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Cardiovascular responses to and modulation of pressure pain sensitivity in normotensive, pain-free women
Scandinavian Journal of Pain 3 (2012) 165–169
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Original experimental
Cardiovascular responses to and modulation of pressure pain sensitivity in normotensive, pain-free women Christine Mohn a,b,∗ , Olav Vassend a , Stein Knardahl c a
Department of Psychology, University of Oslo, Norway Department of Research, Vestre Viken Hospital Trust, Norway c Department of Work Psychology and Physiology, The National Institute of Occupational Health, Oslo, Norway b
a r t i c l e
i n f o
Article history: Received 9 September 2011 Received in revised form 25 November 2011 Accepted 19 December 2011 Keywords: Blood pressure Cardiovascular responding Heart rate Pain sensitivity Pressure pain Skin blood flux
a b s t r a c t Background and purpose: The psychophysiological responses to and modulation of pressure pain stimulation are relatively new areas of investigation. The aims of the present study were to characterize subjective and cardiovascular (CV) responses to pressure pain stimulation, and to examine the relationship between CV responding and pain pressure pain sensitivity. Methods: Thirty-nine pain-free, normotensive women were included in the study and tested during the follicular phase of their menstrual cycles. Pain threshold and tolerance were recorded at the right masseter muscle and the sternum, and visual analogue scales (VAS) were used to rate both pain intensity (the sensory dimension) and discomfort (the affective dimension). Mean arterial pressure (MAP), heart rate (HR), and facial and digital skin blood flux (SBF) were registered continuously. Results: The pain threshold and tolerance were significantly higher at the sternum compared with the masseter, but the level of affective distress was higher at the masseter tolerance point. No associations emerged between pressure pain threshold and tolerance stimulation levels, and the corresponding VAS ratings. Pressure pain stimulation of the masseter induced significant increases in MAP, HR, and a decrease in digital SBF. During sternum pressure stimulation a significant change in HR and digital SBF was observed. There were no significant correlations between CV responding and pressure pain sensitivity. Conclusion: Healthy women seem to display higher pressure pain sensitivity at the masseter region relative to the sternum. Pressure pain stimulation was associated with significant changes in MAP, HR, and SBF, but was not modulated by CV responses. The validity of these findings is strengthened by our control for menstrual cycle events, weekend-related changes in physiology, and CV changes during pain stimulation. Implications: This study extends previous reports of SBF sensitivity to electrocutaneous pain into the field of pressure stimulation. Moreover, this study suggests that the often demonstrated association between high BP and low pain sensitivity may not apply to pressure pain specifically. Alternatively, this finding adds to the literature of gender differences in the relationship between CV responding and acute pain sensitivity in general. © 2011 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction The mulitidimensional nature of pain perception requires the assessment of several aspects of the pain experience. In order to obtain as complete a picture as possible of the individual’s pain experience, subjective and physiological responses to pain stimulation should be described in addition to the pain sensitivity thresholds. Compared with other stimulation methods such as
DOI of refers to article: 10.1016/j.sjpain.2012.02.005. ∗ Corresponding author at: Department of Psychology, University of Oslo, PO Box 1094, Blindern, 0317 Oslo, Norway. Tel.: +47 22 84 51 15; fax: +47 22 84 50 01. E-mail address: [email protected] (C. Mohn).
thermal pain [1], the Subjective and physiological responses to pressure pain are not well known. As substantiated in previous research, measurements of skin blood flux (SBF) may provide valuable indicators of autonomic nervous system (ANS) activity during psychological challenges [2,3]. Moreover, electrocutaneous pain stimulation seems to trigger increases in facial SBF as well as decreases in digital SBF [4,5]. Similar orofacial SBF changes during pain stimulation have been documented by Kemppainen et al. [6,7]. However, as the research on SBF during pain in humans is relatively new, few studies of SBF responses to experimental pain exist. In both normotensive and hypertensive individuals, elevations of arterial pressure may be associated with reduced sensitivity to painful stimuli [8,9]. Although the CV–pain relationship appears
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attenuated or absent altogether in chronic pain groups [10,11], we have recently found that elevated mean arterial pressure (MAP) was associated with reduced pain sensitivity in women with TMD, but not in the pain-free control group [12]. That study employed electrocutaneous and pressure stimulation, whereas the others [10,11] assessed thermal and ischemic pain. Different pain stimulation methods are likely to induce different behavioural, autonomic, and antinociceptive responses [4,13,14]. Moreover, in our previous study of electrocutaneous pain [12] we did not control for certain factors that may modulate pain sensitivity, CV responding or the relationship between those two. These include hormonal effects of menstrual cycle events on pain sensitivity [15] and weekend-related changes in physiology [16]. In addition, the fact that pain stimulation may generate BP increases in its own right could confound the relationship between baseline CVR and subsequent pain sensitivity assessments [17]. Therefore, we control for these factors in the present study. The general rationale behind this study was to extend previous work on psychological and physiological responding during experimental pain in general to pressure pain stimulation in particular. The primary aim is to characterize subjective and physiological responses, including facial and digital SBF, to pressure pain stimulation. The secondary aim is to examine the relationship between CV responses and pressure pain sensitivity while controlling for possible confounders.
2. Materials and methods 2.1. Subjects Thirty-nine Caucasian women (see Table 1 for demographic characteristics) were recruited among graduate students of medicine and psychology of the University of Oslo via the students’ mailing lists. Inclusion criteria were age between 20 and 50 years, and ability to speak and understand spoken and written Norwegian. Exclusion criteria (self reported) were known hypertension, chronic pain, general chronic somatic or mental health problems, pregnancy, and use of regular medication apart from oral contraceptives. The subjects were instructed to refrain from drinking alcohol the last 12 h before the experiment, and to avoid drinking tea or coffee, having large meals, and exercising the last 3 h before the experiment. All subjects were tested in the follicular phase of their menstrual cycle in order to rule out pain sensitivity effects of different endogenous reproductive hormone levels [15]. In order to avoid physiological effects of excessive alcohol and/or tobacco consumption during weekends, no experimental testing took place on Mondays [16]. The present study was conducted in accordance with the Helsinki Declaration and approved by the regional Medical Ethics Committee. All subjects gave their informed consent to the participation, and were informed that they were able to withdraw from the experiment at any time. All subjects received a gift-voucher at the price of 250 NOK (approximately USD 45, September 2011) as compensation for time loss.
Table 1 Demographic characteristics. Age Body mass index Regular physical exercise Smoking Married/cohabiting Divorced/separated Children living at home Age and body mass index in mean. N = 39.
24.8 (SD 3.9) years 20.9 (SD 3.4) 85.0% 15.0% 43.9% None 2.4%
2.2. Instruments Threshold and tolerance of pressure pain: Pressure pain was measured by a pressure algometer (Somedic, Sollentuna, Sweden), with a 1 cm2 diameter probe. The rate of pressure increase is standardized by visual feedback provided by the algometer and was set at 50 kPa/s. Pressure algometry was applied perpendicularly to the central part of the right masseter muscle and the sternum. The subjects were asked to raise their right index finger when the pressure became painful (threshold). Furthermore, the subjects terminated the test by pressing a button when the stimulation became so intense that they wanted to interrupt it (tolerance). Psychological responses to the pain stimulation: Immediately after each pain stimulation trial, the subjects rated pain intensity (VASS, VAS sensory) and discomfort (VAS-A, VAS affective) at threshold and tolerance [13]. This assessment was done by a continuous 100 mm electronic visual analogue scale (eVAS) with the anchors “no pain at all” at the left end and “the worst pain I can imagine” at the right end. The participants rated their pain experience in this way immediately after the pain stimulation trial. They were asked to rate the pain intensity at the threshold level, then pushed the button back to 0, and then rated the pain discomfort at the threshold level, and pushed the button back to 0. The rating of intensity and discomfort at the tolerance level was done in the same manner. Cardiovascular recordings: MAP and heart rate HR were continu˜ method (Ohmeda 2300, Englewood, ously monitored by the Penaz CO, USA). A cuff containing a photoelectronic sensor was attached to the middle phalanx of the third finger on the subjects’ left hand. The subjects’ hand was placed on a padded armrest in order to keep it positioned at the same level as the heart. Laser-doppler skin blood flux (LDF) changes were recorded with a Perimed Multichannel Laser Doppler System (PeriFlux 4001 Master, Perimed, Sweden). Miniature probes (Perimed, Sweden) were attached to the left m. masseter area and to the ventral side of the left thumb. This instrument expresses SBF in arbitrary units, proportional to the velocity and concentration of red blood cells moving in the superficial layer of the skin. Although it is customary to present SBF data as percentages of change from baseline, we report the arbitrary levels of flux to be able to perform withinsubject statistical analyses [4]. All signals were AD-converted, recorded, stored and reduced in a computer (Lab View, National Instruments, Austin, TX, USA). 2.3. Procedure The psychophysiological experiment took place in a sound attenuated and electromagnetically shielded laboratory with the temperature kept constant at 22 ◦ C. The subjects were seated in an upright position in a comfortable, upholstered chair. The experimenter described the function of the instruments and sensors, and was present in the room during the entire experiment. The subjects learned to interrupt the pain stimulation through one trial of pressure pain stimulation at both anatomical sites. The experiment lasted 30–40 min and consisted of randomized sequences of pressure stimulation at the masseter and sternum. All subjects went through three pressure stimulation trials at the right masseter muscle and three pressure stimulation trials at the sternum. Two-minute resting periods between each trial were provided to ascertain that the physiological responses returned to baseline before the next trial. 2.4. Data analysis All statistical analyses were made using SpSS, release 16 (SpSS Inc., Chicago, IL, USA). The correlations between the three measurements of pain threshold and tolerance at both sites were high (i.e.,
C. Mohn et al. / Scandinavian Journal of Pain 3 (2012) 165–169
coefficients in the .68–.89 range, p < .001), with no obvious differences between coefficients obtained from masseter and sternum data. The same pattern emerged from the correlations between corresponding measurements of VAS-S and VAS-A responses. The correlations between the CV response levels during the pain stimulation trials were even higher (i.e., coefficients in the .77–.98 range, p < .001). Hence, in order to increase the reliability of the measurements, aggregated pain and cardiovascular variables were calculated [18]. An aggregated mean of the three pressure pain stimulations at masseter and sternum served as measures of pain sensitivity. Likewise, aggregated means of MAP, HR, and SBF during the second minute of the three relaxation periods (each lasting 2 min) prior to pressure stimulations and MAP, HR, and SBF during the three stimulation trials were calculated. The MAP, HR, and SBF levels during pressure pain stimulation were averaged for the entire stimulation period, which did not last more than 10 s for any subject. Change variables of MAP (MAP) and HR (HR) were computed by subtracting the physiological levels during pre-pain relaxation from the levels reached during the pain stimulation. The distribution of data was studied by box plots, and tests of skewness and kurtosis. With the sample used in this study, results may be unduly influenced by extreme scorers. In some of the analyses, one or two outliers (i.e., scores 3 SD above or below the mean) were excluded. The number of subjects included in the analyses is indicated in each table. Differences in pressure and sternum pain sensitivity and VAS responses to the pain were tested with paired-samples t-tests. Changes in MAP, HR, and SBF from baseline relaxation to pain stimulation were tested with repeated measures ANOVAs with post hoc comparisons. Pearson’s correlation analyses were run of the relationship between pressure pain thresholds and associated VAS ratings, and between CV responses and pain sensitivity indices. Scatter plots were inspected to obtain a visual image of the correlations. Moreover, in order to provide statistical control for the possible influence of MAP and HR during pain stimulation on the relationship between CV responding and subsequent pain sensitivity [17], partial correlation analyses were conducted with pain-level MAP and HR partialled out.
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Table 2 Pressure pain sensitivity.
Pain threshold VAS-sensory VAS-affective Pain tolerance VAS-sensory VAS-affective
Masseter Mean (SD)
Sternum Mean (SD)
t
214.8 (71.7) 3.1 (1.3) 3.2 (1.5) 367.9 (130.9) 6.2 (1.6) 6.3 (1.8)
375.8 (123.1) 1.6 (0.7) 1.3 (0.7) 683.8 (263.9) 3.0 (0.9) 2.8 (1.0)
−10.48*** −0.35 (ns) 4.01*** −11.07*** 0.95 (ns) 2.87**
Baseline pain stimulation: the aggregated assessments. Measurement units: kPa (pressure pain), cm (VAS). t = significance test of the difference between masseter and sternum pain sensitivity. ns = non-significant (2-tailed). N = 37–39. ** p < .01. *** p < .001.
3.2. CV responding As evident from Table 3, statistically significant increases in MAP and HR and significant reductions in digital SBF were observed during pressure pain stimulation compared with baseline. A series of correlations were run between baseline CV responding and masseter pain sensitivity (Table 4). None of the coefficients that emerged from these analyses were statistically significant. Similar correlations were run between baseline CV responding and sternum pain sensitivity (Table 5). Again, none of the coefficients were statistically significant. The increases in MAP and HR during pain stimulation may influence the relationship between relaxation level CVR and subsequent pain sensitivity. Therefore, MAP and HR levels during pain stimulation were controlled for in partial correlation analyses of the relationship between resting level MAP and HR and pain. However, this procedure did not alter the above results in any statistically significant manner (data not shown). 4. Discussion The sternum pain threshold and level of tolerance were significantly higher than that of the masseter. Pressure pain stimulation of the masseter induced significant increases in MAP, HR, a decrease in digital SBF, and immediate affective distress. During sternum pressure stimulation a significant change in HR and digital SBF was observed. No support for the modulating role of CV responding on pressure pain sensitivity was found.
3. Results 4.1. Pressure pain sensitivity 3.1. Pressure pain sensitivity The masseter pain threshold and tolerance were significantly lower, but the VAS-A ratings higher, than the corresponding sternum stimulation levels (Table 2). No significant relationship emerged between pain threshold and tolerance stimulation levels on the one hand, and the associated VAS ratings on the other (correlations in the r .06–.13 range, all ns).
In this study, the sternum pain threshold and level of tolerance were significantly higher than that of the masseter. At the same time, the participants reported significantly more immediate affective distress to the masseter stimulation compared with the sternum pressure. This may explained by the fact that, compared with bone structures, muscular areas may be more sensitive to pain due to being differently innervated by nociceptive structures [19].
Table 3 Cardiovascular responding during pressure pain stimulation.
Relaxation Masseter pain Sternum pain F
MAP Mean (SD)
HR Mean (SD)
SBF face Mean (SD)
SBF finger Mean (SD)
107.6 (13.0) 110.9 (14.5)# 108.8 (13.1) 9.99***
66.7 (9.4) 72.7 (9.5)# 72.1 (9.3)# 58.92***
46.8 (41.2) 51.1 (45.0) 47.5 (42.0) 2.19 ns
204.5 (210.1) 116.5 (105.8)# 197.8 (199.5)# 18.22***
Pain stimulation: the aggregated assessments. MAP: mean arterial pressure, in mmHg. HR: hear rate, in beats/min. SBF: laser Doppler skin blood flux, in arbitrary units. F: significance test of the differences between relaxation and pain stimulation. ns = non-significant. N = 38–39. # Significant change from baseline. *** p < .001.
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Table 4 Correlations between CV responding and masseter pain sensitivity.
Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS
MAP resting .08 .06 .04 .11 −.02 −.05 MAP during pain stim. .04 .16 .10 .03 .03 −.02 MAP-pain −.08 .26 .16 −.17 .12 .07
HR resting .04 .28 .20 −.10 .25 .15 HR during pain stim. .01 .28 .21 −.08 .20 .12 HR-pain −.06 .02 .02 .05 −.11 −.05
Pearson’s correlation analyses of the relationship between MAP and HR, pain threshold and tolerance, and psychological experience of pain stimulation. Resting: the aggregated relaxation period. MAP-pain/HR-pain: change in CVR from the resting period to pain stimulation level. N = 39.
There were no significant associations between the pressure magnitude at threshold and tolerance level, and the corresponding VAS ratings of the pain. Moreover, the VAS ratings of affective distress at sternum pressure tolerance level was not even in the moderate range. Possibly, the method of assessing subjective responses to pain not during, but after, the pain stimulation may have biased the assessments. Alternatively, this is explainable in terms of the VAS method of assessing immediate subjective report of pain intensity and unpleasantness. Other methods, such as the use of numerical rating scales, seem to be more accurate as well as easier to understand [20]. In addition, the VAS method may loose sensitivity at high levels of pain stimulation [21]. 4.2. CV responding We have extended the results of electrocutaneous pain induced digital SBF changes [4] to pressure pain. The finding of nonsignificant changes in facial SBF coupled with significant digital vasoconstriction during pressure pain is at variance with our previous findings of facial vasodilatation and digital vasoconstriction in parallel during electrocutaneous pain [4]. These divergent results may, however, be due to the different qualities of pain these two types of stimulation induce. The physiological response pattern may vary as to whether the noxious stimulation is inflicted on a superficial (cutaneous) or deep (muscular) region [22]. However, in the absence of systematic studies of physiological response patterns to different types of pain, this suggestion remains somewhat speculative. 4.3. CV modulation of pain sensitivity Replicating a previous finding [12], the results from this study suggest no significant relationship between CV responding and pressure pain sensitivity in pain-free women. Several methodological aspects strengthen the validity of this finding. We controlled for menstrual cycle events, weekend-related changes in physiology, and the CV changes during pain stimulation. It may be suggested that pressure pain sensitivity is not as strongly related to CV responding as other types of pain stimulation, e.g., heat pain [10] or ischemic pain [11] have been found
Table 5 Correlations between CV responding and sternum pain sensitivity.
Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS
MAP resting .13 −.17 −.14 .12 −.27 −.23 MAP during pain stim. .11 −.12 −.10 .10 −.27 −.22 MAP-pain .05 .20 .17 −.01 −.07 −.07
HR resting −.14 .23 .29 −.29 .14 .26 HR during pain stim. −.10 .22 .26 −.24 .09 .24 HR-pain .21 −.07 −.08 .22 −.07 .04
Pearson’s correlation analyses of the relationship between MAP and HR, pain threshold and tolerance, and psychological experience of pain stimulation. Resting: the aggregated relaxation period. MAP-pain/HR-pain: change in CVR from the resting period to pain stimulation level. N = 39.
to be. Pressure stimulation triggers different nociceptors than do other types of stimulation. Mechanical stimuli such as pressure stimulation, can activate both cutaneous pressure afferents and deeper receptor systems, whereas heat pain, e.g., mainly activate receptors of the skin [22]. Moreover, pressure pain stimulation seems to exhibit a slower return to baseline [22]. The association between CV responding and the different psychophysical and sensory properties of various methods of pain stimulation is still unknown, although the stimulus-dependent nature of the relationship between CV responding and pain sensitivity has recently been suggested by others [23], who found no significant relationship between resting blood pressure and exercise induced muscle pain. Furthermore, pain from superficial and deep structures seem to trigger separate, integrated patterns of motor, autonomic, and antinociceptive responses [24], coordinated in different parts of the PAG. The dorsolateral PAG triggers a response pattern seen in active responding, i.e., increased arterial pressure, heart rate, and nonopioid analgesia. The ventrolateral PAG controls a response pattern consisting of behavioural inhibition, bradycardia, and opioid hyperalgesia [24]. Superficial pain may evoke irritation and attempts to terminate the stimulation. Pain from deep structures may be associated with rest and immobilization, as would benefit the organism during e.g., inflammation. The topic of defensive responses to different types of pain in humans awaits further elucidation. Sex differences may be a third explanatory factor. Our participants were women, and women may respond to acute pain and danger primarily through the endogenous opioid system, while men may respond primarily with increases in arterial pressure [10]. In a study of exercise-induced CV increases in pain-free, normotensive men [25], increases in systolic blood pressure was linked to decreases in finger pressure pain sensitivity. However, Bruehl et al. [26] reported that increases in systolic blood pressure was related to decreased ratings of finger pressure pain intensity in a sample consisting of both males and female also when sex was held constant in the analyses. Alternatively, the ethnic background of the participants in the different studies may be of importance. The present investigation as well as a previous study [12] employed Caucasian females only, whereas other relevant studies [10,11,26] were conducted with a sample of individuals of Afro-American and Asian as well as Caucasian background. Both pain perception and CV responding may
C. Mohn et al. / Scandinavian Journal of Pain 3 (2012) 165–169
show considerable variation across ethnic groups [27,28]. Moreover, the relationship between CV responding and pain sensitivity has been compared across different ethnic groups, with AfricanAmericans not displaying the significant associations between high systolic BP and low pain sensitivity reported in Caucasians [29,30].
4.4. Limitations When interpreting the results of the present study, certain limitations should be kept in mind. First, all the participants were women. Our findings may not generalize to the male population. Studies elucidating the subjective and physiological responses to pressure pain sensitivity in both men and women are clearly needed. Second, the sample size was relatively small. It is possible that some of the associations between CV parameters and pain sensitivity would have turned out statistically significant had the number of participants been higher. Therefore, the present results are tentative pending further investigations with a larger sample. Third, the present study was correlational. Thus, it was not possible to determine the direction of causality between CV responding and pain sensitivity. So far, it has not been possible to decide whether changes in pain sensitivity are causes or consequences of or non-causally related to CV responding. ˜ Fourth, we employed the Penaz method of measuring MAP and HR. Compared with brachial sphygmomanometry, the finger pressure method may underestimates absolute arterial pressure, but provides accurate measurements of pressure changes [31], which was one of the aims of the present study. Previous relevant studies [10,11,26] did not measure CV parameters continuously. Moreover, brachial sphygmomanometry may generate moderate pressure pain in the subjects, possibly causing interference with the assessment the experimental pain sensitivity that was the aim of our study. Nevertheless, it must be acknowledged that the MAP is influenced more by the diastolic than the systolic pressure, and the systolic pressure seems to be better able to predict pain sensitivity. That our measurements of MAP were not calibrated with pressure values obtained through sphygmomanometry is a limitation of the present study.
5. Conclusion and implications Healthy women seem to display higher pressure pain sensitivity at the masseter region relative to the sternum. Pressure pain stimulation was associated with significant changes in MAP, HR, and SBF, but do not seem to be modulated by CV responses. The validity of these findings is strengthened by our control for menstrual cycle events, weekend-related changes in physiology, and CV changes during pain stimulation. This study extends previous reports of SBF sensitivity to electrocutaneous pain into the field of pressure stimulation. Moreover, this study suggests that the often demonstrated association between high BP and low pain sensitivity may not apply to pressure pain specifically. Alternatively, this finding adds to the literature of gender differences in the relationship between CV responding and acute pain sensitivity in general.
Acknowledgements Mr Øystein Klingenberg, Mr Shahrooz Elka and Dr Dagfinn Matre were responsible for computer programming and maintenance of the electronic equipment. Ms Kjersti Shani Andersen provided technical assistance in the data-collection phase of the experiment.
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Original experimental
Cardiovascular responses to and modulation of pressure pain sensitivity in normotensive, pain-free women Christine Mohn a,b,∗ , Olav Vassend a , Stein Knardahl c a
Department of Psychology, University of Oslo, Norway Department of Research, Vestre Viken Hospital Trust, Norway c Department of Work Psychology and Physiology, The National Institute of Occupational Health, Oslo, Norway b
a r t i c l e
i n f o
Article history: Received 9 September 2011 Received in revised form 25 November 2011 Accepted 19 December 2011 Keywords: Blood pressure Cardiovascular responding Heart rate Pain sensitivity Pressure pain Skin blood flux
a b s t r a c t Background and purpose: The psychophysiological responses to and modulation of pressure pain stimulation are relatively new areas of investigation. The aims of the present study were to characterize subjective and cardiovascular (CV) responses to pressure pain stimulation, and to examine the relationship between CV responding and pain pressure pain sensitivity. Methods: Thirty-nine pain-free, normotensive women were included in the study and tested during the follicular phase of their menstrual cycles. Pain threshold and tolerance were recorded at the right masseter muscle and the sternum, and visual analogue scales (VAS) were used to rate both pain intensity (the sensory dimension) and discomfort (the affective dimension). Mean arterial pressure (MAP), heart rate (HR), and facial and digital skin blood flux (SBF) were registered continuously. Results: The pain threshold and tolerance were significantly higher at the sternum compared with the masseter, but the level of affective distress was higher at the masseter tolerance point. No associations emerged between pressure pain threshold and tolerance stimulation levels, and the corresponding VAS ratings. Pressure pain stimulation of the masseter induced significant increases in MAP, HR, and a decrease in digital SBF. During sternum pressure stimulation a significant change in HR and digital SBF was observed. There were no significant correlations between CV responding and pressure pain sensitivity. Conclusion: Healthy women seem to display higher pressure pain sensitivity at the masseter region relative to the sternum. Pressure pain stimulation was associated with significant changes in MAP, HR, and SBF, but was not modulated by CV responses. The validity of these findings is strengthened by our control for menstrual cycle events, weekend-related changes in physiology, and CV changes during pain stimulation. Implications: This study extends previous reports of SBF sensitivity to electrocutaneous pain into the field of pressure stimulation. Moreover, this study suggests that the often demonstrated association between high BP and low pain sensitivity may not apply to pressure pain specifically. Alternatively, this finding adds to the literature of gender differences in the relationship between CV responding and acute pain sensitivity in general. © 2011 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
1. Introduction The mulitidimensional nature of pain perception requires the assessment of several aspects of the pain experience. In order to obtain as complete a picture as possible of the individual’s pain experience, subjective and physiological responses to pain stimulation should be described in addition to the pain sensitivity thresholds. Compared with other stimulation methods such as
DOI of refers to article: 10.1016/j.sjpain.2012.02.005. ∗ Corresponding author at: Department of Psychology, University of Oslo, PO Box 1094, Blindern, 0317 Oslo, Norway. Tel.: +47 22 84 51 15; fax: +47 22 84 50 01. E-mail address: [email protected] (C. Mohn).
thermal pain [1], the Subjective and physiological responses to pressure pain are not well known. As substantiated in previous research, measurements of skin blood flux (SBF) may provide valuable indicators of autonomic nervous system (ANS) activity during psychological challenges [2,3]. Moreover, electrocutaneous pain stimulation seems to trigger increases in facial SBF as well as decreases in digital SBF [4,5]. Similar orofacial SBF changes during pain stimulation have been documented by Kemppainen et al. [6,7]. However, as the research on SBF during pain in humans is relatively new, few studies of SBF responses to experimental pain exist. In both normotensive and hypertensive individuals, elevations of arterial pressure may be associated with reduced sensitivity to painful stimuli [8,9]. Although the CV–pain relationship appears
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attenuated or absent altogether in chronic pain groups [10,11], we have recently found that elevated mean arterial pressure (MAP) was associated with reduced pain sensitivity in women with TMD, but not in the pain-free control group [12]. That study employed electrocutaneous and pressure stimulation, whereas the others [10,11] assessed thermal and ischemic pain. Different pain stimulation methods are likely to induce different behavioural, autonomic, and antinociceptive responses [4,13,14]. Moreover, in our previous study of electrocutaneous pain [12] we did not control for certain factors that may modulate pain sensitivity, CV responding or the relationship between those two. These include hormonal effects of menstrual cycle events on pain sensitivity [15] and weekend-related changes in physiology [16]. In addition, the fact that pain stimulation may generate BP increases in its own right could confound the relationship between baseline CVR and subsequent pain sensitivity assessments [17]. Therefore, we control for these factors in the present study. The general rationale behind this study was to extend previous work on psychological and physiological responding during experimental pain in general to pressure pain stimulation in particular. The primary aim is to characterize subjective and physiological responses, including facial and digital SBF, to pressure pain stimulation. The secondary aim is to examine the relationship between CV responses and pressure pain sensitivity while controlling for possible confounders.
2. Materials and methods 2.1. Subjects Thirty-nine Caucasian women (see Table 1 for demographic characteristics) were recruited among graduate students of medicine and psychology of the University of Oslo via the students’ mailing lists. Inclusion criteria were age between 20 and 50 years, and ability to speak and understand spoken and written Norwegian. Exclusion criteria (self reported) were known hypertension, chronic pain, general chronic somatic or mental health problems, pregnancy, and use of regular medication apart from oral contraceptives. The subjects were instructed to refrain from drinking alcohol the last 12 h before the experiment, and to avoid drinking tea or coffee, having large meals, and exercising the last 3 h before the experiment. All subjects were tested in the follicular phase of their menstrual cycle in order to rule out pain sensitivity effects of different endogenous reproductive hormone levels [15]. In order to avoid physiological effects of excessive alcohol and/or tobacco consumption during weekends, no experimental testing took place on Mondays [16]. The present study was conducted in accordance with the Helsinki Declaration and approved by the regional Medical Ethics Committee. All subjects gave their informed consent to the participation, and were informed that they were able to withdraw from the experiment at any time. All subjects received a gift-voucher at the price of 250 NOK (approximately USD 45, September 2011) as compensation for time loss.
Table 1 Demographic characteristics. Age Body mass index Regular physical exercise Smoking Married/cohabiting Divorced/separated Children living at home Age and body mass index in mean. N = 39.
24.8 (SD 3.9) years 20.9 (SD 3.4) 85.0% 15.0% 43.9% None 2.4%
2.2. Instruments Threshold and tolerance of pressure pain: Pressure pain was measured by a pressure algometer (Somedic, Sollentuna, Sweden), with a 1 cm2 diameter probe. The rate of pressure increase is standardized by visual feedback provided by the algometer and was set at 50 kPa/s. Pressure algometry was applied perpendicularly to the central part of the right masseter muscle and the sternum. The subjects were asked to raise their right index finger when the pressure became painful (threshold). Furthermore, the subjects terminated the test by pressing a button when the stimulation became so intense that they wanted to interrupt it (tolerance). Psychological responses to the pain stimulation: Immediately after each pain stimulation trial, the subjects rated pain intensity (VASS, VAS sensory) and discomfort (VAS-A, VAS affective) at threshold and tolerance [13]. This assessment was done by a continuous 100 mm electronic visual analogue scale (eVAS) with the anchors “no pain at all” at the left end and “the worst pain I can imagine” at the right end. The participants rated their pain experience in this way immediately after the pain stimulation trial. They were asked to rate the pain intensity at the threshold level, then pushed the button back to 0, and then rated the pain discomfort at the threshold level, and pushed the button back to 0. The rating of intensity and discomfort at the tolerance level was done in the same manner. Cardiovascular recordings: MAP and heart rate HR were continu˜ method (Ohmeda 2300, Englewood, ously monitored by the Penaz CO, USA). A cuff containing a photoelectronic sensor was attached to the middle phalanx of the third finger on the subjects’ left hand. The subjects’ hand was placed on a padded armrest in order to keep it positioned at the same level as the heart. Laser-doppler skin blood flux (LDF) changes were recorded with a Perimed Multichannel Laser Doppler System (PeriFlux 4001 Master, Perimed, Sweden). Miniature probes (Perimed, Sweden) were attached to the left m. masseter area and to the ventral side of the left thumb. This instrument expresses SBF in arbitrary units, proportional to the velocity and concentration of red blood cells moving in the superficial layer of the skin. Although it is customary to present SBF data as percentages of change from baseline, we report the arbitrary levels of flux to be able to perform withinsubject statistical analyses [4]. All signals were AD-converted, recorded, stored and reduced in a computer (Lab View, National Instruments, Austin, TX, USA). 2.3. Procedure The psychophysiological experiment took place in a sound attenuated and electromagnetically shielded laboratory with the temperature kept constant at 22 ◦ C. The subjects were seated in an upright position in a comfortable, upholstered chair. The experimenter described the function of the instruments and sensors, and was present in the room during the entire experiment. The subjects learned to interrupt the pain stimulation through one trial of pressure pain stimulation at both anatomical sites. The experiment lasted 30–40 min and consisted of randomized sequences of pressure stimulation at the masseter and sternum. All subjects went through three pressure stimulation trials at the right masseter muscle and three pressure stimulation trials at the sternum. Two-minute resting periods between each trial were provided to ascertain that the physiological responses returned to baseline before the next trial. 2.4. Data analysis All statistical analyses were made using SpSS, release 16 (SpSS Inc., Chicago, IL, USA). The correlations between the three measurements of pain threshold and tolerance at both sites were high (i.e.,
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coefficients in the .68–.89 range, p < .001), with no obvious differences between coefficients obtained from masseter and sternum data. The same pattern emerged from the correlations between corresponding measurements of VAS-S and VAS-A responses. The correlations between the CV response levels during the pain stimulation trials were even higher (i.e., coefficients in the .77–.98 range, p < .001). Hence, in order to increase the reliability of the measurements, aggregated pain and cardiovascular variables were calculated [18]. An aggregated mean of the three pressure pain stimulations at masseter and sternum served as measures of pain sensitivity. Likewise, aggregated means of MAP, HR, and SBF during the second minute of the three relaxation periods (each lasting 2 min) prior to pressure stimulations and MAP, HR, and SBF during the three stimulation trials were calculated. The MAP, HR, and SBF levels during pressure pain stimulation were averaged for the entire stimulation period, which did not last more than 10 s for any subject. Change variables of MAP (MAP) and HR (HR) were computed by subtracting the physiological levels during pre-pain relaxation from the levels reached during the pain stimulation. The distribution of data was studied by box plots, and tests of skewness and kurtosis. With the sample used in this study, results may be unduly influenced by extreme scorers. In some of the analyses, one or two outliers (i.e., scores 3 SD above or below the mean) were excluded. The number of subjects included in the analyses is indicated in each table. Differences in pressure and sternum pain sensitivity and VAS responses to the pain were tested with paired-samples t-tests. Changes in MAP, HR, and SBF from baseline relaxation to pain stimulation were tested with repeated measures ANOVAs with post hoc comparisons. Pearson’s correlation analyses were run of the relationship between pressure pain thresholds and associated VAS ratings, and between CV responses and pain sensitivity indices. Scatter plots were inspected to obtain a visual image of the correlations. Moreover, in order to provide statistical control for the possible influence of MAP and HR during pain stimulation on the relationship between CV responding and subsequent pain sensitivity [17], partial correlation analyses were conducted with pain-level MAP and HR partialled out.
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Table 2 Pressure pain sensitivity.
Pain threshold VAS-sensory VAS-affective Pain tolerance VAS-sensory VAS-affective
Masseter Mean (SD)
Sternum Mean (SD)
t
214.8 (71.7) 3.1 (1.3) 3.2 (1.5) 367.9 (130.9) 6.2 (1.6) 6.3 (1.8)
375.8 (123.1) 1.6 (0.7) 1.3 (0.7) 683.8 (263.9) 3.0 (0.9) 2.8 (1.0)
−10.48*** −0.35 (ns) 4.01*** −11.07*** 0.95 (ns) 2.87**
Baseline pain stimulation: the aggregated assessments. Measurement units: kPa (pressure pain), cm (VAS). t = significance test of the difference between masseter and sternum pain sensitivity. ns = non-significant (2-tailed). N = 37–39. ** p < .01. *** p < .001.
3.2. CV responding As evident from Table 3, statistically significant increases in MAP and HR and significant reductions in digital SBF were observed during pressure pain stimulation compared with baseline. A series of correlations were run between baseline CV responding and masseter pain sensitivity (Table 4). None of the coefficients that emerged from these analyses were statistically significant. Similar correlations were run between baseline CV responding and sternum pain sensitivity (Table 5). Again, none of the coefficients were statistically significant. The increases in MAP and HR during pain stimulation may influence the relationship between relaxation level CVR and subsequent pain sensitivity. Therefore, MAP and HR levels during pain stimulation were controlled for in partial correlation analyses of the relationship between resting level MAP and HR and pain. However, this procedure did not alter the above results in any statistically significant manner (data not shown). 4. Discussion The sternum pain threshold and level of tolerance were significantly higher than that of the masseter. Pressure pain stimulation of the masseter induced significant increases in MAP, HR, a decrease in digital SBF, and immediate affective distress. During sternum pressure stimulation a significant change in HR and digital SBF was observed. No support for the modulating role of CV responding on pressure pain sensitivity was found.
3. Results 4.1. Pressure pain sensitivity 3.1. Pressure pain sensitivity The masseter pain threshold and tolerance were significantly lower, but the VAS-A ratings higher, than the corresponding sternum stimulation levels (Table 2). No significant relationship emerged between pain threshold and tolerance stimulation levels on the one hand, and the associated VAS ratings on the other (correlations in the r .06–.13 range, all ns).
In this study, the sternum pain threshold and level of tolerance were significantly higher than that of the masseter. At the same time, the participants reported significantly more immediate affective distress to the masseter stimulation compared with the sternum pressure. This may explained by the fact that, compared with bone structures, muscular areas may be more sensitive to pain due to being differently innervated by nociceptive structures [19].
Table 3 Cardiovascular responding during pressure pain stimulation.
Relaxation Masseter pain Sternum pain F
MAP Mean (SD)
HR Mean (SD)
SBF face Mean (SD)
SBF finger Mean (SD)
107.6 (13.0) 110.9 (14.5)# 108.8 (13.1) 9.99***
66.7 (9.4) 72.7 (9.5)# 72.1 (9.3)# 58.92***
46.8 (41.2) 51.1 (45.0) 47.5 (42.0) 2.19 ns
204.5 (210.1) 116.5 (105.8)# 197.8 (199.5)# 18.22***
Pain stimulation: the aggregated assessments. MAP: mean arterial pressure, in mmHg. HR: hear rate, in beats/min. SBF: laser Doppler skin blood flux, in arbitrary units. F: significance test of the differences between relaxation and pain stimulation. ns = non-significant. N = 38–39. # Significant change from baseline. *** p < .001.
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Table 4 Correlations between CV responding and masseter pain sensitivity.
Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS
MAP resting .08 .06 .04 .11 −.02 −.05 MAP during pain stim. .04 .16 .10 .03 .03 −.02 MAP-pain −.08 .26 .16 −.17 .12 .07
HR resting .04 .28 .20 −.10 .25 .15 HR during pain stim. .01 .28 .21 −.08 .20 .12 HR-pain −.06 .02 .02 .05 −.11 −.05
Pearson’s correlation analyses of the relationship between MAP and HR, pain threshold and tolerance, and psychological experience of pain stimulation. Resting: the aggregated relaxation period. MAP-pain/HR-pain: change in CVR from the resting period to pain stimulation level. N = 39.
There were no significant associations between the pressure magnitude at threshold and tolerance level, and the corresponding VAS ratings of the pain. Moreover, the VAS ratings of affective distress at sternum pressure tolerance level was not even in the moderate range. Possibly, the method of assessing subjective responses to pain not during, but after, the pain stimulation may have biased the assessments. Alternatively, this is explainable in terms of the VAS method of assessing immediate subjective report of pain intensity and unpleasantness. Other methods, such as the use of numerical rating scales, seem to be more accurate as well as easier to understand [20]. In addition, the VAS method may loose sensitivity at high levels of pain stimulation [21]. 4.2. CV responding We have extended the results of electrocutaneous pain induced digital SBF changes [4] to pressure pain. The finding of nonsignificant changes in facial SBF coupled with significant digital vasoconstriction during pressure pain is at variance with our previous findings of facial vasodilatation and digital vasoconstriction in parallel during electrocutaneous pain [4]. These divergent results may, however, be due to the different qualities of pain these two types of stimulation induce. The physiological response pattern may vary as to whether the noxious stimulation is inflicted on a superficial (cutaneous) or deep (muscular) region [22]. However, in the absence of systematic studies of physiological response patterns to different types of pain, this suggestion remains somewhat speculative. 4.3. CV modulation of pain sensitivity Replicating a previous finding [12], the results from this study suggest no significant relationship between CV responding and pressure pain sensitivity in pain-free women. Several methodological aspects strengthen the validity of this finding. We controlled for menstrual cycle events, weekend-related changes in physiology, and the CV changes during pain stimulation. It may be suggested that pressure pain sensitivity is not as strongly related to CV responding as other types of pain stimulation, e.g., heat pain [10] or ischemic pain [11] have been found
Table 5 Correlations between CV responding and sternum pain sensitivity.
Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS Pain threshold Sensory VAS Affective VAS Pain tolerance Sensory VAS Affective VAS
MAP resting .13 −.17 −.14 .12 −.27 −.23 MAP during pain stim. .11 −.12 −.10 .10 −.27 −.22 MAP-pain .05 .20 .17 −.01 −.07 −.07
HR resting −.14 .23 .29 −.29 .14 .26 HR during pain stim. −.10 .22 .26 −.24 .09 .24 HR-pain .21 −.07 −.08 .22 −.07 .04
Pearson’s correlation analyses of the relationship between MAP and HR, pain threshold and tolerance, and psychological experience of pain stimulation. Resting: the aggregated relaxation period. MAP-pain/HR-pain: change in CVR from the resting period to pain stimulation level. N = 39.
to be. Pressure stimulation triggers different nociceptors than do other types of stimulation. Mechanical stimuli such as pressure stimulation, can activate both cutaneous pressure afferents and deeper receptor systems, whereas heat pain, e.g., mainly activate receptors of the skin [22]. Moreover, pressure pain stimulation seems to exhibit a slower return to baseline [22]. The association between CV responding and the different psychophysical and sensory properties of various methods of pain stimulation is still unknown, although the stimulus-dependent nature of the relationship between CV responding and pain sensitivity has recently been suggested by others [23], who found no significant relationship between resting blood pressure and exercise induced muscle pain. Furthermore, pain from superficial and deep structures seem to trigger separate, integrated patterns of motor, autonomic, and antinociceptive responses [24], coordinated in different parts of the PAG. The dorsolateral PAG triggers a response pattern seen in active responding, i.e., increased arterial pressure, heart rate, and nonopioid analgesia. The ventrolateral PAG controls a response pattern consisting of behavioural inhibition, bradycardia, and opioid hyperalgesia [24]. Superficial pain may evoke irritation and attempts to terminate the stimulation. Pain from deep structures may be associated with rest and immobilization, as would benefit the organism during e.g., inflammation. The topic of defensive responses to different types of pain in humans awaits further elucidation. Sex differences may be a third explanatory factor. Our participants were women, and women may respond to acute pain and danger primarily through the endogenous opioid system, while men may respond primarily with increases in arterial pressure [10]. In a study of exercise-induced CV increases in pain-free, normotensive men [25], increases in systolic blood pressure was linked to decreases in finger pressure pain sensitivity. However, Bruehl et al. [26] reported that increases in systolic blood pressure was related to decreased ratings of finger pressure pain intensity in a sample consisting of both males and female also when sex was held constant in the analyses. Alternatively, the ethnic background of the participants in the different studies may be of importance. The present investigation as well as a previous study [12] employed Caucasian females only, whereas other relevant studies [10,11,26] were conducted with a sample of individuals of Afro-American and Asian as well as Caucasian background. Both pain perception and CV responding may
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show considerable variation across ethnic groups [27,28]. Moreover, the relationship between CV responding and pain sensitivity has been compared across different ethnic groups, with AfricanAmericans not displaying the significant associations between high systolic BP and low pain sensitivity reported in Caucasians [29,30].
4.4. Limitations When interpreting the results of the present study, certain limitations should be kept in mind. First, all the participants were women. Our findings may not generalize to the male population. Studies elucidating the subjective and physiological responses to pressure pain sensitivity in both men and women are clearly needed. Second, the sample size was relatively small. It is possible that some of the associations between CV parameters and pain sensitivity would have turned out statistically significant had the number of participants been higher. Therefore, the present results are tentative pending further investigations with a larger sample. Third, the present study was correlational. Thus, it was not possible to determine the direction of causality between CV responding and pain sensitivity. So far, it has not been possible to decide whether changes in pain sensitivity are causes or consequences of or non-causally related to CV responding. ˜ Fourth, we employed the Penaz method of measuring MAP and HR. Compared with brachial sphygmomanometry, the finger pressure method may underestimates absolute arterial pressure, but provides accurate measurements of pressure changes [31], which was one of the aims of the present study. Previous relevant studies [10,11,26] did not measure CV parameters continuously. Moreover, brachial sphygmomanometry may generate moderate pressure pain in the subjects, possibly causing interference with the assessment the experimental pain sensitivity that was the aim of our study. Nevertheless, it must be acknowledged that the MAP is influenced more by the diastolic than the systolic pressure, and the systolic pressure seems to be better able to predict pain sensitivity. That our measurements of MAP were not calibrated with pressure values obtained through sphygmomanometry is a limitation of the present study.
5. Conclusion and implications Healthy women seem to display higher pressure pain sensitivity at the masseter region relative to the sternum. Pressure pain stimulation was associated with significant changes in MAP, HR, and SBF, but do not seem to be modulated by CV responses. The validity of these findings is strengthened by our control for menstrual cycle events, weekend-related changes in physiology, and CV changes during pain stimulation. This study extends previous reports of SBF sensitivity to electrocutaneous pain into the field of pressure stimulation. Moreover, this study suggests that the often demonstrated association between high BP and low pain sensitivity may not apply to pressure pain specifically. Alternatively, this finding adds to the literature of gender differences in the relationship between CV responding and acute pain sensitivity in general.
Acknowledgements Mr Øystein Klingenberg, Mr Shahrooz Elka and Dr Dagfinn Matre were responsible for computer programming and maintenance of the electronic equipment. Ms Kjersti Shani Andersen provided technical assistance in the data-collection phase of the experiment.
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