ARTHRITIS & RHEUMATOLOGY Vol. 66, No. 7, July 2014, pp 1800–1810 DOI 10.1002/art.38620 © 2014, American College of Rheumatology

Racial and Ethnic Differences in Older Adults With Knee Osteoarthritis Yenisel Cruz-Almeida,1 Kimberly T. Sibille,1 Burel R. Goodin,2 Megan E. Petrov,2 Emily J. Bartley,1 Joseph L. Riley III,1 Christopher D. King,1 Toni L. Glover,1 Adriana Sotolongo,2 Matthew S. Herbert,2 Jessica K. Schmidt,2 Barri J. Fessler,2 Roland Staud,1 David Redden,2 Laurence A. Bradley,2 and Roger B. Fillingim1 Objective. Knee osteoarthritis (OA) contributes significantly to disability in older individuals, and racial/ethnic minorities are disproportionately affected. The present study aimed to characterize differences in clinical and experimental pain, including pain inhibition, among older African American (AA) and nonHispanic white (NHW) subjects with knee OA. Methods. AA and NHW subjects with knee OA (n ⴝ 267) completed clinical and functional pain assessments, including quantitative sensory testing (QST). We hypothesized that, when compared to NHW subjects, AA subjects would display 1) lower pain tolerance and higher ratings of heat-, mechanical-, and cold-induced pain, 2) greater temporal summation of pain, 3) reduced pain inhibition, and 4) greater clinical pain and poorer function. In addition, we hypothesized that the findings from QST would significantly predict the severity of clinical pain within each race/ethnicity.

Results. AA subjects with knee OA displayed increased pain sensitivity, greater temporal summation, and reduced pain inhibition when compared to NHW subjects with knee OA. Moreover, AA subjects reported greater clinical pain and poorer function. Racial/ethnic differences in clinical pain became nonsignificant when the analyses were controlled for education and annual income, whereas differences in QST findings remained highly significant. Although the extent of pain inhibition predicted the severity of clinical pain in both groups, different QST measures were additionally predictive of clinical pain within each group. Conclusion. The results of this study establish that there are racial/ethnic differences in experimental and clinical pain and function in older individuals with knee OA. Our findings indicating that different QST measures were associated with clinical pain within the 2 racial/ethnic groups, whereas reduced pain inhibition was important in all participants, warrant further study in order to elucidate the common and group-specific pathophysiologic mechanisms contributing to clinical pain in OA.

Supported by NIH grants AG-033906 and AG-039659. The University of Florida Center for Clinical and Translational Science and the University of Alabama at Birmingham Center for Clinical and Translational Science received NIH grants UL1-TR-000064 and UL1TR-000165, respectively, from the National Center for Advancing Translational Sciences and the National Center for Research Resources. 1 Yenisel Cruz-Almeida, MSPH, PhD, Kimberly T. Sibille, MA, PhD, Emily J. Bartley, PhD, Joseph L. Riley III, PhD, Christopher D. King, PhD, Toni L. Glover, PhD, GNP-BC, Roland Staud, MD, Roger B. Fillingim, PhD: University of Florida, Gainesville; 2Burel R. Goodin, PhD, Megan E. Petrov, PhD, Adriana Sotolongo, MPH, Matthew S. Herbert, MS, Jessica K. Schmidt, BS, Barri J. Fessler, MD, MSPH, David Redden, PhD, Laurence A. Bradley, PhD: University of Alabama at Birmingham. Dr. Bradley receives royalties from Up To Date for online reviews of rheumatology literature. Dr. Fillingim owns stock or stock options in Algynomics. Address correspondence to Yenisel Cruz-Almeida, MSPH, PhD, University of Florida, PO Box 103628, Gainesville, FL 326103628. E-mail: [email protected]. Submitted for publication August 13, 2013; accepted in revised form March 4, 2014.

Osteoarthritis (OA) is a major source of years of life lost due to disability in the older population (1), and the knee is the most commonly affected joint. Approximately 1 in 2 people may develop symptomatic knee OA by age 85 years (2). A disproportionate number of racial/ethnic minorities are affected by knee OA (3). Compared to non-Hispanic white (NHW) individuals, a greater proportion of African American (AA) individuals report having knee OA (both radiographic and symptomatic OA) (4). Several investigators have reported greater pain severity among AA subjects compared to NHW subjects with knee OA (5–8), while others have reported no such racial/ethnic differences in 1800

RACIAL DIFFERENCES IN KNEE OSTEOARTHRITIS

the severity of OA pain, including pain in knee OA (9). In addition to racial/ethnic differences in OA-related clinical pain, several studies have reported significantly greater disability among AA subjects compared to white subjects with knee OA (10–12). A complex web of factors contributes to these disparities in OA-related pain and disability, ranging from differences in physiologic pain processing to socioeconomic factors (5,6,9,13–16) and healthcare-related factors (i.e., access to and preferences for treatment) (17,18). A substantial body of literature has addressed racial/ethnic group differences in experimentally induced pain, and these studies have demonstrated, after application of a variety of pain stimuli, greater sensitivity to pain among healthy AA subjects compared to NHW subjects, e.g., findings demonstrating a lower pain threshold and lower tolerance for pain, as well as significantly higher suprathreshold pain ratings, among healthy AA subjects compared to NHW subjects (19– 23). In addition to differences in basal pain sensitivity, there is evidence supporting differences in endogenous pain-modulatory systems (i.e., pain inhibition and facilitation). For example, NHW subjects showed more robust conditioned pain modulation (CPM) compared to AA subjects (24), suggesting that pain-inhibitory function is reduced among healthy AA subjects. Furthermore, AA subjects exhibited greater temporal summation of pain (i.e., repeated application of painful stimuli led to progressively more intense pain) (25), a finding that represents a transient form of central sensitization. Therefore, there is considerable evidence to demonstrate racial/ethnic group differences in pain perception as well as in endogenous pain modulation between healthy AA subjects and healthy NHW subjects. Comparisons of experimental pain sensitivity between racial/ethnic groups may elucidate differences in clinical pain, since the extent of experimental pain sensitivity is predictive of the severity of clinical pain (26–28). However, limited information is available regarding racial/ethnic group differences in experimental pain responses among individuals with knee OA (8), which is particularly important given the public health impact of OA and its greater burden among AA subjects. Moreover, no investigator to date has determined whether experimental measures of basal pain sensitivity and endogenous pain modulation could be related to the extent of clinical pain and disability in a race/ethnicitydependent manner among individuals with knee OA. The aim of the present study was to characterize differences in experimental pain sensitivity, endogenous pain inhibition, clinical pain, and pain-related disability

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among older AA subjects and NHW subjects with knee OA. We hypothesized that, when compared to NHW subjects, AA subjects would display 1) lower pain tolerance and higher ratings of heat-, mechanical-, and cold-induced pain, 2) greater temporal summation of pain, suggesting that central pain sensitization is increased in AA subjects, 3) lower CPM, suggesting that pain inhibition is reduced among AA subjects, and 4) higher levels of self-reported clinical pain and disability as well as poorer performance on functional measures. In addition, we hypothesized that the extent of experimental pain sensitivity would significantly predict the severity of clinical pain within each racial/ethnic group. These hypotheses were also examined after the analyses were adjusted for important confounding factors, including demographic characteristics and OAspecific variables. PATIENTS AND METHODS Study subjects. Individuals between ages 45 years and 85 years who self-identified their race/ethnicity as AA or NHW were enrolled in the study at the University of Florida (UF) and University of Alabama at Birmingham (UAB). Participants were recruited through the community (e.g., posted fliers, radio and print media advertisements, word-of-mouth referrals) and clinic-based recruitment methods between January 2010 and October 2013. The study was approved by the UF and UAB Institutional Review Boards. The general study methods are summarized in Figure 1. Participants presented with unilateral or bilateral symptomatic knee OA, with the diagnosis based on the American College of Rheumatology clinical criteria for knee OA (presence of knee pain, stiffness lasting ⬍30 minutes, and functional limitations) (29), regardless of radiographic evidence. At the time of study entry, posteroanterior and lateral radiographs of the knees were obtained from all participants, with the knees in a bilateral weight-bearing, fixed-flexion position, as described elsewhere (30). Each knee joint was scored for the severity of radiographic OA using the Kellgren and Lawrence grading system (score range 0–4) (31). Participants were excluded if they had any of the following features: 1) prosthetic knee replacement or other clinically significant surgery to the affected knee; 2) uncontrolled hypertension (blood pressure ⬎150/95 mm Hg), heart failure, or history of acute myocardial infarction; 3) peripheral neuropathy; 4) systemic rheumatic disorders including rheumatoid arthritis, systemic lupus erythematosus, and fibromyalgia; 5) daily opioid use; 6) cognitive impairment; or 7) hospitalization for psychiatric illness within the preceding year. General study procedures. After informed consent was obtained, the study participants attended a health assessment session (HAS) and a quantitative sensory testing (QST) session, as previously described (8,32). Each participant completed questionnaires assessing general health and demographic information, including each participant’s age, sex, weight, height, annual household income, and highest level of

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Figure 1. Diagram of the study methods and subject participation. GCPS ⫽ Graded Chronic Pain Scale; WOMAC ⫽ Western Ontario and McMaster Universities Osteoarthritis Index; SPPB ⫽ Short Physical Performance Battery; CPM ⫽ conditioned pain modulation.

education. During the HAS, a study physician (BJF or RS) or nurse practitioner (TLG) completed a brief health history and physical examination, including administration of the Short Physical Performance Battery (SPPB) (as detailed below). To designate each participant’s most painful knee as the index knee for QST procedures, the study physician or nurse practitioner performed joint palpation of the knees. The QST session took place within 4 weeks of the HAS. Individuals completed measures of clinical pain and function (as detailed below), followed by thermal, mechanical, temporal summation, and CPM assessments. The order of the thermal and mechanical tests was counterbalanced, followed by the cold pressor procedure. Thereafter, following a rest period, CPM was assessed. Recorded instructions were played prior to the commencement of all procedures. QST procedures. Thermal. Contact heat stimuli were delivered using a computer-controlled device (Medoc Pathway Pain & Sensory Evaluation System). The thermode position was moved between trials to avoid sensitization and/or habit-

CRUZ-ALMEIDA ET AL

uation of cutaneous receptors. Heat–pain threshold and heat– pain tolerance levels were assessed on both the index knee and the ipsilateral ventral forearm using an ascending method of limits, with a 16 ⫻ 16 mm thermode. For each trial, the probe would start at the baseline temperature (32°C) and increase at a rate of 0.5°C/second until the participant responded by pressing a button. Participants were instructed to press the button when the sensation “first became painful” (i.e., threshold) and also when they “no longer felt able to tolerate the pain” (i.e., tolerance). The temperatures at the time of threshold and tolerance were recorded. The mean temperature from 3 trials was used for analysis. Temporal summation of thermal pain was assessed by verbally rating the intensity of pain evoked by each of 5 brief, repetitive, suprathreshold heat pulses on a scale of 0 (no pain sensation) to 100 (the most intense pain sensation imaginable). Three target temperatures (44°C, 46°C, and 48°C) were delivered by a contact heat-evoked potential stimulator thermode for ⬍1 second, with an ⬃2.5-second interpulse interval during which the temperature of the contactor returned to baseline (32°C). The procedure was terminated if the participant rated the thermal pain at 100. The average rating over the 5 trials, an index of overall sensitivity to suprathreshold heat–pain, and the maximum increase in pain, a measure of temporal summation, were determined for each participant and used in the analyses. The latter was calculated by subtracting the first trial rating from the maximum rating provided at each temperature. Mechanical. Pressure–pain thresholds were evaluated at the medial and lateral aspects of the index knee as well as the ipsilateral quadriceps, trapezius, and dorsal forearm. The order of testing sites was counterbalanced and randomized. For each site, a handheld Medoc digital pressure algometer (Algomed) was applied at a constant rate of 30 kPa/second. The participant was instructed to press a button when the sensation “first became painful,” and the pressure was recorded. An average pressure–pain threshold was determined for each site from 3 trials. The maximum pressure for the knee sites was 600 kPa and 1,000 kPa at the other sites. If participants did not report pain at the maximum pressure level, the procedure was terminated and a pressure of 600 or 1,000 kPa was assigned for that trial. After pressure–pain testing, we assessed sensitivity to punctate mechanical stimuli at the patella and back of the ipsilateral hand, using a calibrated nylon monofilament delivering a target force of 300 grams. Testing sites were randomized. Participants provided verbal pain ratings following a single contact and after 10 contacts, at a rate of 1 contact/ second. Ratings were made on a scale of 0 (no pain sensation) to 100 (the most intense pain sensation imaginable). The procedure was repeated, and the ratings for a single contact and for multiple contacts were summed for analysis. Cold pressor procedure. Following the thermal and mechanical procedures, cold sensitivity was probed with a modified procedure based on the cold pressor task. This procedure involved three 1-minute hand immersions in a cold-water bath (Thermo Scientific Refrigerated Bath) at temperatures of 16°C, 12°C, and 8°C. Participants placed their right hand (up to their wrist) into the water for up to 1 minute or until they wished to stop. During each immersion, participants were instructed to verbally indicate when the cold

RACIAL DIFFERENCES IN KNEE OSTEOARTHRITIS

sensation “first became painful” (i.e., threshold). Participants also provided verbal ratings of pain intensity and unpleasantness at the end of the 1-minute immersion. Verbal ratings of pain intensity and unpleasantness were on a scale of 0 (no pain sensation/unpleasantness) to 100 (the most intense/unpleasant pain sensation imaginable). If a participant withdrew the hand from the water bath before the 1-minute period ended, the withdrawal time was recorded. Conditioned pain modulation. CPM was evaluated by determining the ability of a conditioning stimulus (i.e., coldwater immersion) to diminish the painfulness of a test stimulus (i.e., heat–pain ratings). First, participants rated a series of 5 heat–pain trials on the left ventral forearm to measure baseline sensitivity. Next, participants immersed their right hand into the cold-water bath for 1 minute. Then, participants removed their hand and rated a second series of heat–pain trials. For both the conditioning and the test stimuli, temperatures were tailored to each participant to achieve a stimulus that produced a rating of 40–60 on the 0–100 scale. Measures of clinical pain and function. Graded Chronic Pain Scale (GCPS). The GCPS evaluates global pain severity and pain-related interference over the past 6 months and consists of 7 items related to pain intensity and pain interference (i.e., loss of work days due to pain, interference in daily activities) (33). With a 0–10 numeric rating scale, participants rated the intensity of their current knee pain and the worst and average pain during the past 6 months. These 3 items were averaged and multiplied by 10 to generate a GCPS characteristic pain intensity score. Using the same scale, participants rated the degree to which their knee pain interfered with daily activities (3 items) during the past 6 months, and these 3 items were averaged and multiplied by 10 to generate a GCPS disability score. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). The WOMAC (34) assesses symptoms of knee OA in the past 48 hours. For this study, the 4-point Likert scale version was used. The WOMAC yields 3 subscales, including pain during activities (5 items), stiffness during the day (2 items), and impairments in physical function (17 items), with higher scores indicating worse pain, stiffness, and impairments in physical function. Short Physical Performance Battery. The SPPB (35) was used as an observed measure of functional limitations. The SPPB has been used as a reliable and valid performance-based measure of physical function in many studies (36,37). Components include standing balance, 4-meter gait speed, and chairrising tasks. A single summary performance score is also calculated, ranging from 0 to 12 (with lower scores indicating greater functional limitations) (35,38). Statistical analysis. Data analysis was performed using IBM SPSS software (version 22). Values are expressed as the mean ⫾ SD, unless stated otherwise. We used 2 separate approaches to assess racial/ethnic differences: models excluding confounding variables (i.e., covariates), and models with inclusion of confounding variables. The covariates were selected based on statistically significant pairwise differences between racial/ethnic groups. The racial/ethnic differences were examined using several approaches: 1) by Student’s ttests (i.e., unadjusted model), 2) by analysis of covariance (ANCOVA) with inclusion of age, body mass index (BMI), and study site (i.e., UF or UAB) as covariates (i.e., partially

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adjusted model), and 3) by ANCOVA with inclusion of income and education as additional covariates along with those included in the partially adjusted model (i.e., fully adjusted model). Repeated measures during the mechanical temporal summation procedures were analyzed using repeatedmeasures ANCOVA, with Greenhouse-Geisser correction if the sphericity assumption was not met. Statistical significance for all tests was set at P values less than or equal to 0.05. Reduction of QST variables. Because a large number of QST variables were obtained, these variables were subjected to principal components analysis (PCA) to reduce the number of statistical comparisons undertaken, and to minimize redundancy in the information reflected by the QST variables. PCA was performed with Oblique and Orthogonal rotations for variable reduction, as previously described (39). Several PCA results were compared to determine agreement of primary factor loadings for individual variables. Components with eigenvalues greater than 1 were retained for interpretation. The variables entered in the PCA were heat–pain threshold and heat–pain tolerance at the forearm and knee, pressure– pain at all sites, cold–pain threshold, cold–pain intensity, and cold–pain unpleasantness ratings, punctate–pain ratings at the hand and knee, heat–pain temporal summation at the hand and knee, and punctate–pain temporal summation at the hand and knee. Once the factors were determined, pain index scores were computed from the individual measures by computing Z-scores for each pain measure and averaging the Z-scores

Table 1. Basic characteristics of the subjects with knee osteoarthritis by racial/ethnic group*

Age, mean ⫾ SD years BMI, mean ⫾ SD kg/m2 Sex, no. (%) Female Male Annual income, no. (%) ⬍$19,000 $20,000–$29,000 $30,000 –$39,000 ⬎$40,000 Education, no. (%) High school 2-year college degree 4-year college degree Graduate degree K/L radiographic score, no. (%) Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Test site, no. (%) University of Florida University of Alabama at Birmingham

NHW (n ⫽ 120)

AA (n ⫽ 147)

58.9 ⫾ 8.3 29.9 ⫾ 6.9

55.1 ⫾ 6.5 32.6 ⫾ 7.8

76 (63.3) 44 (36.7)

93 (63.3) 54 (36.7)

17 (14.4) 24 (20.3) 11 (9.3) 66 (55.9)

79 (54.5) 21 (14.5) 20 (13.8) 25 (17.2)

37 (30.8) 26 (21.7) 28 (23.3) 29 (24.2)

87 (59.2) 33 (22.4) 20 (13.6) 7 (4.8)

62 (51.7) 19 (15.8) 18 (15.0) 12 (10.0) 9 (7.5)

73 (49.7) 22 (15.0) 16 (10.9) 22 (15.0) 14 (9.5)

90 (75.0) 30 (25.0)

92 (62.6) 55 (37.4)

P 0.004 0.001 0.991 0.001

0.001

0.634

0.030

* NHW ⫽ non-Hispanic white; AA ⫽ African American; BMI ⫽ body mass index; K/L ⫽ Kellgren/Lawrence.

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Table 2. Results of quantitative sensory testing and measures of clinical pain and function in the subjects with knee osteoarthritis by racial/ethnic group* P NHW (n ⫽ 120) Measures of heat-induced pain Pain threshold, °C Forearm Knee Pain tolerance, °C Forearm Knee Temporal summation of pain§ At 44°C Forearm Knee At 46°C Forearm Knee At 48°C Forearm Knee Measures of mechanical induced pain Pressure–pain threshold, kPa Knee Medial Lateral Quadriceps Trapezius Forearm Punctate-induced pain Pain intensity rating Hand Knee Temporal summation of pain§ Hand Knee Cold pressor procedure At 16°C Pain threshold Pain intensity rating Unpleasantness rating At 12°C Pain threshold Pain intensity rating Unpleasantness rating At 8°C Pain threshold Pain intensity rating Unpleasantness rating Clinical pain and function measures GCPS score Pain intensity Disability WOMAC score Pain Stiffness Function SPPB, total score

AA (n ⫽ 147)

Unadjusted model

Partially adjusted model†

Fully adjusted model‡

42.6 ⫾ 2.8 42.6 ⫾ 2.9

40.9 ⫾ 3.5 41.3 ⫾ 3.5

0.001 0.002

0.001 0.004

0.001 0.007

47.0 ⫾ 2.2 47.0 ⫾ 1.9

45.0 ⫾ 2.6 44.8 ⫾ 3.1

0.001 0.001

0.001 0.001

0.001 0.001

9.5 ⫾ 11.7 7.3 ⫾ 10.6

15.7 ⫾ 17.8 10.8 ⫾ 13.4

0.009 0.066

0.013 0.071

0.005 0.053

9.6 ⫾ 11.8 11.0 ⫾ 15.2

17.1 ⫾ 17.0 15.6 ⫾ 15.4

0.039 0.025

0.075 0.031

0.195 0.078

11.2 ⫾ 12.8 12.6 ⫾ 15.8

17.9 ⫾ 18.9 17.5 ⫾ 18.6

0.001 0.033

0.004 0.038

0.010 0.037

327.7 ⫾ 169.8 355.7 ⫾ 183.0 444.3 ⫾ 234.0 291.6 ⫾ 172.1 264.7 ⫾ 181.3

252.2 ⫾ 149.3 263.2 ⫾ 155.1 387.0 ⫾ 219.4 247.9 ⫾ 170.8 222.7 ⫾ 148.7

0.001 0.001 0.039 0.019 0.035

0.002 0.001 0.031 0.013 0.034

0.011 0.032 0.640 0.305 0.332

7.1 ⫾ 13.3 10.4 ⫾ 14.4

15.4 ⫾ 18.7 21.0 ⫾ 23.4

0.003 0.001

0.001 0.001

0.025 0.022

7.5 ⫾ 12.1 14.4 ⫾ 17.6

23.0 ⫾ 21.3 26.1 ⫾ 19.1

0.001 0.001

0.001 0.001

0.001 0.001

34.2 ⫾ 18.4 28.2 ⫾ 27.2 30.6 ⫾ 27.7

33.2 ⫾ 18.1 37.7 ⫾ 31.6 41.4 ⫾ 32.1

0.673 0.009 0.004

0.379 0.003 0.002

0.168 0.015 0.018

19.7 ⫾ 15.6 54.1 ⫾ 31.9 57.2 ⫾ 30.9

19.8 ⫾ 15.0 64.3 ⫾ 31.9 69.2 ⫾ 31.6

0.960 0.011 0.002

0.886 0.007 0.002

0.656 0.010 0.012

12.9 ⫾ 12.2 69.2 ⫾ 29.0 72.4 ⫾ 28.1

12.1 ⫾ 10.5 75.7 ⫾ 29.1 78.3 ⫾ 28.0

0.557 0.074 0.099

0.412 0.075 0.145

0.414 0.322 0.566

42.6 ⫾ 19.2 37.1 ⫾ 26.3

57.6 ⫾ 23.2 49.5 ⫾ 29.9

0.001 0.001

0.001 0.003

0.037 0.496

6.1 ⫾ 3.6 3.2 ⫾ 1.8 19.0 ⫾ 12.5 10.4 ⫾ 1.7

8.3 ⫾ 4.8 3.6 ⫾ 2.1 27.1 ⫾ 15.9 9.3 ⫾ 1.9

0.001 0.062 0.001 0.001

0.001 0.225 0.001 0.001

0.278 0.771 0.119 0.001

* Values are the mean ⫾ SD. NHW ⫽ non-Hispanic white; AA ⫽ African American; GCPS ⫽ Graded Chronic Pain Scale; WOMAC ⫽ Western Ontario and McMaster Universities Osteoarthritis Index; SPPB ⫽ Short Physical Performance Battery. † Partially adjusted for age, body mass index (BMI), and study site (University of Florida and University of Alabama at Birmingham) as covariates. ‡ Fully adjusted for age, BMI, study site (University of Florida and University of Alabama at Birmingham), annual income (1 ⫽ ⬍$19,000, 2 ⫽ $20,000–$29,000, 3 ⫽ $30,000–$39,000, and 4 ⫽ ⬎$40,000), and education (1 ⫽ high school, 2 ⫽ 2-year college degree, 3 ⫽ 4-year college degree, and 4 ⫽ graduate degree) as covariates. § Temporal summation of pain is a measure of the maximum increase in pain (⌬ pain intensity rating), calculated by subtracting the first trial rating from the maximum rating provided at each temperature (for heat–pain) or subtracting the rating at first contact from the maximum rating among 10 contacts (for punctate–pain).

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from the measures comprising the factors. These Z-scores were entered in a hierarchical multiple regression model to assess the ability of QST measures to predict the severity of clinical pain within each racial/ethnic group, after accounting for demographic and OA-related confounding factors.

RESULTS In total, 267 individuals (147 AA subjects and 120 NHW subjects) participated in the study. Significant racial/ethnic differences were evident with regard to age, BMI, study site, annual income, and education (each P ⬍ 0.05) (Table 1). Racial/ethnic differences in QST and clinical pain/function measures were examined in a model without covariates (i.e., unadjusted model), in a model with age, BMI, and study site as covariates (i.e., partially adjusted model), and in a model with age, BMI, study site, education, and annual income as covariates (i.e., fully adjusted model). The results are displayed in Table 2 and summarized below. Racial/ethnic differences in experimental pain sensitivity. Heat-induced pain. In unadjusted and adjusted analyses, AA subjects with knee OA displayed a significantly lower heat–pain threshold and heat–pain tolerance at the forearm and knee compared to NHW subjects with knee OA (each P ⬍ 0.01). Similarly, there were significant racial/ethnic differences in the temporal summation of pain at the highest temperature (48°C), even in the adjusted models. In all cases, the AA research participants showed higher pain ratings and greater temporal summation than did the NHW research participants. Mechanical-induced pain. AA subjects displayed significantly lower pressure–pain thresholds in the unadjusted and partially adjusted models (each P ⬍ 0.05). After the addition of education and annual income as covariates (i.e., fully adjusted model), only pressure– pain thresholds at the knee remained significantly different between the 2 racial/ethnic groups (P ⬍ 0.05). In addition, AA subjects showed significantly greater punctate–pain ratings and punctate–pain temporal summation compared to NHW subjects (each P ⬍ 0.05) (Table 2 and Figure 2). Cold pressor–induced pain. The cold–pain threshold did not differ between the racial/ethnic groups at any temperature applied (each P ⬎ 0.05). However, AA subjects provided higher ratings of cold–pain intensity and unpleasantness at all temperatures (each P ⬍ 0.05), although this difference became nonsignificant at a temperature of 8°C in the fully adjusted model. Furthermore, at all temperatures, a greater proportion of AA

Figure 2. Temporal summation of a mechanical measure of pain intensity between the racial/ethnic groups. Sensitivity to punctate mechanical stimuli was tested on the back of the ipsilateral hand and at the patella. Participants provided verbal pain ratings (scale of 0–100, ranging from no pain sensation to most intense pain sensation imaginable) following a single contact and after 10 contacts, at a rate of 1 contact/second. Bars show the mean ⫾ SD pain intensity ratings in 147 African Americans and 120 non-Hispanic whites.

subjects (59% at 8°C, 44% at 12°C, 12% at 16°C) compared to NHW subjects (28% at 8°C, 11% at 12°C, 2% at 16°C) withdrew their hand in response to cold pressor pain before 1 minute (each P ⬍ 0.01). Conditioned pain modulation. Significant racial/ ethnic differences in heat–pain ratings emerged from pre– to post–cold-water immersion. At both time points, AA subjects reported greater heat–pain intensity scores than did NHW subjects (mean ⫾ SD 54.6 ⫾ 24.2 versus 46.9 ⫾ 26.5; P ⫽ 0.04). In assessing the CPM response, the change in heat–pain ratings from pre– to post–coldwater immersion differed by race/ethnicity (P ⫽ 0.012). The heat–pain ratings from NHW subjects did not significantly change from pre– to post–cold-water immersion (from 46.9 ⫾ 26.1 to 46.9 ⫾ 26.6), whereas in the AA subjects, there was a significant increase in heat–pain intensity ratings from pre– to post–cold-water immersion (from 52.6 ⫾ 24.4 to 56.5 ⫾ 24.1). Racial/ethnic differences in measures of clinical pain and function. As compared to NHW subjects with knee OA, AA subjects with knee OA reported significantly more intense clinical pain and significantly greater disability on the GCPS and WOMAC indices (each P ⬍ 0.01), both in the unadjusted model and in the partially adjusted model. However, when education and annual income were included as covariates, racial/ethnic group differences in the WOMAC measures and GCPS scores for disability were nonsignificant, whereas group differ-

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Table 3. Results of principal components analysis of experimental pain measures in African American subjects compared to non-Hispanic white subjects with knee osteoarthritis*

Pain measures Measures of cold-induced pain At 16°C Pain intensity rating Unpleasantness rating Pain threshold At 12°C Pain intensity rating Unpleasantness rating Pain threshold At 8°C Pain intensity rating Unpleasantness rating Pain threshold Pressure–pain threshold (kg) Quadriceps Knee Lateral Medial Trapezius Forearm Measures of heat-induced pain Temporal summation of pain (⌬ pain intensity rating) At 44°C Forearm Knee At 46°C Forearm Knee At 48°C Forearm Knee Pain threshold (°C) Forearm Knee Pain tolerance (°C) Forearm Knee Measures of punctate-induced Pain intensity rating Hand Knee Temporal summation of pain (⌬ pain intensity rating) Hand Knee Variance of measures % variance Cumulative % variance

Coldinduced pain

Pressureinduced pain

Heatinduced pain

Temporal summation of heat-induced pain

Punctateinduced pain

Temporal summation of punctateinduced pain

0.759 0.718 ⴚ0.665

⫺0.116 ⬍0.100 0.263

⫺0.104 ⫺0.135 ⬍0.100

0.110 ⬍0.100 ⬍0.100

0.195 0.163 0.146

0.158 0.203 ⬍0.100

0.880 0.842 ⴚ0.777

⬍0.100 ⬍0.100 0.232

⬍0.100 ⬍0.100 0.132

0.145 0.131 ⬍0.100

0.158 0.248 0.225

0.136 0.159 ⬍0.100

0.828 0.774 ⴚ0.729

⫺0.101 ⬍0.100 0.233

⫺0.147 ⬍0.100 0.170

⬍0.100 ⬍0.100 ⬍0.100

0.156 0.244 0.238

0.133 0.141 ⬍0.100

⫺0.159

0.858

0.195

⬍0.100

⬍0.100

⬍0.100

⫺0.109 ⫺0.139 ⫺0.143 ⫺0.221

0.840 0.834 0.816 0.815

0.188 0.216 0.151 0.172

⬍0.100 ⬍0.100 ⬍0.100 ⬍0.100

⫺0.131 ⫺0.134 ⬍0.100 ⬍0.100

⫺0.100 ⫺0.121 ⬍0.100 ⬍0.100

0.127 ⬍0.100

⬍0.100 ⬍0.100

⫺0.126 ⬍0.100

0.689 0.721

⬍0.100 ⬍0.100

⬍0.100 0.184

⬍0.100 ⬍0.100

⬍0.100 ⬍0.100

⫺0.114 ⬍0.100

0.784 0.758

⬍0.100 0.205

⬍0.100 ⬍0.100

⬍0.100 ⬍0.100

⫺0.126 ⬍0.100

⫺0.129 ⬍0.100

0.714 0.679

⬍0.100 ⬍0.100

⫺0.145 0.112

⫺0.157 ⫺0.112

0.268 0.221

0.790 0.748

⬍0.100 ⫺0.222

⬍0.100 ⫺0.227

⫺0.170

⫺0.217 ⬍0.100

0.213 0.206

0.789 0.833

⬍0.100 ⫺0.154

⬍0.100 ⫺0.154

⬍0.100 ⫺0.118

0.205 0.162

⫺0.220 ⫺0.210

⫺0.193 ⫺0.197

⬍0.100 ⬍0.100

0.821 0.840

⬍0.100 ⬍0.100

0.203 0.225

⫺0.183 ⫺0.141

⫺0.142 ⫺0.128

0.137 0.148

⬍0.100 0.137

0.817 0.817

31.8 31.8

11.9 43.7

6.6 61.5

11.1 54.9

5.4 66.8

4.1 70.9

* Several principal components analysis results were compared to determine agreement of primary factor loadings for individual variables. Boldface indicates primary factor loadings, determined using principal components analysis with an Orthogonal rotation.

ences in the GCPS scores for pain intensity remained significant. With regard to functional limitations, the SPPB scores were significantly lower among AA subjects compared to NHW subjects (P ⬍ 0.001), both in the unadjusted model and in the fully adjusted model.

Associations among measures of clinical pain, function, and experimental pain. The PCA yielded 6 modality-specific components: 1) heat–pain (threshold and tolerance at the forearm and knee), 2) pressure– pain (threshold at all sites), 3) cold–pain (threshold, pain

RACIAL DIFFERENCES IN KNEE OSTEOARTHRITIS

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Table 4. Hierarchical multiple regression analysis of predictors of the severity of clinical pain by racial/ethnic group* Non-Hispanic whites

WOMAC pain Step 1 Age Sex BMI K/L score Study site Education Annual income Step 2 Cold–pain Punctate TS Pressure–pain Heat–pain TS Heat–pain Punctate–pain CPM GCPS pain Step 1 Age Sex BMI K/L score Study site Education Annual income Step 2 Cold–pain Punctate TS Pressure–pain Heat–pain TS Heat–pain Punctate–pain CPM

␤

t

P

⫺0.126 ⫺0.106 ⫺0.151 ⫺0.108 ⫺0.020 ⫺0.230 ⫺0.243

⫺1.41 ⫺1.21 1.56 1.10 ⫺0.22 ⫺2.48 ⫺2.59

0.160 0.227 0.120 0.272 0.825 0.015 0.011

0.100 0.234 0.070 0.131 0.024 0.162 ⫺0.069

0.90 2.14 0.60 1.40 0.22 1.48 ⫺0.78

0.365 0.035 0.547 0.164 0.820 0.140 0.435

⫺0.145 ⫺0.048 0.141 0.087 ⫺0.066 ⫺0.255 ⫺0.184

⫺1.60 ⫺0.54 1.44 0.87 ⫺0.72 ⫺2.71 ⫺1.94

0.111 0.586 0.153 0.382 0.473 0.008 0.055

0.241 0.212 ⫺0.055 0.196 0.008 0.194 ⫺0.212

2.30 2.04 ⫺0.50 2.21 0.08 1.87 ⫺2.53

0.024 0.044 0.616 0.029 0.934 0.064 0.013

African Americans R

⌬R

0.21

0.21

2

0.35

0.20

0.42

2

0.14

0.20

0.22

␤

t

P

⫺0.002 0.063 0.221 0.155 ⫺0.283 ⫺0.178 ⫺0.079

⫺0.02 0.76 2.48 1.83 ⫺3.22 ⫺1.83 ⫺0.74

0.982 0.448 0.014 0.068 0.002 0.068 0.458

⫺0.074 0.161 0.240 0.015 0.064 0.141 ⫺0.154

⫺0.92 1.90 2.67 0.18 0.74 1.66 ⫺2.01

0.357 0.060 0.009 0.851 0.461 0.099 0.046

⫺0.111 ⫺0.009 0.209 0.196 ⫺0.142 ⫺0.170 ⫺0.124

⫺1.31 ⫺0.110 2.31 2.26 ⫺1.58 ⫺1.71 ⫺1.14

0.190 0.913 0.023 0.025 0.116 0.089 0.256

⫺0.037 0.166 0.201 0.025 0.112 0.305 ⫺0.228

⫺0.47 2.02 2.31 0.31 1.34 3.71 ⫺3.09

0.635 0.046 0.022 0.752 0.181 0.000 0.002

R2

⌬R2

0.24

0.24

0.35

0.11

0.21

0.21

0.39

0.18

* WOMAC ⫽ Western Ontario and McMaster Universities Osteoarthritis Index; BMI ⫽ body mass index; K/L ⫽ Kellgren/Lawrence; TS ⫽ temporal summation; CPM ⫽ conditioned pain modulation; GCPS ⫽ Graded Chronic Pain Scale.

intensity, and unpleasantness ratings), 4) punctate– pain (pain ratings at the hand and knee), 5) punctate– pain (temporal summation at the hand and knee), and 6) heat–pain (temporal summation at the hand and knee) (Table 3). These pain index scores, as well as CPM scores, were subsequently included in the 2 regression models. Two separate, hierarchical multiple regression analyses were performed to assess the ability of experimental pain measures to predict the severity of clinical pain as measured by the WOMAC and GCPS in each racial/ethnic group (Table 4). Preliminary analyses were conducted to ensure that there was no violation of the assumptions of normality, linearity, multicollinearity, and homoscedasticity. Age, sex, BMI, study site, education, annual income, and radiographic severity of knee OA were entered as covariates in step 1, followed by the QST measures in step 2. In the final model, increased punctate–pain tem-

poral summation was a significant predictor of greater WOMAC pain intensity scores among NHW subjects. Among AA subjects, increased pressure–pain sensitivity and decreased CPM were predictive of greater WOMAC pain intensity scores. Moreover, among the NHW research participants, increased punctate–pain and heat–pain temporal summations, increased cold– pain sensitivity, and decreased CPM were significant predictors of greater GCPS characteristic pain intensity scores. Among the AA research participants, increased punctate–pain and pressure–pain sensitivities, increased punctate–pain temporal summation, and decreased CPM were significant predictors of greater GCPS characteristic pain intensity scores. DISCUSSION The present study aimed to characterize differences in experimental pain sensitivity, CPM, clinical

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pain, and pain-related disability among older AA subjects and NHW subjects with knee OA. First, AA subjects displayed significantly greater sensitivity to all experimental pain stimuli, including greater temporal summation of pain, compared to NHW subjects, suggesting that central sensitization is increased in AA subjects with knee OA. Second, the CPM task revealed that concurrently applied cold pain did not produce any reductions in heat–pain ratings in the NHW subjects, while it produced increased heat–pain ratings in the AA subjects, indicating that AA subjects with knee OA display pain facilitation. Third, AA subjects reported higher levels of clinical pain, disability, and poorer functional performance relative to NHW subjects, even after the analyses were controlled for age, BMI, and study site. Interestingly, group differences in most clinical variables became nonsignificant when the models were additionally controlled for education and annual income, whereas racial/ethnic differences in the QST measures were not impacted by education and income. Finally and notably, the association between QST measures and clinical pain differed between the racial/ethnic groups, suggesting the possibility that there are distinct OA pathophysiologic mechanisms between racial/ethnic groups. Limited information is currently available regarding racial/ethnic differences in experimental pain sensitivity among older adults with knee OA (8). To date, studies examining experimental pain responses across racial/ethnic groups have primarily included healthy young participants, and these studies have generally not controlled for important confounders (20,23). Consistent with previous findings in studies of healthy adults (19), racial/ethnic differences in experimental pain sensitivity were observed across multiple stimulus techniques in our knee OA subjects. In addition to increased basal pain sensitivity, AA subjects experienced greater temporal summation of pain compared to NHW subjects, suggesting that there is increased central sensitization (a pain-facilitatory mechanism) in AA subjects with knee OA. This was further supported by the CPM procedure. While the NHW subjects did not exhibit significant pain inhibition—consistent with previous studies of knee OA (40) and nonclinical samples in this age range (41)—the AA subjects displayed significant pain facilitation. Taken together, our findings regarding racial/ethnic differences in endogenous pain-modulatory mechanisms in individuals with knee OA extend the findings previously demonstrated in healthy adults (20,42). The present investigation also determined racial/

CRUZ-ALMEIDA ET AL

ethnic group differences in measures of clinical pain, disability, and function. Although most clinical measures significantly differed between the 2 racial/ethnic groups after adjustment for age, BMI, and study site, only GCPS characteristic pain intensity scores and SPPB function scores remained statistically significantly different when the analyses were also adjusted for education and annual income. Similarly, in a study of older adults attending a multidisciplinary pain center, some, but not all, of the associations between race/ethnicity and measures of pain and disability were mediated by the neighborhood levels of education and income (43). Similar to our findings, Ang and colleagues (9) found no racial differences in clinical pain, as assessed using the WOMAC, after analyses were controlled for socioeconomic status (SES). It is possible that the differences in the measures used in our study may account for some of the discrepancy, since the WOMAC captures pain within the past 48 hours, whereas the GCPS captures momentary and recent pain within the past 6 months. Nevertheless, researchers who have investigated health disparities caution against interpreting analyses that include SES as a covariate as a way to model racial differences (for review, see ref. 44). Some authors argue that race represents a social construct, and SES is a consequence of race; therefore, it is very difficult to disentangle the independent effects of these variables. These researchers suggest that studies with larger sample sizes can be stratified by SES, to better model the complex interactions between race and SES. A major aim of the present study was to determine whether experimental pain sensitivity could be a significant predictor of the severity of clinical pain within racial/ethnic groups, even after accounting for important demographic and OA-related confounders. Our results suggest that QST measures do indeed predict the severity of clinical pain, although which QST measures were predictive varied between the 2 racial/ethnic groups. Specifically, pressure–pain sensitivity was only predictive of clinical pain within our AA subjects, whereas heat– pain and cold–pain temporal summations were only predictive of clinical pain within the NHW subjects. Similar racial/ethnic group differences in experimental pain responses (i.e., phenotypes) have been reported in healthy individuals (38), possibly reflecting underlying racial/ethnic differences in the structure and function of the somatosensory system. This difference in predictors supports the idea that there are distinct pathophysiologic mechanisms, beyond cultural and socioeconomic factors, contributing to the differences in clinical pain between the racial/ethnic groups.

RACIAL DIFFERENCES IN KNEE OSTEOARTHRITIS

Nevertheless, deficient pain inhibition was a significant predictor of the severity of clinical pain in both racial/ethnic groups, thus supporting the notion that pain-modulatory systems have an important role in chronic pain (45). Future research is needed to address these mechanistically based differences and similarities among the racial/ethnic groups. The present investigation has several limitations worth noting. First, the lack of significant effects of CPM in the study sample might be attributable to the methods used, although previous studies have also shown an absence of CPM in this age group and in this patient population (40,41). Second, the cross-sectional nature of the study precludes conclusions regarding the direction of association between experimental and clinical pain measures. Third, the study population was largely composed of community-dwelling adults with mild-tomoderate levels of knee pain, and samples consisting of patients with different characteristics, such as those from clinical settings, may yield different results. Finally, large studies are needed to examine the complex relationships and interactions between education, income, and race in relation to chronic pain in health disparities research. This study extends the findings regarding racial/ ethnic differences in experimental pain sensitivity, clinical pain, disability, and function among individuals with knee OA. The findings also highlight the potential importance of SES, which should be further examined. Moreover, our findings indicating that the QST measures associated with clinical pain differ between the 2 racial/ethnic groups suggests that future research is needed to evaluate the possibility that different underlying mechanisms contribute to clinical pain across racial/ethnic groups. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Cruz-Almeida had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Cruz-Almeida, Riley, King, Glover, Sotolongo, Herbert, Schmidt, Staud, Redden, Bradley, Fillingim. Acquisition of data. Cruz-Almeida, Sibille, Goodin, Bartley, King, Glover, Sotolongo, Herbert, Schmidt, Fessler, Bradley. Analysis and interpretation of data. Cruz-Almeida, Petrov, Riley, King, Sotolongo, Herbert, Schmidt, Redden, Bradley, Fillingim.

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3. 4.

5.

6.

7.

8.

9.

10.

11.

12. 13.

14. 15. 16. 17.

18. 19.

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