion reflex (NFR). PAIN 2008;134:91–6.
[11]. Cleeland CS, Gonin R, Baez L, Loehrer P, Pandya KJ. Pain and treatment of pain in minority patients with cancer. The Eastern Cooperative Oncology Group Minority Outpatient Pain Study. Ann Intern Med 1997;127:813–16.
[12]. Cohen S, Kamarck T, Mermelstein R. Perceived stress scale. Measuring stress: a guide for health and social scientists. Menlo Park, CA: Mind Garden, Inc, 1994.
[13]. Colloca L, Benedetti F. Nocebo hyperalgesia: how anxiety is turned into pain. Curr Opin Anaesthesiol 2007;20:435–9.
[14]. Compas BE, Haaga DA, Keefe FJ, Leitenberg H, Williams DA. Sampling of empirically supported psychological treatments from health psychology: smoking, chronic pain, cancer, and bulimia nervosa. J Consult Clin Psychol 1998;66:89–112.
[15]. Crombez G, Vlaeyen JW, Heuts PH, Lysens R. Pain-related fear is more disabling than pain itself: evidence on the role of pain-related fear in chronic back pain disability. PAIN 1999;80:329–39.
[16]. Cruz-Almeida Y, Sibille KT, Goodin BR, Petrov ME, Bartley EJ, Riley JL, King CD, Glover TL, Sotolongo A, Herbert MS. Racial and ethnic differences in older adults with knee osteoarthritis. Arthritis Rheumatol 2014;66:1800–10.
[17]. Derogatis LR. SCL-90-R: symptom checklist-90-R: administration, scoring & procedures manual. Minneapolis: National Computer Systems, Inc, 1994.
[18]. Deyo RA, Mirza SK, Martin BI. Back pain prevalence and visit rates: estimates from U.S. national surveys, 2002. Spine 2006;31:2724–7.
[19]. Edwards CL, Fillingim RB, Keefe F. Race, ethnicity and pain. PAIN 2001;94:133–7.
[20]. Edwards RR. Individual differences in endogenous pain modulation as a risk factor for chronic pain. Neurology 2005;65:437–43.
[21]. Edwards RR, Doleys DM, Fillingim RB, Lowery D. Ethnic differences in pain tolerance: clinical implications in a chronic pain population. Psychosom Med 2001;63:316–23.
[22]. Edwards RR, Fillingim RB. Ethnic differences in thermal pain responses. Psychosom Med 1999;61:346–54.
[23]. Edwards RR, Moric M, Husfeldt B, Buvanendran A, Ivankovich O. Ethnic similarities and differences in the chronic pain experience: a comparison of African American, Hispanic, and white patients. Pain Med 2005;6:88–98.
[24]. Ehrhardt MD, Gray KN, Kuhn BL, Lannon EW, Palit S, Sturycz CA, Guereca YM, Payne MF, Hellman NM, Toledo TA, Hahn BJ, Shadlow JO, Rhudy JL. A qualitative analysis of pain meaning: results from the Oklahoma Study of Native American Pain Risk (OK-SNAP). J Pain 2019;20:S4.
[25]. Eide PK. Wind-up and the NMDA receptor complex from a clinical perspective. Eur J Pain 2000;4:5–15.
[26]. Emery CF, France CR, Harris J, Norman G, Vanarsdalen C. Effects of progressive muscle relaxation training on nociceptive flexion reflex threshold in healthy young adults: a randomized trial. PAIN 2008;138:375–9.
[27]. Emery CF, Keefe FJ, France CR, Affleck G, Waters S, Fondow MD, McKee DC, France JL, Hackshaw KV, Caldwell DS, Stainbrook D. Effects of a brief coping skills training intervention on nociceptive flexion reflex threshold in patients having osteoarthritic knee pain: a preliminary laboratory study of sex differences. J Pain Symptom Manage 2006;31:262–9.
[28]. Farrell M, Gibson S. Age interacts with stimulus frequency in the temporal summation of pain. Pain Med 2007;8:514–20.
[29]. Ferucci ED, Templin DW, Lanier AP. Rheumatoid arthritis in American Indians and Alaska Natives: a review of the literature. Semin Arthritis Rheum 2005;34:662–7.
[30]. Fillingim RB, Maixner W, Girdler SS, Light KC, Sheps DS, Mason GA. Ischemic but not thermal pain sensitivity varies across the menstrual cycle. Psychosom Med 1997;559:512.
[31]. Fritz MS, MacKinnon DP. Required sample size to detect the mediated effect. Psychol Sci 2007;18:233–9.
[32]. Goodin BR, Bulls HW, Herbert MS, Schmidt J, King CD, Glover TL, Sotolongo A, Sibille KT, Cruz-Almeida Y, Staud R. Temporal summation of pain as a prospective predictor of clinical pain severity in adults aged 45 years and above with knee osteoarthritis: ethnic differences. Psychosom Med 2014;76:302.
[33]. Green CR, Anderson KO, Baker TA, Campbell LC, Decker S, Fillingim RB, Kaloukalani DA, Lasch KE, Myers C, Tait RC, Todd KH, Vallerand AH. The unequal burden of pain: confronting racial and ethnic disparities in pain. Pain Med 2003;4:277–94.
[34]. Hastie BA, Riley JL III, Fillingim RB. Ethnic differences in pain coping: factor structure of the coping strategies questionnaire and coping strategies questionnaire-revised. J Pain 2004;5:304–16.
[35]. Hayes AF. Introduction to mediation, moderation, and conditional process analysis: a regression-based approach. New York, NY: Guilford Publications, 2017.
[36]. Hinrichs-Rocker A, Schulz K, Järvinen I, Lefering R, Simanski C, Neugebauer EA. Psychosocial predictors and correlates for chronic post-surgical pain (CPSP)–a systematic review. Eur J Pain 2009;13:719–30.
[37]. Holroyd KA, Nash JM, Pingel JD, Cordingley GE, Jerome A. A comparison of pharmacological (amitriptyline HCL) and nonpharmacological (cognitive-behavioral) therapies for chronic tension headaches. J Consult Clin Psychol 1991;59:387.
[38]. Huber FA, Kuhn BL, Lannon EW, Sturycz CA, Payne MF, Hellman N, Toledo TA, Guereca YM, DeMuth M, Palit S, Shadlow JO, Rhudy JL. Less efficient endogenous inhibition of spinal nociception predicts chronic pain onset: a prospective analysis from the Oklahoma Study of Native American Pain Risk (OK-SNAP). J Pain 2019;20(suppl):S40.
[39]. Jimenez N, Garroutte E, Kundu A, Morales L, Buchwald D. A review of the experience, epidemiology, and management of pain among American Indian, Alaska native, and Aboriginal Canadian peoples. J Pain 2011;12:511–22.
[40]. Kim HJ, Yang GS, Greenspan JD, Downton KD, Griffith KA, Renn CL, Johantgen M, Dorsey SG. Racial and ethnic differences in experimental pain sensitivity: systematic review and meta-analysis. PAIN 2017;158:194–211.
[41]. Komiyama O, Kawara M, De Laat A. Ethnic differences regarding tactile and pain thresholds in the trigeminal region. J Pain 2007;8:363–9.
[42]. Leake J, Jozzy S, Uswak G. Severe dental caries, impacts and determinants among children 2-6 years of age in Inuvik Region, Northwest Territories, Canada. J Can Dent Assoc 2008;74:519.
[43]. Loeser JD, Melzack R. Pain: an overview. Lancet 1999;353:1607–9.
[44]. Lu Q, Zeltzer L, Tsao J. Multiethnic differences in responses to laboratory pain stimuli among children. Health Psychol 2013;32:905.
[45]. Lundberg M, Grimby-Ekman A, Verbunt J, Simmonds M. Pain-related fear: a critical review of the related measures: Pain research and treatment, 2011. pp. 2011.
[46]. Mauldin J, Cameron HD, Jeanotte D, Solomon G, Jarvis JN. Chronic arthritis in children and adolescents in two Indian health service user populations. BMC Musculoskelet Disord 2004;5:30.
[47]. McCracken LM, Matthews AK, Tang TS, Cuba SL. A comparison of Blacks and Whites seeking treatment for chronic pain. Clin J Pain 2001;17:249–55.
[48]. Meagher MW, Arnau RC, Rhudy JL. Pain and emotion: effects of affective picture modulation. Psychosom Med 2001;63:79–90.
[49]. Mechlin B, Heymen S, Edwards CL, Girdler SS. Ethnic differences in cardiovascular-somatosensory interactions and in the central processing of noxious stimuli. Psychophysiology 2011;48:762–73.
[50]. Mechlin MB, Maixner W, Light KC, Fisher JM, Girdler SS. African Americans show alterations in endogenous pain regulatory mechanisms and reduced pain tolerance to experimental pain procedures. Psychosom Med 2005;67:948.
[51]. Morley S, Eccleston C, Williams A. Systematic review and meta-analysis of randomized controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headache. PAIN 1999;80:1–13.
[52]. Naliboff B, Rhudy JL. Anxiety and functional pain disorders. In: EA Mayer, MC Bushnell, editors. Functional pain syndromes: presentation and pathophysiology. Seattle: IASP Press, 2009. pp. 185–214.
[53]. Piché M, Arsenault M, Rainville P. Cerebral and cerebrospinal processes underlying counterirritation analgesia. J Neurosci 2009;29:14236–46.
[54]. Preacher KJ, Hayes AF. SPSS and SAS procedures for estimating indirect effects in simple mediation models. Behav Res Methods Instrum Comput 2004;36:717–31.
[55]. Preacher KJ, Hayes AF. Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models. Behav Res Methods 2008;40:879–91.
[56]. Rahim-Williams B, Riley JL III, Williams AK, Fillingim RB. A quantitative review of ethnic group differences in experimental pain response: do biology, psychology, and culture matter? Pain Med 2012;13:522–40.
[57]. Rhee H. Prevalence and predictors of headaches in US adolescents. Headache 2000;40:528–38.
[58]. Rhudy JL, Dubbert PM, Parker JD, Burke RS, Williams AE. Affective modulation of pain in substance dependent veterans. Pain Med 2006;7:483–500.
[59]. Rhudy JL, France CR, Bartley EJ, McCabe KM, Williams AE. Psychophysiological responses to pain: further validation of the nociceptive flexion reflex (NFR) as a measure of nociception using multilevel modeling. Psychophysiology 2009;46:939–48.
[60]. Rhudy JL, Hellman N, Sturycz CA, Toledo TA, Palit S. Modified biofeedback (Conditioned Biofeedback) promotes antinociception by increasing the nociceptive flexion reflex threshold and reducing temporal summation of pain: a controlled trial. J Pain 2019. doi: 10.1016/j.jpain.2019.1010.1006.
[61]. Rhudy JL, Lannon EW, Kuhn BL, Palit S, Payne MF, Sturycz CA, Hellman N, Güereca YM, Toledo TA, Coleman HB, Thompson KA, Fisher JM, Herbig SP, Barnoski KB, Chee L, Shadlow JO. Sensory, affective, and catastrophizing reactions to multiple stimulus modalities: results from the Oklahoma Study of Native American Pain Risk. J Pain 2019;20:965–79.
[62]. Rhudy JL, Lannon EW, Kuhn BL, Palit S, Payne MF, Sturycz CA, Hellman N, Guereca YM, Toledo TA, Huber F, Demuth MJ, Hahn BJ, Chaney JM, Shadlow JO. Assessing peripheral fibers, pain sensitivity, central sensitization, and descending inhibition in Native Americans: main findings from the Oklahoma Study of Native American Pain Risk. PAIN 2020:161:388–404.
[63]. Rhudy JL, Martin SL, Terry EL, France CR, Bartley EJ, DelVentura JL, Kerr KL. Pain catastrophizing is related to temporal summation of pain, but not temporal summation of the nociceptive flexion reflex. PAIN 2011;152:794–801.
[64]. Rhudy JL, Meagher MW. Fear and anxiety: divergent effects on human pain thresholds. PAIN 2000;84:65–75.
[65]. Rhudy JL, Williams AE. Gender differences in pain: do emotions play a role? Gend Med 2005;2:208–26.
[66]. Riley JL, Cruz-Almeida Y, Glover TL, King CD, Goodin BR, Sibille KT, Bartley EJ, Herbert MS, Sotolongo A, Fessler BJ. Age and race effects on pain sensitivity and modulation among middle-aged and older adults. J Pain 2014;15:272–82.
[67]. Riley JL III, Wade JB, Myers CD, Sheffield D, Papas RK, Price DD. Racial/ethnic differences in the experience of chronic pain. PAIN 2002;100:291.
[68]. Robinson ME, Biolosky JE, Bishop MD, Price DD, George SZ. Supra-threshold scaling, temporal summation, and after-sensation: relationships to each other and anxiety/fear. J Pain Res 2010;3:25–32.
[69]. Ross E, Huber F, Kuhn B, Lannon E, Sturycz C, Payne M, Hellman N, Toledo T, Güereca Y, Palit S, Demuth M, Shadlow JO, Rhudy JL. Assessing chronic pain onset in Native Americans: follow-up results from the Oklahoma Study of Native American Pain Risk (OK-SNAP). J Pain 2019;20:S33.
[70]. Ruehlman LS, Karoly P, Newton C. Comparing the experiential and psychosocial dimensions of chronic pain in African Americans and Caucasians: findings from a national community sample. Pain Med 2005;6:49–60.
[71]. Sheffield D, Biles PL, Orom H, Maixner W, Sheps DS. Race and sex differences in cutaneous pain perception. Psychosom Med 2000;62:517.
[72]. Slade GD, Diatchenko L, Bhalang K, Sigurdsson A, Fillingim RB, Belfer I, Max MB, Goldman D, Maixner W. Influence of psychological factors on risk of temporomandibular disorders. J Dent Res 2007;86:1120–5.
[73]. Spielberger CD. State-trait anxiety inventory. Palo-Alto: Consulting Psychologists Press, 1983.
[74]. Staud R, Price DD, Robinson ME, Vierck CJ Jr. Body pain area and pain-related negative affect predict clinical pain intensity in patients with fibromyalgia. J Pain 2004;5:338–43.
[75]. Sullivan MJL, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychol Assess 1995;7:524–32.
[76]. Terry EL, Thompson KA, Rhudy JL. Experimental reduction of pain catastrophizing modulates pain report but not spinal nociception as verified by mediation analyses. PAIN 2015;156:1477–88.
[77]. Todd KH. Pain assessment and ethnicity. Ann Emerg Med 1996;27:421–3.
[78]. Turner JA, Clancy S. Comparison of operant behavioral and cognitive-behavioral group treatment for chronic low back pain. J Consult Clin Psychol 1988;56:261.
[79]. USDHHS. Summary of health statistics for U.S. adults: national health interview survey, 2009. In: HaH Services, editor. Hyattsville: DHHS, 2010.
[80]. Wang H, Papoiu ADP, Coghill RC, Patel T, Wang N, Yosipovitch G. Ethnic differences in pain, itch and thermal detection in response to topical capsaicin: African Americans display a notably limited hyperalgesia and neurogenic inflammation. Br J Dermatol 2010;162:1023–9.
[81]. Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 Health survey manual and interpretation guide. Boston: The Health Institute New England Medical Center, 1993.
[82]. Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 1988;54:1063.
[83]. Wilcox RR. Understanding and applying basic statistical methods using R. Hoboken, NJ: John Wiley & Sons, 2016.
[84]. Woodrow KM, Friedman GD, Siegelaub AB, Collen MF. Pain tolerance: differences according to age, sex and race. Psychosom Med 1972;34:548–56.
[85]. Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. PAIN 1991;44:293.
[86]. Yarnitsky D. Role of endogenous pain modulation in chronic pain mechanisms and treatment. PAIN 2015;156:S24–31.
[87]. Yarnitsky D, Granot M, Granovsky Y. Pain modulation profile and pain therapy: between pro- and antinociception. PAIN 2014;155:663–5.

Quantitative sensory testing; Ethnic differences; Native Americans; Pain modulation; Pain-related affect; Mediation

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.