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Ethnic Differences in Diffuse Noxious Inhibitory Controls (DNIC)

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Title: Ethnic Differences in Diffuse Noxious Inhibitory Controls (DNIC)
Physical Description: 1 online resource (44 p.)
Language: english
Creator: Campbell, Claudia M
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: differences, dnic, ethnic, experiemental, nfr, pain
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Pain is a complex, multidimensional phenomenon influenced by multiple biological and psychosocial variables. Considerable evidence has demonstrated that the experience of both clinical and experimental pain differs among ethnic groups, with African Americans generally reporting greater sensitivity to chronic and experimentally induced pain; however, little research has examined the origins of these differences. It is important to understand potential ethnic differences in pain perception, because this may have important implications for diagnosing and treating pain. Differences in central pain-inhibitory mechanisms could potentially explain the differences in pain reports by African American and Non-Hispanic white individuals; however, standard laboratory pain measures do not directly assess pain inhibitory mechanisms. One method frequently used in this regard is assessment of diffuse noxious inhibitory controls (DNIC). DNIC, or counterirritation, refers to the process whereby one noxious stimulus inhibits the perception of a second painful stimulus. This phenomenon is thought to reflect descending inhibition of pain signals. The current study evaluated responses to two commonly used experimental pain procedures in healthy young adults from two different ethnic groups: African Americans and non-Hispanic whites. Perceptual responses (e.g., pain threshold, pain ratings) as well as physiological responses (e.g., blood pressure, emg response) were assessed. Assessment of the NFR threshold, or RIII response, is highly correlated with subjective pain thresholds, such that increases in stimulus intensity are associated with increased pain perception and is therefore frequently used in pain research. The NFR is based on the measurement of stimulus-induced spinal reflexes, and allows standardized placement and a high level of reproducibility. This measure allowed for assessment of both self-reported pain and to quantify an individual?s physiological response. This was utilized along with an ischemic task for counter-irritation. The findings of this study provide evidence of ethnic differences in the NFR and suggest group differences in the level of physiological activation of the nociceptive system. Additionally, African Americans experienced reduced endogenous pain modulation relative to whites, which suggests significant differences in descending pain inhibition. No ethnic differences were observed in reflex rates or cardiovascular response. The findings of this study may contribute to observed ethnic differences in clinical and experimental pain findings.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Claudia M Campbell.
Thesis: Thesis (Ph.D.)--University of Florida, 2007.
Local: Adviser: Fillingim, Roger B.
Local: Co-adviser: Robinson, Michael E.

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Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2007
System ID: UFE0015241:00001

Permanent Link: http://ufdc.ufl.edu/UFE0015241/00001

Material Information

Title: Ethnic Differences in Diffuse Noxious Inhibitory Controls (DNIC)
Physical Description: 1 online resource (44 p.)
Language: english
Creator: Campbell, Claudia M
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2007

Subjects

Subjects / Keywords: differences, dnic, ethnic, experiemental, nfr, pain
Clinical and Health Psychology -- Dissertations, Academic -- UF
Genre: Psychology thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Pain is a complex, multidimensional phenomenon influenced by multiple biological and psychosocial variables. Considerable evidence has demonstrated that the experience of both clinical and experimental pain differs among ethnic groups, with African Americans generally reporting greater sensitivity to chronic and experimentally induced pain; however, little research has examined the origins of these differences. It is important to understand potential ethnic differences in pain perception, because this may have important implications for diagnosing and treating pain. Differences in central pain-inhibitory mechanisms could potentially explain the differences in pain reports by African American and Non-Hispanic white individuals; however, standard laboratory pain measures do not directly assess pain inhibitory mechanisms. One method frequently used in this regard is assessment of diffuse noxious inhibitory controls (DNIC). DNIC, or counterirritation, refers to the process whereby one noxious stimulus inhibits the perception of a second painful stimulus. This phenomenon is thought to reflect descending inhibition of pain signals. The current study evaluated responses to two commonly used experimental pain procedures in healthy young adults from two different ethnic groups: African Americans and non-Hispanic whites. Perceptual responses (e.g., pain threshold, pain ratings) as well as physiological responses (e.g., blood pressure, emg response) were assessed. Assessment of the NFR threshold, or RIII response, is highly correlated with subjective pain thresholds, such that increases in stimulus intensity are associated with increased pain perception and is therefore frequently used in pain research. The NFR is based on the measurement of stimulus-induced spinal reflexes, and allows standardized placement and a high level of reproducibility. This measure allowed for assessment of both self-reported pain and to quantify an individual?s physiological response. This was utilized along with an ischemic task for counter-irritation. The findings of this study provide evidence of ethnic differences in the NFR and suggest group differences in the level of physiological activation of the nociceptive system. Additionally, African Americans experienced reduced endogenous pain modulation relative to whites, which suggests significant differences in descending pain inhibition. No ethnic differences were observed in reflex rates or cardiovascular response. The findings of this study may contribute to observed ethnic differences in clinical and experimental pain findings.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Claudia M Campbell.
Thesis: Thesis (Ph.D.)--University of Florida, 2007.
Local: Adviser: Fillingim, Roger B.
Local: Co-adviser: Robinson, Michael E.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2007
System ID: UFE0015241:00001


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ETHNIC DIFFERENCES IN DIFFUSE NOXIOUS INHIBITORY CONTROLS (DNIC)


By

CLAUDIA M. CAMPBELL




















A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA


2007

































Copyright 2007 Claudia M. Campbell















ACKNOWLEDGMENTS

I thank my mentor, Roger Fillingim, and committee members Michael Robinson,

Garry Geffken and Henrietta Logan. I would also like to thank Christopher France,

consultant on this dissertation, for his technical support. I also appreciate the members of

the Sensory Testing Laboratory for their continued support and encouragement through

my schooling. Finally, I thank my friends and family for their constant support

throughout this process.
















TABLE OF CONTENTS



A C K N O W L E D G M E N T S ......... .................................................................................... iii

L IST O F T A B L E S ..................................................................... .....................

LIST OF FIGURES ......... ......................... ...... ........ ............ vi

ABSTRACT .............. ............................................. vii

CHAPTER

1 IN T R O D U C T IO N ............................................................................. .............. ...

2 RESEARCH DESIGN AND METHODS ......................................... ...............5

N ociceptive Flexion R eflex A ssessm ent ........................................... .....................7
T e st S tim u lu s ................................................................................................................ 8
Conditioning Stimulus .................. .................. ...................... .... ........ 8
P sy chological M easures........... ...... .................................................... ........ ........ ...8

3 DATA REDUCTION AND ANALYSIS ..............................................................10

4 R E S U L T S ............................................................................................................. 12

5 D ISC U S SIO N ...................................................... 19

APPENDIX

A DNIC CHAN GES SCORES.......................................................... ............... 26

B Q U E ST IO N N A IR E S .................................................................. ......... .................27

L IST O F R E F E R E N C E S ......................................................................... .................... 1

B IO G R A PH IC A L SK E TCH ..................................................................... ..................36
















LIST OF TABLES


Table p

4-1. Demographic information, means (SD) for baseline pain tasks, and
psychological factors by ethnicity ......................................................................... 14

4-2. Means (SD) for DNIC and DNICs ratings averaged across each segment.
Ischemic ratings represent summed responses during the DNIC and DNICs
p o rtio n s ...................................... .................................................. .1 5

4-3. Correlations between attention ratings and pain ratings and reflex frequency
during D N IC .............................................................................................. 15

4-4. Means (SD) for cardiovascular responses at baseline, DNIC and Sham for
African Am ericans and whites. ........................................ .......................... 15

4-5. Change Score means (SD) for cardiovascular responses in African Americans
and whites during DN IC and Sham .................................... ........................ 16
















LIST OF FIGURES


Figure page

2 -1 T im elin e Session 2 ................... .... .......................... .. ...... ........ .......... .. ....

4-1 NFR (SD) in mA for African Americans and whites ...............................................16

4-2 Difference scores (SD) for verbal responses during DNIC and SHAM
assess ents......................................................................... ..... ... ... 17

4-3 Difference scores for reflex frequency during DNIC and SHAM assessments, as
well as post and post 2 assessments for African Americans and whites.................. 18















Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

ETHNIC DIFFERENCES IN DIFFUSE NOXIOUS INHIBITORY CONTROLS (DNIC)

By

Claudia M. Campbell

August 2007

Chair: Roger B. Fillingim
Cochair: Michael R. Robinson
Major: Psychology

Pain is a complex, multidimensional phenomenon influenced by multiple biological

and psychosocial variables. Considerable evidence has demonstrated that the experience

of both clinical and experimental pain differs among ethnic groups, with African

Americans generally reporting greater sensitivity to chronic and experimentally induced

pain; however, little research has examined the origins of these differences. It is

important to understand potential ethnic differences in pain perception, because this may

have important implications for diagnosing and treating pain. Differences in central pain-

inhibitory mechanisms could potentially explain the differences in pain reports by

African American and Non-Hispanic white individuals; however, standard laboratory

pain measures do not directly assess pain inhibitory mechanisms. One method frequently

used in this regard is assessment of diffuse noxious inhibitory controls (DNIC). DNIC,

or counterirritation, refers to the process whereby one noxious stimulus inhibits the

perception of a second painful stimulus. This phenomenon is thought to reflect









descending inhibition of pain signals. The current study evaluated responses to two

commonly used experimental pain procedures in healthy young adults from two different

ethnic groups: African Americans and non-Hispanic whites. Perceptual responses (e.g.,

pain threshold, pain ratings) as well as physiological responses (e.g., blood pressure, emg

response) were assessed.

Assessment of the NFR threshold, or RIII response, is highly correlated with

subjective pain thresholds, such that increases in stimulus intensity are associated with

increased pain perception and is therefore frequently used in pain research. The NFR is

based on the measurement of stimulus-induced spinal reflexes, and allows standardized

placement and a high level of reproducibility. This measure allowed for assessment of

both self-reported pain and to quantify an individual's physiological response. This was

utilized along with an ischemic task for counter-irritation.

The findings of this study provide evidence of ethnic differences in the NFR and

suggest group differences in the level of physiological activation of the nociceptive

system. Additionally, African Americans experienced reduced endogenous pain

modulation relative to whites, which suggests significant differences in descending pain

inhibition. No ethnic differences were observed in reflex rates or cardiovascular

response. The findings of this study may contribute to observed ethnic differences in

clinical and experimental pain findings.














CHAPTER 1
INTRODUCTION

Considerable evidence has demonstrated that the experience of both clinical and

experimental pain differs across ethnic groups, with the most substantial evidence

demonstrating greater sensitivity to clinical and experimentally induced pain in AA

compared to non-Hispanic whites. Recently, several investigators have noted ethnic

differences in pain-related symptoms among a variety of chronic pain conditions (Green

et al 2003). Edwards and colleagues (2001) found higher levels of pain and disability

among AA relative to white patients seen in a multidisciplinary pain center. Other

studies also indicate that AA with chronic pain report higher levels of pain

unpleasantness, greater pain-related emotional distress, and increased pain behaviors

relative to whites (Riley et al. 2002; Green et al. 2003).

Because ethnic differences in clinical pain responses can be influenced by factors

such as disease severity and disparities in pain treatment, it is important to examine

ethnic differences in pain perception among healthy individuals (Todd 1996;Stewart et al.

1996;Cleeland et al. 1997;McCracken et al. 2001). Laboratory studies also suggest

increased experimental pain sensitivity among African Americans as compared to whites

(Zatzick and Dimsdale, 1990). For instance, lower heat pain thresholds and tolerances

were reported decades ago among African American subjects compared to whites by

Chapman and Jones (1944), and increased sensitivity to heat pain among African

Americans has been reported more recently by Edwards and Fillingim (1999) as well as

Sheffield and colleagues (2000); particularly for measures of pain unpleasantness.









Similarly, cold pressor pain tolerances were lower in a combined group of African

Americans and Hispanics in comparison to whites (Walsh et al. 1989). Additionally,

African Americans report greater intensity and unpleasantness in response to a modified

ischemic task when compared to whites, using a standardized rating scale (Campbell et

al. 2004). Finally, results from our laboratory indicated significantly lower tolerance for

heat pain, ischemic pain and cold pressor pain in African Americans when compared to

whites. Ratings of intensity and unpleasantness of supra-threshold heat pain were also

higher among African Americans than whites (Campbell et al. 2005). Thus, ethnic

differences in both clinical and experimental pain responses have been widely reported;

however, most previous studies have not attempted to examine the origins of these

differences.

Differences in central pain-inhibitory mechanisms could potentially explain the

differences in pain reports by African American and Non-Hispanic white individuals;

however, standard laboratory pain measures do not directly assess pain inhibitory

mechanisms. One method frequently used in this regard is assessment of diffuse noxious

inhibitory controls (DNIC). DNIC, or counterirritation, refers to the process whereby one

noxious stimulus inhibits the perception of a second painful stimulus. This phenomenon

is thought to reflect descending inhibition of pain signals (Le Bars et al. 1979a; Price and

McHaffie 1988). DNIC is presumed to operate through activation of descending

supraspinal inhibitory pathways initiated by release of endogenous opioids (Le Bars et al.

1979b;Kraus et al. 1981;Roby-Brami et al. 1987;De Broucker et al. 1990).

The DNIC system has been examined extensively in non-human animals with early

studies focused on the mechanisms involved in the process of DNIC; however, more









recent studies in humans have utilized the process in order to examine possible

deficiencies in descending inhibitory processes in certain populations. For example, sex

differences (Staud et al. 2003), and age differences (Edwards et al. 2003a) have been

observed in DNIC, suggesting differing endogenous pain inhibition across certain groups.

Clinical pain conditions such as fibromyalgia (Lautenbacher and Rollman 1997;Kosek

and Hansson 1997;Staud et al. 2003), osteoarthritis (Kosek and Ordeberg 2000), trapezius

myalgia (Leffler et al. 2002a), rheumatoid arthritis (Leffler et al. 2002b), and peripheral

nerve injury (Bouhassira et al. 2003) also show evidence of impaired DNIC responses;

suggesting a possible role for dysregulation of pain inhibitory systems in the acquisition

or maintenance of the condition (Staud et al. 2003). Ethnic differences in DNIC may

suggest that deficiencies in central inhibitory mechanisms may contribute to the more

robust clinical and experimental pain responses often observed in African Americans.

Use of pain rating scales as a primary method of assessing pain perception is a

frequently used and practical option; however, group differences pain reports could be

related to group differences in use of the pain scales (e.g. see Campbell, et al, 2004).

Thus, electrophysiological alternatives, such as the nociceptive flexion reflex (NFR), may

provide important information regarding ethnic group differences in nociceptive

responses, which may be less susceptible to the biases that may influence subjective

rating scales (Skljarevski and Ramadan 2002). The NFR is based on the measurement of

stimulus-induced spinal reflexes (Willer 1977), and can be administered in a

standardization fashion, and has been shown to have adequate reproducibility.

Assessment of the NFR threshold, or RIII reflex, is highly correlated with subjective pain

thresholds, such that increases in stimulus intensity are associated with increased pain









perception (Willer 1977; Peters et al. 1992; Skljarevski and Ramadan 2002). This

methodology permits assessment of both self-reported pain and quantification of an

individual's physiological response. While numerous studies have examined changes in

subjective pain threshold and NFR changes during counterirritation procedures, no

studies to date have systematically examined ethnic differences in the NFR or DNIC.

This study was designed to further elucidate the nature of ethnic differences in pain

perception by investigating responses to DNIC using the NFR, testing the hypothesis that

African Americans, relative to non-Hispanic whites, may be deficient in endogenous pain

modulation.














CHAPTER 2
RESEARCH DESIGN AND METHODS

The final study sample consisted of fifty-seven healthy young adults (29 African

American, 28 non-Hispanic white). One white individual discontinued participation

following the baseline session, all other subjects completed the protocol. Demographic

information is presented in Table 3-1. The University of Florida Institutional Review

Board approved all study procedures. All subjects participated in two experimental

sessions, lasting up to 2 hours; women were scheduled during their follicular phase (i.e.

days 4-9 of the menstrual cycle) to reduce variability associated with the menstrual cycle

(Riley et al. 1999). During the first session, verbal and written informed consent were

obtained; after which participants completed a health history questionnaire, which

indicated that all were in good health and had no prior history of pain problems, then

complete a series of questionnaires assessing demographic information, mood,

catastrophizing, and hypervigilance (described in detail below). Ethnicity was

determined using self-report. Following completion of the questionnaires participants

were instrumented (see procedure below), and rested for 10 minutes, after which their

blood pressures was measured for five minutes using an automated blood pressure cuff,

then their NFR threshold was determined.

During the second session, one DNIC assessment was conducted, as well as one

sham DNIC (DNICs) assessment, during which an ischemic cuff was not inflated, these

procedures were conducted in a counterbalanced order. Mood questionnaires were

completed prior to NFR instrumentation, and participant's right arm maximum grip









strength was measured. A ten-minute rest period was then observed, followed by five

minutes of continuous blood pressure readings. The level of electrical stimulation

delivered during the DNIC procedure was individually determined for each subject in

order to produce moderate pain, (i.e. a rating of 45 on a 0-100 scale, where 0 = no

sensation and 100 = the strongest imaginable sensation of any kind). Repeated

assessment of the nociceptive flexion reflex at this stimulus intensity was conducted each

minute for five minutes during each of the following time periods: 1) 5-minute baseline

period; 2) five minutes ofischemic arm pain (or sham ischemic procedure); 3) five-

minute post ischemic (or sham) time period. Following completion of this sequence, a

10-minute rest period was observed, after which responses to another 5 minutes of

electrical stimulation were assessed. After a 15-minute rest period this sequence was

conducted in the same manner, under the condition (DNIC vs. sham) that was not

administered during the first sequence. Following both the DNIC and DNICs sequences

participants rated their attention to the sensation in their right arm while the cuff was on,

their attention to the sensation in their ankle (the site of electrical stimulation) during the

time the cuff was on their right arm, as well as the degree to which the sensation in their

ankle differed due to the cuff on a -100 to 100 scale (-100 = much weaker, 100 = much

stronger).


Figure 1
5 rmn TimeLine Session 2
blkod


Figure 2-1. Timeline Session 2









Nociceptive Flexion Reflex Assessment

Subjects underwent electrical stimulation delivered via a bar electrode applied to

the left sural nerve using Digitimer DS7A constant current stimulator (Herfordshire, UK).

The nociceptive withdrawal reflex was assessed using two, 12 mm disposable Conmed

(Utica, NY) electrodes, one placed over the left biceps femoris muscle, the other placed

over the reference sight, which was on the left lateral epicondyle of the femur. All sights

were cleaned and gently abraded to achieve an impedance of less than 10,000 Ohms prior

to electrode placement. Participants were comfortably seated in a recliner in order to

maintain a 60-degree angle of the knee. Electrical stimulation was applied in a series of

ascending and descending steps. A 5-pulse train (1 ms pulse duration, 3 ms inter-pulse

interval) was administered approximately once every 30 seconds. During reflex

assessment, participants rated the perceived intensity of each pulse using a 0 to 100 rating

scale (0=no sensation and 100=strongest imaginable sensation of any kind). Stimulation

intensity began at 0 milli-amps (mA) and increased in 2mA steps until the nociceptive

withdrawal reflex was obtained (or a maximum intensity of 40mA, or termination was

requested by the participant). Stimulus intensity was then decreased in ImA steps until

the reflex was no longer observed. This procedure was repeated using ImA steps so that

the nociceptive withdrawal reflex appeared and subsided three times in total. Reflex

threshold was defined as the average of the peaks during the three sequences. During the

second session, stimulation was delivered at the intensity of the participant's nociceptive

flexion reflex threshold, then increased until a rating of 50 was obtained, following which

stimulation was reduced by .2 mA until a rating of 30 was reached. The stimulation

intensity at a rating of 45 was calculated and used in all subsequent testing.









Test Stimulus

In order to elicit consistent responses, electrical stimulation during the DNIC and

sham procedures was set at the intensity rated as 45 by the individual participant. This

stimulation intensity was determined at the beginning of the second session as follows.

Electrical stimulation was delivered at the intensity of the participant's nociceptive

flexion reflex threshold (from session 1), then increased until a rating of 50 was obtained,

following which stimulation was reduced by .2 mA until a rating of 30 was reached. The

stimulation intensity at a rating of 45 was calculated and used in all subsequent testing.

Conditioning Stimulus

Ischemic pain was induced using a modified submaximal effort tourniquet

procedure adapted from France and Suchowiecki (1999). Following five minutes of NFR

testing, participants completed 2 minutes of handgrip exercises, at which time their arm

was elevated for 30-seconds, then the cuff was inflated to a pressure of 240 mm Hg (or

not in the sham procedure). Five minutes of ischemic arm pain was conducted with

concurrent NFR administration. At 30-second intervals, participants rated the intensity of

their arm pain on 0 to 20 box scales (Coghill and Gracely, 1996). After five minutes of

arm occlusion (or the sham procedure), the cuff was deflated and RIII was continued for

an additional 5 minutes.

Psychological Measures

In order to determine the contribution of psychosocial factors to group differences

in experimental pain responses, including DNIC, subjects completed the following

psychological questionnaires.

The Pain Catastrophizing Scale (PCS) (Sullivan et al. 1995) consists of 14 items

rated on a 5-point scale ranging from 0 (not at all) to 4 (all the time). Participants are









instructed to indicate the degree to which they have specified thoughts and feelings when

experiencing pain. The measure assesses three dimensions of catastrophizing:

rumination, magnification, and helplessness. The PCS has been validated for both

clinical and nonclinical samples (Sullivan et al. 1995;Osman et al. 2000).

The Kohn Reactivity Scale (Kohn 1985) consists of 24 items that assess an

individual's level of reactivity or central nervous system arousability and has been used

as a measure of hypervigilance (McDermid et al. 1996). This measure has been shown to

correlate negatively with pain tolerance (Dubreuil and Kohn 1986) and has been reported

to have adequate internal consistency, ranging from alpha of 0.73 to 0.83 (Kohn 1985).

The Frid Scale (FRID) is a 10 item, 5-point Likert scale assessing expectancies and

attitudes regarding experimental pain procedures. The measure consists of three

subscales including Psychological Involvement in the experiment, Negative Expectancies

regarding the experiment, and Efficacy and Control beliefs (Frid et al. 1979).

The Visual Analogue Mood Scale (VAMS) consists of 8 horizontal 100 mm VAS

scales representing different aspects of mood. Participants were asked to mark their

current mood by placing a vertical mark on the line. The VAMS was has been shown to

have adequate validity (Killgore 1999).














CHAPTER 3
DATA REDUCTION AND ANALYSIS

Mean NFR values and verbal ratings of pain corresponding to the reflex threshold

among African Americans and non-Hispanic whites were calculated, and analysis of

variance (ANOVA) was conducted to characterize ethnic differences in the NFR and pain

perception.

To examine differences in reflex activity during DNIC, the total number of

reflexes occurring during the five minute pre-DNIC (or sham) and DNIC (or sham)

assessment periods was computed. Then, a difference score (total number of pre-DNIC

reflexes minus during DNIC reflexes) was calculated for each subject. A 2 (group) X 2

(condition: DNIC vs. sham) mixed model ANOVA was then conducted to determine the

reliability of differences in DNIC between ethnic groups, using the change score as the

dependent variable. Analysis of electrical pain ratings was conducted in a similar

fashion. Specifically, the average electrical pain rating was computed for each time

period (pre-DNIC or pre-sham, during DNIC or during sham), and these changes scores

were used as dependent measures in mixed model ANOVAs, as described for reflex

activity.

The time course of post-DNIC effects was examined using the same approach as

described for DNIC analyses. Briefly, reflexes and pain ratings were averaged across the

two 5-minute post-DNIC (and sham) time periods (immediately after and 10 minutes

after). Then, difference scores were created by subtracting the post-DNIC (or sham)

averages from the baseline (i.e. pre-DNIC or sham) average. Finally, separate 2 (ethnic









group) X 2 (DNIC vs. sham) mixed-model ANOVAs were conducted on each of the

change scores (reflexes and ratings) from each time period (immediately post and 10

minutes post) in order to characterize the after effects of DNIC.

Correlational analyses were conducted to examine associations between

psychological variables and baseline responses to electrical pain, including NFR intensity

and ratings of electrical pain. Similar correlational analyses were conducted to examine

associations between psychological variables and the magnitude of DNIC, including

DNIC change scores for both reflex measures and pain ratings.














CHAPTER 4
RESULTS

No ethnic group differences in sex, age, body mass index or impedance were

observed. Analysis of variance revealed significant ethnic group differences in NFR

reflex (F (1,50)=5.10, p = .028; effect size = .61), with African Americans demonstrating

a reflex at a lower stimulus intensity relative to non-Hispanic whites, displayed

graphically in Figure 3-1. Despite the difference in intensity required to elicit a reflex

between the two groups, verbal ratings of pain corresponding with the reflex did not

differ. Baseline data for the pain tasks are presented in Table 3-1. However, the intensity

at which participants rated a 45, used to stimulate participants during DNIC and DNICs

testing, significantly differed by ethnic group (F (1,54)=5.77, p = .019); therefore, the two

groups received significantly different levels of electrical stimulation during the DNIC

procedures.

The conditioning stimulus produced substantial reductions in pain ratings for all

participants during the DNIC condition when compared with DNICs condition (p < .001).

The DNIC condition produced significantly greater reductions in verbal pain ratings

among whites when compared with African Americans (F(1,55)=4.05, p = .049; effect

size .65). These data are presented graphically in Figure 3-2. The number of reflexes

was significantly lower during DNIC versus DNICs stimulation (F(1,43)=14.78, p <

.001), and this reduction in frequency of reflex was similar across ethnic groups.

ANOVAs revealed no group differences in ratings of ischemic pain during either the

DNIC or DNICs condition. Analysis of variance was conducted in order to characterize









the after effects of DNIC and the possible influence of ethnicity. No group differences

were observed at the post DNIC and DNICs measurements, with both African Americans

and whites returning to baseline pain ratings and baseline reflex activity during the 5-

minute period following DNIC stimulation (see Figures 3-2 and 3-3).

Cardiovascular responses were evaluated in order to examine changes in blood

pressure and heart rate reactivity during DNIC and potential differences in ethnicity. No

significant group or condition differences emerged for any of the cardiovascular

responses, see Tables 3-4 and 3-5. Ratings of attention focused on the arm, ankle and the

degree to which the sensation in their ankle differed due to the cuff did not differ by

group. These ratings were not correlated with magnitude of DNIC among African

Americans; however, among whites, increased attention to the arm predicted greater

reductions in electrical pain during DNIC, and increased attention to the arm was

positively correlated with reflex frequency during DNIC, while attention to the ankle and

ratings of how much the ankle sensation felt due to the ischemic procedure was

negatively correlated with reflex frequency (see Table 3-3). However, ethnic group

differences in DNIC remained significant even when the analysis was repeated using an

ANCOVA controlling for subjects ratings of attention to the arm (F (1,54)=5.46, p=.023).

No ethnic group differences emerged for any of the psychological variables (see

Table 3-1). Correlational analyses were conducted examining associations between

responses to psychological questionnaires and NFR threshold. Psychological

Involvement (a subscale of the FRID scale) and Positive Mood were positively correlated

with NFR (r= .30, p =.02; r=.35, p<.01), and the rumination subscale of the PCS was

negatively correlated with NFR (r=-.29, p=.03). The pattern of correlations was









consistent across both ethnic groups. In order to determine whether these psychological

variables mediated ethnic group differences in the NFR threshold, analyses were repeated

controlling for each of the three psychological measures that were associated with the

NFR. Ethnic group differences remained significant after controlling for positive mood

(F(1,50)=5.24, p=.026) and psychological involvement (F(1,50)=4.38, p=.041), and were

marginally significant (F(1,50)=3.63, p=.063) after controlling for rumination. Thus,

these psychological variables do not appear to mediate ethnic group differences in NFR

thresholds. None of the psychological variables was significantly correlated with the

magnitude of DNIC.

Table 4-1. Demographic information, means (SD) for baseline pain tasks, and
psychological factors by ethnicity.
Variable AA (n=29) Whites (n=28)
Age (SD) 23.7 (7.1) 25.3 (8.6)
Sex (% female) 51.7 57.7
BMI (SD) 23.66 (5.19) 23.34 (3.36)
Impedance in Q (SD) 4.05 (2.83) 4.89 (2.60)
NFR Reflex* in mA (SD) 14.99 (8.98) 20.95 (10.45)
NFR Rating (SD) 42.85 (20.68) 50.37 (25.44)
DNIC, DNICs Intensity 1.86 (.96) 2.46 (.92)
VAMS Positive Mood 178.52 (65.73) 171.96 (56.1)
VAMS Negative Mood 29.93 (33.38) 23.43 (33.38)
FRID Negative Expectancies 5.5 (1.83) 5.07 (1.44)
FRID Efficacy and Control Beliefs 11.78 (1.89) 12.55 (1.95)
FRID Psychological Involvement 11.67 (1.83) 11.91 (2.15)
PCS Rumination 1.11 (1.92) .32(1.15)
PCS Magnification .11 (.35) .07 (.19)
PCS Helplessness .55 (2.97) 0 (0)
PCS Catastrophizing 1.78 (4.03) .39(1.15)
KOHN Score 68.69 (14.69) 66.04 (9.38)
p <.05









Table 4-2. Means (SD) for DNIC and DNICs ratings averaged across each segment.
Ischemic ratings represent summed responses during the DNIC and DNICs
portions.
Variable AA (n=29) Whites (n=28)
DNIC Baseline 0-100 36.71 (14.21) 39.44 (16.36)
DNIC* 0-100 31.90 (13.56) 29.73 (13.02)
DNIC Post 0-100 34.55 (14.29) 36.94 (16.32)
DNIC 10min Post 0-100 36.26 (13.87) 38.60 (16.41)
DNICs Baseline 0-100 38.17 (11.76) 35.99 (14.23)
DNICs 0-100 37.02 (14.17) 35.49 (15.25)
DNICs Post 0-100 36.51 (15.21) 36.49 (17.11)
DNICs 10min Post 0-100 37.88 (14.5) 37.60 (14.71)
Ischemic Rating DNIC 0-20 109.34 (46.61) 119.75 (41.85)
Ischemic Rating DNICs 0-20 5.48 (13.45) 10.54 (22.47)
*p <.05

Table 4-3. Correlations between attention ratings and pain ratings and reflex frequency
during DNIC.

Ethn y Difference Deg Attn to Deg Attn to Deg different
Ethnicity ^ 11 Deg different
Scores arm ankle
African Pain Ratings .02 -.09 -.04
Americans Reflex Freq. .12 .001 -.09
Whit Pain Ratings .46* -.27 .32
Whites
Reflex Freq. .41 -.49* -.47*
*p <.05

Table 4-4. Means (SD) for cardiovascular responses at baseline, DNIC and Sham for
African Americans and whites.

Variable African Americans (SD) Whites (SD)
Baseline Systolic BP 108.27 (10.14) 108.69 (8.37)
Baseline Diastolic BP 62.11 (7.62) 61.22 (6.86)
Baseline Mean Arterial Pressure 78.64 (8.11) 77.99 (6.71)
Baseline Heart Rate 67.3 (11.3) 64.56 (9.42)
DNIC Systolic BP 112.53 (11.58) 113.99 (9.73)
DNIC Diastolic BP 67.19(8.7) 66.86 (7.54)
DNIC Mean Arterial Pressure 84.95 (9.55) 85.09 (7.4)
DNIC Heart Rate 67.24 (11.09) 65.07 (10.07)
Sham Systolic BP 110.05 (9.09) 110.53 (8.14)
Sham Diastolic BP 64.28 (8.94) 63.88 (7.82)
Sham Mean Arterial Pressure 80.98 (8.4) 80.92 (6.98)
Sham Heart Rate 66.79 (9.67) 64.69 (8.67)












Table 4-5. Change Score means (SD) for cardiovascular responses in African Americans
and whites during DNIC and Sham.
Change Scores AA (n=29) Whites (n=28)
DNIC Sham DNIC Sham
Systolic BP -4.26 (7.17) -1.78 (5.36) -5.29 (6.02) -1.84 (4.72)
Diastolic BP -5.08 (3.94) -2.17 (4.07) -5.64 (3.74) -2.66 (3.78)
Mean Arterial Pressure -6.31 (5.71) -2.34 (5.52) -7.11 (4.51) -2.94 (4.21)
Heart Rate .06 (6.32) .51 (4.48) -.51 (6.87) -.13 (5.72)


* African Americans Non Hispanic Whites


10


R3 Reflex


Figure 4-1. NFR (SD) in mA for African Americans and whites









Non Hispanic Whites


10


0


DNIC


Sham


* African Americans Non Hispanic Whites


I


DNIC


I


Post 1


Sham


DNIC


B

Figure 4-2. Difference scores (SD) for verbal responses during DNIC and SHAM
assessments. A) Difference scores of pain ratings during DNIC and Sham. B)
Difference scores of pain ratings during DNIC and Sham for Postl and Post2.


Post 2


Sham


I I I I I


* African Americans








* African Americans


Sham


* African Americans Non Hispanic Whites


I


Sham


DNIC


B
Figure 4-3. Difference scores for reflex frequency during DNIC and SHAM assessments,
as well as post and post 2 assessments for African Americans and whites. A)
Difference scores of reflexes during DNIC and Sham. B) Difference scores of
reflexes during DNIC and Sham for Postl and Post2.


0


DNIC


DNIC


Post 1


Sham


Post 2


I ANMOE l l U L


Non Hispanic Whites


/













CHAPTER 5
DISCUSSION

The findings of this study provide evidence of ethnic differences in the NFR, such

that African Americans required less electrical stimulation to produce a spinally-mediated

nociceptive muscle reflex. Because the NFR is thought to be a more objective

physiological nociceptive measure, the current findings add additional substance to the

existing evidence that African American individuals may demonstrate greater sensitivity

to noxious stimuli compared to whites. The NFR is based on measurement of stimulus-

induced spinal reflexes and is therefore thought to be independent of the reporting biases

sometimes associated with subjective pain ratings. Our findings suggest the factors

contributing to ethnic differences in pain sensitivity may do so in part by altering

nociceptive responses at the spinal level. The mechanisms underlying ethnic group

differences in this spinally-mediated nociceptive reflex cannot be determined from this

study; however, based on the current available evident, the most likely explanation may

be that descending pain inhibition may be more robust among whites, which could reduce

the nociceptive reflex. In this regard, Mechlin and colleagues (2005) recently

demonstrated that stress-induced pain regulatory mechanisms involving blood pressure,

norepinephrine, and cortisol functioned more effectively among whites than African

Americans. It is worth noting that ethnic group differences in descending pain

modulation could be mediated by fundamental biological differences, via psychosocial

factors (e.g. expectations, pain beliefs) and/or the combination of these factors. Indeed,

our findings demonstrate associations between the NFR and psychological variables.









Specifically, greater psychological involvement and higher positive mood correlated

positively with NFR, while higher scores on the rumination subscale of the Pain

Catastrophizing Scale predicted lower NFR. While these psychological variables did not

mediate the group differences we observed in the NFR, it is plausible that other

psychological processes not assessed in this study may have contributed to the group

difference.

Previous research exploring psychological correlates of NFR have provided mixed

results. For example, neither catastrophizing nor anxiety were found to be associated

with NFR, while both variables predicted subjective pain ratings in response to electrical

stimulation (France et al., 2002; French et al., 2005). It may be important to note that

France and colleagues used the catastrophizing subscale of the Coping Strategies

Questionnaire (CSQ), while we assessed catastrophizing with the PCS, which yields

separate subscales, one of which (i.e. the Helplessness subscale) is equivalent to the CSQ

catastrophizing scale. Indeed, our results showed an association only between the

Rumination subscale of the PCS, and the Helplessness subscale was not associated with

the NFR. Thus, it may be that only specific components of catastrophizing predict NFR

thresholds.

Other investigators have reported significant psychological modulation of NFR

thresholds. For example, induction of positive and negative mood increased and

decreased the NFR, respectively (Rhudy, et al, 2005). Moreover, a brief session of pain

coping skills training significantly increased NFR thresholds among patients with

osteoarthritis of the knee (Emery, et al, 2006), and hypnotic analgesia also increased NFR

thresholds (Kiernan et al., 1995; Wade, et al, 1997). Thus, previous research provides









additional evidence that psychological manipulations can influence NFR thresholds, and

the present study extends these findings, providing further support for psychological

contributions to NFR thresholds. The role of psychosocial processes in mediating ethnic

group differences in the NFR merits additional investigation.

The results of the current study further indicate that African Americans experienced

reduced DNIC relative to whites, which suggests significant differences in endogenous

pain inhibition between African Americans and whites. This may be one factor

contributing to observed ethnic differences in clinical and experimental pain findings.

The process under which DNIC operates is thought to reflect influences of complex

descending inhibitory systems, potentially mediated by endogenous opioids. However,

studies examining DNIC under conditions of administration of an opioid antagonist, such

as naloxone, have provided mixed results. Naloxone administration has been shown to

block descending pain inhibition, resulting in no DNIC-induced analgesic effect in some

studies (Willer et al., 1990); however, others have demonstrated no effects of opioid

blockade on DNIC (Edwards et al., 2004, Le Bars et al., 1992). Thus, the exact

mechanisms whereby DNIC produces its effects are unknown. Indeed, it seems likely

that the hypoalgesic effects of a conditioning stimulus could result from multiple

biological and psychosocial processes, whose relative importance may vary across

studies.

Another possible contributor to DNIC could be cardiovascular responses. While

cardiovascular reactivity has been associated with hypoalgesia (Bruehl et al. 1997;

McCubbin and Bruehl, 1994), the link between DNIC and cardiovascular reactivity has

received minimal attention. A recent study (Mechlin et al, 2005) examined regulatory









mechanisms involving stress-induced increases in blood pressure, norepinephrine, and

cortisol functioning on pain response in African Americans and whites, and found these

physiological changes to be more strongly associated with reduction of pain responses

among white participants. While our results are generally consistent with those of

Mechlin in that we also observed more effective endogenous pain inhibition among

whites, cardiovascular reactivity was not associated with the magnitude of DNIC in either

ethnic group in the current study. This may be due to the low level of cardiovascular

reactivity observed during the tourniquet procedure in our study.

The effects of DNIC are thought to be long-lasting when a conditioning stimulus is

applied to heterotopic areas of the body (Le Bars et al. 1979a; Dickenson and Le Bars

1983;Villanueva and Le Bars 1995). In humans, heterotopic noxious stimuli inhibitthe

spinal nociceptive flexion (RIII) reflex, which is controlled by spinal transmission of

nociceptive signals (Willer et al. 1984;Willer et al. 1989). In our sample, while the

conditioning stimulus reduced the frequency of NFR reflexes for the group as a whole, no

ethnic differences in reduction of reflexes were evident. Moreover, the effects of DNIC

in this study were relatively brief, as pain ratings and NFR frequency returned to baseline

immediately after the cessation of the conditioning stimulus.

One potential explanation of the DNIC response might be distraction from the test

stimulus by the conditioning stimulus. Some previous research would argue that DNIC is

not simply a form of distraction. For example, many studies have reported that the

analgesic effects of DNIC outlast the conditioning stimulus with which it was elicited by

several minutes and up to several days (LeBars et al., 1992; Willer et al., 1990). DNIC

has been used in dental pain studies, where ischemic arm pain and ice applied to the hand









not only increased the tolerance of dental pain, but also reduced sensitivity and swelling

around teeth (Willer et al., 1990). DNIC has also been shown to reduce the NFR reflex

(in humans and nonhuman animals), which is thought to be less influenced by distraction

(Le Bars et al., 1992). DNIC effects have been observed in paraplegic and tetrapalegic

patients (Roby Brami et al., 1987), whose actual RIII reflexes did not differ from normal

controls (spinal reflexes intact), suggesting that DNIC activates descending inhibitory

pathways modulating the spinal transmission of nociceptive information. Nonetheless,

distraction could be a potential mechanism adding to DNIC's effectiveness. Several

investigators have examined this connection. Willer and colleagues (1990) had

participants perform mental calculation during several different pain tasks, attempting to

induce DNIC, which did not occur. Edwards and others (2003; 2004) asked participants

about distraction effects, and had them read vignettes, without DNIC effects. Finally,

Staud and colleagues (2003) examined differences between fibromyalgia patients and

healthy women, as well as comparing a sample of healthy men and women. A traditional

DNIC and a DNIC plus distraction task was employed using temporal summation of heat

pain and a hot water bath. Participants were verbally reminded to attend to one stimulus

over the other. Significant sex differences emerged and both DNIC and DNIC plus

distraction produced significant effects. The DNIC plus distraction was somewhat more

effective in men and in fibromyalgia patients. This study suggests that DNIC effects may

be enhanced when paired with distraction.

While we did not observe long-lasting differences in reflex rates or emg activity,

attentional ratings were obtained. Ratings of distraction by the conditioning stimulus

predicted greater DNIC-induced reductions in electrical pain ratings (but not reductions









in NFR frequency), but only among whites. However, the ethnic group differences in

DNIC remained significant after controlling for distraction ratings. Thus, distraction may

have contributed to the DNIC effect on electrical pain ratings, but does not appear to

account for the ethnic group difference in DNIC.

Several limitations should be considered when interpreting the results of the present

study. First, all of the tasks were acute, controlled painful laboratory experiences over

which the participants had control; therefore, these results may be less generalizable to a

clinical pain population. However, the clinical relevance of DNIC has previously been

demonstrated by multiple investigators (Edwards et al. 2003b; Kosek & Ordeberg, 2000).

Another possible limitation may come from stimulating participants at different

intensities depending on their verbal ratings pain. Most studies examining DNIC using

the NFR use 120% of an individual's NFR threshold; however, in our sample this would

have caused great differences in individual's pain ratings of the stimuli. This may have

contributed to our inability to observe ethnic group differences in reflex rates. Another

limitation may be the possibility of habituation with frequent use of the NFR stimuli, one

per minute; however, previous results show habituation to be highly dependent on the

interstimulus interval, and observed habituation with stimulation every 5 seconds, but no

habituation with stimulation 25 seconds apart (Sandrini, et al, 2005).

These limitations notwithstanding, our findings provide evidence of ethnic

differences in the NFR as well as ethnic group differences in the effects of ischemic arm

pain on ratings of electrical pain, but not on NFR reflex frequency. We also observed

associations between psychological factors and the NFR, though these variables did not

account for the observed ethnic differences. The current findings provide further









evidence for the existence of ethnic differences in experimental pain perception, and

suggest potential ethnic group differences in inhibitory processes, though the mechanisms

underlying this effect are not known. Though this type of endogenous pain modulation

has received extensive attention in recent years and considerable evidence has amassed

for its experimental utility, the current finding of ethnic differences in DNIC does not

necessarily explain clinical or experimental differences observed in pain perception.

Future studies should focus on the clinical relevance and implications for care, such as

studying ethnic differences in DNIC in clinical pain models. Future studies may also

pursue a better understanding of the mechanisms involved in ethnic differences in DNIC

by examining the role of distraction and other psychological factors as well as the

possible contribution of endogenous opioids. .














APPENDIX A
DNIC CHANGES SCORES

Change Score means (SD) for ratings and reflexes in African Americans and whites.

Change Scores AA (n=29) Whites (n=28)
DNIC Sham DNIC Sham
Ratings During 4.81 (5.1) 1.14 (7.4) 9.7 (9.4) .49 (6.3)
Ratings Post 2.16(7.26) 1.66 (9.29) 2.51 (6.1) -.5 (7.09)
Ratings Post 2 .45 (6.71) .28 (9.53) .84 (7.1) -1.61 (7.99)
Reflexes During .55 (1.12) .34 (.77) .43 (.96) -.07 (.81)
Reflexes Post .5 (1.18) .45 (1.3) .39 (.99) .13 (1.01)
Reflexes Post 2 .32 (1.36) .41 (1.1) .65 (1.37) 0 (1.45)














APPENDIX B
QUESTIONNAIRES

PCS

Directions: Everyone experiences painful situations at some point in their lives. Such
experiences may include headaches, tooth pain, joint or muscle pain. People are often
exposed to situations that may cause pain such as illness, injury, dental procedures, or
surgery. We are interested in the types of thoughts and feelings that you have when you
are in pain. Listed below are 14 statements describing different thoughts and feelings that
may be associated with pain. Using the following scale, please indicate the degree to
which you have these thoughts and feelings when you are experiencing pain.

0 not at all I1 to a slight degree 2 to a moderate degree 3 to a great degree 4 all the time

1. I worry all the time about whether it will end.

2. I feel I can't go on.

3. It's terrible and I think it's never going to get any better.

4. It's awful and I feel that it overwhelms me.

5. I feel I can't stand it anymore.

6. I become afraid that the pain will get worse.

7. I keep thinking of other painful events.

8. I anxiously want the pain to go away.

9. I can't seem to get it out of my mind.

10. I keep thinking about how much it hurts.

11. I keep thinking about how badly I want the pain to stop.

12. There's nothing I can do to reduce the intensity of the pain.

13. I wonder whether something serious may happen.

14. I feel my life isn't worth living.









Kohn
The items which follow all concern your feelings and experience in common, everyday
situations. There are no right or wrong answers. Please just answer each item as
honestly as you can; however, please work quickly, as your first impression is quite
likely to be the most accurate. For each item, place the number that best represents your
reaction to the item-statement in the space to the right:
1, if you Disagree Strongly with the statement.
2, if you Disagree with the statement.
3, if you Neither Disagree Nor Agree with the statement.
4, if you Agree with the statement.
5, if you Agree Strongly with the statement.

1. If I went on an ocean voyage I'd be sure to get seasick.
2. Jumping right into ice-cold water doesn't bother me.
3. I can't stand driving fast at night.
4. I can often work well when I'm feeling quite sick.
5. I need strict quiet to study or think well.
6. Being out on really cold days doesn't bother me as much as most people.
7. I can't stand staying in a sauna or steam bath for very long.
8. There are very few midway rides that make me uncomfortable.
9. I've often had motion sickness.
10. I can concentrate on what I'm doing even when I'm in pain.
11. I could never bathe or shower in ice-cold water.
12. I can work reasonably well even when I feel emotionally upset.
13. I can always feel when it's time to come in form the cold.
14. Driving fast at night doesn't bother me.
15. I could never study when I'm feeling sick.
16. I've hardly ever had motion sickness.
17. I avoid the cold outdoors as much as I can during the worst of the winter.
18. There are times when I enjoy an ice-cold shower or bath.
19. I can't stand a lot of midway rides.
20. Pain doesn't bother me as much as it does most people.
21. I can't stand much hard physical labor.
22. I'd be very surprised if I got seasick on an ocean voyage.










23. It would take a lot to make me jump into ice-cold lake water.

24. I like staying in saunas or steam-baths longer than most people
can stand to stay




FRID SCALE

Please indicate in the alternatives given below how you think right now.


1. I want to avoid the situation


2. I believe I can tolerate the pain




3. I see the experience as a challenge




4. I think the procedure will be painful




5. I know that nothing concerning this
experiment "can really hurt me"


6. I care that other people may notice my
weaknesses


7. I think this experiment will be interesting




8. I expect to suffer unpleasant after- effects




9. I believe that my participation is
important




10. I expect to be in control of the situation


1
not at
all

1
not at
all

1
not at
all

1
not at
all

1
not at
all

1
not at
all

1
not at
all

1
not at
all

1
not at
all

1
not at
all


2 3 4 5
very much
so

2 3 4 5
very much
so

2 3 4 5
very much
so

2 3 4 5
very much
so

2 3 4 5
very much
so

2 3 4 5
very much
so

2 3 4 5
very much
so

2 3 4 5
very much
so

2 3 4 5
very much
so

2 3 4 5
very much
so












VAMS
Please indicate how you are feeling right now by placing one mark on each line. The
mark should be placed along the line at the point that best reflects how you feel right
now.



Neutral Tense




Neutral Sad




Neutral Happy




Neutral Tired




Neutral Angry




Neutral Energetic


Relaxed


Neutral















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BIOGRAPHICAL SKETCH

Claudia M. Campbell received her Bachelor of Science degree in psychology with

a minor in women's studies from the University of Florida in 2001. As a result of her

interdisciplinary background, she developed an interest in the psychological aspects of

diversity, specifically in the field of pain research. Upon completion of her bachelor's

degree, Ms. Campbell accepted a research assistant position in the sensory testing

laboratory of Dr. Roger Fillingim. Thus, she has been able to pursue her research

endeavors investigating sex and ethnic differences in pain perception. She received her

Master of Science degree in clinical psychology from the University of Florida in 2004

and continues her work through the pursuit of a doctoral degree in clinical and health

psychology at the University of Florida.

Ms. Campbell has also been the recipient of several awards from the American

Pain Society, which include a Citation Award, acceptance into their "Residence

Program" and four Young Investigator Awards, the latter two of which facilitated travel

to the national meetings. Current memberships include the American Pain Society and

the Disparities Special Interest Group of the American Pain Society.





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ETHNIC DIFFERENCES IN DIFFUSE NOXI OUS INHIBITORY CONTROLS (DNIC) By CLAUDIA M. CAMPBELL A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2007

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Copyright 2007 Claudia M. Campbell

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iii ACKNOWLEDGMENTS I thank my mentor, Roger Fillingim, and committee members Michael Robinson, Garry Geffken and Henrietta Logan. I woul d also like to thank Christopher France, consultant on this dissertation, for his technical support. I also appr eciate the members of the Sensory Testing Laboratory for their continued support and encouragement through my schooling. Finally, I thank my friends and family for their constant support throughout this process.

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iv TABLE OF CONTENTS page ACKNOWLEDGMENTS.................................................................................................iii LIST OF TABLES...............................................................................................................v LIST OF FIGURES...........................................................................................................vi ABSTRACT......................................................................................................................v ii CHAPTER 1 INTRODUCTION........................................................................................................1 2 RESEARCH DESIGN AND METHODS....................................................................5 Nociceptive Flexion Reflex Assessment......................................................................7 Test Stimulus................................................................................................................8 Conditioning Stimulus..................................................................................................8 Psychological Measures................................................................................................8 3 DATA REDUCTION AND ANALYSIS...................................................................10 4 RESULTS...................................................................................................................12 5 DISCUSSION.............................................................................................................19 APPENDIX A DNIC CHANGES SCORES.......................................................................................26 B QUESTIONNAIRES..................................................................................................27 LIST OF REFERENCES...................................................................................................31 BIOGRAPHICAL SKETCH.............................................................................................36

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v LIST OF TABLES Table page 4-1. Demographic information, means (SD) for baseline pain tasks, and psychological factors by ethnicity............................................................................14 4-2. Means (SD) for DNIC and DNICs ratings averaged across each segment. Ischemic ratings represent summed responses during the DNIC and DNICs portions.....................................................................................................................15 4-3. Correlations between attention rati ngs and pain ratings and reflex frequency during DNIC.............................................................................................................15 4-4. Means (SD) for cardiovascular re sponses at baseline DNIC and Sham for African Americans and whites.................................................................................15 4-5. Change Score means (SD) for cardi ovascular responses in African Americans and whites during DNIC and Sham..........................................................................16

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vi LIST OF FIGURES Figure page 2-1 Timeline Session 2.....................................................................................................6 4-1 NFR (SD) in mA for African Americans and whites...............................................16 4-2 Difference scores (SD) for verbal responses during DNIC and SHAM assessments...............................................................................................................17 4-3 Difference scores for reflex freque ncy during DNIC and SHAM assessments, as well as post and post 2 assessments for African Americans and whites..................18

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vii Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy ETHNIC DIFFERENCES IN DIFFUSE NOXI OUS INHIBITORY CONTROLS (DNIC) By Claudia M. Campbell August 2007 Chair: Roger B. Fillingim Cochair: Michael R. Robinson Major: Psychology Pain is a complex, multidimensional phenom enon influenced by multiple biological and psychosocial variables. Considerable ev idence has demonstrated that the experience of both clinical and experimental pain differs among ethnic groups, with African Americans generally reporting greater sensitiv ity to chronic and experimentally induced pain; however, little research has examined the origins of these differences. It is important to understand potential ethnic differe nces in pain perception, because this may have important implications for diagnosing and treating pain. Differences in central paininhibitory mechanisms could potentially ex plain the differences in pain reports by African American and Non-Hispanic white individuals; however, standard laboratory pain measures do not directly assess pain in hibitory mechanisms. One method frequently used in this regard is assessment of diffuse noxious inhibitory controls (DNIC). DNIC, or counterirritation, refers to the process whereby one noxious stimulus inhibits the perception of a second painful stimulus. This phenomenon is thought to reflect

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viii descending inhibition of pain signals. The current study evaluated responses to two commonly used experimental pain procedures in healthy young adults from two different ethnic groups: African American s and non-Hispanic whites. Perceptual responses (e.g., pain threshold, pain ratings) as well as physi ological responses (e.g., blood pressure, emg response) were assessed. Assessment of the NFR threshold, or RIII response, is highly correlated with subjective pain thresholds, such that increase s in stimulus intensity are associated with increased pain perception and is therefore frequently used in pain research. The NFR is based on the measurement of stimulus-induced spinal reflexes, and allows standardized placement and a high level of reproducibility. This measure allowed for assessment of both self-reported pain and to quantify an individuals physio logical response. This was utilized along with an ischemic task for counter-irritation. The findings of this study provide eviden ce of ethnic differences in the NFR and suggest group differences in the level of physiological activati on of the nociceptive system. Additionally, African Americans experienced reduced endogenous pain modulation relative to whites, which suggests significant differences in descending pain inhibition. No ethnic differences were obs erved in reflex rates or cardiovascular response. The findings of this study may c ontribute to observed ethnic differences in clinical and experiment al pain findings.

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1 CHAPTER 1 INTRODUCTION Considerable evidence has demonstrated that the experience of both clinical and experimental pain differs across ethnic gr oups, with the most substantial evidence demonstrating greater sensitivity to clinical and experime ntally induced pain in AA compared to non-Hispanic whites. Recently, several investigators have noted ethnic differences in pain-related symptoms among a variety of chronic pain conditions (Green et al 2003). Edwards and colleagues (2001) found higher levels of pain and disability among AA relative to white patients seen in a multidisciplinary pain center. Other studies also indicate that AA with chronic pain report higher levels of pain unpleasantness, greater pain-related emotional distress and increased pain behaviors relative to whites (Riley et al 2002; Green et al. 2003). Because ethnic differences in clinical pa in responses can be influenced by factors such as disease severity and disparities in pain treatment, it is important to examine ethnic differences in pain perception among h ealthy individuals (Todd 1996;Stewart et al. 1996;Cleeland et al. 1997;McCracken et al. 2001). Laboratory st udies also suggest increased experimental pain sensitivity am ong African Americans as compared to whites (Zatzick and Dimsdale, 1990). For instance, lower heat pain thresholds and tolerances were reported decades ago among African Am erican subjects compared to whites by Chapman and Jones (1944), and increased sensitivity to heat pain among African Americans has been reported more recently by Edwards and Fillingim (1999) as well as Sheffield and colleagues (2000); particularly for measures of pain unpleasantness.

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2 Similarly, cold pressor pain tolerances we re lower in a combin ed group of African Americans and Hispanics in comparison to whites (Walsh et al. 1989). Additionally, African Americans report greater intensity a nd unpleasantness in response to a modified ischemic task when compared to whites, us ing a standardized ra ting scale (Campbell et al. 2004). Finally, results from our laboratory indicated significantly lower tolerance for heat pain, ischemic pain and cold pressor pa in in African American s when compared to whites. Ratings of intensity and unpleasantness of supra-thre shold heat pain were also higher among African Americans than whites (Campbell et al. 2005). Thus, ethnic differences in both clinical and experimental pain responses have been widely reported; however, most previous studies have not attempted to ex amine the origins of these differences. Differences in central pain-inhibitory mechanisms could potentially explain the differences in pain reports by African Amer ican and Non-Hispanic white individuals; however, standard laboratory pain measures do not direct ly assess pain inhibitory mechanisms. One method frequently used in this regard is assessment of diffuse noxious inhibitory controls (DNIC). DNIC, or counterirritation, refers to the process whereby one noxious stimulus inhibits the perception of a second painful stimulus. This phenomenon is thought to reflect descending inhibition of pa in signals (Le Bars et al. 1979a; Price and McHaffie 1988). DNIC is presumed to ope rate through activation of descending supraspinal inhibitory pathways initiated by release of endogenous opioi ds (Le Bars et al. 1979b;Kraus et al. 1981;Roby-Brami et al. 1987;De Broucker et al. 1990). The DNIC system has been examined extensively in non-human animals with early studies focused on the mechanisms involved in the process of DNIC; however, more

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3 recent studies in humans have utilized th e process in order to examine possible deficiencies in descending i nhibitory processes in certain populations. For example, sex differences (Staud et al. 2003), and age differe nces (Edwards et al. 2003a) have been observed in DNIC, suggesting di ffering endogenous pain inhibiti on across certain groups. Clinical pain conditions such as fibrom yalgia (Lautenbacher and Rollman 1997;Kosek and Hansson 1997;Staud et al. 2003), osteoarthr itis (Kosek and Orde berg 2000), trapezius myalgia (Leffler et al. 2002a), rheumatoid ar thritis (Leffler et al. 2002b), and peripheral nerve injury (Bouhassira et al. 2003) also show evidence of impaired DNIC responses; suggesting a possible role for dys regulation of pain inhibitory systems in the acquisition or maintenance of the condition (Staud et al. 2003). Ethnic diffe rences in DNIC may suggest that deficiencies in central inhibitory mechanisms may contribute to the more robust clinical and experiment al pain responses often obs erved in African Americans. Use of pain rating scales as a primary method of assessing pa in perception is a frequently used and practical option; however, group differen ces pain reports could be related to group differences in use of the pa in scales (e.g. see Campbell, et al, 2004). Thus, electrophysiological alternatives, such as the nociceptive flexion reflex (NFR), may provide important information regarding ethnic group differences in nociceptive responses, which may be less susceptible to the biases that may influence subjective rating scales (Skljarevski and Ramadan 2002). The NFR is based on the measurement of stimulus-induced spinal reflexes (Willer 1977), and can be administered in a standardization fashion, and has been s hown to have adequate reproducibility. Assessment of the NFR threshold, or RIII refle x, is highly correlated with subjective pain thresholds, such that increases in stimulus intensity are associated with increased pain

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4 perception (Willer 1977; Peters et al. 1992; Skljarevski and Ramadan 2002). This methodology permits assessment of both self-r eported pain and qua ntification of an individuals physiological res ponse. While numerous studies have examined changes in subjective pain threshold and NFR change s during counterirritation procedures, no studies to date have systematically examin ed ethnic differences in the NFR or DNIC. This study was designed to further elucidate the nature of ethnic differences in pain perception by investigating responses to DNI C using the NFR, testing the hypothesis that African Americans, relative to non-Hispanic whites, may be deficient in endogenous pain modulation.

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5 CHAPTER 2 RESEARCH DESIGN AND METHODS The final study sample consisted of fift y-seven healthy young adults (29 African American, 28 non-Hispanic white). One wh ite individual discontinued participation following the baseline session, all other subjec ts completed the prot ocol. Demographic information is presented in Table 3-1. Th e University of Florida Institutional Review Board approved all study procedures. All s ubjects participated in two experimental sessions, lasting up to 2 hours; women were sc heduled during their follicular phase (i.e. days 4-9 of the menstrual cycle) to reduce va riability associated w ith the menstrual cycle (Riley et al. 1999). During the first session, ve rbal and written informed consent were obtained; after which participants comple ted a health history questionnaire, which indicated that all were in good health and ha d no prior history of pain problems, then complete a series of questionnaires assessing demographic information, mood, catastrophizing, and hypervigila nce (described in detail below). Ethnicity was determined using self-report. Following completion of the questi onnaires participants were instrumented (see procedure below), a nd rested for 10 minutes, after which their blood pressures was measured for five minutes using an automated blood pressure cuff, then their NFR threshold was determined. During the second session, one DNIC assessm ent was conducted, as well as one sham DNIC (DNICS) assessment, during which an ischemic cuff was not inflated, these procedures were conducted in a counterbal anced order. Mood questionnaires were completed prior to NFR instrumentation, a nd participants right arm maximum grip

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6 strength was measured. A te n-minute rest period was then observed, followed by five minutes of continuous blood pressure readi ngs. The level of electrical stimulation delivered during the DNIC procedure was indi vidually determined for each subject in order to produce moderate pain, (i.e. a rating of 45 on a 0-100 scale, where 0 = no sensation and 100 = the strongest imaginab le sensation of any kind). Repeated assessment of the nociceptive flex ion reflex at this stimulus intensity was conducted each minute for five minutes during each of th e following time periods: 1) 5-minute baseline period; 2) five minutes of ischemic arm pain (or sham ischemic procedure); 3) fiveminute post ischemic (or sham) time period. Following completion of this sequence, a 10-minute rest period was observed, after wh ich responses to another 5 minutes of electrical stimulation were assessed. After a 15-minute re st period this sequence was conducted in the same manner, under the condition (DNIC vs. sham) that was not administered during the first sequence. Following both the DNIC and DNICS sequences participants rated their attent ion to the sensation in their right arm while the cuff was on, their attention to the sensation in their ankle (t he site of electrical stimulation) during the time the cuff was on their right arm, as well as the degree to which the sensation in their ankle differed due to the cuff on a -100 to 100 scale (-100 = much weaker, 100 = much stronger). Figure 2-1. Timeline Session 2

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7 Nociceptive Flexion Reflex Assessment Subjects underwent electrical stimulation delivered via a bar electrode applied to the left sural nerve using Digitimer DS7A constant current stimulator (Herfordshire, UK). The nociceptive withdrawal reflex was assess ed using two, 12 mm disposable Conmed (Utica, NY) electrodes, one placed over the left biceps femoris muscle, the other placed over the reference sight, which was on the left la teral epicondyle of the femur. All sights were cleaned and gently abraded to achieve an impedance of less than 10,000 Ohms prior to electrode placement. Participants were co mfortably seated in a recliner in order to maintain a 60-degree angle of the knee. Electr ical stimulation was a pplied in a series of ascending and descending steps. A 5-pulse train (1 ms pulse duration, 3 ms inter-pulse interval) was administered approximately once every 30 seconds. During reflex assessment, participants rated the perceived intensity of each pulse using a 0 to 100 rating scale (0=no sensation and 100=strongest imagin able sensation of any kind). Stimulation intensity began at 0 milli-amps (mA) and increased in 2mA steps until the nociceptive withdrawal reflex was obtaine d (or a maximum intensity of 40mA, or termination was requested by the participant). Stimulus intensity was then decreased in 1mA steps until the reflex was no longer observed. This proced ure was repeated using 1mA steps so that the nociceptive withdrawal reflex appeared a nd subsided three times in total. Reflex threshold was defined as the average of the peaks during the three sequences. During the second session, stimulation was delivered at th e intensity of the pa rticipants nociceptive flexion reflex threshold, then increased unt il a rating of 50 was obtained, following which stimulation was reduced by .2 mA until a ra ting of 30 was reached. The stimulation intensity at a rating of 45 was calculated and used in all subs equent testing.

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8 Test Stimulus In order to elicit consiste nt responses, electrical st imulation during the DNIC and sham procedures was set at the intensity rate d as 45 by the individual participant. This stimulation intensity was determined at the beginning of the second session as follows. Electrical stimulation was delivered at the intensity of the participants nociceptive flexion reflex threshold (from session 1), th en increased until a rating of 50 was obtained, following which stimulation was reduced by .2 mA until a rating of 30 was reached. The stimulation intensity at a rating of 45 was calculated and used in all subsequent testing. Conditioning Stimulus Ischemic pain was induced using a modi fied submaximal effort tourniquet procedure adapted from France and Suchowi ecki (1999). Following five minutes of NFR testing, participants completed 2 minutes of handgrip exercises, at which time their arm was elevated for 30-seconds, then the cuff was inflated to a pressu re of 240 mm Hg (or not in the sham procedure). Five minutes of ischemic arm pain was conducted with concurrent NFR administ ration. At 30-second intervals, par ticipants rated th e intensity of their arm pain on 0 to 20 box scales (Coghill and Gracely, 1996). After five minutes of arm occlusion (or the sham procedure), the cuff was deflated and RIII was continued for an additional 5 minutes. Psychological Measures In order to determine the contribution of psychosocial factors to group differences in experimental pain responses, includi ng DNIC, subjects completed the following psychological questionnaires. The Pain Catastrophizing Scale (PCS) (Sullivan et al. 1995) consists of 14 items rated on a 5-point scale ranging fr om 0 (not at all) to 4 (all the time). Participants are

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9 instructed to indicate the degree to which they have sp ecified thoughts and feelings when experiencing pain. The measure assesse s three dimensions of catastrophizing: rumination, magnification, and helplessness. The PCS has been validated for both clinical and nonclinical samples (Sulli van et al. 1995;Osman et al. 2000). The Kohn Reactivity Scale (Kohn 1985) consists of 24 items that assess an individuals level of reactivit y or central nervous system arousability and has been used as a measure of hypervigilance (McDermid et al. 1996). This measure has been shown to correlate negatively with pain tolerance (D ubreuil and Kohn 1986) and has been reported to have adequate internal consistency, ranging from alpha of 0.73 to 0.83 (Kohn 1985). The Frid Scale (FRID) is a 10 item, 5-point Like rt scale assessing expectancies and attitudes regarding experimental pain pro cedures. The measure consists of three subscales including Psychological Involvement in the experiment, Negative Expectancies regarding the experiment, and Efficacy a nd Control beliefs (Frid et al. 1979). The Visual Analogue Mood Scale (VAMS) consists of 8 horizontal 100 mm VAS scales representing different aspects of mood. Participants were asked to mark their current mood by placing a vertical mark on th e line. The VAMS was has been shown to have adequate validity (Killgore 1999).

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10 CHAPTER 3 DATA REDUCTION AND ANALYSIS Mean NFR values and verbal ratings of pain corresponding to the reflex threshold among African Americans and non-Hispanic wh ites were calculated, and analysis of variance (ANOVA) was conducted to characterize ethnic differences in the NFR and pain perception. To examine differences in reflex acti vity during DNIC, the total number of reflexes occurring during the five minute pre-DNIC (or sham) and DNIC (or sham) assessment periods was computed. Then, a di fference score (total number of pre-DNIC reflexes minus during DNIC reflexes) was calcu lated for each subject. A 2 (group) X 2 (condition: DNIC vs. sham) mixed model ANO VA was then conducted to determine the reliability of differences in DNIC between ethnic groups, using the change score as the dependent variable. Analysis of electri cal pain ratings was conducted in a similar fashion. Specifically, the av erage electrical pain rating was computed for each time period (pre-DNIC or pre-sham, during DNIC or during sham), and these changes scores were used as dependent measures in mi xed model ANOVAs, as de scribed for reflex activity. The time course of post-DNIC effects was examined using the same approach as described for DNIC analyses. Briefly, reflexes and pain ratings were averaged across the two 5-minute post-DNIC (and sham) time peri ods (immediately after and 10 minutes after). Then, difference scores were cr eated by subtracting th e post-DNIC (or sham) averages from the baseline (i.e. pre-DNIC or sham) average. Finally, separate 2 (ethnic

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11 group) X 2 (DNIC vs. sham) mixed-model ANOVAs were conducted on each of the change scores (reflexes and ratings) from each time period (immediately post and 10 minutes post) in order to characte rize the after effects of DNIC. Correlational analyses were conducted to examine associations between psychological variables and base line responses to electrical pain, including NFR intensity and ratings of electrical pain. Similar corr elational analyses were conducted to examine associations between psychological variable s and the magnitude of DNIC, including DNIC change scores for both refl ex measures and pain ratings.

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12 CHAPTER 4 RESULTS No ethnic group differences in sex, ag e, body mass index or impedance were observed. Analysis of variance revealed si gnificant ethnic group differences in NFR reflex (F (1,50)=5.10, p = .028; effect size = .61), with African Americans demonstrating a reflex at a lower stimulus intensity re lative to non-Hispanic whites, displayed graphically in Figure 3-1. De spite the difference in intensit y required to elicit a reflex between the two groups, verbal ratings of pain correspondi ng with the reflex did not differ. Baseline data for the pain tasks are pr esented in Table 3-1. However, the intensity at which participants rated a 45, used to stimulate participants during DNIC and DNICS testing, significantly differed by ethnic gr oup (F (1,54)=5.77, p = .019); therefore, the two groups received significantly different leve ls of electrical stimulation during the DNIC procedures. The conditioning stimulus produced substant ial reductions in pain ratings for all participants during the DNIC cond ition when compared with DNICS condition (p < .001). The DNIC condition produced significantly grea ter reductions in verbal pain ratings among whites when compared with African Americans (F(1,55)=4.05, p = .049; effect size .65). These data are presented graphically in Figure 3-2. The number of reflexes was significantly lower during DNIC versus DNICS stimulation (F(1,43)=14.78, p < .001), and this reduction in frequency of reflex was similar across ethnic groups. ANOVAs revealed no group differences in rati ngs of ischemic pain during either the DNIC or DNICs condition. Analysis of varian ce was conducted in order to characterize

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13 the after effects of DNIC and the possible influence of ethni city. No group differences were observed at the post DNIC and DNICs me asurements, with both African Americans and whites returning to baseline pain ratings and baseline reflex activity during the 5minute period following DNIC stimulati on (see Figures 3-2 and 3-3). Cardiovascular responses were evaluate d in order to examine changes in blood pressure and heart rate reactiv ity during DNIC and potential di fferences in ethnicity. No significant group or condition differences em erged for any of the cardiovascular responses, see Tables 3-4 and 35. Ratings of attention focu sed on the arm, ankle and the degree to which the sensation in their ankl e differed due to the cuff did not differ by group. These ratings were not correlated with magnitude of DNIC among African Americans; however, among whites, increased attention to the arm predicted greater reductions in electrical pa in during DNIC, and increased attention to the arm was positively correlated with reflex frequency dur ing DNIC, while attention to the ankle and ratings of how much the ankle sensation felt due to the ischemic procedure was negatively correlated with reflex frequency (see Table 3-3). However, ethnic group differences in DNIC remained significant even when the analysis was repeated using an ANCOVA controlling for subjects ratings of attention to the arm (F (1,54)=5.46, p=.023). No ethnic group differences emerged for any of the psychological variables (see Table 3-1). Correlational analyses were conducted examining associations between responses to psychological questionnaires and NFR th reshold. Psychological Involvement (a subscale of the FRID scale) and Positive Mood were positively correlated with NFR (r= .30, p =.02; r=.35, p<.01), and the rumination subscale of the PCS was negatively correlated with NFR (r=-.29, p= .03). The pattern of correlations was

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14 consistent across both ethnic groups. In orde r to determine whether these psychological variables mediated ethnic group differences in the NFR threshold, analyses were repeated controlling for each of the three psychological measures that were associated with the NFR. Ethnic group differences remained si gnificant after contro lling for positive mood (F(1,50)=5.24, p=.026) and psychological i nvolvement (F(1,50)=4.38, p=.041), and were marginally significant (F(1,50)=3.63, p=.063) after controlling for rumination. Thus, these psychological variables do not appear to mediate ethnic group differences in NFR thresholds. None of the psychological vari ables was significantly correlated with the magnitude of DNIC. Table 4-1. Demographic information, mean s (SD) for baseline pain tasks, and psychological factors by ethnicity. Variable AA (n=29) Whites (n=28) Age (SD) 23.7 (7.1) 25.3 (8.6) Sex (% female) 51.7 57.7 BMI (SD) 23.66 (5.19) 23.34 (3.36) Impedance in (SD) 4.05 (2.83) 4.89 (2.60) NFR Reflex* in mA (SD) 14.99 (8.98) 20.95 (10.45) NFR Rating (SD) 42.85 (20.68) 50.37 (25.44) DNIC, DNICs Intensity 1.86 (.96) 2.46 (.92) VAMS Positive Mood 178.52 (65.73) 171.96 (56.1) VAMS Negative Mood 29.93 (33.38) 23.43 (33.38) FRID Negative Expectancies 5.5 (1.83) 5.07 (1.44) FRID Efficacy and Control Beliefs 11.78 (1.89) 12.55 (1.95) FRID Psychological Involvement 11.67 (1.83) 11.91 (2.15) PCS Rumination 1.11 (1.92) .32 (1.15) PCS Magnification .11 (.35) .07 (.19) PCS Helplessness .55 (2.97) 0 (0) PCS Catastrophizing 1.78 (4.03) .39 (1.15) KOHN Score 68.69 (14.69) 66.04 (9.38) p < .05

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15 Table 4-2. Means (SD) for DNIC and DNICs ratings averaged across each segment. Ischemic ratings represent summed responses during the DNIC and DNICs portions. Variable AA (n=29) Whites (n=28) DNIC Baseline 0-100 36.71 (14.21) 39.44 (16.36) DNIC* 0-100 31.90 (13.56) 29.73 (13.02) DNIC Post 0-100 34.55 (14.29) 36.94 (16.32) DNIC 10min Post 0-100 36.26 (13.87) 38.60 (16.41) DNICs Baseline 0-100 38.17 (11.76) 35.99 (14.23) DNICs 0-100 37.02 (14.17) 35.49 (15.25) DNICs Post 0-100 36.51 (15.21) 36.49 (17.11) DNICs 10min Post 0-100 37.88 (14.5) 37.60 (14.71) Ischemic Rating DNIC 0-20 109.34 (46.61) 119.75 (41.85) Ischemic Rating DNICs 0-20 5.48 (13.45) 10.54 (22.47) *p < .05 Table 4-3. Correlations between attention ratings and pain ratings and reflex frequency during DNIC. Ethnicity Difference Scores Deg Attn to arm Deg Attn to ankle Deg different Pain Ratings .02 -.09 -.04 African Americans Reflex Freq. .12 .001 -.09 Pain Ratings .46* -.27 .32 Whites Reflex Freq. .41* -.49* -.47* *p < .05 Table 4-4. Means (SD) for cardiovascular responses at baseline, DNIC and Sham for African Americans and whites. Variable African Americans (SD) Whites (SD) Baseline Systolic BP 108.27 (10.14) 108.69 (8.37) Baseline Diastolic BP 62.11 (7.62) 61.22 (6.86) Baseline Mean Arterial Pressure 78.64 (8.11) 77.99 (6.71) Baseline Heart Rate 67.3 (11.3) 64.56 (9.42) DNIC Systolic BP 112.53 (11.58) 113.99 (9.73) DNIC Diastolic BP 67.19 (8.7) 66.86 (7.54) DNIC Mean Arterial Pressure 84.95 (9.55) 85.09 (7.4) DNIC Heart Rate 67.24 (11.09) 65.07 (10.07) Sham Systolic BP 110.05 (9.09) 110.53 (8.14) Sham Diastolic BP 64.28 (8.94) 63.88 (7.82) Sham Mean Arterial Pressure 80.98 (8.4) 80.92 (6.98) Sham Heart Rate 66.79 (9.67) 64.69 (8.67)

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16 Table 4-5. Change Score means (SD) for car diovascular responses in African Americans and whites during DNIC and Sham. AA (n=29) Whites (n=28) Change Scores DNIC Sham DNIC Sham Systolic BP -4.26 (7.17) 1.78 (5.36) -5.29 (6.02) -1.84 (4.72) Diastolic BP -5.08 (3.94) 2.17 (4.07) -5.64 (3.74) -2.66 (3.78) Mean Arterial Pressure -6.31 ( 5.71) -2.34 (5.52) -7.11 (4.51) -2.94 (4.21) Heart Rate .06 (6.32) .51 (4.48) -.51 (6.87) -.13 (5.72) 10 15 20 25 30 35 R3 ReflexmA African Americans Non Hispanic Whites Figure 4-1 NFR (SD) in mA for African Americans and whites

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17 0 10 20 30 40 50 DNICSham African Americans Non Hispanic Whites A -5 5 15 25 35 45 DNICShamDNICSham Post 1 Post 2 African Americans Non Hispanic Whites B Figure 4-2. Difference scores (SD) for verbal responses during DNIC and SHAM assessments. A) Difference scores of pain ratings during DNIC and Sham. B) Difference scores of pain ratings dur ing DNIC and Sham for Post1 and Post2.

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18 -1 0 1 2 3 4 5 DNICSham African Americans Non Hispanic Whites A -1 0 1 2 3 4 5 DNICShamDNICSham Post 1 Post 2 African Americans Non Hispanic Whites B Figure 4-3. Difference scores for reflex frequency during DNIC and SHAM assessments, as well as post and post 2 assessments for African Americans and whites. A) Difference scores of reflexes during DNI C and Sham. B) Difference scores of reflexes during DNIC and Sh am for Post1 and Post2.

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19 CHAPTER 5 DISCUSSION The findings of this study provide evidence of ethnic differences in the NFR, such that African Americans required less electri cal stimulation to produce a spinally-mediated nociceptive muscle reflex. Because the NFR is thought to be a more objective physiological nociceptive measure, the curren t findings add additional substance to the existing evidence that African American individuals may demonstrate greater sensitivity to noxious stimuli compared to whites. Th e NFR is based on measurement of stimulusinduced spinal reflexes and is therefore thought to be indepe ndent of the reporting biases sometimes associated with subjective pain ratings. Our findings suggest the factors contributing to ethnic differences in pain sensitivity may do so in part by altering nociceptive responses at the spinal level. The mechanisms underlying ethnic group differences in this spinally-mediated nocicep tive reflex cannot be determined from this study; however, based on the current availabl e evident, the most likely explanation may be that descending pain inhibition may be more robust among whites, which could reduce the nociceptive reflex. In this regard Mechlin and colleagues (2005) recently demonstrated that stress-induced pain re gulatory mechanisms involving blood pressure, norepinephrine, and cortisol functioned mo re effectively among whites than African Americans. It is worth noting that et hnic group differences in descending pain modulation could be mediated by fundamental biological differences, via psychosocial factors (e.g. expectations, pain beliefs) and/or the combinati on of these factors. Indeed, our findings demonstrate asso ciations between the NFR a nd psychological variables.

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20 Specifically, greater psychological involve ment and higher positive mood correlated positively with NFR, while higher scores on the rumination subscale of the Pain Catastrophizing Scale predicted lower NFR. While these psychological variables did not mediate the group differences we observed in the NFR, it is plausible that other psychological processes not assessed in this study may have cont ributed to the group difference. Previous research exploring psychological correlates of NFR have provided mixed results. For example, neither catastrophizi ng nor anxiety were found to be associated with NFR, while both variables predicted subj ective pain ratings in response to electrical stimulation (France et al., 2002; French et al ., 2005). It may be important to note that France and colleagues used the catastrophi zing subscale of the Coping Strategies Questionnaire (CSQ), while we assessed catas trophizing with the PCS, which yields separate subscales, one of which (i.e. the Help lessness subscale) is equivalent to the CSQ catastrophizing scale. Ind eed, our results showed an association only between the Rumination subscale of the PCS, and the Help lessness subscale was not associated with the NFR. Thus, it may be that only speci fic components of catastrophizing predict NFR thresholds. Other investigators have reported significant psychol ogical modulation of NFR thresholds. For example, induction of positive and negative mood increased and decreased the NFR, respectivel y (Rhudy, et al, 2005). Moreove r, a brief session of pain coping skills training significantly incr eased NFR thresholds among patients with osteoarthritis of the knee (Emery, et al, 2006), and hypnotic analgesia also increased NFR thresholds (Kiernan et al., 1995; Wade, et al 1997). Thus, previous research provides

PAGE 29

21 additional evidence that psychological manipul ations can influence NFR thresholds, and the present study extends these findings, pr oviding further support for psychological contributions to NFR thresholds. The role of psychosocial processes in mediating ethnic group differences in the NFR mer its additional investigation. The results of the current study further in dicate that African Am ericans experienced reduced DNIC relative to whites, which sugge sts significant diffe rences in endogenous pain inhibition between African Americans and whites. This may be one factor contributing to observed ethnic differences in clinical and experimental pain findings. The process under which DNIC operates is thoug ht to reflect infl uences of complex descending inhibitory system s, potentially mediated by endogenous opioids. However, studies examining DNIC under conditions of ad ministration of an opioid antagonist, such as naloxone, have provided mixed results. Na loxone administration has been shown to block descending pain inhibiti on, resulting in no DNIC-induced analgesic effect in some studies (Willer et al., 1990); however, others have demonstrated no effects of opioid blockade on DNIC (Edwards et al., 2004, Le Bars et al ., 1992). Thus, the exact mechanisms whereby DNIC produces its e ffects are unknown. Indeed, it seems likely that the hypoalgesic effects of a conditio ning stimulus could result from multiple biological and psychosocial processes, w hose relative importance may vary across studies. Another possible contributor to DNIC coul d be cardiovascular responses. While cardiovascular reactivity has been associat ed with hypoalgesia (Bruehl et al. 1997; McCubbin and Bruehl, 1994), the link between DNIC and car diovascular reactivity has received minimal attention. A recent study (Mechlin et al, 2005) examined regulatory

PAGE 30

22 mechanisms involving stress-induced increase s in blood pressure, norepinephrine, and cortisol functioning on pain response in Af rican Americans and whites, and found these physiological changes to be more strongly asso ciated with reduction of pain responses among white participants. While our results are generally consistent with those of Mechlin in that we also observed more effective endogenous pain inhibition among whites, cardiovascular reactivity was not associated with the magnitude of DNIC in either ethnic group in the current study. This may be due to the low level of cardiovascular reactivity observed during the tour niquet procedure in our study. The effects of DNIC are thought to be long-lasting when a conditioning stimulus is applied to heterotopic areas of the body (Le Bars et al 1979a; Dickenson and Le Bars 1983;Villanueva and Le Bars 1995). In hum ans, heterotopic noxious stimuli inhibit the spinal nociceptive flexion (RIII) reflex, whic h is controlled by sp inal transmission of nociceptive signals (Willer et al. 1984;Willer et al. 1989). In our sample, while the conditioning stimulus reduced the frequency of NFR reflexes for the group as a whole, no ethnic differences in reduction of reflexes we re evident. Moreover, the effects of DNIC in this study were relatively brief, as pain ratings and NFR frequency returned to baseline immediately after the cessation of the conditioning stimulus. One potential explanation of the DNIC res ponse might be distraction from the test stimulus by the conditioning stimulus. Some pr evious research would argue that DNIC is not simply a form of distraction. For exam ple, many studies have reported that the analgesic effects of DNIC outla st the conditioning stimulus with which it was elicited by several minutes and up to several days (LeB ars et al., 1992; Willer et al., 1990). DNIC has been used in dental pain studies, where ischemic arm pain and ice applied to the hand

PAGE 31

23 not only increased the tolerance of dental pain, but also reduc ed sensitivity and swelling around teeth (Willer et al., 1990). DNIC has also been shown to reduce the NFR reflex (in humans and nonhuman animals), which is th ought to be less influenced by distraction (Le Bars et al., 1992). DNIC ef fects have been observed in paraplegic and tetrapalegic patients (Roby Brami et al., 1987), whose actua l RIII reflexes did not differ from normal controls (spinal reflexes inta ct), suggesting that DNIC activ ates descending inhibitory pathways modulating the spinal transmission of noc iceptive information. Nonetheless, distraction could be a potent ial mechanism adding to DNICs effectiveness. Several investigators have examined this connection. Willer and colleagues (1990) had participants perform mental ca lculation during several different pain tasks, attempting to induce DNIC, which did not occur. Edwards and others (2003; 2004) asked participants about distraction effects, and had them read vignettes, without DNIC effects. Finally, Staud and colleagues (2003) examined differe nces between fibromyalgia patients and healthy women, as well as comparing a sample of healthy men and women. A traditional DNIC and a DNIC plus distraction task was em ployed using temporal summation of heat pain and a hot water bath. Participants were verbally reminded to attend to one stimulus over the other. Significant sex differe nces emerged and both DNIC and DNIC plus distraction produced significant effects. Th e DNIC plus distracti on was somewhat more effective in men and in fibromyalgia patients. This study suggests that DNIC effects may be enhanced when paired with distraction. While we did not observe long-lasting diffe rences in reflex rates or emg activity, attentional ratings were obtained. Ratings of distraction by the conditioning stimulus predicted greater DNIC-induced reductions in electrical pain ratings (but not reductions

PAGE 32

24 in NFR frequency), but only among whites. However, the ethnic group differences in DNIC remained significant after controlling fo r distraction ratings. Thus, distraction may have contributed to the DNIC ef fect on electrical pain rati ngs, but does not appear to account for the ethnic group difference in DNIC. Several limitations should be considered when interpreting the resu lts of the present study. First, all of th e tasks were acute, controlled pa inful laboratory experiences over which the participants had cont rol; therefore, these results may be less generalizable to a clinical pain population. Howeve r, the clinical relevance of DNIC has previously been demonstrated by multiple investigators (Edwar ds et al. 2003b; Kosek & Ordeberg, 2000). Another possible limitation may come from stimulating participants at different intensities depending on their verbal ratings pain. Most studies examining DNIC using the NFR use 120% of an individuals NFR thre shold; however, in our sample this would have caused great differences in individuals pain ra tings of the stimuli. This may have contributed to our inability to observe ethnic group differences in reflex rates. Another limitation may be the possibility of habituation with frequent use of the NFR stimuli, one per minute; however, previous results show habituation to be hi ghly dependent on the interstimulus interval, and obs erved habituation with stimul ation every 5 seconds, but no habituation with stimul ation 25 seconds apart (S andrini, et al, 2005). These limitations notwithstanding, our fi ndings provide evidence of ethnic differences in the NFR as well as ethnic group differences in the effects of ischemic arm pain on ratings of electrical pain, but not on NFR reflex frequency. We also observed associations between psychological factors and the NFR, though these variables did not account for the observed ethnic differences The current findings provide further

PAGE 33

25 evidence for the existence of ethnic differen ces in experimental pain perception, and suggest potential ethnic group di fferences in inhibitory processes, though the mechanisms underlying this effect are not known. Though th is type of endogenous pain modulation has received extensive attention in recent ye ars and considerable evidence has amassed for its experimental utility, the current fi nding of ethnic differences in DNIC does not necessarily explain clinical or experimental differences observed in pain perception. Future studies should focus on the clinical re levance and implications for care, such as studying ethnic differences in DNIC in clinical pain models. Future studies may also pursue a better understanding of the mechanisms involved in ethnic differences in DNIC by examining the role of distraction and other psychological factors as well as the possible contribution of endogenous opioids.

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26 APPENDIX A DNIC CHANGES SCORES Change Score means (SD) for ratings and reflexes in African Americans and whites. AA (n=29) Whites (n=28) Change Scores DNIC Sham DNIC Sham Ratings During 4.81 (5.1) 1.14 (7.4) 9.7 (9.4) .49 (6.3) Ratings Post 2.16 (7.26) 1.66 (9.29) 2.51 (6.1) -.5 (7.09) Ratings Post 2 .45 (6.71) .28 (9.53) .84 (7.1) -1.61 (7.99) Reflexes During .55 (1.12) .34 (.77) .43 (.96) -.07 (.81) Reflexes Post .5 (1.18) .45 (1.3) .39 (.99) .13 (1.01) Reflexes Post 2 .32 (1.36) .41 (1.1) .65 (1.37) 0 (1.45)

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27 APPENDIX B QUESTIONNAIRES PCS Directions : Everyone experiences painful situations at some point in their lives. Such experiences may include headaches, tooth pai n, joint or muscle pain. People are often exposed to situations that may cause pain such as illness, injury, dental procedures, or surgery. We are interested in the types of thoughts and feelings that you have when you are in pain. Listed below are 14 statements de scribing different thoughts and feelings that may be associated with pain. Using the follo wing scale, please indicate the degree to which you have these thoughts and feelin gs when you are experiencing pain. 0 not at all 1 to a slight degree 2 to a moderate degree 3 to a great degree 4 all the time 1.______ I worry all the time about whether it will end. 2.______ I feel I can't go on. 3.______ It's terrible and I think it' s never going to get any better. 4.______ It's awful and I feel that it overwhelms me. 5.______ I feel I can't stand it anymore. 6.______ I become afraid that the pain will get worse. 7.______ I keep thinking of other painful events. 8.______ I anxiously want the pain to go away. 9.______ I can't seem to get it out of my mind. 10.______I keep thinking about how much it hurts. 11.______I keep thinking about how badly I want the pain to stop. 12.______There's nothing I can do to reduce the intensity of the pain. 13.______I wonder whether something serious may happen. 14.______I feel my life isn't worth living.

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28 Kohn The items which follow all concern your f eelings and experience in common, everyday situations. There are no ri ght or wrong answers. Please just answer each item as honestly as you can; however, please work quickly, as your first impression is quite likely to be the most accurate. For each item place the number that best represents your reaction to the item-statemen t in the space to the right: 1, if you Disagree Strongly with the statement. 2, if you Disagree with the statement. 3, if you Neither Disagree Nor Agree with the statement. 4, if you Agree with the statement. 5, if you Agree Strongly with the statement. 1. If I went on an ocean voyage Id be sure to get seasick. _____ 2. Jumping right into ice-cold wa ter doesnt bother me. _____ 3. I cant stand driving fast at night. _____ 4. I can often work well when Im feeling quite sick. _____ 5. I need strict quiet to stu dy or think well. _____ 6. Being out on really cold days doesnt bother me as much as most people. _____ 7. I cant stand staying in a sauna or steam bath for very long. _____ 8. There are very few midway rides that make me uncomfortable. _____ 9. Ive often had motion sickness. _____ 10. I can concentrate on what Im doing even when Im in pain. _____ 11. I could never bathe or shower in ice-cold water. _____ 12. I can work reasonably well even when I feel emotionally upset. _____ 13. I can always feel when its time to come in form the cold. _____ 14. Driving fast at night doesnt bother me. _____ 15. I could never study when Im feeling sick. _____ 16. Ive hardly ever had motion sickness. _____ 17. I avoid the cold outdoors as much as I can during the worst of the winter. _____ 18. There are times when I enjoy an ice-cold shower or bath. _____ 19. I cant stand a lot of midway rides. _____ 20. Pain doesnt bother me as much as it does most people. _____ 21. I cant stand much hard physical labor. _____ 22. Id be very surprised if I got seasick on an ocean voyage. _____

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29 23. It would take a lot to make me ju mp into ice-cold lake water. _____ 24. I like staying in sa unas or steam-baths longer than most people can stand to stay _____ FRID SCALE Please indicate in the alternatives given below how you think right now 1. I want to avoid the situation 2. I believe I can tolerate the pain 3. I see the experience as a challenge 4. I think the procedure will be painful 5. I know that nothing concerning this experiment can really hurt me 6. I care that other people may notice my weaknesses 7. I think this experiment will be interesting 8. I expect to suffer unpleasant aftereffects 9. I believe that my participation is important 10. I expect to be in control of the situation 1 2 3 4 5 not at very much all so 1 2 3 4 5 not at very much all so 1 2 3 4 5 not at very much all so 1 2 3 4 5 not at very much all so 1 2 3 4 5 not at very much all so 1 2 3 4 5 not at very much all so 1 2 3 4 5 not at very much all so 1 2 3 4 5 not at very much all so 1 2 3 4 5 not at very much all so 1 2 3 4 5 not at very much all so

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30 VAMS Please indicate how you are feeling right now by placing one mark on each line. The mark should be placed along the line at the po int that best reflects how you feel right now. Neutral Tense Neutral Sad Neutral Happy Neutral Tired Neutral Angry Neutral Energetic Neutral Relaxed

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31 LIST OF REFERENCES Bouhassira D, Danziger N, Attal N, Guirim and F. Comparison of the pain suppressive effects of clinical and experimental painful conditioning stimuli. Brain 2003;126:1068-1078. Campbell CM, Edwards RR, Fillingim RB. Ethni c differences in responses to multiple experimental pain stimuli. Pain 2005;113:20-26. Campbell TS, Hughes JW, Girdler SS, Mai xner W, Sherwood A. Relationship of ethnicity, gender, and ambulatory blood pre ssure to pain sensitivity: Effects of individualized pain rating scales. J Pain 2004;5:183-191. Chapman WP, Jones CM. Variations in cutaneous and visceral pain sensitivity in normal subjects. J Clin Invest 1944;23:81-91. Cleeland CS, Gonin R, Baez L, Loehrer P, Pandya KJ. Pain and treatment of pain in minority patients with cancer. The Ea stern Cooperative Oncology Group Minority Outpatient Pain Study. Annals of Internal Medicine 1997;127:813-816. Coghill RC, Gracely RH. Validation of combined numerical-analog descriptor scales for rating pain intensity and pain unpleasantness. Proc Amer Pain Soc 15, 86. 1996. De Broucker T, Cesaro P, Willer JC, Le Bars D. Diffuse noxious inhibitory controls in man. Involvement of th e spinoreticular tract. Brain 1990;113:12231234. Dickenson AH, Le Bars D. Diffuse noxious inhibitory controls (DNIC) involve trigeminothalamic and spinothalamic neurones in the rat. Exp Brain Res 1983;49:174-180. Dubreuil DL, Kohn PM. Reactivity and respons e to pain. Pers Indiv Diff 1986;7:907-909. Edwards CL, Fillingim RB, Keefe FJ. Race, ethnicity and pain: a review. Pain 2001;94:133-137. Edwards RR, Fillingim RB. Ethnic differences in thermal pain responses. Psychosom Med 1999;61:346-354. Edwards RR, Fillingim RB, Ness TJ. Age-re lated differences in endogenous pain modulation: a comparison of diffuse noxious inhibitory controls in healthy older and younger adults. Pain 2003a;101:155-165.

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32 Edwards RR, Ness TJ, Fillingim RB. Endogenous opioids, blood pressure, and diffuse noxious inhibitory controls: a preliminary study. Percept Mot Skills 2004;99(2):679-687. Edwards RR, Ness TJ, Weigent DA, Fillingim RB. Individual differences in diffuse noxious inhibitory controls (DNIC): associ ation with clinical variables. Pain 2003b;106:427-437. Emery CF, Keefe FJ, France CR, Affleck G, Waters S, Fondow MD, McKee DC, France JL, HAckshaw KV, Cladwell DS, Stainbrook D. Effects of a brief coping skills training intervention on noci ceptive flexion reflex threshold in patients having osteoarthritic knee pain: a preliminary la boratory study of sex differences. J Pain Symptom Manage 2006;31(3):262-269. France CR, Suchowiecki S. A comparison of di ffuse noxious inhibitory controls in men and women. Pain 1999;81:77-84. France CR, France JL, al'Absi M, McIntyre D. Catastrophizing is relate d to pain ratings, but not nociceptive flexion reflex threshold. Pain 2002;99(3):459-463. French DJ, France CR, France JL, Amott LF. The influence of acute anxiety on assessment of nociceptive flexion reflex thresholds in healthy young adults. Pain 2005;114(3):358-363. Frid M, Singer G. Hypnotic analgesia in c onditions of stress is partially reversed by naloxone. Psychopharmacology 1979;63(3):211-212. 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;4:277-294. Kiernan BD, Dane JR, Phillips LH, Price DD. Hypnotic analgesia reduces R-III nociceptive reflex: further evidence concerning the multifactorial nature of hypnotic analgesia. Pain 1995;60(1):39-47. Killgore WD. The visual analogue mood scale: can a single-ite m scale accurately classify depressive mood state? Psychol Rep 1999;85:1238-1243. Kohn PM. Sensation-seeking, augmenting-reduc ing, and strength of the nervous system. In: Spence JT, Izard DE, editors. Mo tivation, Emotion, and Personality. Amsterdam: Elsevier, 1985. pp. 167-173. Kosek E, Hansson P. Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimul ation (HNCS) in fibromyalgia patients and healthy subjects. Pain 1997;70:41-51.

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33 Kosek E, Ordeberg G. Lack of pressu re pain modulation by heterotopic noxious conditioning stimulation in patients with painful osteoarthritis before, but not following, surgical pain relief. Pain 2000;88:69-78. Kraus E, Le Bars D, Besson JM. Behavioral confirmation of "diffuse noxious inhibitory controls" (DNIC) and evidence for a ro le of endogenous opiates. Brain Res 1981;206:495-499. Lautenbacher S, Rollman GB. Possible deficien cies of pain modulation in fibromyalgia. Clinical Journal of Pain 1997;13:189-196. Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neur ones in the rat. Pain 1979a;6:283-304. Le Bars D, Dickenson AH, Besson JM. Diffuse noxious inhibitory controls (DNIC). II. Lack of effect on non-convergent neur ones, supraspinal involvement and theoretical implications. Pain 1979b;6:305-327. Le Bars D, Villanueva L, Bouhassira D, W iller JC. Diffuse noxious inhibitory controls (DNIC) in animals and in man. Patol Fiziol Eksp Ter 1992;P 55-65. Leffler AS, Hansson P, Kosek E. Somatosens ory perception in a remote pain-free area and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from long-term trapezius myalgi a. Eur J Pain 2002a;6:149-159. Leffler AS, Kosek E, Lerndal T, Nordmark B, Hansson P. Somatosensory perception and function of diffuse noxious inhibitory cont rols (DNIC) in patients suffering from rheumatoid arthritis. Eur J Pain 2002b;6:161-176. McCracken LM, Matthews AK, Tang TS, Cuba SL. A comparison of blacks and whites seeking treatment for chronic pa in. Clin J Pain 2001;17:249-255. McDermid AJ, Rollman GB, McCain GA. Ge neralized hypervigilance in fibromyalgia: evidence of perceptual amp lification. Pain 1996;66:133-144. 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 procedur es. Psychosom Med 2005;67(6):948-956. Osman A, Barrios FX, Gutierrez PM, Kopper BA Merrifield T, Grittmann L. The Pain Catastrophizing Scale: further psychometric evaluation with adult samples. J Behav Med 2000;23:351-365. Price DD, McHaffie JG. Effects of heteroto pic conditioning stimuli on first and second pain: a psychophysical evaluation in hu mans [see comments]. Pain 1988;34:245252.

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34 Riley JL, Wade JB, Myers CD, Sheffield D, Papas RK, Price DD. Racial/ethnic differences in the experience of chronic pain. Pain 2002;100:291-298. Riley JLIII, Robinson ME, Wise EA, Pri ce DD. A meta-analytic review of pain perception across the menstrua l cycle. Pain 1999;81:225-235. Rhudy JL, Williams AE, McCabe KM, Nguyen MA, Rambo P. Affective modulation of nociception at spinal an d supraspinal levels. Ps ychophysiology 2005;42(5):579587. Roby-Brami A, Bussel B, Willer JC, Le Bars D. An electrophysiological investigation into the pain-relieving e ffects of heterotopic noc iceptive stimuli. Brain 1987;110:1497-1508. Sandrini G, Milanov I, Malaguti S, Nigrelli MP Moglia A, Nappi G. Effects of hypnosis on diffuse noxious inhibitory cont rols. Physiol Behav 2000;69:295-300. Sandrini G, Serrao M, Rossi P, Romaniello A, Cruccu G, Willer JC. The lower limb flexion reflex in humans. Pr og Neurobiol 2005;77(6):353-395. Sheffield D, Biles PL, Orom H, Maixner W, Sheps DS. Race and sex differences in cutaneous pain perception. Psychosom Med 2000;62:517-523. Skljarevski V, Ramadan NM. The nociceptive fl exion reflex in humans -review article. Pain 2002;96:3-8. Staud R, Robinson ME, Vierck CJ, Jr., Price DD. Diffuse noxious inhibitory controls (DNIC) attenuate temporal summation of second pain in normal males but not in normal females or fibromyalgia patients. Pain 2003;101:167-174. Stewart WF, Lipton RB, Liberman J. Vari ation in migraine prevalence by race. Neurology 1996;47:52-59. Sullivan MJ, Bishop S, Pivik J. The Pain Catastrophizing Scale: development and validation. Psychological Assessment 1995;7:524-532. Todd KH. Pain assessment and ethnicity. A nnals of Emergency Medicine 1996;27:421423. Villanueva L, Le Bars D. The activation of bulbo-spinal controls by peripheral nociceptive inputs: diffuse noxious inhib itory controls. [Review] [96 refs]. Biological Research 1995;28:113-125. Willer JC. Comparative study of perceived pain and nociceptive flexion reflex in man. Pain 1977;3:69-80. Willer JC, De Broucker T, Le Bars D. Encoding of nociceptive thermal stimuli by diffuse noxious inhibitory controls in hum ans. J Neurophysiol 1989;62:1028-1038.

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35 Willer JC, Le Bars D, De Broucker T. Diffu se noxious inhibitory controls in man: involvement of an opioidergic link. Eur J Pharmacol 1990;182:347-355. Willer JC, Roby A, Le Bars D. Psychophysic al and electrophysiological approaches to the pain-relieving effects of heterotopic nociceptive stimuli. Brain 1984;107:10951112. Zatzick DF, Dimsdale JE. Cultural variations in response to painful stimuli. Psychosom Med 1990;52:544-557.

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36 BIOGRAPHICAL SKETCH Claudia M. Campbell received her Bachelor of Science degree in psychology with a minor in womens studies from the Universi ty of Florida in 2001. As a result of her interdisciplinary background, she developed an interest in the psyc hological aspects of diversity, specifically in the fi eld of pain research. Upon completion of her bachelors degree, Ms. Campbell accepted a research a ssistant position in the sensory testing laboratory of Dr. Roger Fillingim. Thus, she has been able to pursue her research endeavors investigating sex and ethnic differences in pain perception. She received her Master of Science degree in clinical ps ychology from the University of Florida in 2004 and continues her work through the pursuit of a doctoral degree in c linical and health psychology at the University of Florida. Ms. Campbell has also been the recipien t of several awards from the American Pain Society, which include a Citatio n Award, acceptance into their Residence Program and four Young Investigator Awards, the latter two of which facilitated travel to the national meetings. Current memberships include the American Pain Society and the Disparities Special Interest Group of the American Pain Society.


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