ann. behav. med. DOI 10.1007/s12160-013-9563-x
ORIGINAL ARTICLE
Pain Hypervigilance is Associated with Greater Clinical Pain Severity and Enhanced Experimental Pain Sensitivity Among Adults with Symptomatic Knee Osteoarthritis Matthew S. Herbert, M.A. & Burel R. Goodin, Ph.D. & Samuel T. Pero IV, B.S. & Jessica K. Schmidt, B.A. & Adriana Sotolongo, M.P.H. & Hailey W. Bulls, B.S. & Toni L. Glover, Ph.D., GNP-BC & Christopher D. King, Ph.D. & Kimberly T. Sibille, Ph.D. & Yenisel Cruz-Almeida, M.S.P.H., Ph.D. & Roland Staud, M.D. & Barri J. Fessler, M.D., M.S.P.H. & Laurence A. Bradley, Ph.D. & Roger B. Fillingim, Ph.D.
# The Society of Behavioral Medicine 2013
Abstract Background Pain hypervigilance is an important aspect of the fear-avoidance model of pain that may help explain individual differences in pain sensitivity among persons with knee osteoarthritis (OA).
M. S. Herbert (*) : B. R. Goodin : J. K. Schmidt : H. W. Bulls College of Arts and Sciences, Department of Psychology, University of Alabama at Birmingham, 1825 University Blvd., Shelby 177E, Birmingham, AL 35294, USA e-mail: [email protected] S. T. Pero IV, College of Dentistry, Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville, FL 32610, USA A. Sotolongo : B. J. Fessler : L. A. Bradley School of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA T. L. Glover : C. D. King : K. T. Sibille : Y. Cruz-Almeida College of Dentistry, Comprehensive Center for Pain Research, University of Florida, Gainesville, FL 32610, USA T. L. Glover College of Nursing, University of Florida, Gainesville, FL 32610, USA T. L. Glover : R. Staud : R. B. Fillingim Pain Research and Intervention Center of Excellence (PRICE), Gainesville, University of Florida, Gainesville, FL 32610, USA R. Staud College of Medicine, University of Florida, Gainesville, FL 32610, USA
Purpose The purpose of this study was to examine the contribution of pain hypervigilance to clinical pain severity and experimental pain sensitivity in persons with symptomatic knee OA. Methods We analyzed cross-sectional data from 168 adults with symptomatic knee OA. Quantitative sensory testing was used to measure sensitivity to heat pain, pressure pain, and cold pain, as well as temporal summation of heat pain, a marker of central sensitization. Results Pain hypervigilance was associated with greater clinical pain severity, as well as greater pressure pain. Pain hypervigilance was also a significant predictor of temporal summation of heat pain. Conclusions Pain hypervigilance may be an important contributor to pain reports and experimental pain sensitivity among persons with knee OA. Keywords Pain hypervigilance . Knee osteoarthritis . Experimental pain
Introduction The most prominent and disabling symptom of knee osteoarthritis (OA) is pain. The well-documented discordance between radiographic and symptomatic knee OA [1, 2] suggests the experience of pain in individuals with knee OA cannot be fully explained by peripheral pathophysiology alone. Indeed, psychosocial factors, such as anxiety, depression, and coping style, have been implicated in OA-related pain and disability [3–5]. The fear-avoidance model of pain provides a suitable heuristic for conceptualizing the contributions of psychosocial
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factors to the experience of OA-related pain [6]. This model posits that a cycle of pain chronicity and disability may be initiated when the appraisal of pain is influenced by negative psychosocial factors. The resultant maladaptive appraisal gives rise to pain-related fear and anxiety, as well as associated safety-seeking behaviors such as avoidance/escape, which can be adaptive in the acute pain stage, but paradoxically exacerbate persistent pain. The long-term consequences, such as enhanced disability or depression, in turn may lower the threshold at which subsequent pain is detected and/or enhance the intensity of the pain experience. Hypervigilance represents an important aspect of the fearavoidance model that may contribute to OA-related pain. Rollman [7] defined hypervigilance as an enhanced state of sensory sensitivity accompanied by an exaggerated scan or search for threatening information. It has been proposed that some individuals who live with chronic or recurrent pain may develop a pain-specific “hypervigilance” as a result of continual effort to detect painful sensations and other pain-related information, which may in turn exacerbate the pain experience [8]. Generalized hypervigilance (i.e., heightened vigilance for internal and external signals in addition to pain) and painspecific hypervigilance have been studied in several samples of adults with disorders characterized by recurrent or persistent pain. For example, pain hypervigilance was positively associated with greater pain intensity, emotional distress, psychosocial disability, and pain-related health care utilization in patients with chronic back pain [9]. McDermid [10] showed that patients with fibromyalgia and rheumatoid arthritis reported greater generalized hypervigilance and displayed greater sensitivity to experimental pain compared to controls. The association of pain hypervigilance with increased clinical and experimental pain may be related to central sensitization, a phenomenon in which nociceptive pathways in the central nervous system become sensitized by repeated or sustained nociceptive input [11]. Evidence of central sensitization has been demonstrated in a number of disorders characterized by chronic or recurrent pain [12, 13], including knee OA [14]. Theorists have posited that some OA patients may have a greater propensity to develop central sensitization, which may underlie the discordance between symptomatic and radiographic OA [15]. Although the impact of psychosocial factors on central sensitization has yet to be well characterized, pain hypervigilance has been postulated to play a role in central sensitization via descending pain modulatory pathways [16]. The relationship between pain hypervigilance and central sensitization has not been examined among persons with knee OA. Therefore, in the present study, temporal summation of heat pain, a widely used quantitative sensory testing method that invokes neural mechanisms related to central sensitization [17], was specifically examined in relation to pain hypervigilance. We also sought to determine whether pain
hypervigilance is related to reports of clinical OA pain and disability. In addition, to determine the relationship between pain hypervigilance and pain modality, three major types of stimuli used in laboratory pain research (i.e., heat pain, pressure pain, and cold pain) were assessed. The following hypotheses were tested: (1) pain hypervigilance will predict greater severity of clinical pain and disability; (2) pain hypervigilance will predict greater sensitivity to experimental pain stimuli beyond what can be explained by clinical pain; and (3) pain hypervigilance will predict greater temporal summation of heat pain after adjusting for confounding variables, including clinical pain. Demographic variables (age, ethnicity, gender, and education) and depressive symptoms were statistically controlled for in all analyses. In addition, clinical pain intensity and situational passive coping were added as additional covariates for analyses examining experimental pain sensitivity.
Methods Participants The current study is part of a larger ongoing project that aims to enhance the understanding of biopsychosocial factors contributing to pain and functional limitations among individuals with knee osteoarthritis (Understanding Pain and Limitations in Osteoarthritic Disease, UPLOAD). The UPLOAD study is a multi-site investigation that recruits participants at the University of Alabama at Birmingham and the University of Florida. The individuals described in the current study were recruited at both study sites between January 2010 and May 2012. The measures and procedures described below are limited to those involved in the current study. Participants consisted of 168 community-dwelling adults with symptomatic knee OA recruited via posted fliers, radio and print media advertisements, orthopedic clinic recruitment, and word-of-mouth referral. Criteria for inclusion into the study were as follows: (1) between 45 and 85 years of age, (2) unilateral or bilateral symptomatic knee osteoarthritis based upon American College of Rheumatology clinical criteria [18], and (3) availability to complete the two-session protocol. Individuals were excluded from participation if they met any of the following criteria: (1) prosthetic knee replacement or other clinically significant surgery to the affected knee; (2) uncontrolled hypertension, 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 [Mini Mental Status Exam (MMSE) score≤22]; (7) excessive anxiety regarding protocol procedures (e.g., blood draws and controlled noxious
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stimulation procedures); and (8) hospitalization within the preceding year for psychiatric illness. On the day of testing, individuals were instructed to refrain from using opioid analgesic medications taken on an “as needed” (i.e., PRN) basis. All procedures were reviewed and approved by the University of Alabama at Birmingham and the University of Florida Institutional Review Boards. Participants provided informed consent and were compensated for their participation. After screening, all participants completed the health assessment session. The following demographic and health data were obtained: self-reported sex, age, ethnicity, years of school completed, as well as health history that included information pertaining to whether individuals had any mental or physical health conditions that required hospitalization in the past year. Next, an index of cognitive capacity, the MMSE, was administered to determine if cognitive or attentional deficits were present that would rule out participation in a study of pain responses. Additionally, all individuals underwent a bilateral knee joint evaluation by an experienced examiner (i.e., the study rheumatologist or study nurse practitioner). As part of the health assessment session, participants completed a battery of psychosocial and clinical pain measures. Between 1 and 4 weeks following the health assessment session, participants completed a session of quantitative sensory testing for the assessment of experimental pain sensitivity. Prior to commencing the quantitative sensory session, participants were provided with audio-recorded instructions regarding how to rate the intensity of the pain produced by the experimental pain stimuli on a “0–100” numeric rating scale, such that 0 = no pain and 100 = the most intense pain imaginable.
Psychosocial Questionnaires Pain Vigilance and Awareness Questionnaire (PVAQ) The PVAQ was developed as a measure of attention to pain [9]. The PVAQ consists of 16 items that asks respondents to indicate on a six-point scale (0=“never” to 5=“always”) the degree to which each description of pain behavior corresponds with their behavior. The PVAQ has satisfactory internal consistency (Cronbach’s alpha=0.86), test–retest reliability (r = 0.80), and convergent validity [9, 19, 20]. Center for Epidemiologic Studies Depression Scale (CESD) The CES-D is a 20-item self-report tool that measures symptoms of depression including depressed mood, guilt/ worthlessness, helplessness/hopelessness, psychomotor retardation, loss of appetite, and sleep disturbance [21]. The total score of the CES-D (range 0–60) was used in the current study as an estimate of the degree of participants’ depressive symptomatology. The validity and internal consistency of the CES-
D in the general population and persons with chronic pain have been reported to be acceptable [22, 23]. Situational Passive Coping (SPC) The SPC scale consists of four items that are answered on a 1–5 Likert scale. This questionnaire was administered directly after quantitative sensory testing to determine the degree that passive coping strategies were utilized during the procedures (e.g., “I felt that if the pain got any worse, I wouldn’t be able to tolerate it.”). The four items on this scale were subsequently averaged together (range 1–5) such that higher mean scores were representative of greater use of passive cognitive coping strategies. Items on the SPC have previously been shown to correlate with pain responses during quantitative sensory testing [24]. In addition, the internal consistency of this scale was adequate (Cronbach’s alpha=0.76). Clinical Pain Western Ontario McMaster Universities Osteoarthritis Scale (WOMAC) pain subscale The WOMAC pain subscale consists of five questions answered on a 0–4 Likert scale. On this subscale, respondents report the degree of arthritis-related knee pain during everyday activities (e.g., walking, sitting, and standing) over the last 48 h. The WOMAC pain subscale is a reliable and valid measure of clinical pain [25]. Clinical Disability The Knee Injury and Osteoarthritis Outcome Score–Physical Function Short-Form (KOOS-PS) is a seven-item scale derived from the full-length KOOS that measures difficulties with physical activities (e.g., rising from bed, kneeling, and squatting) due to knee pain [26]. The internal consistency and test–retest reliability of the KOOS-PS is satisfactory in persons with knee OA [26]. Quantitative Sensory Testing Thermal Heat A series of controlled thermal stimulation procedures were used to assess heat pain sensitivity, particularly heat pain threshold and heat pain tolerance. Heat pain threshold refers to the temperature at which a person first perceives the heat stimulus to be painful. Heat pain tolerance refers to the maximum level of pain that a person is able to tolerate. Heat pain threshold and tolerance were assessed using a Medoc Pathway Neurosensory Analyzer (Medoc, Ltd., Ramat Yishai, Israel) with a 16 × 16 mm thermode using an ascending method of limits procedure. From a baseline of 32 °C, probe temperature increased at a rate of 0.5 °C/s until participants responded by pressing a button to indicate when they
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first felt pain and when they were no longer able to tolerate the pain. Heat pain threshold and tolerance were assessed on individuals’ index knee and ipsilateral ventral forearm. If a participant had bilateral knee pain, the knee with a greater amount of reported pain intensity was designated as the index knee. In cases where an equal amount of pain intensity was endorsed in both knees, the index knee was randomized. Three trials of heat pain threshold and three trials of heat pain tolerance were completed separately on the index knee and ventral ipsilateral forearm for each individual (six trials of heat pain threshold and heat pain tolerance per individual). The position of the thermode was altered slightly between trials (though it remained on the index knee and ventral forearm). For each measure at each anatomical site, the average of all three trials was computed for use in subsequent analyses. Temporal Summation of Heat Pain After assessment of heat pain threshold and heat pain tolerance, participants underwent a second thermal procedure with repeated trials of suprathreshold heat pulses applied to the index knee and ipsilateral ventral forearm. Participants were instructed to verbally rate the intensity of peak pain of five brief pulses on a scale of 0 (no pain) to 100 (the most intense pain imaginable). The procedure was terminated if the participant rated the thermal pain at 100. For each temperature and site, a change score was calculated by subtracting the first rating from the highest rating during the five repeated trials. This change score was used as an index of temporal summation [27]. Target temperatures were delivered by a Contact Heat-Evoked Potential Stimulator (CHEPS; Medoc) thermode for less than 1 s, with an approximately 2.5-s inter-pulse interval during which the temperature of the contactor returned to a baseline of 32 °C. During the temporal summation trials at the index knee and ipsilateral forearm, three different temperatures were used (44, 46, and 48 °C) for a total of six trials (three at the knee and three at the forearm). Consistent with previous investigators [28, 29], the lastobservation-carried-forward method was used to handle missing data during the temporal summation procedures. Mechanical Pressure To determine mechanical pain sensitivity at the site of clinical pain, six total trials of pressure pain threshold were assessed at the medial (three trials) and lateral (three trials) joint lines of the index knee using a handheld Medoc digital pressure algometer. Additionally, pressure pain thresholds were assessed at the ipsilateral quadriceps, trapezius, and dorsal forearm. To assess pressure pain threshold, the examiner applied pressure at a rate of 30 kPa per second and the participant was instructed to press a button when the stimulus
“first becomes painful,” at which time the device recorded the pressure in kilopascals. The averages of the three trials for the medial knee and lateral knee as well as the ipsilateral quadriceps, trapezius, and forearm were calculated to create an overall pressure pain sensitivity score. Cold Pressor Each participant completed a series of hand immersions in a cold-water bath (Neslab, RTE-111, Portsmouth, NH) at temperatures of 16, 12, and 8 °C, with 5 min separating each exposure. Participants were first instructed regarding the differences between pain intensity and pain unpleasantness. Next, they were instructed to place their hand in the coldwater bath up to their wrist for as long as possible up to 60 s. Participants were informed they could remove their hand from the cold water at any time if the pain became intolerable. Immediately after participants removed their hand, they rated the intensity and unpleasantness of any pain they were experiencing using 0 to 100 numeric rating scales. In addition to ratings of intensity and unpleasantness, a measure of cold pain tolerance was captured. Specifically, cold pain tolerance was measured as the time at which participants removed their hand from the cold water. Data Analysis Hypothesis 1 Two separate linear regression models were used to determine the predictive value of pain hypervigilance on WOMAC pain and KOOS-PS scores. The following a priori covariates were added to the regression model: age, ethnicity (0=non-Hispanic White, 1=African American), gender (0=female, 1=male), education (0=high school or less, 1=some college or more), and depressive symptoms as measured by the CES-D. Hypothesis 2 Linear regression was similarly used to assess the relationship between pain hypervigilance and experimental pain responses, with the exception of cold pain tolerance, which was assessed by binary logistic regression. The latter procedure was used because the majority of participants completed the full duration of cold-water exposure (maximum 60 s) at each measured temperature. Therefore, to avoid statistical problems associated with abnormal distributions, cold pain tolerance was dichotomized. Specifically, participants were classified as “tolerant” if they did not remove their hand for the full 60-s immersion and classified as “intolerant” if they removed their hand before the full 60 s. In addition to controlling for demographic characteristics as described above, the WOMAC pain subscale and SPC scale were included as
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additional covariates to determine if pain hypervigilance explained variance in quantitative sensory testing beyond ratings of clinical pain and situation specific coping, respectively. Lastly, cold pain tolerance was added as a covariate for pain intensity and pain unpleasantness analyses for each respective temperature to determine if pain hypervigilance differentiated pain ratings beyond what cold-water exposure could explain. Hypothesis 3 Before assessing temporal summation of heat pain, paired t tests analyzing the difference between the first and highest pain ratings were inspected to verify significant temporal summation prior to determining its relationship with pain hypervigilance. Linear regression was used to determine the relationship between pain hypervigilance and temporal summation of heat pain while controlling for age, ethnicity, gender, education, depression, WOMAC pain, and SPC. Due to the large number of statistical analyses performed, corrections for multiple testing were employed. To accomplish this, we first categorized our dependent variables into separate “families” based on stimulus type. These are (1) clinical outcomes (WOMAC pain, KOOS-PS), (2) thermal heat (heat pain thresholds and tolerances at the forearm and knee), (3) mechanical pressure (pressure pain thresholds at the lateral knee, medial knee, forearm, quadriceps, and trapezius), (4) cold pressor (pain intensity/unpleasantness ratings and cold pain tolerance), and (5) temporal summation of heat pain. We then performed a Holm–Bonferroni procedure to obtain corrected P values [30]. Briefly, for each “family,” obtained P values were ordered from lowest to highest. The lowest P value was then compared to the P value obtained using a standard Bonferroni correction [i.e., 0.05/C (where C is the number of tests performed within a given “family”)]. If the P value was lower than this adjusted P value, the next lowest P value was compared to an alpha correction of 0.05/C −1. This procedure is continued until the first non-significant test is obtained. For all analyses, Cohen’s f 2 effect sizes are presented where appropriate. Per Cohen’s guidelines, f 2 =0.02 is considered a small effect, f 2 =0.15 a medium-sized effect, and f 2 =0.35 a large effect [31]. All variables had complete data except temporal summation of heat pain. Because only a small number of data were missing for temporal summation of heat pain (n ranged from 162 to 166), missing cases were deleted listwise. All analyses were carried out using SPSS, version 19.
Results Demographic variables (age, ethnicity, gender, and education), clinical characteristics (CES-D), and mean PVAQ scores of research participants are presented in Table 1. Participants
Table 1 Characteristics of participants
N
168 56.9 (7.66) 124 (73.8 %)
Data presented as means (SD) or count (%)
Mean age (SD) Female gender Ethnicity Non-Hispanic White African American
87 (51.8 %) 81 (48.2 %)
Education High school or less Some college or more CES-D (SD) PVAQ (SD)
70 (41.7 %) 98 (58.3 %) 16.14 (5.81) 44.26 (15.53)
CES-D Center for Epidemiologic Studies Depression Scale, possible range=0–60; PVAQ Pain Vigilance and Awareness Questionnaire, possible range=0–80
were primarily female (73.8 %) with a mean age of 56.9 (±7.66). The first-order intercorrelations among the PVAQ and control variables are presented in Table 2. Greater scores on the PVAQ were associated with being younger in age (P < 0.05), African American (P
ORIGINAL ARTICLE
Pain Hypervigilance is Associated with Greater Clinical Pain Severity and Enhanced Experimental Pain Sensitivity Among Adults with Symptomatic Knee Osteoarthritis Matthew S. Herbert, M.A. & Burel R. Goodin, Ph.D. & Samuel T. Pero IV, B.S. & Jessica K. Schmidt, B.A. & Adriana Sotolongo, M.P.H. & Hailey W. Bulls, B.S. & Toni L. Glover, Ph.D., GNP-BC & Christopher D. King, Ph.D. & Kimberly T. Sibille, Ph.D. & Yenisel Cruz-Almeida, M.S.P.H., Ph.D. & Roland Staud, M.D. & Barri J. Fessler, M.D., M.S.P.H. & Laurence A. Bradley, Ph.D. & Roger B. Fillingim, Ph.D.
# The Society of Behavioral Medicine 2013
Abstract Background Pain hypervigilance is an important aspect of the fear-avoidance model of pain that may help explain individual differences in pain sensitivity among persons with knee osteoarthritis (OA).
M. S. Herbert (*) : B. R. Goodin : J. K. Schmidt : H. W. Bulls College of Arts and Sciences, Department of Psychology, University of Alabama at Birmingham, 1825 University Blvd., Shelby 177E, Birmingham, AL 35294, USA e-mail: [email protected] S. T. Pero IV, College of Dentistry, Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville, FL 32610, USA A. Sotolongo : B. J. Fessler : L. A. Bradley School of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA T. L. Glover : C. D. King : K. T. Sibille : Y. Cruz-Almeida College of Dentistry, Comprehensive Center for Pain Research, University of Florida, Gainesville, FL 32610, USA T. L. Glover College of Nursing, University of Florida, Gainesville, FL 32610, USA T. L. Glover : R. Staud : R. B. Fillingim Pain Research and Intervention Center of Excellence (PRICE), Gainesville, University of Florida, Gainesville, FL 32610, USA R. Staud College of Medicine, University of Florida, Gainesville, FL 32610, USA
Purpose The purpose of this study was to examine the contribution of pain hypervigilance to clinical pain severity and experimental pain sensitivity in persons with symptomatic knee OA. Methods We analyzed cross-sectional data from 168 adults with symptomatic knee OA. Quantitative sensory testing was used to measure sensitivity to heat pain, pressure pain, and cold pain, as well as temporal summation of heat pain, a marker of central sensitization. Results Pain hypervigilance was associated with greater clinical pain severity, as well as greater pressure pain. Pain hypervigilance was also a significant predictor of temporal summation of heat pain. Conclusions Pain hypervigilance may be an important contributor to pain reports and experimental pain sensitivity among persons with knee OA. Keywords Pain hypervigilance . Knee osteoarthritis . Experimental pain
Introduction The most prominent and disabling symptom of knee osteoarthritis (OA) is pain. The well-documented discordance between radiographic and symptomatic knee OA [1, 2] suggests the experience of pain in individuals with knee OA cannot be fully explained by peripheral pathophysiology alone. Indeed, psychosocial factors, such as anxiety, depression, and coping style, have been implicated in OA-related pain and disability [3–5]. The fear-avoidance model of pain provides a suitable heuristic for conceptualizing the contributions of psychosocial
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factors to the experience of OA-related pain [6]. This model posits that a cycle of pain chronicity and disability may be initiated when the appraisal of pain is influenced by negative psychosocial factors. The resultant maladaptive appraisal gives rise to pain-related fear and anxiety, as well as associated safety-seeking behaviors such as avoidance/escape, which can be adaptive in the acute pain stage, but paradoxically exacerbate persistent pain. The long-term consequences, such as enhanced disability or depression, in turn may lower the threshold at which subsequent pain is detected and/or enhance the intensity of the pain experience. Hypervigilance represents an important aspect of the fearavoidance model that may contribute to OA-related pain. Rollman [7] defined hypervigilance as an enhanced state of sensory sensitivity accompanied by an exaggerated scan or search for threatening information. It has been proposed that some individuals who live with chronic or recurrent pain may develop a pain-specific “hypervigilance” as a result of continual effort to detect painful sensations and other pain-related information, which may in turn exacerbate the pain experience [8]. Generalized hypervigilance (i.e., heightened vigilance for internal and external signals in addition to pain) and painspecific hypervigilance have been studied in several samples of adults with disorders characterized by recurrent or persistent pain. For example, pain hypervigilance was positively associated with greater pain intensity, emotional distress, psychosocial disability, and pain-related health care utilization in patients with chronic back pain [9]. McDermid [10] showed that patients with fibromyalgia and rheumatoid arthritis reported greater generalized hypervigilance and displayed greater sensitivity to experimental pain compared to controls. The association of pain hypervigilance with increased clinical and experimental pain may be related to central sensitization, a phenomenon in which nociceptive pathways in the central nervous system become sensitized by repeated or sustained nociceptive input [11]. Evidence of central sensitization has been demonstrated in a number of disorders characterized by chronic or recurrent pain [12, 13], including knee OA [14]. Theorists have posited that some OA patients may have a greater propensity to develop central sensitization, which may underlie the discordance between symptomatic and radiographic OA [15]. Although the impact of psychosocial factors on central sensitization has yet to be well characterized, pain hypervigilance has been postulated to play a role in central sensitization via descending pain modulatory pathways [16]. The relationship between pain hypervigilance and central sensitization has not been examined among persons with knee OA. Therefore, in the present study, temporal summation of heat pain, a widely used quantitative sensory testing method that invokes neural mechanisms related to central sensitization [17], was specifically examined in relation to pain hypervigilance. We also sought to determine whether pain
hypervigilance is related to reports of clinical OA pain and disability. In addition, to determine the relationship between pain hypervigilance and pain modality, three major types of stimuli used in laboratory pain research (i.e., heat pain, pressure pain, and cold pain) were assessed. The following hypotheses were tested: (1) pain hypervigilance will predict greater severity of clinical pain and disability; (2) pain hypervigilance will predict greater sensitivity to experimental pain stimuli beyond what can be explained by clinical pain; and (3) pain hypervigilance will predict greater temporal summation of heat pain after adjusting for confounding variables, including clinical pain. Demographic variables (age, ethnicity, gender, and education) and depressive symptoms were statistically controlled for in all analyses. In addition, clinical pain intensity and situational passive coping were added as additional covariates for analyses examining experimental pain sensitivity.
Methods Participants The current study is part of a larger ongoing project that aims to enhance the understanding of biopsychosocial factors contributing to pain and functional limitations among individuals with knee osteoarthritis (Understanding Pain and Limitations in Osteoarthritic Disease, UPLOAD). The UPLOAD study is a multi-site investigation that recruits participants at the University of Alabama at Birmingham and the University of Florida. The individuals described in the current study were recruited at both study sites between January 2010 and May 2012. The measures and procedures described below are limited to those involved in the current study. Participants consisted of 168 community-dwelling adults with symptomatic knee OA recruited via posted fliers, radio and print media advertisements, orthopedic clinic recruitment, and word-of-mouth referral. Criteria for inclusion into the study were as follows: (1) between 45 and 85 years of age, (2) unilateral or bilateral symptomatic knee osteoarthritis based upon American College of Rheumatology clinical criteria [18], and (3) availability to complete the two-session protocol. Individuals were excluded from participation if they met any of the following criteria: (1) prosthetic knee replacement or other clinically significant surgery to the affected knee; (2) uncontrolled hypertension, 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 [Mini Mental Status Exam (MMSE) score≤22]; (7) excessive anxiety regarding protocol procedures (e.g., blood draws and controlled noxious
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stimulation procedures); and (8) hospitalization within the preceding year for psychiatric illness. On the day of testing, individuals were instructed to refrain from using opioid analgesic medications taken on an “as needed” (i.e., PRN) basis. All procedures were reviewed and approved by the University of Alabama at Birmingham and the University of Florida Institutional Review Boards. Participants provided informed consent and were compensated for their participation. After screening, all participants completed the health assessment session. The following demographic and health data were obtained: self-reported sex, age, ethnicity, years of school completed, as well as health history that included information pertaining to whether individuals had any mental or physical health conditions that required hospitalization in the past year. Next, an index of cognitive capacity, the MMSE, was administered to determine if cognitive or attentional deficits were present that would rule out participation in a study of pain responses. Additionally, all individuals underwent a bilateral knee joint evaluation by an experienced examiner (i.e., the study rheumatologist or study nurse practitioner). As part of the health assessment session, participants completed a battery of psychosocial and clinical pain measures. Between 1 and 4 weeks following the health assessment session, participants completed a session of quantitative sensory testing for the assessment of experimental pain sensitivity. Prior to commencing the quantitative sensory session, participants were provided with audio-recorded instructions regarding how to rate the intensity of the pain produced by the experimental pain stimuli on a “0–100” numeric rating scale, such that 0 = no pain and 100 = the most intense pain imaginable.
Psychosocial Questionnaires Pain Vigilance and Awareness Questionnaire (PVAQ) The PVAQ was developed as a measure of attention to pain [9]. The PVAQ consists of 16 items that asks respondents to indicate on a six-point scale (0=“never” to 5=“always”) the degree to which each description of pain behavior corresponds with their behavior. The PVAQ has satisfactory internal consistency (Cronbach’s alpha=0.86), test–retest reliability (r = 0.80), and convergent validity [9, 19, 20]. Center for Epidemiologic Studies Depression Scale (CESD) The CES-D is a 20-item self-report tool that measures symptoms of depression including depressed mood, guilt/ worthlessness, helplessness/hopelessness, psychomotor retardation, loss of appetite, and sleep disturbance [21]. The total score of the CES-D (range 0–60) was used in the current study as an estimate of the degree of participants’ depressive symptomatology. The validity and internal consistency of the CES-
D in the general population and persons with chronic pain have been reported to be acceptable [22, 23]. Situational Passive Coping (SPC) The SPC scale consists of four items that are answered on a 1–5 Likert scale. This questionnaire was administered directly after quantitative sensory testing to determine the degree that passive coping strategies were utilized during the procedures (e.g., “I felt that if the pain got any worse, I wouldn’t be able to tolerate it.”). The four items on this scale were subsequently averaged together (range 1–5) such that higher mean scores were representative of greater use of passive cognitive coping strategies. Items on the SPC have previously been shown to correlate with pain responses during quantitative sensory testing [24]. In addition, the internal consistency of this scale was adequate (Cronbach’s alpha=0.76). Clinical Pain Western Ontario McMaster Universities Osteoarthritis Scale (WOMAC) pain subscale The WOMAC pain subscale consists of five questions answered on a 0–4 Likert scale. On this subscale, respondents report the degree of arthritis-related knee pain during everyday activities (e.g., walking, sitting, and standing) over the last 48 h. The WOMAC pain subscale is a reliable and valid measure of clinical pain [25]. Clinical Disability The Knee Injury and Osteoarthritis Outcome Score–Physical Function Short-Form (KOOS-PS) is a seven-item scale derived from the full-length KOOS that measures difficulties with physical activities (e.g., rising from bed, kneeling, and squatting) due to knee pain [26]. The internal consistency and test–retest reliability of the KOOS-PS is satisfactory in persons with knee OA [26]. Quantitative Sensory Testing Thermal Heat A series of controlled thermal stimulation procedures were used to assess heat pain sensitivity, particularly heat pain threshold and heat pain tolerance. Heat pain threshold refers to the temperature at which a person first perceives the heat stimulus to be painful. Heat pain tolerance refers to the maximum level of pain that a person is able to tolerate. Heat pain threshold and tolerance were assessed using a Medoc Pathway Neurosensory Analyzer (Medoc, Ltd., Ramat Yishai, Israel) with a 16 × 16 mm thermode using an ascending method of limits procedure. From a baseline of 32 °C, probe temperature increased at a rate of 0.5 °C/s until participants responded by pressing a button to indicate when they
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first felt pain and when they were no longer able to tolerate the pain. Heat pain threshold and tolerance were assessed on individuals’ index knee and ipsilateral ventral forearm. If a participant had bilateral knee pain, the knee with a greater amount of reported pain intensity was designated as the index knee. In cases where an equal amount of pain intensity was endorsed in both knees, the index knee was randomized. Three trials of heat pain threshold and three trials of heat pain tolerance were completed separately on the index knee and ventral ipsilateral forearm for each individual (six trials of heat pain threshold and heat pain tolerance per individual). The position of the thermode was altered slightly between trials (though it remained on the index knee and ventral forearm). For each measure at each anatomical site, the average of all three trials was computed for use in subsequent analyses. Temporal Summation of Heat Pain After assessment of heat pain threshold and heat pain tolerance, participants underwent a second thermal procedure with repeated trials of suprathreshold heat pulses applied to the index knee and ipsilateral ventral forearm. Participants were instructed to verbally rate the intensity of peak pain of five brief pulses on a scale of 0 (no pain) to 100 (the most intense pain imaginable). The procedure was terminated if the participant rated the thermal pain at 100. For each temperature and site, a change score was calculated by subtracting the first rating from the highest rating during the five repeated trials. This change score was used as an index of temporal summation [27]. Target temperatures were delivered by a Contact Heat-Evoked Potential Stimulator (CHEPS; Medoc) thermode for less than 1 s, with an approximately 2.5-s inter-pulse interval during which the temperature of the contactor returned to a baseline of 32 °C. During the temporal summation trials at the index knee and ipsilateral forearm, three different temperatures were used (44, 46, and 48 °C) for a total of six trials (three at the knee and three at the forearm). Consistent with previous investigators [28, 29], the lastobservation-carried-forward method was used to handle missing data during the temporal summation procedures. Mechanical Pressure To determine mechanical pain sensitivity at the site of clinical pain, six total trials of pressure pain threshold were assessed at the medial (three trials) and lateral (three trials) joint lines of the index knee using a handheld Medoc digital pressure algometer. Additionally, pressure pain thresholds were assessed at the ipsilateral quadriceps, trapezius, and dorsal forearm. To assess pressure pain threshold, the examiner applied pressure at a rate of 30 kPa per second and the participant was instructed to press a button when the stimulus
“first becomes painful,” at which time the device recorded the pressure in kilopascals. The averages of the three trials for the medial knee and lateral knee as well as the ipsilateral quadriceps, trapezius, and forearm were calculated to create an overall pressure pain sensitivity score. Cold Pressor Each participant completed a series of hand immersions in a cold-water bath (Neslab, RTE-111, Portsmouth, NH) at temperatures of 16, 12, and 8 °C, with 5 min separating each exposure. Participants were first instructed regarding the differences between pain intensity and pain unpleasantness. Next, they were instructed to place their hand in the coldwater bath up to their wrist for as long as possible up to 60 s. Participants were informed they could remove their hand from the cold water at any time if the pain became intolerable. Immediately after participants removed their hand, they rated the intensity and unpleasantness of any pain they were experiencing using 0 to 100 numeric rating scales. In addition to ratings of intensity and unpleasantness, a measure of cold pain tolerance was captured. Specifically, cold pain tolerance was measured as the time at which participants removed their hand from the cold water. Data Analysis Hypothesis 1 Two separate linear regression models were used to determine the predictive value of pain hypervigilance on WOMAC pain and KOOS-PS scores. The following a priori covariates were added to the regression model: age, ethnicity (0=non-Hispanic White, 1=African American), gender (0=female, 1=male), education (0=high school or less, 1=some college or more), and depressive symptoms as measured by the CES-D. Hypothesis 2 Linear regression was similarly used to assess the relationship between pain hypervigilance and experimental pain responses, with the exception of cold pain tolerance, which was assessed by binary logistic regression. The latter procedure was used because the majority of participants completed the full duration of cold-water exposure (maximum 60 s) at each measured temperature. Therefore, to avoid statistical problems associated with abnormal distributions, cold pain tolerance was dichotomized. Specifically, participants were classified as “tolerant” if they did not remove their hand for the full 60-s immersion and classified as “intolerant” if they removed their hand before the full 60 s. In addition to controlling for demographic characteristics as described above, the WOMAC pain subscale and SPC scale were included as
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additional covariates to determine if pain hypervigilance explained variance in quantitative sensory testing beyond ratings of clinical pain and situation specific coping, respectively. Lastly, cold pain tolerance was added as a covariate for pain intensity and pain unpleasantness analyses for each respective temperature to determine if pain hypervigilance differentiated pain ratings beyond what cold-water exposure could explain. Hypothesis 3 Before assessing temporal summation of heat pain, paired t tests analyzing the difference between the first and highest pain ratings were inspected to verify significant temporal summation prior to determining its relationship with pain hypervigilance. Linear regression was used to determine the relationship between pain hypervigilance and temporal summation of heat pain while controlling for age, ethnicity, gender, education, depression, WOMAC pain, and SPC. Due to the large number of statistical analyses performed, corrections for multiple testing were employed. To accomplish this, we first categorized our dependent variables into separate “families” based on stimulus type. These are (1) clinical outcomes (WOMAC pain, KOOS-PS), (2) thermal heat (heat pain thresholds and tolerances at the forearm and knee), (3) mechanical pressure (pressure pain thresholds at the lateral knee, medial knee, forearm, quadriceps, and trapezius), (4) cold pressor (pain intensity/unpleasantness ratings and cold pain tolerance), and (5) temporal summation of heat pain. We then performed a Holm–Bonferroni procedure to obtain corrected P values [30]. Briefly, for each “family,” obtained P values were ordered from lowest to highest. The lowest P value was then compared to the P value obtained using a standard Bonferroni correction [i.e., 0.05/C (where C is the number of tests performed within a given “family”)]. If the P value was lower than this adjusted P value, the next lowest P value was compared to an alpha correction of 0.05/C −1. This procedure is continued until the first non-significant test is obtained. For all analyses, Cohen’s f 2 effect sizes are presented where appropriate. Per Cohen’s guidelines, f 2 =0.02 is considered a small effect, f 2 =0.15 a medium-sized effect, and f 2 =0.35 a large effect [31]. All variables had complete data except temporal summation of heat pain. Because only a small number of data were missing for temporal summation of heat pain (n ranged from 162 to 166), missing cases were deleted listwise. All analyses were carried out using SPSS, version 19.
Results Demographic variables (age, ethnicity, gender, and education), clinical characteristics (CES-D), and mean PVAQ scores of research participants are presented in Table 1. Participants
Table 1 Characteristics of participants
N
168 56.9 (7.66) 124 (73.8 %)
Data presented as means (SD) or count (%)
Mean age (SD) Female gender Ethnicity Non-Hispanic White African American
87 (51.8 %) 81 (48.2 %)
Education High school or less Some college or more CES-D (SD) PVAQ (SD)
70 (41.7 %) 98 (58.3 %) 16.14 (5.81) 44.26 (15.53)
CES-D Center for Epidemiologic Studies Depression Scale, possible range=0–60; PVAQ Pain Vigilance and Awareness Questionnaire, possible range=0–80
were primarily female (73.8 %) with a mean age of 56.9 (±7.66). The first-order intercorrelations among the PVAQ and control variables are presented in Table 2. Greater scores on the PVAQ were associated with being younger in age (P < 0.05), African American (P
