Psychophysiology, 51 (2014), 267–276. Wiley Periodicals, Inc. Printed in the USA. Copyright © 2013 Society for Psychophysiological Research DOI: 10.1111/psyp.12168

Does exercise induce hypoalgesia through conditioned pain modulation?

LAURA D. ELLINGSON,a,b KELLI F. KOLTYN,b JEE-SEON KIM,c and DANE B. COOKa,b a

William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin, USA Department of Kinesiology, University of Wisconsin-Madison, Madison, Wisconsin, USA c Department of Educational Psychology, University of Wisconsin-Madison, Madison, Wisconsin, USA b

Abstract Pain sensitivity decreases with exercise. The mechanisms that underlie this exercise-induced hypoalgesia (EIH) are unclear. Our purpose was to investigate conditioned pain modulation (CPM) as a potential mechanism of EIH. Sixteen women completed pain testing during three sessions: painful exercise, nonpainful exercise, and quiet rest. Intensity and unpleasantness ratings to noxious heat stimuli were assessed at baseline and during and following each session. Results showed that pain sensitivity decreased significantly during both exercise sessions (p < .05), but not during quiet rest. Effect size calculations showed that the size of the hypoalgesic response was greater following painful exercise than nonpainful exercise. Our results suggest that exercise-induced muscle pain may contribute to the magnitude of EIH. However, as pain sensitivity also decreased following nonpainful exercise, CPM is not likely the primary mechanism of EIH. Descriptors: Pain, Exercise, Hypoalgesia, Mechanism, Modulation, Kaatsu

Diffuse noxious inhibitory controls (DNIC) constitute a supraspinal, pain inhibitory mechanism involving endogenous opioids and serotonin that is best understood as a case of “pain inhibits pain” (Chitour, Dickenson, & Le Bars, 1982; Le Bars, Chitour, Kraus, Dickenson, & Besson, 1981; Le Bars, Dickenson, & Besson, 1979). This mechanism is activated when two painful stimuli are applied to two distinct areas (i.e., receptive fields) of the body. The first pain, referred to as the conditioning stimulus, triggers inhibition of wide dynamic range neurons in the dorsal horn of the spinal cord to reduce the perception of the second pain, referred to as the test stimulus. Similar to the characteristics of EIH, the stronger the initial pain stimulus (exercise or conditioning stimulus) the greater the reduction in pain sensitivity to experimental pain stimuli (test stimulus) (Oono, Wang, Svensson, & Arendt-Nielsen, 2011; Willer, De Broucker, & Le Bars, 1989; Willer, Roby, & Le Bars, 1984). Moreover, reductions in pain sensitivity for both EIH and DNIC have been shown to extend beyond the initial stimulus (Koltyn, 2000; Willer et al., 1989). Because the term DNIC refers to a specific lower brainstem mechanism that cannot be directly addressed in humans, the term conditioned pain modulation (CPM) has been adopted as the human analog of DNIC (Yarnitsky, 2010). Aerobic exercise is capable of inducing muscle pain. The mechanisms that underlie exercise-induced muscle pain are unknown, but likely involve the buildup of numerous noxious biochemicals combined with increased intramuscular pressure associated with muscle contractions (Ellingson & Cook, 2013; O’Connor & Cook, 1999). It is notable that moderate intensity quadriceps

Exercise influences pain perception (Koltyn, 2000; O’Connor & Cook, 1999). Research shows that healthy individuals experience a decrease in pain sensitivity in response to exercise (Koltyn, 2000). This decrease, termed exercise-induced hypoalgesia (EIH), occurs during and following higher intensities and longer durations of aerobic exercise that are often experienced as painful (Hoffman et al., 2004; Koltyn, 2002). Thus, exercise has the capacity to both induce and relieve pain. This apparent contradiction forms the basis for this experiment, which was designed to assess a potential mechanism underlying the influence of exercise on pain regulatory mechanisms in women. Several hypotheses have been developed to explain the mechanism(s) responsible for EIH. The foremost of these implicate the endogenous opioid system and the cardiovascular system, specifically exercise-induced elevations in blood pressure. However, data concerning opiodergic and cardiovascular mechanisms have been equivocal (Janal, Colt, Clark, & Glusman, 1984; Koltyn & Umeda, 2006; Umeda, Newcomb, Ellingson, & Koltyn, 2010). It has also been suggested that EIH could be caused by an endogenous pain inhibitory mechanism termed diffuse noxious inhibitory controls (Kosek & Lundberg, 2003; Tracey & Dunckley, 2004).

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This manuscript is based on data collected as part of the doctoral dissertation of Laura D. Ellingson. Address correspondence to: Dane B. Cook, Department of Kinesiology, 2000 Observatory Drive, University of Wisconsin-Madison, Madison, WI 53706. E-mail: [email protected] 267

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L.D. Ellingson et al. rently taking opioids, high-dose antidepressants, and/or cardiovascular medications. Women were the focus of this study as they experience higher rates of pain and are at greater risk for developing chronic pain conditions for which exercise has been shown to be an efficacious treatment (Greenspan et al., 2007; Häuser, Thieme, & Turk, 2010), a focus of our lab. Potential participants were contacted by phone and screened for eligibility. Twenty-four women met criteria. Three of these declined to participate, and 21 completed all testing procedures. Participants were compensated $60 for their time.

pain is produced by both short duration, high intensity, and longer duration, moderate intensity cycle ergometry (Cook, O’Connor, Eubanks, Smith, & Lee, 1997; O’Connor & Cook, 2001), which is similar to exercise protocols that have been shown to induce EIH (Koltyn, 2002). Thus, EIH may involve the triggering of CPM via exercise-induced muscle pain. There is limited evidence in support of a potential CPM mechanism of EIH. Tracey and Dunckley (2004) proposed that the decrease in pain perception following distance running described in a study by Janal and colleagues (1984) could be an example of CPM. It was suggested that distance running is often painful and, consequently, may have acted as a conditioning stimulus, decreasing pain sensitivity after exercise. However, pain associated with running was not assessed and, consequently, the role of CPM in EIH could not be addressed. The possibility of CPM as a mechanism for EIH was more directly explored by Kosek and Lundberg (2003). They examined the effects of isometric exercise on pain threshold assessed at both the contracting muscle and a distant muscle in order to determine the specificity of the pain inhibitory response (i.e., segmental vs. generalized). Results showed that isometric exercise led to generalized increases in pain threshold and that the isometric contractions were painful for all but one participant. Consequently, CPM was proposed as a potential mechanism underlying EIH. However, the study by Kosek and Lundberg did not include a nonpainful exercise comparison condition, and analyses to determine if exercise-induced muscle pain was related to changes in pain thresholds were not conducted. The purpose of this research was to test whether CPM is a potential mechanism of EIH. As a first step, it was important to disentangle the influence of pain on EIH from other confounds that can occur during painful exercise. We were particularly concerned with other potential mechanisms of EIH that can occur during longer duration and higher intensity exercise (e.g., cardiovascular, neuroendocrine, and hormonal contributions). Consequently, we chose a short duration, low intensity exercise stimulus that would allow us to manipulate pain while holding intensity and duration constant. Specifically, we examined the influences of painful exercise, nonpainful exercise, and quiet rest on heat pain sensitivity. It was hypothesized that hypoalgesia would occur during and following painful cycling exercise and would not occur during or following nonpainful cycling exercise or quiet rest.

Procedures The Institutional Review Board approved all experimental procedures, and written consent was obtained from each participant. Participants completed three separate testing sessions: painful exercise, nonpainful exercise, and quiet rest (see Figure 1 for an illustration of the experimental design). Sessions were conducted in a sound-attenuated, temperature-controlled room at approximately the same time of day (± 1 h), and sessions were separated by at least 1 week in order to minimize the potential carryover effects from previous sessions on later sessions. Prior to each session, participants were asked to refrain from caffeine for 4 h, cigarettes for 2 h, and alcohol, exercise, and pain medication for 24 h. A verbal compliance check was done at the beginning of each session, and all participants indicated they had followed pretesting instructions. At each of the three visits, participants completed a series of questionnaires. These included a demographic questionnaire (session 1 only), the short form of the McGill Pain Questionnaire to assess baseline bodily pain (Melzack, 1987), and a brief health history to ensure participants were healthy in the 24 h before each session. Several mood measures including the Profile of Mood States (McNair, Lorr, & Droppleman, 1971) and the State-Trait Anxiety Inventory (Spielberger, Gorsuch, & Luschene, 1970) were also collected at the beginning of each session based on evidence that mood state can influence pain perception (Ruiz-Aranda, Salguero, & Fernández-Berrocal, 2010). Additionally, physical activity behaviors were measured for 7 days during the time between the first and second testing sessions using the ActiGraph accelerometer (ActiGraph LLC, Pensacola, FL). Determination and assessment of the test stimulus. Noxious heat served as the test stimulus. Heat was chosen over other experimental pain stimuli (e.g., pressure) because the intensity of the stimulus can be controlled precisely (e.g., within 0.10 of a degree), stimuli can be delivered rapidly (8°C/second), and heat stimuli do not result in tissue damage, making it possible to deliver stimuli repeatedly to the same location. On the first day of testing, participants underwent psychophysical heat pain testing to assess their range of pain sensitivity and determine the temperature that would be used as the test stimulus in subsequent testing procedures. Seven

Method Participants Participants were recruited from a database of people who volunteered in previous studies in our lab and from the local community. Volunteers were eligible if they were (a) female, (b) 20 to 45 years of age, (c) able to perform cycling exercise, (d) not currently suffering from chronic or acute pain symptoms, and (e) not cur-

Session (PE, NPE, QR) TS TIME 0 (minutes)

1

Recovery

TS

TS

TS

5

7

9

TS 10

15

TS 20

Figure 1. Timeline for study procedures. TS = test stimulus (10-s heat stimuli); PE = painful exercise; NPE = nonpainful exercise; QR = quiet rest.

Mechanisms of exercise-induced hypoalgesia temperatures (43–49°C in 1°C increments) were applied to the palm of the right hand using a Medoc TSA-2001 Thermal Sensory analyzer with a 900 mm2 Peltier thermode (Medoc Advanced Medical Systems, Minneapolis MN). Stimuli lasted 10 s with a 1-min interstimulus interval. Each temperature was presented twice in a random order for a total of 14 stimuli. The baseline temperature for all heat testing procedures was 35°C, and temperature increased at a rate of 8°C/second. Following each heat stimulus, participants were asked to rate its pain intensity and pain unpleasantness using the Gracely Box SL category ratio pain rating scales (0–20) (Gracely, McGrath, & Dubner, 1978). Standardized instructions were given to all participants. Briefly, they were instructed that pain intensity is defined as how much the stimulus hurts and that pain unpleasantness is defined as how bothersome the stimulus is, and that they should attempt to differentiate these two dimensions of pain. From these data, linear regression analysis of temperatures to pain ratings was used to determine the temperature that corresponded to 8 or “mild ” pain intensity on the 0–20 pain rating scale. A mild pain stimulus was chosen for the test stimulus as CPM is more likely to occur when the conditioning stimulus is stronger or more salient than the test stimulus (Le Bars et al., 1979). Noxious thermal stimuli at this temperature then served as the test stimulus in the CPM paradigm and were used for all subsequent heat pain testing procedures. Presentations of the test stimulus were 10 s in duration and occurred at baseline, minutes 5, 7, and 9 during each session and minutes 5 and 10 during the recovery period. Experimental sessions. On the first day of testing, participants completed suprathreshold heat pain testing and the first of their three experimental sessions. Sessions were counterbalanced to minimize potential order effects, and participants were not informed of which experimental condition would occur during each testing day until after baseline test stimulus was presented. For each session, heat pain testing did not commence until participants had acclimated to laboratory conditions for a minimum of 40 min. During this standardized acclimation period, participants completed questionnaires and received instructions regarding study procedures, as detailed below. Nonpainful exercise. The nonpainful exercise session consisted of 10 min of cycling exercise on an Ergometrics 800 cycle ergometer (Ergoline, Bitz, Germany) at 60 watts followed by a 10-min recovery period during which participants remained seated on the bike and did not pedal. During exercise, participants were instructed to maintain a pace of 50–55 revolutions per minute, and to rest their hands lightly on the handlebars of the cycle ergometer to allow for monitoring of blood pressure (see Cardiovascular Monitoring section below) as well as to allow for periodic presentations of the test stimulus to the right palm. The relatively low intensity and short duration of exercise was chosen specifically, as pilot testing performed prior to the study as well as previous research suggested that this duration and intensity would be nonpainful for most individuals (Cook et al., 1997). This also allowed us to hold duration and intensity of exercise constant while manipulating pain (see below). Painful exercise. The painful exercise session was identical to nonpainful exercise with the addition of thigh-sized (20.5-cm width) blood pressure cuffs (American Diagnostic Corporation, Hauppauge, NY) placed around the quadriceps of both legs, equidistant between the knee and the hip. Cuffs were inflated and maintained at 90 mmHg, a level insufficient to completely block

269 blood flow to or from the legs (Gallagher et al., 2001). Cuff pressure was maintained throughout the exercise session by visually monitoring the pressure gauge and immediately adding pressure if it dropped below 90 mmHg. Use of thigh cuffs was designed to induce moderate pain similar to that experienced during more strenuous exercise through increasing intramuscular pressure, increasing the deformation of muscle tissue during contraction, and enhancing the buildup of noxious biochemicals in the exercising leg muscles. This exercise-induced muscle pain served as the conditioning stimulus for the CPM paradigm. We chose to induce leg muscle pain using the cuffs in combination with aerobic exercise in order to isolate the influence of exercise-induced muscle pain on EIH and to allow for a comparable nonpainful exercise condition that involved an identical workload (i.e., controlling for exercise intensity and duration). One alternative would have been to manipulate exercise intensity and/or duration to induce naturally occurring leg muscle pain. This was considered but would have added a number of uncontrolled variables (in addition to intensity and duration of exercise) such as other cardiorespiratory changes associated with higher intensity exercise. Further, this design would not have allowed for a nonpainful condition that was matched for intensity and duration. For both practical and experimental considerations, we chose a design that better isolated the influence of muscle pain on EIH as a first test of our hypothesis. Pilot testing conducted in our lab demonstrated that inflation of the cuffs to 90 mmHg during quiet rest on the bike did not induce leg muscle pain and did not influence pain intensity or unpleasantness ratings to noxious heat stimuli. Moreover, participants in the current study did not report leg muscle pain during inflation of the cuffs at rest. These data suggest that the pain experienced during the painful exercise condition resulted from a combination of muscular contractions and cuff inflation. Quiet rest. The quiet rest session consisted of 10 min of quiet rest while seated on the stationary bicycle followed by a 10-min period during which pain testing procedures and all other assessments were identical to the other sessions. Assessment of the conditioning stimulus. At minutes 1, 2, 3, 4, 6, 8, and 10 during each session, leg muscle pain intensity (LMPI) was assessed using a 0–10 muscle pain intensity scale designed and validated specifically to measure muscle pain during exercise (Cook et al., 1997). Ratings of perceived exertion (RPE) were assessed at the same time points using Borg’s well-validated 6–20 RPE scale (Borg, 1998). For both scales, standardized instructions were given to all participants. For LMPI, they were instructed that pain is defined as the intensity of hurt that is felt in the exercising leg muscles, that each number on the scale represents a category of sensation that is ordered according to its intensity, and that the verbal anchors (e.g., “weak pain,” “strong pain,” etc.) should be used to help determine the level of pain intensity experienced at a particular moment. LMPI assessments continued at each minute during the recovery period until ratings returned to baseline. For RPE, participants were instructed that the scale should be used to determine the intensity of effort or stress felt in the legs only during exercise/quiet rest, that each number represents a category of sensation that is ordered according to its intensity, and that the verbal anchors (e.g., “light,” “somewhat hard,” etc.) should be used to help determine the level of effort at that particular moment. Additionally, participants were provided with cognitive anchors at the high and low ends of the perceptual continuum. Participants were instructed that a 6 on the RPE scale corresponds to no exertion at all

270 (e.g., sitting in a chair without moving) and 20 corresponds to the highest level of exertion they could ever imagine doing (e.g., finishing a marathon). At the end of each of the two exercise sessions, participants completed the short form of the McGill Pain Questionnaire (SF-MPQ) to qualitatively describe pain in their exercising leg muscles during cycling. This allowed for comparisons of muscle pain during cycling with the addition of thigh cuffs with previous data describing muscle pain experienced during higher intensity, longer duration cycling exercise (Cook et al., 1997). Cardiovascular monitoring. As exercise-induced increases in blood pressure have been suggested as a potential mechanism of EIH (Koltyn & Umeda, 2006), blood pressure and HR were assessed at baseline and monitored continuously throughout the exercise and recovery periods using the Ohmeda 2300 Blood Pressure Monitor (Finapres, Englewood, CO). The Finapres cuff was placed on the middle finger of the left hand. Because Finapres data are collected on a beat-to-beat basis and there is variability from beat to beat, blood pressure and heart rate (HR) data were averaged across the last 15 s of each minute in order to get a more stable measurement. Statistical Analyses A power analysis was conducted a priori using G * Power 3 (version 3.1.3) to estimate sample size for detecting a session (painful exercise, nonpainful exercise, quiet rest) by time of assessment for the test stimulus (baseline, minutes 5, 7, 9, 15, and 20) interaction in a repeated measures design with three conditions and six time points. To calculate sample size, the significance level (α) was set to 0.05, minimum power was set to 0.80, and the effect size was estimated to be moderate (f = 0.25), based on previous research showing a moderate effect for decreases in pain sensitivity during and following exercise in typical EIH studies (Koltyn, 2000). Results from this analysis indicated that 15 participants would yield a power of 0.88. Data were analyzed using SAS 9.2 for the linear mixed model analyses. SPSS 19.0 was used to determine normality of the data for ANOVA, for calculation of descriptive data, correlations, and reliability analyses. Physical activity data were processed and analyzed as follows. Standard criteria for inclusion of accelerometer data were applied—at least 10 h of valid wear time for a minimum of 3 weekdays and 1 weekend day (Troiano et al., 2008; Ward, Evenson, Vaughn, Rodgers, & Troiano, 2005). In-house software was used to process this information to calculate the average number of minutes per day spent doing sedentary, light, moderate, and vigorous physical activity. Cut points for accelerometer counts per minutes were as follows: sedentary < 100; light = 101–760; moderate = 761–5,724; vigorous > 5,725 (Freedson, Melanson, & Sirard, 1998; Matthews, 2005; Matthews et al., 2008). To determine whether the order of sessions influenced heat pain ratings, two separate repeated measures analyses of variance (ANOVAs) were performed with time and session as independent variables, session order as a covariate, and heat pain intensity and unpleasantness ratings as dependent variables. Differences in cardiovascular measures and RPE among sessions were assessed using four separate repeated measures ANOVAs with session and time as independent variables and HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), and RPE as dependent variables. To determine the reliability of heat pain testing, intraclass correlation (ICC) analyses were conducted for heat pain intensity and unpleasantness ratings during quiet rest

L.D. Ellingson et al. with a two-way mixed model and absolute agreement for the six time points tested. For the primary statistical analysis, two linear mixed model analyses were conducted using the SAS PROC MIXED procedure. For both analyses, session was included as a categorical independent variable and time of assessment was included as a continuous variable nested within session (Session × Time, 3 × 1). Heat pain intensity and pain unpleasantness ratings were the dependent variables. Baseline ratings for pain intensity and unpleasantness were included as part of the dependent variable in order to assess the trajectory of pain sensitivity over time for each session. The mixed model approach was chosen specifically to control for blood pressure differences between conditions by including it as a time-varying covariate in our analyses. This procedure was also chosen to deal with potential violations in sphericity, as it allows for estimating separate values for each variance and covariance in the covariance matrix. Due to the moderate but nonsignificant differences in heat pain ratings to the test stimulus at baseline across conditions, baseline ratings were included as the first time point in the mixed model analyses. Mean arterial pressure (MAP) was used in the mixed model analyses, because of the significant elevations in both SBP and DBP during painful exercise. As previous research has implicated SBP responses to exercise as a potential mechanism of EIH, similar analyses were conducted with SBP as the time-varying covariate. To further explore potential relationships between blood pressure and pain sensitivity, bivariate correlation analyses were also conducted between pain intensity and unpleasantness ratings and MAP for each session at each time point. Univariate analyses of change scores from baseline for heat pain ratings were conducted to determine whether heat pain perception changed differentially among sessions at each time point. Effect sizes were calculated using Cohen’s d to assess the magnitude of EIH (e.g., changes in pain intensity and unpleasantness from baseline) at each time point during each session. Cut points for effect size determination were operationally defined based on Cohen (1969) as follows: small < 0.50, medium = 0.50–0.80, large > 0.80. To determine the influence of leg muscle pain during exercise on changes in heat pain sensitivity, first, a repeated measures ANOVA was conducted to compare leg muscle pain intensity between the exercise sessions. Session (painful and nonpainful exercise) and time of assessment (minutes 1, 2, 3, 4, 6, 8, and 10 and minutes 1 and 3 during recovery) were the independent variables, and leg muscle pain intensity was the dependent variable. Correlations (Pearson’s r) were then calculated between peak leg muscle pain intensity and peak EIH (greatest decrease in heat pain intensity and heat pain unpleasantness from baseline) during the painful exercise condition. Data from the SF-MPQ administered after exercise were used to describe the muscle pain experienced during painful exercise. These data were then used to make qualitative comparisons with previous reports of muscle pain during cycling as well as during ischemic muscle pain. The α for achieving significance was set to 0.05 for all primary analyses, and the Holm-Bonferroni method was used for follow-up analyses to control for multiple comparisons. Results Twenty-one women completed all testing procedures. Of these, five did not rate the conditioning stimulus as painful (i.e., CPM could not be assessed) and were consequently excluded from all analyses. Thus, data from 16 participants (mean age 30.6 ± 6.2) are

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Table 1. Baseline Cardiovascular, Pain, and Mood Assessments for the Three Sessions

Baseline assessments Cardiovascular measures

Heart rate (bpm) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) MPQ bodily pain VAS (mm) Test stimulus INT (0–20 scale) Test stimulus UNP (0–20 scale) Tension Depression Anger Vigor Fatigue Confusion State Anxiety

Pain measures Mood measures (POMS, STAI)

QR Mean (SD)

NPE Mean (SD)

PE Mean (SD)

69.88 (13.70) 99.88 (9.28) 64.81 (7.37) 7.00 (16.34) 8.75 (3.40) 4.44 (2.44) 4.56 (4.29) 4.19 (8.57) 2.50 (3.86) 14.93 (7.96) 7.06 (5.70) 4.93 (4.29) 29.13 (9.61)

70.12 (13.88) 102.31 (10.84) 65.00 (4.65) 4.81 (9.20) 9.31 (2.84) 4.31 (2.56) 3.62 (3.73) 3.93 (5.17) 1.56 (2.85) 17.81 (5.63) 2.87 (3.57)* 4.56 (3.46) 27.19 (6.89)

64.75 (12.87) 100.81 (10.41) 63.81 (6.40) 5.81 (16.17) 10.94 (3.36) 6.13 (1.76) 2.93 (3.06) 3.25 (8.81) 0.93 (1.48) 18.25 (6.16) 2.43 (4.61)* 3.69 (3.57) 27.25 (7.61)

n = 16. Note. Repeated measures ANOVAs were used to assess baseline differences. QR = quiet rest; NPE = nonpainful exercise; PE = painful exercise; INT = pain intensity rating; UNP = pain unpleasantness rating.; PPI = present pain intensity. *Significantly different from QR, p = .002.

presented. All participants were college graduates, premenopausal, and nonsmokers. On average, participants were 168.43 ± 3.79 cm tall and weighed 67.22 ± 10.79 kg with a body mass index in the normal range of 23.68 ± 3.54. All participants reported being in good health for each of the testing sessions. No participants reported taking antidepressants, opioids, or cardiovascular medications. Baseline assessments of cardiovascular measures, bodily pain, mood measures, and test stimulus ratings are presented in Table 1. Accelerometer data showing the physical activity behaviors of participants is presented in Table 2. Cardiovascular measures and ratings of perceived exertion collected during each session are presented in Table 3. The average temperature used for the test stimulus was 46.2 ± 1.9°C. There were no significant differences in baseline assessments for intensity and unpleasantness ratings of the test stimulus, or cardiovascular or mood measures, with the excep-

Table 2. Physical Activity Behaviors Accelerometer (average minutes/day)

Wear time Sedentary Light Moderate Vigorous

894 ± 54 596 ± 69 183 ± 45 103 ± 30 11 ± 13

tion of fatigue (p = .002). However, fatigue was not significantly related to any of the primary outcome variables (p > .05). Exercise-Induced Muscle Pain and Pain Sensitivity Leg muscle pain was significantly greater during painful as compared to nonpainful exercise, F(1,15) = 29.58, p < .0001. On average, participants rated their peak leg muscle pain during painful exercise as “moderately painful” or 2.8 ± 1.8 on the 0–10 LMPI scale; peak muscle pain during nonpainful exercise was rated as less than “very faint pain” or 0.22 ± 0.52. Leg muscle pain ratings returned to baseline levels for all participants by 3 min following completion of painful exercise and within 1 min following completion of nonpainful exercise. Because the nonpainful exercise session was not pain free for all participants, we ran our primary analyses with and without the two individuals who reported “very faint” to “weak” muscle pain during the nonpainful session. Results were not significantly different with or without the inclusion of these individuals. There were no significant main effects (p > .05) or interactions (p > .05) based on session order. Results from the reliability analysis for heat pain testing demonstrated a high degree of test-retest reliability for both pain intensity (ICC = 0.91, p < .0001) and unpleasantness (ICC = 0.84, p < .0001) ratings during quiet rest. The linear mixed model analyses of heat pain ratings

Table 3. Cardiovascular Measures and Ratings of Perceived Exercise Collected During the First 10 Min of Each Session

Cardiovascular Measures

RPE (6–20 scale)

Heart rate (avg. bpm) Systolic blood pressure (avg. mmHg) Diastolic blood pressure (avg. mmHg) Mean arterial pressure (avg. mmHg) Peak Average

Note. QR = quiet rest; NPE = nonpainful exercise; PE = painful exercise. *Significantly greater than QR, p < .05. †Significantly greater than NPE, p < .05.

QR Mean (SD)

NPE Mean (SD)

PE Mean (SD)

76.14 (12.33) 109.36 (13.43) 65.53 (7.89) 79.92 (7.99) 6.00 (0) 6.00 (0)

108.58 (13.72)* 126.40 (19.35)* 66.86 (10.45) 83.29 (9.29) 9.53 (1.86)* 5.51 (1.41)*

104.92 (14.21)* 141.19 (18.31)*† 75.70 (11.50)*† 96.09 (11.76)*† 13.25 (2.57)*† 11.69 (2.35)*†

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12

Quiet Rest Non-Painful Exercise Painful Exercise

Pain Intensity Ratings (0-20)

10

8

6

4

2

10 minutes post

5 minutes post

Minute 9

Minute 7

Minute 5

Baseline

0

Figure 2. Heat pain intensity ratings at each time point during each session (n = 16). Values are mean ± SEM.

partially supported our primary hypothesis, showing a significant Session × Time interaction for both pain intensity, F(2,214) = 7.60, p = .0006 (see Figure 2), and pain unpleasantness, F(2,214) = 8.85, p = .0002 (see Figure 3). Simple main effects for session showed

that heat pain intensity changed significantly over time during painful exercise, F(1,71) = 30.36, p < .0001, and nonpainful exercise, F(1,71) = 15.79, p = .0002, but not during quiet rest. Similarly, heat pain unpleasantness changed significantly over time

8

6

4

2

Figure 3. Heat pain unpleasantness ratings at each time point during each session (n = 16). Values are mean ± SEM.

10 minutes post

5 minutes post

Minute 9

Minute 7

Minute 5

0 Baseline

Pain Unpleasantness Ratings (0 -20)

Quiet Rest Non-Painful Exercise Painful Exercise

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Table 4. Effect Size (Cohen’s d) Comparing the Hypoalgesic Effect (Change in Heat Pain Intensity and Unpleasantness Ratings from Baseline) Heat pain intensity

During session

Minute 5 Minute 7 Minute 9 Minute 15 Minute 20

Recovery

Heat pain unpleasantness

PE

NPE

QR

PE

NPE

QR

0.81** 1.31** 1.81** 1.06** 0.98**

0.61* 0.91** 1.05** 0.75* 0.67*

0.06 0.64* 0.63* 0.24 0.07

1.29** 2.05** 2.26** 1.30** 1.30**

0.35 0.66* 0.69* 0.65* 0.48

0.01 0.75* 0.54* 0.15 0.01

Note. PE = painful exercise; QR = quiet rest; NPE = nonpainful exercise. *medium effect; **large effect.

during painful exercise, F(1,71) = 37.57, p < .0001, and nonpainful exercise, F(1,69) = 17.55, p < .0001, but not during quiet rest. Similar results for the linear mixed model analyses were obtained using SBP as the time-varying covariate in place of MAP. Comparisons of change scores for heat pain ratings among sessions demonstrated that both pain intensity (PI) and pain unpleasantness (PU) decreased significantly more during painful exercise than during quiet rest at minute 9 during exercise (PI: F(1,15) = 8.64, p = .010; PU: F(1,15) = 7.35, p = .014) and minutes 15 (PI: F(1,15) = 7.21, p = .010; PU: F(1,15) = 10.88, p = .005) and 20 (PI: F(1,15) = 11.91, p = .004; PU: F(1,15) = 8.25, p = .012) during recovery. Pain intensity and unpleasantness decreased significantly more during painful exercise than during nonpainful exercise at minute 9 only (PI: F(1,15) = 9.03, p = .009; PU: F(1,15) = 7.98, p = .013). Changes in heat pain intensity and unpleasantness ratings were not significantly different between nonpainful exercise and quiet rest at any time point. Effect size calculations (Cohen’s d, see Table 4) demonstrated large hypoalgesic effects for heat pain intensity and unpleasantness at each time point during the painful exercise session. During nonpainful exercise, the hypoalgesic effects were smaller in magnitude falling in the moderate to large range for intensity and the small to moderate range for unpleasantness. During quiet rest, the

0

1

2

3

4

5

6

hypoalgesic effect sizes were small for both pain intensity and pain unpleasantness at minutes 5, 15, and 20 and moderate at minutes 7 and 9, potentially due to the shorter interstimulus interval for these stimuli. Peak leg muscle pain during painful exercise was significantly and inversely related to peak EIH (change in pain ratings from baseline) for pain intensity (r = −.50, p = .014; see Figure 4). For this analysis, one participant’s decrease in pain intensity was more than 2 standard deviations below the mean for the group. Based on a priori determined data-inclusion criteria, this participant was excluded for this analysis only, and results are presented for the remaining 15 participants. Peak leg muscle pain was also significantly related to peak EIH for pain unpleasantness (r = −.61, p = .006). Thus, the greater the exercise-induced leg muscle pain, the greater the hypoalgesic effect for both the intensity and affective dimensions of heat pain sensitivity. Results from the SF-MPQ described the muscle pain experienced during painful exercise as qualitatively similar to muscle pain experienced during cycling. The most common descriptors chosen were heavy (n = 7), tiring (n = 6), aching (n = 6), throbbing (n = 5), cramping (n = 4), and gnawing (n = 4), the same words that have been used to describe muscle pain during cycle ergometry (Cook et al., 1997; O’Connor & Cook, 2001). This is qualitatively

7

0

R² = 0.25

-2 -4 -6 -8 -10 -12 -14 -16

1

2

3

4

5

6

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Peak Leg Muscle Pain Intensity

Peak Decrease in Pain Unpleasantness

Peak Decrease in Pain Intensity

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Peak Leg Muscle Pain Intensity

Figure 4. Relationship between peak leg muscle pain intensity and peak EIH (change in heat pain intensity (n = 16) and heat pain unpleasantness (n = 16) ratings from baseline) during the painful exercise session.

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different than descriptions of ischemic muscle pain, which include pressing, wrenching, burning, exhausting, wretched, annoying, penetrating, and squeezing (Chen & Treede, 1985). This suggests that our participants experienced painful exercise that was qualitatively similar to that experienced under more natural exercise conditions. Blood Pressure and Pain Sensitivity Results from the repeated measures ANOVA showed that MAP was significantly different among sessions, F(2,16) = 8.89, p = .003. Results for the primary mixed model analysis showed that MAP was significant for both heat pain intensity, F(2,214) = 7.60, p = .01, and heat pain unpleasantness, F(2,214) = 7.42, p = .007. MAP was then included as a covariate in the analyses of simple main effects to assess its influence in these models. Results demonstrated a significant effect for MAP during the quiet rest session for pain unpleasantness, F(1,71) = 4.37, p = .04, but not for pain intensity (p > .05). MAP was not significant for pain intensity or unpleasantness during either exercise session (p > .05). Similar results were obtained using SBP as the time-varying covariate in place of MAP. Results from the correlation analyses demonstrated that MAP was not significantly related to pain intensity or unpleasantness ratings during either exercise session. During the quiet rest session, MAP was significantly related to heat pain intensity and unpleasantness ratings, but only at minute 20 (PI: r = −.58, p = .03; PU: r = −.56, p = .04). Discussion This experiment was designed to test whether CPM is a mechanism of EIH. In partial support of our hypotheses, both intensity and affective ratings to noxious heat decreased significantly from baseline during and following aerobic cycling exercise that was painful. However, there was also a significant, albeit smaller magnitude, decrease in pain ratings during the nonpainful exercise session. Thus, the results do not support CPM as a primary mechanism of EIH and suggest that multiple mechanisms are likely involved. Although the results do not support CPM as a primary mechanism of EIH, the data do add to the evidence demonstrating that the painfulness of exercise may contribute to the magnitude of the hypoalgesic effect. Previously, Janal and colleagues (1984) reported a decrease in pain sensitivity following a potentially painful bout of long distance running. However, pain associated with the running was not assessed. More recently Kosek and Lundberg (2003) found that pain-inducing isometric exercise led to an increase in pressure pain thresholds for several sites around the body. This generalized decrease in sensitivity is consistent with involvement of CPM. However, while pain associated with the contractions was measured, and the contractions were painful for all but one participant, analysis of the relationship between muscle pain and increases in pain thresholds were not conducted. Nor was there a condition of nonpainful isometric exercise with which to make comparisons. Without a nonpainful exercise condition, it is impossible to determine if changes in pain sensitivity are specific to muscle pain induced through exercise or result from some other aspect of exercise itself. Our results extend upon this previous research by showing that aerobic cycling that was painful had a relatively larger hypoalgesic effect on pain intensity and unpleasantness than a comparable session of nonpainful cycling exercise, performed at the same intensity and for the same duration, but that nonpainful exercise was also capable of producing EIH. Further-

more, our results demonstrated that the decreases in pain sensitivity were significantly and inversely correlated to the exercise-induced muscle pain during painful exercise. This experiment is also unique in that we assessed both the intensity and affective components of pain rather than treating pain as a unidimensional construct. Previous research in the areas of DNIC and CPM has largely limited pain assessments to a single intensity dimension. Evidence from neuroimaging research has demonstrated the importance of assessing both dimensions of pain perception, given that the intensity and affective aspects of pain are subserved by separate afferent pathways (spinothalamic vs. spinomesencephalic tracts) and unique patterns of brain activity (Tölle et al., 1999; Willis & Westlund, 1997). Previous research from our lab demonstrated a stronger association between participation in regular high intensity physical activity and decreased affective responses to experimental pain than between physical activity and pain intensity (Ellingson, Colbert, & Cook, 2012). Results from the present study suggest that exercise-induced pain may influence both the intensity and affective dimensions of pain with a larger hypoalgesic effect for pain unpleasantness and a stronger correlation occurring between leg muscle pain ratings and pain unpleasantness ratings to heat pain stimuli. The decrease in pain sensitivity during the nonpainful exercise session was unexpected, given the evidence that higher intensity/ longer duration bouts of aerobic exercise are more likely to elicit EIH than lower intensity and/or short duration exercise (Hoffman et al., 2004; Koltyn, 2002). However, to date few studies have included a systematic manipulation of aerobic exercise intensity (Hoffman et al., 2004), and the sole review article examining the relationship between EIH and aerobic exercise intensity (Koltyn, 2002) found that, while EIH was more consistently elicited after higher intensity exercise, there have been reported cases of EIH occurring in response to lower intensity, short duration bouts of aerobic exercise (Kemppainen, Paalasmaa, Pertovaara, Alila, & Johansson, 1990; Vierck et al., 2001). Our results demonstrate that low-intensity, short-duration, nonpainful aerobic exercise is capable of eliciting EIH suggesting a potential pain-related benefit for engaging in even low intensity exercise. These results are consistent with previous work from our lab demonstrating that a single low intensity bout of exercise can induce EIH and improve symptoms in fibromyalgia patients (Newcomb, Koltyn, Morgan, & Cook, 2011). Exercise training has been shown to be an efficacious treatment for numerous chronic pain conditions (Stegner, Shields, Meyer, & Cook, 2013). It is plausible that the therapeutic benefits of exercise training in chronic pain patients result in part through the hypoalgesic effects of acute exercise (i.e., EIH). There are several alternative explanations for our results. It is possible that painful exercise was simply more distracting than nonpainful exercise and therefore resulted in more robust changes from baseline. However, recent evidence comparing CPM protocols with and without distraction suggests that CPM acts independently from distraction (Moont, Pud, Sprecher, Sharvit, & Yarnitsky, 2010). It is also possible that both painful and nonpainful exercise resulted in the release of opioids, leading to a decrease in pain sensitivity. These potential mechanisms may work independent of or in conjunction with CPM mechanisms, and future EIH research aimed at selectively manipulating multiple variables (e.g., endogenous opioid, distraction) will be necessary to test their relative contributions (Janal et al., 1984; Moont et al., 2010). We chose to include mean arterial pressure in our statistical model based on the large body of evidence demonstrating an

Mechanisms of exercise-induced hypoalgesia

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inverse relationship between blood pressure and pain sensitivity (Koltyn & Umeda, 2006). Changes in the cardiovascular system (e.g., blood pressure), have been suggested as a potential mechanism that underlies EIH, and two recent studies have directly tested this hypothesis. Ring and colleagues (Ring, Edwards, & Kavussanu, 2008) conducted a study to assess the effects of isometric exercise on pain ratings and the nociception flexion reflex, a physiological measure associated with pain, and also to determine whether EIH is mediated by increases in arterial blood pressure. Results showed that pain sensitivity decreased and blood pressure increased during exercise, and an analysis of mediation indicated that blood pressure accounted for the effects of isometric exercise on pain ratings. Subsequently, Umeda and colleagues (2010) examined the dose relationship between duration of isometric handgrip exercise, pain sensitivity, and blood pressure. Results showed that exercise increased blood pressure in a dose-response manner and that pain sensitivity decreased in response to the exercise stimulus. However, the reduction was roughly equivalent across durations, and a dose-response relationship for pain sensitivity was not evident. In our study, mean arterial pressure was significantly higher during painful exercise than nonpainful exercise and was a significant factor in the overall model. However, subsequent analyses showed that MAP was significantly associated with pain ratings only for the quiet rest session, not exercise. Thus, evidence from our experimental manipulations suggests that exercise-induced increases in blood pressure were not a significant contributor to the exercise-induced hypoalgesic response. It may be that a greater magnitude of change is necessary for blood pressure to contribute to EIH. Future research using higher intensity and longer duration exercise is necessary to fully test the influence that blood pressure has on hypoalgesia during and after exercise. There were a number of potential limitations in this study. This study included a small sample of healthy women. Thus, these results may not generalize to men, older adults, or patient populations. Our design necessitated multiple pain assessments in order to document the pattern of changes in sensitivity during and following exercise. Additionally, the testing location was kept the same in order to minimize potential rating differences due to differences in sensitivity around the body. Habituation to noxious heat is known to occur in healthy individuals, especially when stimuli are delivered repeatedly to the same site on the body with relatively short (< 1 min) interstimulus intervals (Greffrath, Baumgärtner, & Treede, 2007). Although we had 2 min between heat stimuli, our effect size data suggest that habituation may have occurred. This was particularly apparent in the quiet rest condition where pain ratings were stable from baseline to 5 min into the session, but decreased moderately (though not significantly) at minutes 7 and 9 before returning to baseline levels following the quiet rest period.

Thus, repeated heat pain testing, particularly for those stimuli that were delivered close together, may explain the decrease in ratings during quiet rest. Because each participant served as her own control, any changes due to habituation were accounted for in the statistical model. Further, the magnitude of change in the painful exercise condition (effect sizes ranging from d = 0.81 to 2.26) was larger than seen during quiet rest (effect sizes ranging from d = 0.01 to 0.75) and remained below baseline throughout recovery. These results suggest that changes in pain ratings seen during and following painful exercise were greater than what would be expected solely from habituation. This makes habituation an unlikely explanation for the observed exercise-induced hypoalgesic responses. This study did not include a “cuffs-only” condition. As detailed in the Methods section, pilot testing demonstrated that wearing thigh cuffs inflated to 90 mmHg during quiet rest was not painful and did not influence pain sensitivity to noxious heat. We therefore chose to reduce participant burden by not including a cuffs-only condition in the current study. As a result, we were not able to account for the influence of nonpainful, light pressure on subsequent pain responses. Another potential limitation is that the phase of the menstrual cycle was not controlled for in the design of this study. There is some evidence to suggest that pain sensitivity varies across the menstrual cycle. However, there is also a large body of research demonstrating a lack of variation (Sherman & LeResche, 2006). For example, a recent well-conducted study examining sensitivity to several different modalities of experimental pain across four time points during the menstrual cycle found that heat pain sensitivity did not differ while sensitivity to other modalities did (Teepker, Peters, Vedder, Schepelmann, & Lautenbacher, 2010). Moreover, it was recently demonstrated that, regardless of absolute differences in sensitivity across the menstrual cycle, conditioned pain modulation does not vary (Bartley & Rhudy, 2012). Because baseline pain testing was conducted at the beginning of each session, and these ratings were included in the statistical model, variation in sensitivity was accounted for in the analyses. Our results demonstrate that conditioned pain modulation is likely not a primary mechanism of EIH. However, this study adds to the body of evidence showing that exercise-induced muscle pain can influence the magnitude of the hypoalgesic response observed during and following exercise. Using exercise as a model to stimulate the muscle nociceptive system is important for furthering our knowledge of the mechanisms underlying acute and chronic muscle pain and hypoalgesia. Future research including both males and females and assessing other exercise and experimental pain modalities is warranted to determine the extent of involvement of exercise-induced muscle pain in pain modulation.

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