فشار خون بالا و حساسیت به درد: اثرات جنسیت و واکنش پذیری قلبی عروقی

Abstract Repeatedly, hypertensives have been found to appraise physical stressors as less aversive than normotensives. The main aim of the present study was to examine the effects of gender and cardiovascular reactivity in the relationship between hypertension and appraisal of pain. Forty-two unmedicated hypertensives and 21 normotensive controls of both genders were exposed to an electric current stimulus, while various cardiovascular parameters and pre-stressor anxiety were measured. In general, hypertensive women, but not men, showed diminished pain sensitivity compared to their normotensive counterparts. When the analyses were repeated with controlling for cardiovascular reactivity, the between-group effects were no longer significant. The results indicate that (i) profound gender differences exist in hypertension-related pain sensitivity and (ii) these effects seem to be mediated, at least partly, by cardiovascular reactivity.

. Introduction Repeatedly, elevated blood pressure has been found to be associated with diminished sensitivity to painful physical stimulation. This has been demonstrated for electrical (Zamir et al., 1980), thermal (Sheps et al., 1992), and finger pressure pain stimulation techniques (Bruehl et al., 1992). Moreover, also in normotensive samples, an inverse relationship between blood pressure and perceived painfulness of physical stressors has been obtained (Bruehl et al., 1992). This inverse relationship has been found in both between-subjects (Zamir and Shuber, 1980) and within-subjects designs (Dworkin et al., 1979), in animal (Randich and Maixner, 1984) as well as in human studies (Sheps et al., 1992). However, until now, most studies on the relationship between cardiovascular activity and pain sensitivity have been conducted on male subjects (Zamir and Shuber, 1980, Elbert et al., 1988, Bruehl et al., 1992 and Sheps et al., 1992). The few studies conducted on both genders have revealed conflicting results. For instance, Fillingim and Maixner (1996) found an inverse association between resting systolic blood pressure (SBP) and pain sensitivity only in men, not in women. In another study, partially a reverse effect was found: resting SBP and blood pressure reactivity to a speech task were associated with lower pain sensitivity to a thermal stimulus only in women (Bragdon et al., 1994). The latter outcome is in agreement with an investigation showing that parental history of hypertension was related to lower retrospective pain ratings after venipuncture in women, not in men (France et al., 1994). In light of these discrepancies, in the present study, the primary aim was to examine gender differences in various pain conditions more systematically. In most studies showing diminished pain sensitivity in hypertensives, subjects had little control over the physically aversive stimuli (Zamir and Shuber, 1980, Bruehl et al., 1992 and Sheps et al., 1992). Therefore, it may be hypothesized that having little control over a stressor moderates the relationship between hypertension and pain sensitivity. For instance, Rau et al. (1994) argued that their failure to find differences in pain threshold between hypertensives and normotensives may be attributed to the fact that the participants had some feeling of control over the stimulus: as soon as the pain threshold was reached, the stimulation was stopped by the participants. Therefore, in the present study, electric stimulation was used both in an externally controlled condition, in which stimulus intensity was controlled automatically by a computer and a self-controlled condition, in which the participants themselves had full control over stimulus intensity. Furthermore, it has been proposed that stimulus duration and frequency may be important variables influencing the pathways involved in antinociception (Terman et al., 1984). For example, it has been suggested that in exposure to short-duration aversive stimuli, an opioid system may be involved, whereas non-opioid mechanisms may predominate when the organism is exposed to stressors of long-duration (Terman et al., 1984). It is conceivable that involvement of qualitatively different systems might also influence the degree of antinociception (Randich and Maixner, 1984). In the present study, the externally controlled condition included two subconditions: one with only a few slow, relatively long stimuli and one in which more frequent, but short stimuli were presented. Furthermore, it was examined whether appraisal of pain would be related to indices of cardiovascular reactivity, a putative risk factor or marker for hypertension ( Manuck et al., 1990). Bruehl et al. (1992) demonstrated that SBP reactivity during a finger pressure stimulus trial was positively related to pain ratings, in contrast to negative correlations with baseline SBP. Similar results were obtained in another study ( Peckerman et al., 1991). However, France and Stewart (1995) recently found that heart rate and blood pressure reactivity to a cold pressor test were negatively related to pain ratings obtained during an ischemic pain stressor. All three studies were conducted on healthy young male normotensive subjects, indicating that sample characteristics probably did not account for the difference. Bruehl et al. (1992) attributed their effect to pain-induced arousal or anticipatory anxiety on blood pressure. France and Stewart (1995) argued that exaggerated general cardiovascular responsiveness to stressors may be associated with diminished pain appraisal, possibly via baroreceptor stimulation ( Dworkin et al., 1979). Although occasionally negative findings were obtained with respect to the role of baroreceptor stimulation ( France et al., 1991 and Rau et al., 1994), the majority of the evidence strongly suggests mediation by the baroreceptors: links have been reported between afferent pathways of the baroreceptors to central nervous system areas involved in pain perception ( Randich and Maixner, 1984) and also direct associations have been found between experimental baroreceptor stimulation and diminished pain sensitivity ( Dworkin et al., 1979 and Elbert et al., 1988). In the literature on hypertension and self-reported stress, diagnosis or awareness of hypertension has often been regarded as an important confounding variable. Whereas diagnosed hypertensives frequently report more medical symptoms (Monk, 1980 and Zonderman et al., 1986) and more life stress (Myers and Miles, 1981) than individuals with normal blood pressures, undiagnosed or unaware hypertensives sometimes report even less medical symptoms (Davies, 1970 and Kidson, 1973) and life stress (Linden and Feuerstein, 1983 and Theorell et al., 1986) than normotensive persons. Although the baroreceptor mechanism—which has been suggested to be responsible for hypertension-related effects on pain appraisal (Dworkin et al., 1979 and Randich and Maixner, 1984)—is expected to be equally effective in aware and unaware hypertensives (Dworkin et al., 1979), in order to control for any potential confounding effect of hypertension awareness/diagnosis, in the present study both aware and unaware hypertensives were included. The main hypotheses were: (a) hypertensives have higher pain threshold and tolerance levels, especially in conditions with limited-control, (b) hypertensives show greater cardiovascular reactivity during the task, and (c) the relationships mentioned in (a) are (partly) mediated by the cardiovascular response differences between the groups. In addition, given the earlier inconsistencies in the research outcomes, no specific gender differences were anticipated.

Results Because the two hypertensive groups exhibited very similar scores for most variables regarding pain sensitivity, pre-stressor anxiety, and cardiovascular parameters, data of these two groups were pooled in all analyses. The only clear difference between the hypertensive groups was revealed during analyses of the pre-experiment mood items. Only one significant effect emerged, concerning reported Irritation During the Day [F(2, 55)=3.58, p<0.05], indicating that aware hypertensives experienced the most feelings of irritation during the day (M=2.67, Full-size image (<1 K)=1.24), normotensives intermediate levels (M=2.00, Full-size image (<1 K)=1.12), and unaware hypertensives being the least irritated (M=1.76, Full-size image (<1 K)=0.83). 3.1. Pain sensitivity In each group, three persons were suspected to potentially have had cream leakage between the two parts of the electrode, as indexed by both extremely low resistance (below 0.5 kΩ) and reaching repeatedly the maximum possible current intensity during the trials. These participants were excluded from the analyses2. For the means and standard deviations of the groups, see Table 2. Table 2. Pain sensitivity: means (mA) and standard deviationsa Normotensives Hypertensives Pain Variable Women (n=6–7) Men (n=10) Women (n=16) Men (n=16) F(p) Pain threshold Condition 1 1.64 (0.74) 2.74 (0.78) 2.25 (0.89) 2.32 (0.56) 4.34* Condition 2 1.65 (0.76) 3.05 (1.09) 2.47 (0.94) 2.79 (0.86) 2.84# Condition 3 2.66 (1.12) 4.44 (0.93) 3.82 (1.04) 4.56 (0.91) Pain tolerance Condition 1 2.28 (1.18) 3.74 (0.86) 3.00 (1.11) 3.59 (0.89) 3.77# Condition 2 2.17 (1.04) 4.02 (1.09) 3.28 (1.17) 3.79 (1.06) a Condition 1, self-controlled intensity; Condition 2, automatic intensity control (slow rise); Condition 3, automatic intensity control (fast rise). Only (marginally) significant effects involving Group are shown: Group×Gender interaction (italic fonts) and Group×Condition interaction (normal fonts). *p<0.05; # p<0.08. Table options 3.2. Pain threshold In the analysis on pain threshold, two main effects emerged. First, a Condition main effect [F(2, 42)=101.74, p<0.001] indicated that the pain thresholds became higher with later conditions. A Gender main effect [F(1, 42)=10.41, p<0.01] revealed that men had higher thresholds than women. No Group main effect was obtained [F(1,42)=1.95, p<0.10]. However, the Group×Gender interaction appeared significant [F(1, 42)=4.34, p<0.05]. Post hoc analyses showed that while no effects were present for men (p>0.10), among women, hypertensives exhibited higher pain thresholds than normotensive individuals [F(1, 18)=4.73, p<0.05]. Finally, a trend for a Group×Condition interaction [F(2, 42)=2.84, p=0.07] reflected the tendency for hypertensives to have higher pain thresholds than normotensives in the last condition only. No Gender×Condition interaction, nor the three-way interaction (Group×Gender×Condition) emerged. 3.3. Pain tolerance Slightly different results were obtained for pain tolerance. The Condition main effect was only a trend now [F(1, 44)=3.43, p=0.07], pointing at the tendency for higher tolerances in the second condition than in the first. Men tolerated higher intensities than women [F(1, 43)=10.75, p<0.01]. Again, no Group main effect was obtained [F(1, 43)=1.93, p>0.10]. The Group×Gender interaction approached significance [F(1, 43)=3.77, p=0.06]. Post hoc analyses showed that, although no differences existed between the male groups (p>0.10), female hypertensives tended to tolerate higher intensities than female normotensives [F(1, 19)=4.26, p=0.053]. No other interaction effects were obtained. 3.4. Cardiovascular measures 3.4.1. Baseline First, baseline differences between the groups were examined by means of 2 (Group)×2 (Gender) analyses of variance. These ANOVAs were based on overall means across all rest periods. None of the variables showed a Group×Gender interaction or a Gender main effect (all ps>0.10). There was, however, a significant main effect of Group on IBI [F(1, 52)=4.71, p<0.05], showing higher resting heart rates in hypertensives, compared with normotensives: 784.9 ms (SD=105.6) versus 852.5 ms (SD=115.7), respectively. As one may expect, large differences were found between the groups on SBP [150.4 mmHg (19.2) versus 118.1 mmHg (9.8), F(1, 52)=44.43, p<0.001] and DBP [99.6 mmHg (16.8) versus 76.6 mmHg (7.5), F(1, 52)=30.74, p<0.001]. Hypertensives also exhibited smaller baroreflex slopes [5.73 ms/mmHg (2.62) versus 7.96 ms/mmHg (3.06), F(1, 49)=7.63, p<0.01]. There were no significant differences between the groups on the number of sequences [3.92 (2.33) for hypertensives and 4.95 (2.00) for normotensives, F(1, 49)=2.57, p>0.10]. 3.4.2. Reactivity No three-way interaction (Group×Gender×Condition) emerged for any of the cardiovascular reactivity variables (see Table 3). For IBI, the only significant effect was a main effect of Condition [F(2, 43)=5.28, p<0.01], indicating heart rates becoming slower in the later conditions. With respect to blood pressure, men showed larger responses than women [F(1, 44)=13.03, p=0.001 for SBP and F(1, 44)=14.46, p<0.001 for DBP], and hypertensives reacted more strongly than their normotensive counterparts [F(1, 44)=6.13, p<0.05 for SBP and F(1, 44)=5.31, p<0.05 for DBP]. Besides these main effects, no other effects were significant for blood pressure. Only a trend for SBP towards a smaller difference between the hypertensives and normotensives in the second condition emerged [F(2, 43)=2.79, p=0.07]. For the baroreflex reactivity, only two effects were significant. First, a Gender×Condition interaction for the slope [F(2, 31)=6.31, p<0.01] showed that in the first and third condition, men enhanced their baroreflex sensitivity more than women, whereas in the second condition the reverse was true. Finally, a Condition main effect [F(2, 31)=13.30, p<0.001], reflected the slopes being the lowest in the second condition and highest in the third condition. Table 3. Cardiovascular reactivity: means and standard deviationsa Normotensives Hypertensives Variable Women (n=5–8) Men (n=10–11) Women (n=10–18) Men (n=11–19) F (p) IBI Cond 1 7.0 (40.3) −4.5 (42.0) −4.9 (35.3) 6.1 (26.2) 5.28c** Cond 2 11.4 (22.2) 5.5 (41.4) 2.8 (35.9) 15.5 (26.7) Cond 3 16.6 (28.1) 8.1 (35.1) 9.9 (38.5) 19.0 (26.7) SBP Cond 1 10.8 (8.2) 21.4 (6.9) 20.2 (9.6) 25.5 (6.6) 6.13g* Cond 2 13.3 (8.2) 23.5 (6.9) 19.8 (8.5) 25.5 (7.8) 2.79g×c# Cond 3 13.0 (9.7) 22.9 (8.5) 20.1 (8.1) 27.9 (8.4) 13.0s*** DBP Cond 1 5.0 (3.8) 9.4 (3 4) 8.1 (4.7) 13.0 (4.0) 5.31g* Cond 2 5.3 (3.4) 10.3 (3.7) 7.5 (8.7) 12.5 (5.1) 14.5s*** Cond 3 6.0 (3.8) 9.9 (3 4) 8.3 (4 9) 13.8 (5.7) Slope Cond 1 0.34 (1.92) 0.69 (1.81) −0.10 (1.30) 0.89 (1.54) 13.3c*** Cond 2 0.40 (1.32) −0.58 (2.07) −0.17 (0.88) −0.38 (1.83) 6.31s×c** Cond 3 1.13 (2.35) 0.50 (2.99) 0.05 (0.99) 1.86 (3.04) a Cond, Condition (see note Table 2). Slope, regression slope of the up-sequences (in ms/mmHg). *p<0.05, **p<0.01, ***p<0.001, # 0.05<p<0.09. c, Condition main effect; g, Group main effect; s, Gender main effect; g×c, Group×Condition interaction; s×c, Gender×Condition interaction. Table options 3.5. Role of cardiovascular reactivity and anxiety in pain sensitivity To assess the role of the cardiovascular reactivity parameters in pain sensitivity, first, Pearson’s product-moment correlation coefficients were computed. All coefficients regarding correlations between blood pressure and both pain threshold and pain tolerance were positive, but only in the following cases significance was (nearly) reached: pain threshold in the third condition with SBP and DBP reactivity during that task (r=0.30, p<0.05 and r=0.34, p<0.05, respectively) and pain tolerance with DBP reactivity in the first condition (r=0.25, p=0.088). No other correlations, including those with baroreceptor activity, emerged. The analyses on group differences regarding pain sensitivity described above were performed again with those cardiovascular reactivity variables as covariates, which showed some (r>0.20; p<0.10) association with the pain or appraisal measures. This involved only SBP and DBP. However, when meeting the parallelism assumption was tested, it was found that the βs of the regression line of the pain variables on SBP were different between women (β=0.34) and men (β=−0.25). Therefore, an analysis of covariance was applied using separate slopes for men and women ( Maxwell and Delaney, 1990, pp. 406–420). Residuals (studentized deleted) were computed from the linear regression of the pain measures on SBP- and DBP-reactivity for men and women separately (only SBP entered the analyses). These residuals were used in the new analyses, instead of the original pain variables. Applying this procedure, the Group×Gender interactions were no longer significant [F(1, 42)=2.72, p>0.10 for pain threshold and F(1, 43)=1.55, p>0.10 for pain tolerance, respectively]. Also the Group×Condition interaction for pain threshold disappeared [F(2, 42)=1.72, p>0.10]. Pre-stressor anxiety tended to be negatively correlated with both pain threshold and pain tolerance, especially during the second pain stimulation condition, but only one correlation proved to be significant: pre-stressor anxiety with pain tolerance in the second condition (r=−0.29, p<0.05). When the between-group analyses on pain sensitivity were run again with pre-stressor anxiety as a covariate, the Group×Gender interaction effects became slightly smaller: F(1, 41)=3.80, p=0.058 for pain threshold and F(1, 42)=2.78, p=0.10 for pain tolerance.